Parenting Behavior

C H A P T E R

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Parenting Behavior Joseph S. Lonstein Neuroscience Program and Department of Psychology, Michigan State University, East Lansing, MI, USA

Mariana Pereira, Joan I. Morrell Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ, USA

Catherine A. Marler Neuroscience Training Program and Department of Psychology, University of Wisconsin, Madison, WI, USA

INTRODUCTION The reproductive venture in mammals typically begins with the task of choosing a mate and is followed by the copulatory interactions that culminate in the joining of ova and sperm. For almost all mammals, reproduction and its behavioral correlates do not end there. Most mothers give birth to young that are unprepared for an independent life ex utero, thus requiring that the neonates receive prolonged and intense parental care for their sheer survival. Caregiving by most animals is highly sexually dimorphic,1,2 so for the majority of offspring this nurturance is provided by their mothers and is termed maternal behavior. In animals that have a relatively rare reproductive strategy involving biparental care, fathers will provide paternal behavior. In addition, caregiving may not be restricted to the parents and can be displayed by other willing participants, including the neonate’s older siblings or other close relatives, who provide beneficial alloparental behavior. Potential caregivers are often not spontaneously interested in young or may not be able to adequately care for them even if interested in doing so. Through the process of pregnancy and parturition, a profound neurobehavioral transition occurs in maternally inexperienced female mammals such that any clumsiness or indifference to neonates, or even outright aggression toward them, is replaced by skillful and tender caregiving. Of course, caregivers other than biological mothers

Knobil and Neill’s Physiology of Reproduction, Fourth Edition http://dx.doi.org/10.1016/B978-0-12-397175-3.00051-X

do not gestate and give birth to offspring, so there must be alternative means that promote their nurturant behaviors. The literature detailing the physiology of mammalian parental behaviors has been reviewed numerous times with tremendous thought and detail. The goal of this chapter is not to again exhaustively review this large literature, and we refer readers elsewhere for details not found herein.3,4 We instead highlight what we view as the major scientific advances in our understanding of the endocrinology, sensory regulation, and neurobiology of nurturant behaviors displayed by mothers, fathers, and sometimes alloparental “helpers.” Similar to the reductionistic study of most mammalian behaviors, the physiology of parenting is best understood in laboratory rodents. This is justified by their exceptionally successful breeding within a laboratory environment, the broad social acceptance for their use in basic research, a wealth of existing knowledge about their endocrinology and neurobiology, and the important belief that such an evolutionarily conserved behavior as parenting will have similar biological underpinning across mammals. Indeed, sufficient investigation of nonrodent parents, including sheep, rabbits, and primates, provides richness to this literature and ample data that allow one to detect potential universals, as well as species-specific mechanisms, involved in this biologically complex, incredibly motivated, and evolutionarily essential mammalian social behavior.

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© 2015 Elsevier Inc. All rights reserved.

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Historical Perspective Studying the biological mechanisms underlying parental behavior has a century-long history. Some of the earliest research on this topic refers to observational or experimental work on the endocrine, sensory, or neural basis of copulation in rodents and other small mammals; thus, we can presume that the study of parenting behavior arose from and was informed by the study of mating behavior. Cross-fertilization between these fields still occurs today, which is understandable given the discrete set of sensory, endocrine, and neurobiological faculties that animals have available to conduct a wide range of reproductive and other social activities. Contemplating the similarities or differences among behaviors, such as parenting and mating, will continue to provide valuable insight into the biological mechanisms underlying them both.5,6 Questions asked in the very early studies of mothering were quite similar to those asked today. For example, the search for bloodborne factors that are released during pregnancy or lactation and involved in maternal caregiving was studied as early as 1925 by Stone,7 who surgically conjoined virgin and pregnant female rats in hopes of finding accelerated maternal responding in the conjoined virgin. Stone’s study was unsuccessful, but reasonable given that parabiotic methods had previously shown that bloodborne factors could travel from one animal to affect the physiology of another.8 Such parabiotic studies were resurrected by Terkel and ­Rosenblatt almost 50 years later, who did find enhanced maternal responding in the conjoined virgins (see the section­ Hormones Most Significant for the Onset of Maternal Behavior in Rodents, Sheep, and Humans).9,10 The 1920s also saw reports that particular patterns of ovarian activity were correlated with mating in female rats and that ovarian hormones could induce copulation when exogenously administered.11,12 Either in response to these studies, or simply consistent with the zeitgeist, a flurry of studies emerged soon thereafter reporting that mothering would be displayed by dogs given extracts from the urine of pregnant women13 and that maternal behavior could be seen in a nulliparous monkey14 or in virgin rats15 given crude extracts of the pituitary gland. The next few decades saw numerous, but often methodologically compromised and contradictory, studies attempting to pinpoint the ovarian and pituitary secretions that could induce or inhibit mothering. Some reported that ovarian hormones could only inhibit mothering,16 while others found that seemingly any ovarian, pituitary, or thyroid hormone could promote maternal behavior when given alone or in combination.17 Buried amongst such discrepant results were findings that later became fundamental concepts in the current field studying parenting behavior. For example, prolactin (PRL) has

been known for decades to promote the onset of maternal behavior in ovarian hormone–primed nulliparous rats.18 Also, it has long been known that after hormones promote the onset of maternal behavior in many species, endocrine factors are unnecessary for maintaining the behavior (through a process termed “eroticization” by ­Steinach19) such that ovariectomy or hypophysectomy has little effect on postpartum mothers’ general interest in pups.15,20 Early studies also demonstrated the still often-used paradigm of maternal “sensitization” (see the section Hormones Most Significant for the Onset of Maternal Behavior), in which nulliparous rats with no exogenous hormone treatment and no interest in pups begin to perform caregiving behaviors after repeated exposure to neonates.15,21 Some early misconceptions about the endocrinology of mothering were not clarified, however, until as late as the 1960s. These included that neither PRL nor progesterone could alone promote maternal behavior in virgin female rats and instead required the assistance of other endocrine factors.22–24 One of these factors is now known to be estradiol, although at least two studies from the 1960s (which can retrospectively be seen as the beginning of the “modern era” for the biological study of maternal behavior) could not demonstrate estradiol’s effects, probably because the temporal sequences of the exogenous hormones given were endocrinologically incorrect (see the section Hormones Most Significant for the Onset of Maternal Behavior).24,25 Extant research on the hormonal regulation of caregiving behaviors shown by male mammals also began almost a century ago, but often had the goal of inducing maternallike behaviors in species of males that were not naturally paternal. These studies included observations of femalelike interest in pups by guinea pigs and rats that were peripubertally castrated and given ovarian grafts19,26 and the display of maternal-like behavior in male rats given anterior pituitary implants during adulthood.27 Brown has more recently criticized this strategy as misguided for understanding paternal behavior in any naturally biparental species because a female-oriented focus leads one to incorrectly assume that the endocrine and neural factors underlying maternal behavior are similarly responsible for paternal behaviors in fathers.28 As far as we can determine, the earliest work manipulating the endocrine system of any spontaneously paternal male mammal was studies from the 1930s that found no effects of hypophysectomy on the paternal behavior of male laboratory mice.20 Studies of the steroid hormones involved in a paternal male primate came much later, with Wilson and Vessey’s 196829 report that castrated male rhesus macaques (Macaca mulatta)— albeit a species that is still not particularly paternal in natural environments—are particularly prone to exhibit paternal behaviors and Alexander’s 197030 suggestion that the androgen withdrawal occurring across seasons in the

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Components of Parental Care

more naturally paternal male Japanese macaque (Macaca fuscata) was associated with males’ increased paternal play with young. As seen in the section Hormones Most ­Significant for Paternal Behaviors, endocrinological studies of the now exemplar rodent models used to study the natural occurrence of fathering—California mice (Peromyscus californicus), prairie voles (Microtus ochrogaster), and dwarf hamsters (Phodopus campbelli)—began to emerge just less than two decades ago. With regard to the sensory control of parenting, there was evidence 80 years ago that blinding or anosmia had little effect on nest building or other maternal behaviors in postpartum rats. Beach and Jaynes32 later systematically provided many additional insights into this question, again partly drawing on previous work studying the sensory control of copulatory behavior in rats and other small mammals.33,34 By studying the effects of individual and multiple desensitizations on retrieval of pups, Beach and Jaynes laid the groundwork for our understanding that maternal responding in rats was under “multisensory control.” More recent studies re-examining the sensory control of retrieval and other maternal behaviors in primiparous laboratory rats, and the responses of human mothers to infant sensory cues, support many of Beach and Jayne’s early conclusions that no single sensory modality is indispensable for most mothering behaviors (see the section Sensory Control of Maternal Care). Starting in the 1930s, electrolytic or aspiration lesions were employed to study the central nervous system control of maternal behavior, but these studies produced discrepant results for decades.35 The cerebral cortex was the first focus of this work and, once again, it took some lead from research that had unsuccessfully sought to find the cortical “sexual center” in male rabbits.36 In his studies examining cortical control of mothering as an exemplar innate behavior, Beach found that the amount of cortical tissue loss was proportional to the temporospatial disorganization of the females’ maternal behaviors but that the location of the cortical loss was mostly irrelevant.37,38 Around the same time, Stone39 and Davis40 also reported that substantial decortication abolished maternal behavior. Later experiments did indicate cortical specificity for mothering,41 though, and suggested that earlier cortical lesion effects on maternal behavior were partly due to subcortical damage.42,43 The first clear evidence for a subcortical influence on caregiving behaviors came from Fisher in 1956,44 who described how nest building and sometimes retrieval and licking the pups could be elicited in a small number of male rats that received infusions of sodium testo­ sterone sulfate into the medial, but not lateral, preoptic area. Prepartum lesions of the ventromedial preoptic area were later reported to have no consequence on postpartum maternal behavior, while ventromedial

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nucleus lesions elicited infanticide.45 Given what we now know about the roles of the preoptic area and ventromedial hypothalamus in maternal behavior (see the section Brain Control of Maternal Behaviors), both of these findings would be surprising if reported today. Other studies around this time found that lesions of the lateral hypothalamus, septum, hippocampus, or mammillary bodies disrupted mothering in female rats42,43,46,47 and that lesions of the septum and cingulate cortex could sometimes produce negative consequences on mothering in postpartum mice.48,49 It will be seen in this chapter that significant advances in experimental methodology—including more widespread use of and greater sophistication in neuroanatomical tracing, the ability to use genomic responses or regional oxygen utilization to visualize the activity of multiple brain sites simultaneously, and the development of techniques to manipulate the rodent genome—have permitted the field to move away from using lesions to conduct this type of site-by-site analysis of the neural structures required for parental behavior and instead provide a more network- or integrative systems-level understanding of how the brain controls caregiving behaviors (see the section Brain Control of Maternal Behaviors).

COMPONENTS OF PARENTAL CARE Successful parenting results from parents’ increased attraction to infants, the perfection of infant-directed caregiving behaviors, and modification of existing capabilities that are not even oriented toward the offspring but nonetheless promote their survival. Some of these modifications in non-offspring directed behaviors include blunted emotional reactivity that may help parents focus on the needs of their young,50 enhanced cognitive skills that may optimize parental responding to the neonates and other aspects of the environment,51 and aggressiveness toward potentially infanticidal intruders. This last modification is outside the scope of this review, so we refer readers elsewhere for information about the hormonal and neural control of maternal aggression.52,53 It is important to begin the discussion about the components of parental care by first highlighting that the nature of parental attraction to infants differs considerably among species. Polytocous rodents such as laboratory rats, mice, and rabbits that give birth to many offspring can discriminate between their own and unrelated pups, but form no exclusive bonds with them. In laboratory environments, these mothers will indiscriminately care for any conspecific or even nonconspecific neonates. Such generous mothering could be a laboratory artifact, but

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instead might be relevant in natural environments when lactating mothers communally nest.54,55 In contrast to these rodents, maternal sheep form an impressively selective bond with their offspring at parturition that prevents foster caregiving. Unlike either example, most human mothers form an intense bond with their infants, but this bond is not exclusive and the possibility of caregiving toward other infants of course remains. There are also considerable differences among species in their parental repertoires, which often lies in the fact that parent–offspring interactions are necessarily dyadic, involving reciprocal stimulation between the participants,56 so adult responses tremendously depend on the characteristics of the offspring. These include the newborn’s neurobehavioral competency for independent survival. Neurobehaviorally undeveloped neonates (termed altricial offspring) are often offspring of small, short-gestationed mammals, such as rodents, rabbits, dogs, and cats; at birth, they have a limited ability to thermoregulate, locomote, see, or hear. Even more extreme are the altricial young of some species that appear almost embryonic at birth, such as some marsupials that are born after an unusually brief gestation and spend their early postnatal life within their mother’s pouch to seemingly finish up what was unaccomplished during in utero development.57 In contrast to these altricial offspring, relatively neurobehaviorally developed neonates (termed precocial offspring) often arise from longer gestating mammals such as sheep, horses, and guinea pigs; they are born furred, with eyes wide open, and are surprisingly mobile. Such differences between altricial and precocial young are relevant for understanding the relationships among the hormonal profiles of nonhuman animals, that of our own species, and females’ caregiving behaviors. One salient example is that while both the sheep (∼147 days) and human (∼280 days) have lengthy pregnancies, sheep give birth to precocious offspring, whereas human offspring are relatively altricial. The durations of hormone exposure in these species are more similar to each other than, say, to that of laboratory rats, but maternal interactions with young at parturition differ tremendously. Thus, the hormonal patterns during and after pregnancy, and the developmental state of the young at birth, must all be considered to accurately uncover the neurobiological mechanisms driving maternal care in any given species. Based on their developmental stage, one might expect that maternal care is frequent and protracted toward altricial young, but infrequent and brief toward precocious young. This is not necessarily the case. Startlingly, whereas altricial rat pups are in the nest with their mothers for 70–90% of the time,58 altricial rabbit pups receive only 3 min of maternal care each day.59 Similarly, precocious ungulates are either “cached” away and visited by the mother just a few times per day60 or are members of species that follow close behind their mothers

and remain within steps of her most of the time.61 Species differences in the fat, protein, and water content of maternal milk allow such variation in the frequency of mammalian caregiving to exist.62 Regardless of the neonate’s developmental stage at birth, offspring-directed behaviors may seem to be a seamless thread of activities, but a closer look reveals that they are instead a collection of behavioral routines and subroutines that are appropriate to study both individually and collectively. This study is often facilitated by careful observation of the individual behaviors displayed, and then grouping them into meaningful categories of activities that might involve particular parts of the parents’ bodies, are most often temporally associated, or appear to have similar or interdependent purposes. This task can be difficult because not all mammalian parents display the same repertoire of behaviors and universal categorization of parental activities may be impossible. Even so, many researchers have distinguished active parental behaviors from inactive parental behaviors. Active parental behaviors include many of the hallmarks of caregiving, including establishing a place where mother–offspring interactions can occur, which is often called nest building. For many animals, including most small rodents with altricial young, this involves transporting suitable materials to a central location and manipulating them into a safe and secure nest. Active parenting also often involves carrying displaced offspring from one place to another using the mouth, hands, or arms, or more passively allowing the offspring to cling to the parent’s fur to hitch a ride. Carrying or retrieving neonates is easily quantifiable in both the field and laboratory, but it is important to note that its propensity is not universal. It is mostly unnecessary and even impossible in precocious species with heavy or highly mobile young, and it is also rare even in some relatively altricial species. These include prairie voles­ (M. ochrogaster), whose pups are born with teeth that help maintain attachment to the mother,63 and rabbits who nurse at the bottom of a deep burrow from which the pups cannot easily escape.64 Cleaning the offspring is another common active parental behavior and is performed by nonprimates by using the mouth to lick or gently nibble, but in primates it also involves the parents’ hands. In many mammals, these active maternal behaviors are often performed in preparation for prolonged periods of inactive nursing, the behaviors involved in transferring mother’s milk to the infants. Lactation (i.e., milk production and letdown) is not a behavior, and there is a tremendous amount of information known about this physiological process that can be found elsewhere. (see Chapter 46; and Refs 65,66). With regard to nursing behavior, in response to offspring suckling some mothers undergo a transition from a highly active state to one of inactivity and quiescence, which in laboratory rats, cats, and primates

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Considerations for Understanding the Hormonal Regulation of Maternal Care

involves slow-wave sleep.67–69 Only during these periods of quiescence does milk letdown occur in rats.70 In rabbits and pigs, suckling elicits behavioral inactivity, but it is associated with increased cortical firing rather than a depression.71,72 Many four-legged mothers that are simultaneously nursing multiple offspring will assume a distinctive posture, termed kyphosis,73 which involves limb rigidity and an upward flexion of the spinal column. This nursing posture provides additional room for young to breathe, move, and suckle while underneath their mother. Kyphosis is more likely to occur earlier in lactation than later and is the optimal position for milk letdown during early lactation in laboratory rats.74 In addition to kyphosis, mothers can be readily observed lying prone on top of the young with little limb support or found lying in a supine position next to or under the pups. These latter postures may be especially common when mothers are either fatigued by the rigidity of kyphosis, when offspring are too large for the entire litter to fit under her, or when older pups initiate nursing from a recumbent mother.73

CONSIDERATIONS FOR UNDERSTANDING THE HORMONAL REGULATION OF MATERNAL CARE The hormonal profile of pregnancy and the peripartum period is crucial for supporting the developing fetus, while at the same time prepares “the expectant brain” and the periphery for the expression of maternal behavior and other required physiological processes such as lactation (see Chapter 44). Extensive experimental evidence has demonstrated that estradiol, progesterone, PRL, and sometimes oxytocin (OT) can play crucial roles in the onset of maternal behavior in rodents and ungulates, with the addition of cortisol important in primates. A remarkable feature of the hormonal profiles over a wide range of species is the similarity of the hormones and their temporal course during pregnancy, parturition, and the postpartum period. Another remarkable feature is that not only do the maternal ovaries, adrenals, and anterior pituitary act as hormonal sources during pregnancy, as they do during all reproductive phases, but the placenta and fetus individually and together are also powerful sources of hormones unique to pregnancy that can act peripherally and perhaps centrally. Basic information about this hormonal profile is essential for understanding the state changes in the female brain that increase maternal motivation and her readiness to provide care to the young. Because these hormones act on the periphery and brain via their respective families of hormone receptors, it is also critically important to understand how reproductive state

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alters hormone receptor expression, affects the dominance of particular subcategories of receptors, and how these receptors are influenced by their ligands to influence neuronal activity and maternal responding. In pregnant and postpartum mammals, the hormonal profiles of rodents and humans have been the best studied, but some additional models including sheep have significantly added to our understanding of this topic. Each nonhuman animal model possesses different features of face, construct, and predictive validity for the hormonal basis of parenting in humans, but no single model provides a complete picture homologous to what is known from humans. Even so, each model holds uniquely useful characteristics for examining the emergence and continuation of maternal behavior. For example, a valuable feature of the laboratory rat model is that while rats do recognize their own young, their assiduous and rapid care for the young of other individuals facilitates many laboratory studies. On the other hand, a crucial and fascinating feature of caregiving in sheep is the selective mother–offspring bond, which is based on individual recognition and memory of lamb cues, and which may inform some aspects of maternal bonding in humans. Correlating hormone levels in the pregnant and parturient female with the expression of maternal behaviors is an important approach to examining the hormonal basis for maternal behavior in all species examined, and really the only approach available to do so in humans. When considering the major changes in the hormonal milieu for the three exemplar species discussed in detail below, it is absolutely crucial to consider the extent to which the maternal brain is bathed in this milieu: that is, whether the blood–brain barrier does or does not prevent the hormones of interest from reaching the brain. It is generally accepted that steroid hormones readily access the brain, but most peptide hormones of peripheral origin are more highly regulated or almost completely restricted from access. Some peptides, including those in the PRL family, gain access via peptide-specific transporter systems that result in cerebrospinal fluid levels being highly correlated with plasma levels.75 However, less than 3% of most other peripherally circulating peptides without such transporter systems, including OT and arginine–vasopressin (AVP), enter the brain.76 While there is limited evidence that the blood–brain barrier is not altered by pregnancy,77 the access of such peptides to the brain during this time has not been experimentally examined in detail, so great caution is warranted when attempting to extrapolate peripheral (plasma and saliva) peptide hormone titers to what may be found in the brain. In addition, the marked advantages of animal models for examining the hormones necessary for the onset of maternal behavior allow experiments that provide causal evidence because the removal of glands

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and supplementation of hormones are readily possible. There are substantial limits to such reductionist approaches, however, because disrupting the endocrine and physiological demands of pregnancy, parturition, and lactation can inadvertently confound analysis of the behavioral outcomes of most interest. The brain itself is also a source of steroid hormones and peptides that act as neuromodulators, including OT and AVP. As would be expected for neuromodulators, site-specific release of OT and AVP has been confirmed and can be independent from plasma levels.78,79 Although independent brain and peripheral release has been demonstrated, it is also the case that OT and AVP are released intracerebrally at parturition and during suckling in apparent coordination with peripheral release, suggesting a hormonally coordinated linking of central and peripheral events in mothers.80 A great deal of recent research on laboratory rats and mice has been devoted to studying how naturally occurring genetic variation among individuals or genetic manipulations reveal important features about the endocrine and other neurochemical bases of mothering. The most gene-specific manipulations for probing the endocrine and neuroendocrine basis of maternal behavior have been carried out with transgenic laboratory mice, and most of these have used global and lifelong knockout (KO) of specific endocrine system genes.81 It is invaluable to realize that transgenic manipulations of receptors of ligands that mediate the hormonal underpinnings of maternal behavior can have the unintended consequence of altering fertility or the capacity to maintain pregnancy and undergo parturition. This makes it impossible to examine the hormonal and other factors involved in naturally occurring postpartum behavior, but does permit investigation of how these females respond to pups after repeated exposure to them in a maternal sensitization paradigm (described in detail below), which is thought to be non–hormonally controlled. It is also important to recognize that the neurobiological control of maternal-like responses in females that have not undergone pregnancy and parturition could differ from those that have experienced these reproductive events. Furthermore, because different strains of nulliparous rats and mice vary in their baseline maternal responsiveness,2,82,83 careful consideration of the variability in these baselines is crucial because high spontaneous maternal behavior may be confused with the impact of endocrine system gene KO, which may be subtle in strains with spontaneous maternal caregiving. Thus, there is a heightened requirement in studies of transgenic models to make a faithful comparison of the impact of the genetic manipulation on the baseline postpartum or virgin maternal performance in the same strain. This issue of “background matters” has also been demonstrated for male sexual behavior in gene-disrupted mice,84 making

this a generalizable consideration important for all studies examining the genetics of behavior. Regardless of the form of genetic or other manipulation, experiments impacting natural postpartum maternal behavior offer the most interpretable data when quantitative information is included about parturition behavior to verify that offspring are delivered alive and cleaned of amniotic membranes, that offspring viability is measured soon after parturition (including litter size and weight in rodents), and that the mothers are lactating normally (including repeated measurement of offspring weight or postmortem mammary gland weights). Because of the dyadic nature of mothering, further crucial inclusions include regularly assessing offspring vigor and replacing any sickly young with healthy foster young of a similar age, and maintaining a species-typical number of offspring for each mother to interact with. For studies of behavior after global or lifelong knockouts of any protein, it is also necessary to consider the possibility that behavioral resilience or alteration might be due to redundant proteins that take a larger than usual role or compensation by functionally associated molecules that otherwise would not be involved. A further complication is the case in which a ligand normally regulates the expression of its own receptor, for example regulation of the OT receptor by its ligand, but where the receptor is normal even in the absence of OT, suggesting that other molecules have taken over its usual role.85 Also importantly, the absence of some proteins during development may generate very different functional alterations than if the proteins are absent only during adulthood. While conditional gene inactivation approaches may limit some of these problems by allowing temporal or spatial restriction of the KO or knockin, they bring other issues that have recently been discussed in the context of the androgen receptor KO models.86,87 Frequently encountered limits of the conditional activation systems include the completeness of the excision (i.e., a knockout that is really a knockdown), the confounding influence of the floxing itself, and the leakiness of Cre activation into off-target cells or tissues. In the best circumstances, proof of effectiveness and target specificity can mitigate these problems, while in the worst cases the KO model being studied does not allow one to make interpretable conclusions.

HORMONES MOST SIGNIFICANT FOR THE ONSET OF MATERNAL BEHAVIOR IN RODENTS, SHEEP, AND HUMANS Harking back to Stone’s early parabiotic studies examining if bloodborne factors were involved in mothering behaviors,7 Rosenblatt and Terkel reported in 1968 and 1972 that injecting plasma from early-postpartum laboratory rats into virgins, or commingling their

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Hormones Most Significant for the Onset of Maternal Behavior in Rodents, Sheep, and Humans

circulatory systems, dramatically reduced the latency to show maternal responding (Figure 51.1).9,10 Transferring periparturitional blood was by far the most effective. An almost innumerable number of endocrine events occur across the weeks or months of pregnancy and parturition, and up to years of lactation depending on the species. Are they all required for mothering behaviors? Responding to foster pups by laboratory rats increases dramatically in the final days of pregnancy, presumably in preparation for the litter’s appearance at parturition.88 In laboratory rats, the duration of pregnancy before surgically terminating it via Caesarean procedures is positively associated with females’ maternal responsiveness, and at least 16 days of rising estrogens and exposure to placental hormones followed by the withdrawal of progesterone is needed for a robust onset of maternal behavior.89,90 Of course, successful pregnancies normally terminate with parturition, when offspring would naturally first be available to the female. Because some aspects of maternal behavior appear prepartum and are displayed by late-pregnancy terminated rats, the physical processes of parturition are clearly not required for the onset of maternal behavior.

FIGURE 51.1  Mean and range of the number of days of pup exposure for nulliparous female rats to begin retrieving pups. Females were exposed to pups alone (Pup Induced), were exposed to pups after receiving an injection of blood plasma from a recently parturient and maternal female (M → V Injection), or were exposed to pups during and after a 6 h transfusion of blood from a recently parturient and maternal female (M → V Transfusion). Transfusion from a parturient female very rapidly induced retrieval in the nulliparous rats. Source: Modified from Terkel and Rosenblatt, 1972.10

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Even though the onset of mothering does not require the sensory input of parturition, including vaginocervical stimulation, or the ingestion of placentae and amniotic fluid, these factors can still have positive effects on mothering in some laboratory rats.91,92 Vaginocervical stimulation naturally received during parturition is required, however, for the onset of mothering in many female prairie voles (M. ochrogaster)93 and wild house mice94 that remain unresponsive to pups or even infanticidal through the end of pregnancy. In contrast to most laboratory rats, sheep do not become more maternal as parturition approaches and the visceral events of either natural delivery or experimentally produced vaginocervical stimulation are needed for motherhood and development of the mother–young bond. Indeed, epidural anesthesia is a major impediment to the onset of their maternal behavior,95 and receipt of vaginocervical stimulation must occur within a short time frame before the appearance of a lamb to avoid its total rejection by the ewe.96 While treatment with exogenous estradiol, progesterone, and central OT can induce maternal responsiveness even without vaginocervical stimulation in ewes, this is much more difficult to achieve than in the rat. In the natural situation, both peripheral and central systems are coordinated by the processes of parturition, and vice versa, for maternal behavior in ewes (discussed further below). In humans, the now common use of Caesarean delivery has revealed that vaginal delivery is not required for their maternal responsiveness, but vaginal delivery is associated with greater maternal neural and behavioral sensitivity to infant cues as well as more positive maternal mental health,97,98 all perhaps related to the endocrine and other chemical factors released during parturition. While the hormonally induced changes to the maternal brain instituted by pregnancy and the peripartum period are vital for neural sensitivity to offspring cues and the display of maternal behavior in the early postpartum period, after parturition the presence of hormones becomes progressively less important. The maintenance of maternal behavior is instead regulated by interaction with the offspring, with the dyad becoming an interactive duo that produces changes in maternal behaviors according to the needs of the developing offspring. Indeed, mothers and offspring of probably all mammalian species spend progressively less time with each other as the offspring become more physically and motorically independent.99,100 A nonhormonal maintenance of maternal behavior is supported by many studies showing that removal of the pituitary, ovary, or adrenal glands does not terminate postpartum maternal behavior.3 There may be some changes in postpartum maternal behavior after removal of these glands, but they are quite subtle compared to their role in the onset of maternal behavior. For example, adrenalectomy has

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little effect on retrieval, nest building, and nursing in postpartum rats, but it does increase how long mothers lick their pups and alters where licking is focused on the pups’ bodies.101 Similarly in the ewe, after postparturitional acceptance of the lamb, hormones are not required for maintaining maternal care and the mother’s interaction with the lamb is instead crucial.102 In humans, postpartum interaction between the mother and infant optimizes ongoing mothering, although there seems to be continuing modulatory roles for maternal OT and cortisol in regulating this interaction.103,104

Mothering without Pregnancy or Parturition? In some species, mothering-like behavior is possible without undergoing pregnancy and parturition—which is sometimes common in parental males, juvenile siblings, or genetically related nulliparous adult females— indicating that there are multiple means by which the neural substrates for parenting can be activated. Most virgin adult and juvenile laboratory rats of both sexes can be experimentally stimulated to perform some maternal behaviors simply by continuously exposing them to pups. Because these caregivers cannot lactate, the health of the foster pups is maintained by once- or twice-daily rotation to lactating surrogates. The emergence of such pup-induced or sensitized maternal behavior in nulliparous female rats usually takes up to 6–10 days of exposure and alters females’ behavior from avoiding the pups to avid caregiving. This sensitized maternal caregiving is thought to be hormone independent because it is not prevented or even greatly delayed by removing the adult subject’s gonads, pituitary gland, or adrenals before initiating the exposure to pups.105 The maternal-like behavior of sensitized rats may be impressive, but it does differ from the behavior of naturally parturient females in its deficient retrieval, pup licking, and nursing (Figure 51.2).106,107 The relationship between sensitized and postpartum maternal behavior has also been compared within subjects, and there is a positive correlation between how rapidly adult nulliparous rats sensitize and how often they later lick their own offspring after giving birth,108 but there is no relationship between sensitization during juvenile life and postpartum behavior in the same female rats.109 Sensitization has also been used in various strains of mice, but both laboratory house mice (Mus) and deer mice (Peromyscus) have high levels of baseline caregiving, again an important but sometimes overlooked consideration regarding their use for studying the hormonal or neural basis of maternal behavior. There is no evidence that nulliparous sheep are susceptible to any sensitization of maternal behavior, and sensitization has been demonstrated to not be readily achievable in other species, including rabbits.110

FIGURE 51.2  Duration of time (Mean + SEM) that suckled and nonsuckled postpartum rats, and maternally sensitized nulliparous rats, took to retrieve each pup to the nest (top panel) and spent licking the pups (bottom panel). Different letters above bars indicate significant differences between groups. Maternally sensitized nulliparous rats were deficient in both measures compared to postpartum mothers. Source: Modified from Lonstein et al., 1999.107

The sensitization paradigm has been combined with knowledge about the hormonal progression of pregnancy to establish that after days 17–19 of pregnancy, female rats are fully maternal within one day of pup exposure. Additionally, treating nulliparous female rats with exogenous hormones for 2 weeks using a profile roughly mimicking that of mid- to late pregnancy can quickly induce mothering. This can even be accomplished in male rats! The optimal sequence of hormones that can instill mothering in laboratory rats, and probably numerous other species, is now known to involve (1) first exposing animals to estradiol, (2) subsequent introduction of progesterone, (3) administering PRL near the conclusion of the ovarian steroid treatment, and (4) the withdrawal of progesterone at the very end of treatment.111–115 Hormones are clearly not required for human parenting. The most salient evidence for this is that the adoption of human children in times of need, or simply by preference, yields fully parental adults obviously without

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pregnancy or parturition in the adoptive parent. As discussed in the work of Fleming and her colleagues,4,104 human parental behavior is more heavily influenced by experiential and cultural factors that parents bring to caregiving. Cultural conditions can introduce factors that are unique and in some cases more difficult to the adoptive parent–child dyad (e.g., preadoptive abuse, abandonment, or long-term institutionalization), but adoption in humans is a remarkably robust and successful process for both parents and children under a wide range of circumstances.116–118

Endocrine Profiles of Pregnancy Involved in the Onset of Mothering Laboratory Rodents Estrogen: Circulating estrogens during pregnancy in rats and mice are generally low and similar to diestrus until about 16 days after insemination, after which there is a gradual increase until parturition,112,119,120 when plasma levels of estradiol meet and exceed those found during the estrus cycle peak.121 Soon after parturition, there is a further brief increase during the postpartum estrus (leading to sexual receptivity ∼9 h later), but circulating estrogens are otherwise low during early lactation, then slowly rise across midlactation and even more as weaning and the resumption of estrus cyclicity approaches (Figure 51.3).122,123 In early pregnancy, the corpora lutea resulting from the liberated ova produce the steroidogenic substrates for estrogen synthesis, as well as the estradiol itself, so only estrogens are produced in large amounts.124 This differs from late pregnancy, when the placentae produce the androgens that are released into the general circulation and from which estradiol is then produced by the corpora lutea.125–127 During lactation, the corpora lutea of pregnancy regress, and the corpora lutea of the postpartum ovulation become functionally dominant.123 The presence of estradiol always induces a more rapid onset of maternal behavior than that observed in its absence.3,4 It has a crucial role in the preparatory nest building displayed prepartum and for the immediate onset of all other maternal behaviors at parturition. A rapid onset of maternal behavior can be induced by just the first 10–13 days of pregnancy, or in nulliparous rats by 10–13 days of treatment with exogenous estradiol, if the animals are then given a triggering dose of estradiol.89,102,128,129 In fact, depending on the females’ endocrine state, even a single high dose of estradiol benzoate can shorten the latency for nulliparous rats to show maternal behavior.129 In studies using a surgical model involving hysterectomy of pregnant females with or without ovariectomy, there is a much more rapid onset of maternal behavior when the ovary and its secretion of estradiol remain intact.102 However, this does not occur

FIGURE 51.3  Schematic representation of circulating plasma levels of estradiol (EST), progesterone (PROG), and prolactin (PRL) across pregnancy and parturition in laboratory rats, laboratory mice, and sheep. Source: Modified from Rosenblatt and Siegel, 1981.102

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until after day 13 of pregnancy and is sensitive to the postsurgical timing of when young are introduced.90,130 Most of estradiol’s effects on the maternal brain and behavior have long been assumed to occur genomically through activation of estrogen receptors, which have been well characterized in their distribution and density in relevant brain regions across pregnancy.131,132 Indeed, most of the manipulations used to induce a rapid onset of maternal behavior involve a long time course of action consistent with that required for steroids to act genomically. More recently, however, Stolzenberg et al.133 revealed the argument that estradiol also appears to act over a shorter time course, theoretically via nongenomic membrane estrogen receptors, for a rapid onset of maternal behavior. Mice of both sexes with a lifelong and total absence of estrogen receptor alpha (ERα KO) have profoundly impaired reproductive function.81,134 Thus, testing maternal behavior in these infertile virgin ERα KO females, which have a high rate of infanticide (40–80%),135 is necessarily restricted to sensitization. Responding to pups appears to be reduced in ERα KO females,81 but others have demonstrated in aromatase KO mice of a similar background strain that maternal responding does not depend on estrogens.136 Neuron-specific conditional KO of ERα or estrogen receptor beta (ERβ) indicates that the global reproductive deficits are primarily due to the loss of ERα.137 While global ERα KO and double ERKO (i.e., both α and β isoforms) limit the ability to study maternal behavior in naturally parturient animals, these ER knockouts have revealed valuable information about estradiol’s influence on anxiety138 and its molecular mechanisms. It had been suggested that estrogens can still act in these classical ERKO models via a membrane receptor or other novel ER-binding molecule (a possible novel ER transcript),84 but others have found from another global ERKO model that does not contain this transcript that it has a limited role in reproduction.134 Although ERKO models generally have notable limits on the questions they can be used to ask, they do inform our understanding of maternal behavior in the larger context of emotional state and the neurobiological mechanisms of steroid action. The hope is that as transgenic applications develop,139 the temporal and spatial limits of these earlier models will yield more specific information. For example, a conditional ERKO aimed only at the gonadotrophs of the anterior pituitary has been developed and resulted in subfertile females that completed pregnancy and parturition, but had smaller and fewer litters; unfortunately, no analysis of maternal behavior was included.140 Downregulating ERα using RNA interference is another promising approach to achieve higher temporal and spatial resolution for studying estradiol’s influence on mothering.141 Testosterone: Testosterone is an obligatory precursor to estradiol synthesis in the ovary and brain, usually in

a paracrine or intracrine manner that rapidly produces estradiol, so there is usually no increase in plasma testosterone.142 During late pregnancy, however, the rat placenta produces the androgenic substrate for synthesis of most estrogens. This results in a lesser known rise in circulating androgens (testosterone and dihydrotestosterone) from very low levels (0.4–0.8 ng/ml) early in pregnancy to sustained and remarkable levels (2.8 ng/ ml) during the second half of pregnancy.125,143 These levels are very high compared to that seen in cycling females, in which testosterone and dihydrotestosterone are found at 0.2 ng/ml to 0.4–0.5 ng/ml preceding the surge in luteinizing hormone.127,144 These levels in late-pregnant females are even higher than those seen in male rats (1.1–2.3 ng/ml).145 Immediately after parturition, androgen levels drop and remain low until estrus cycling recommences. Such elevated plasma testosterone has not been reported in pregnant sheep, but high testosterone titers have been observed in pregnant mice146 and rabbits,147 where again the locations of estradiol synthesis and its testosterone precursor are in different tissues. While no studies have examined the effect of this androgen surge on maternal behavior in rats or mice, in rabbits it is perhaps uniquely involved in their nest building because it loosens chest hairs that females pull out and use to line the maternal nest.148 Androgens act on androgen receptors (ARs) located in specific tissues of the reproductive system and sites within the brain. In the brain, ARs exist in abundance in both males and females, are found on both neurons and glia, and act genomically as well as possibly nongenomically.149,150 The AR has been a target in KO models for studying parenting and other aspects of reproduction. The first models were naturally occurring—complete androgen-insensitivity syndrome (CIAS, also known as testicular feminization mutation) in males and the XO genotype in females in which the single X chromosome had a mutated AR gene—but conditional gene-targeting approaches more recently yielded both global and tissue and cell-specific ARKO models.86,87 One conditional model targeting the brain revealed that AR-mediated androgen action is not required for ovulation, mating, pregnancy, or lactation.151 These females are less fertile and have fewer pups, but lactation is sufficient for normal growth of the smaller litters. No studies using these ARKO models have provided a detailed analysis of the females’ maternal behavior. Progesterone: Beginning as early as days 3–5 of pregnancy in the laboratory rat, circulating progesterone levels climb as high or up to 10-fold higher than the peak values seen during the estrus cycle and remain there for 17–18 days. Thus, a sustained high level of progesterone is one of the most remarkable features of the endocrine milieu of pregnancy. Beginning around day 19 of

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pregnancy, progesterone levels markedly fall such that at parturition, they are lower than that seen at any point in the estrus cycle (Figure 51.3).120,152,153 The temporal course of circulating progesterone in pregnant laboratory mice varies somewhat among strains, but generally peaks at days 15–17 of pregnancy and falls on the day before parturition (day 18) to half their peak levels.146,154 On the day of parturition in rats and mice, levels fall even further after a brief postpartum estrus to very low levels, but at least in laboratory rats there is a mostly ignored elevation again between postpartum days 3 and 10, and thereafter it remains low until postweaning cycling resumes.155 Progesterone is the sina qua non for maintaining pregnancy in mammals, and withdrawal of progesterone at the end of natural pregnancy or a pregnancy-like regimen of hormones is necessary for the onset of maternal behavior. Progesterone has been demonstrated in pregnancyterminated (hysterectomized and/or ovariectomized) and at-term pregnancy models to prevent an inappropriately early display of maternal behavior, and withdrawal of progesterone prepartum facilitates a rapid onset of mothering.130,156 Similarly, nulliparous rats treated with exogenous progesterone require its removal for estradiol to potently stimulate mothering.157 Evidence that progesterone at the end of pregnancy masks heightened maternal interest, rather than itself increases maternal interest simply by its withdrawal, is indicated by the fact that nulliparous rats given only progesterone followed or not by its withdrawal remain disinterested in pups.158 Importantly, progesterone only masks maternal behavior during late pregnancy or near the end of a pregnancylike hormone regimen because during the early phase of estradiol exposure, progesterone synergizes with estradiol to promote maternal responding. In nulliparous rats, progesterone pretreatment reduces the dose of estradiol needed to reduce maternal sensitization latencies, and the combination of estradiol and progesterone followed by withdrawal of the latter is more effective in stimulating maternal responding than providing estradiol alone.112,157 In laboratory mice, prepartum nest building depends on high circulating progesterone.159 The onset of lactation also requires the presence and withdrawal of progesterone.65,66 It was noted above that progesterone rises again beginning around the third postpartum day in rats. Early work suggested that the absence of the ovaries has no effect on postpartum maternal behavior,160 although recently it was reported that postpartum ovariectomy slightly reduces maternal licking of pups and that nursing is somewhat impeded when circulating progesterone is experimentally elevated during early lactation.161 The opposite result, increased nursing, is found when progesterone is elevated during later lactation, so perhaps the second decline in progesterone starting around day 10 postpartum contributes to the decline in maternal behavior in rats.162

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The first progesterone receptor KO (PRKO) mice were designed to delete both the A and the B forms of the receptor, and both sexes sustained numerous endocrine deficits, including that females were unable to ovulate.163 Subsequent work with isoform-specific deletions of either PR form A or B has demonstrated that PR-A KO alone leads to sterility in female mice, as well as severe uterine dysfunction, while hormonal responses of the mammary gland are mediated by PR-B.164 Homozygous PR-B KO females are fertile, maintain pregnancy, and deliver viable, full litters of pups.165 Unfortunately, nothing has been reported regarding the maternal behaviors of any PRKO females. Adrenal steroids: Normal adrenal function and circulating levels of adrenal steroids optimize fertility and other needs of the female and her offspring during pregnancy, parturition, and lactation. Basal glucocorticoid levels rise in rats during late pregnancy and particularly at parturition, and thereafter return to levels more typical of early pregnancy, although there may be a flattened circadian rhythm of glucocorticoid release.166 A notable condition of the postpartum period is that it is a time of stress hyporesponsiveness. When confronted with a variety of potential physical or psychological threats, females during mid- to late lactation exhibit a blunting of the hypothalamic–pituitary–adrenal response (see Chapter 44; and Ref. 167). An interesting feature of this hyporesponsive period is that some stressors, such as predator odor and intruders, evoke a normal stress response when the dam is in the presence of the pups,168 suggesting a gating of the response that involves the cognitive capacity of the mother and her assessment of immediate threats to the litter. Despite these complex alterations in glucocorticoid release in mother rats, there is no evidence that they are absolutely required for maternal behavior, as adrenalectomized females initiate and then maintain maternal behavior.169 Detailed early studies of maternal behavior showed that the presence of the adrenal glands does facilitate the speed and completeness of caregiving in naturally pregnant females,170,171 but others found that adrenal secretions inhibited maternal behavior.172,173 More recent work demonstrates small but significant decreases in some components of mothering after adrenalectomy, including licking (rarely measured in early studies) and the duration of time spent in the nest, both of which could be increased by exogenous corticosterone obtained through the females’ drinking water (Figure 51.4).101 However, chronically high postpartum corticosterone via daily injections of the hormone reduces nursing,174 and it has also been recently seen that an acute injection of the synthetic glucocorticoid, dexamethasone, impairs retrieval of pups and reduces the duration of nursing over a 30 min period following injection. Acute injection of dexamethasone also reduced peripheral PRL

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FIGURE 51.4  Duration of time (Mean + SEM) spent licking the pups by adrenalectomized, postpartum rats that received various doses of corticosterone in their drinking water. *Significantly more pup licking compared to dams that received no replacement corticosterone. Source: Modified from Rees and Fleming, 2004.101

and OT levels measured in the dams after a 15 min suckling interaction with pups, which may be a cause or consequence of the deficit in maternal behavior.175 In nulliparous rats, higher endogenous circulating corticosterone tends to delay maternal sensitization, and after adrenalectomy exogenous corticosterone given through drinking water or a subcutaneous pellet reduces pup licking and time spent in the nest by sensitized females that are already maternal.176 The different consequences of adrenalectomy and/or chronic corticosterone replacement on the maternal behavior of parturient and sensitized rats clearly highlight that the endocrine and other physiological determinants of their mothering are not identical. It also appears from these studies that the effects of adrenal steroids on maternal responses may have a sphere of subtle influences that require careful consideration, including whether foster or related pups are used during testing and the postpartum stage and degree of experience of the mothers. In sum, the literature supports the view that corticosterone is not necessary for the initiation or maintenance of maternal behavior in rats, but that it modulates the intensity and timing of caregiving behaviors. It is essential to note that even such subtle influences on maternal behavior can have a significant impact on offspring development.177 Prolactin and its family members: PRL and three functionally related but less well-known hormones, decidual luteotrophin and placental lactogens I and II, are important during rat pregnancy because they help maintain steroidogenesis in the corpus lutea of pregnancy and prepare the mammary glands for lactation.66 Despite their structural differences, all four protein hormones exert their effects by binding to the short or long form of the PRL receptor. Both forms of the PRL receptors are expressed and regulated differentially across

reproductive states in the corpus lutea, mammary gland, and brain (see Chapter 12; and Refs 178–182). The source of PRL itself during the estrous cycle and during early pregnancy is the anterior pituitary. During early pregnancy, PRL is secreted in two daily surges, one nocturnal and one diurnal.183,184 At the same time, decidual luteotrophin is secreted by the decidua of the uterus, so PRL is thereafter no longer required to maintain pregnancy even though the anterior pituitary continues to release it.181 Subsequently, in midpregnancy serum PRL from pituitary origin is substantially lower than what is found in cycling females, and decidual luteotrophin disappears while placental lactogens, first I and then II, become the predominant lactogens in the general circulation.120 During the second half of pregnancy in rats, pituitary PRL secretion is inhibited by placental lactogens through negative feedback on the brain, but this is alleviated in the last few days of pregnancy. The pituitary then releases a substantial prepartum surge of PRL (Figure 51.3). During the postpartum period, PRL has a critical role on the mammary gland for milk production and in the corpus lutea for progesterone synthesis.123 Of course, suckling stimulation by pups is a powerful regulator of PRL release, such that there is a sharp increase especially when a female rat is separated from and then reunited with her pups. This is observed even after transecting the galactophores (milk ducts), which leaves the sensory capacity of the nipples intact but prevents suckling-induced milk letdown.185 Maternally sensitized nulliparae do not respond to the presence of pups with an elevation in PRL, though.186 Across the first 4 days after parturition, PRL levels rise such that they are 2–3 times higher than the maximum of the estrous cycle and remain so during the first 10 days of lactation, after which they decline quickly and remain relatively low until the end of the postpartum period and when estrus cycling resumes.121,123,183 PRL greatly facilitates the onset of maternal behavior that is initiated by ovarian hormones. Systemic injection of PRL included in a regimen of exogenous estradiol and progesterone, followed by withdrawal of the latter, notably reduces maternal sensitization latencies.111,112,187 Moreover, Bridges and colleagues demonstrated that administering these ovarian hormones cannot decrease maternal sensitization latencies in ovariectomized female rats if they have also been hypophysectomized, and that ectopic pituitary grafts can reinstate the hormones’ effects.188 Even so, late-term hypophysectomy does not interfere with parturition or the onset of maternal behavior, which is presumably because by that time placental lactogens have assumed the major role in providing PRL to the maternal brain and periphery. Access of PRL to the brain occurs via an active transport mechanism, possibly related to the abundant PRL receptors in the choroid plexus.189 Grattan and colleagues

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report that there may also be differential sensitivity, and possibly increased brain access, of PRL to some hypothalamic regions involved in the feedback regulation of PRL by dopaminergic neurons of the arcuate nucleus.190 There is also evidence that PRL is synthesized by intracerebrally projecting neurons within the brain and in the neurons of somatosensory ganglia, and that it can be released site specifically in the female rat brain independent of peripheral release.78,191 In laboratory mice, postpartum maternal nest building is facilitated by PRL,159 but estradiol-mediated retrieval in ovariectomized mice that do not already spontaneously retrieve is unaffected by PRL depletion.192 Mouse models exploring the role of PRL in maternal behavior have included the use of complete knockouts of either PRL or its receptors. As reviewed in depth by Kuroda et al.,81 the earliest studies of PRL KO mice showed that the maternal responding of the virgin females is normal. Either another PRL-like ligand must be engaged in a compensatory mechanism in the adults or PRL is not absolutely required for maternal behavior in the virgin laboratory mouse. An ontological consideration is that PRL family ligands may crucially act during fetal development in brain regions needed for maternal behavior and that this remains intact because the numerous ligands are not eliminated by the PRL KO alone. These limitations highlight the importance of choosing background strains of mice for KO that are not spontaneously maternal as virgins, and so might not require the hormone in question in the first place. In contrast to eliminating the gene coding for PRL, KO of the PRL receptor gene does diminish maternal behavior.193 Thus, it has been speculated that there is a role for PRL in these mice that can be filled by other ligands, possibly the placental lactogens acting during pregnancy in subjects with normal PRL receptors, but not in the absence of the PRL receptors.4 Oxytocin: OT is released during the beginning of pregnancy as a result of mating stimuli, and it may participate in the twice-daily PRL surges that maintain the corpus lutea necessary for steroid secretion,85 but any relevance for this early OT in later maternal behavior is unknown. Preparturitional restraint of peripheral OT secretion is important to avoid premature contractions of the uterus or milk ducts, but during pregnancy OT does rise up to twofold over that observed in nonpregnant males and female rats and humans, with a peak at parturition and later peaks during suckling in all species examined.194,195 During pregnancy, there are modifications of the hypothalamic magnocellular system involving retraction of astrocytic processes separating OT cells, thereby allowing more synchronous firing when a bolus of OT is needed for peripheral processes, including parturition or milk letdown (see Chapter 13; and Refs 196,197). There is considerable evidence that OT can promote the onset of maternal behavior but it is not required for

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maintenance of the behavior once established. Prepartum destruction of the hypothalamic sites containing OT cells impairs all aspects of mothering after parturition, but lesions performed postpartum have only small effects.198,199 OT from peripheral plasma is probably not involved because its access to the brain is extremely limited.76 Some have argued that peripherally secreted OT as measured in plasma predicts release within the central nervous system,200,201 but there can be brain-site-specific OT release and action independent of plasma levels.79,202 The best evidence clearly indicates that OT facilitates maternal behavior by acting as a neuromodulator within the brain, and is released from a well-described network of neurons sometimes in association with other events, including parturition and nursing.80,203,204 Evidence of OT’s modulatory role in postpartum maternal caregiving has been established by classical approaches, including infusing it into the brain or, conversely, infusing OT antiserum or receptor antagonists into the cerebral ventricles or relevant brain regions. These studies in rats involve postpartum females, pregnancyterminated females, and pup-sensitized virgins.108,204–207 There are also positive relationships between facets of the brain’s OT systems with the propensity to display some postpartum maternal behaviors, including kyphosis and licking of pups (Figure 51.5).108,208 Early studies of the role of OT in maternal behavior sometimes compared it with the effects of the closely related “control” neuropeptide, AVP. In contrast to these early works, where the effects of AVP were explained by its actions on the OT system, more recent research indicates that AVP acting on its own receptors also regulates maternal behaviors toward pups and maternal aggression.204 Transgenic mice have revealed a tremendous, often surprising, body of evidence about OT’s modulatory role in maternal behavior. Mice with total global KO of the gene coding for OT give birth normally but have marked deficits in milk letdown. No deficits in maternal behavior were initially reported in these KO mice,209 but more detailed analysis of OT KO mice subsequently revealed deficits in both retrieval and licking.210 Because maternal behaviors are less affected in these OT KO mice than probably was expected, compensation by other systems (e.g., AVP) may have occurred or the strain used to create these particular KO mice has a high baseline level of spontaneous maternal behavior that was only slightly blunted.209 In fact, it is valuable to note that in female wild house mice that are infanticidal as virgins, intracerebral infusion of OT dramatically promotes mothering.211 Knockout of the CD38 gene that codes for a protein critical for calcium-induced OT release does not impair the fertility, pregnancy, or parturition, and curiously also does not affect lactation in laboratory mice. This may be explained by the fact that while these mice have reduced circulating OT, it is sufficient for milk letdown.

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apparently normal lactation, they are plagued by pup mortality of unknown etiology. The surprising retention of maternal function of these OT receptor KO mice may depend upon residual OT receptors within the forebrain, or p ­ ossibly ­compensation from other brain regions outside the targeted brain region. An example of such c­ ompensatory mechanisms comes from the periphery and is related to OT’s luteotrophic effect, such that prostaglandins take over this function in the absence of the OT receptor, ­calling attention to the fact that compensatory responses in the KO models may be more wide ranging than is currently proposed in many studies.

FIGURES 51.5 [125I]OTA binding in the mPOA and BSTv (adjacent brain sites critical for active maternal behaviors; see the section Hormones Most Significant for the Onset of Maternal Behavior) of postpartum female rats that had previously displayed high or low maternal responsivity (i.e., high or low licking and nursing). Highly responsive females had greater [125I]OTA binding in both brain sites compared to less responsive females. Source: Modified from Champagne et al., 2001.108

This CD38 KO does produce behavioral deficits, including slower retrieval, disorganized retrieval, and slower return to nursing after a disruption,212 suggesting that brain OT release in these animals is insufficient to maintain normal mothering. The most specific action of OT in the brain and periphery is via a single isoform of the OT receptor, which increases in number as pregnancy progresses and at parturition.213 A total KO of the OT receptor in the brain and periphery revealed that parturition is surprisingly normal, but that lactation is not possible, and some aspects of postpartum or spontaneous virgin maternal behavior are reduced but not absent.214 The maternal behavior deficits in this OT receptor KO are also probably more subtle than expected, again suggesting compensatory responses by other systems. Using a conditional OT receptor KO confined to the forebrain, and hence sparing the peripheral receptors and their function, others reported no impairment in maternal behavior, although pup licking was not assessed.213 While these mice have

Sheep Estrogen and progesterone: Virgin ewes are either indifferent or aggressive toward lambs, and, unlike rodents, they remain so even if they have prolonged exposure to young. This is radically changed by pregnancy, parturition, and a brief interaction with the offspring postpartum. Levels of estrogens are low during pregnancy and rise only very late and briefly in the peripartum period to a level approximately five times that seen at the peak of the estrus cycle. They then fall within hours after delivery.102,215,216 Circulating progesterone levels are also very low in early pregnancy but rise later in pregnancy and are sustained at approximately four times the peak amounts found during the estrus cycle.102,216 As pregnancy progresses in sheep, the source of progesterone shifts from the ovary to the placenta.217 The progesterone rise as pregnancy progresses in ewes is similar to what is found in rats, such that levels are high until they rapidly fall a few days before parturition, and then remain at low levels through the early postpartum period (Figure 51.3).102,215 The high estradiol and low progesterone during very late pregnancy and the early postpartum period are positively related to maternal responsiveness in ewes, including lamb grooming, acceptance of suckling attempts, and maternal vocalizations by the ewe.102,215 Maternally experienced ewes show increased responding to newborn lambs about 10 days before parturition,218 presumably facilitated by the change in circulating hormones during late pregnancy. The hormones of late pregnancy also mediate the process where sheep withdraw from their herd before parturition, and give birth to and bond with their offspring in relative isolation. This isolation behavior is considered one of the earliest signs of maternal responsiveness in the pregnant ewe.219 Fifty to sixty percent of multiparous ewes can be stimulated into maternal acceptance using 7–30 days of exogenous estradiol and progesterone treatment, with the best acceptance found with regimens involving high estradiol and low progesterone.219–221 Unlike rodents, physiological levels of estrogens alone are insufficient to stimulate complete maternal behavior in sheep, but

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together with the sensory input and OT release during vaginocervical stimulation (which is also insufficient alone), most primiparous ewes will completely and rapidly accept lambs.96,221–223 During the postpartum period, there is a hormonally established window of sensitivity to offspring during which the ewe must physically interact with the lamb and display placentophagia in order for them to form a preference for their own lambs. These activities have to occur within 4–12 h after parturition, and their effects usually begin to wane within 6 h of parturition.218,224 The hormonal and visceral somatosensory stimuli, the chemosensory stimulation from the newborn lamb and amniotic fluids, and the auditory stimuli provided by low-pitched “lambing” bleats from the ewe provide the basis for bonding between the ewe and her offspring. Adrenal steroids: Plasma cortisol levels are elevated during late gestation and lactation in ewes.220 Cortisol levels during parturition are negatively associated with the onset of affiliative behaviors exhibited by the ewe to the lamb, but breeds that are more maternally responsive have higher levels of cortisol during the postpartum period.220 It remains to be seen whether these higher levels simply do not interfere with maternal attentiveness, or possibly promote it, as has been suggested for humans (discussed further in this chapter). In support, ­hypothalamic–pituitary–adrenal (HPA) axis stimulation in sheep, along with additional hormonal treatments, can facilitate maternal acceptance by nulliparous ewes.4,220 There is also evidence that the induction of parturition with exogenous dexamethasone shortens the sensitive period for bonding with the lamb due to reduced postpartum estrogens, which normally maintain this sensitive period.218,224 Prolactin and its family members: Similar to other species, basal PRL is low during most of pregnancy in sheep, but there is a substantial increase in the days immediately before parturition to reach levels somewhat higher than those seen in cycling females.102,225 Placental lactogens also follow a similar pattern to that seen in other species, with sustained levels during later pregnancy and higher levels when two or more fetuses are being gestated.226 An important difference between the scientific literature on rodents and ewes is that there is little evidence that PRL is required for the ewe’s maternal behavior or bonding with the lamb.4,219 Oxytocin: Plasma OT levels peak at parturition in ewes, then fall to levels similar to prepartum levels within 24 h after parturition. They remain low during the postpartum period except for peaks associated with suckling by the lamb.220 Plasma OT does not vary across breeds of sheep with higher versus lower maternal care, and peripheral OT is not thought to be relevant for the onset or maintenance of their maternal behavior.220 Instead, Kendrick and colleagues have used

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microdialysis to assess OT release and infusion of OT to demonstrate that the location of OT action to promote mothering is intracerebral, particularly the olfactory bulb and paraventricular hypothalamus (PVN).95,202,227 These investigators and others have also demonstrated that opioids acting within the brain facilitate maternal responsiveness, including regulating OT release, which is dissimilar to the disruptive effects of opioids on mothering in laboratory rats (see the section Brain Control of Maternal Behaviors).228

Humans Due to the dramatic expansion of the cerebral cortex that occurred during primate evolution, mothering by humans is thought to be more cognitively based and greatly emancipated from the hormonal events often necessary for the stereotypical and reflexive caregiving behaviors displayed by many other animals.229 Studying the hormonal basis of maternal or parental behavior in nonhuman and human primates is, of course, much more difficult than studying the nonprimate models described in this chapter. Some very significant work has been possible in nonhuman primates, though, and demonstrates roles for estrogens, cortisol, PRL, and OT that echo information found in nonprimates as well as some findings in humans.230 The greatest limits to studying this question in humans is that most experiments can only investigate circulating levels of hormones assayed in plasma or saliva and correlate those measures to naturally occurring variance in behavior. An additional difficulty is the complex and highly varied nature of human maternal responsiveness, which limits generating an operational definition of maternal behavior that is relatively simple in animals with more stereotyped behaviors. Nonetheless, some laboratories have created useful observer-based operational scales that are appropriate for defining features of human mothering and they have correlated those measures with hormone levels.231,232 The complicated issues introduced by our emotional states and traits affecting our behavior have usually been addressed by statistically considering data obtained by self-report or clinically administered psychological scales examining state (current affective state, postpartum depression, and anxiety) or trait features of our personalities (depression across life, personality, and pathology).233 Given the demonstration from animal models that hormones are important for the initiation of maternal behavior, many studies of maternal behavior in humans pay close attention to hormone levels during pregnancy and soon after giving birth. Indeed, this strategy has provided the best clues about possible hormonal influences in humans.231,234 While the role of hormones in human mothers is mostly without the causal proof available

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from studies of nonhumans, the natural endocrine patterns during this period have been well documented, which is essential for uncovering any role for hormones in human mothering. Estrogen, testosterone, and progesterone: As with other mammals, the human placenta and the fetus contribute to the endocrine state of the mother, particularly during the late second and third trimesters, so delivery results in a rapid reduction in many circulating hormones within 24–48 h. Humans and nonhuman primates have been consistently reported to have a temporal course of estrogens and progesterone during pregnancy that is similar, but not identical, to those described in the rat and sheep models described here. Estrogens rise more steadily across pregnancy in humans so that in the second and third trimesters, plasma levels are 10–100 times those seen at the highest points of the menstrual cycle (e.g., the midluteal phase).75,235–238 These levels remain high at delivery but fall substantially by the third postpartum day, such that they are below menstrual cycle levels by day 14 postpartum and remain low for up to 12 weeks postpartum in lactating women.238,239 In ­nonbreastfeeding women, the endocrine changes consistent with the resumption of cyclicity begin in the first month postpartum (Figure 51.6).240 Less frequently analyzed or discussed for human pregnancy and the peripartum period is plasma testosterone. Similar to the rat, human circulating testosterone during the third trimester is three times the level found at the highest point in cycling women (i.e., midluteal).238 While concentrations of testosterone are substantially less than those of estradiol during pregnancy (3 versus 82 nm/l), it remains at these levels for much longer than that occurring during the menstrual cycle, and so is a unique feature of the endocrine milieu of pregnancy. Progesterone levels rise steadily across human pregnancy such that in the second and third trimesters, they are about 100 times higher than the levels found during the follicular phase of the menstrual cycle and 6–50 times higher than the maximal levels of the luteal phase of the cycle.75,237,238 In terms of relative concentration,

progesterone is the dominant gonadal steroid hormone in human pregnancy, being 10-fold that of even the substantially elevated estrogens.237,238 Until late pregnancy, progesterone levels follow a pattern similar to that discussed here for other animal models.235,236 Unlike other placental mammals such as rats, mice, and rabbits that have precipitous drops in plasma progesterone just before parturition, human circulating progesterone does not drop so substantially until after the fetus and placenta are expelled. In fact, only on the first day postpartum does progesterone fall precipitously to levels similar to what is found during the luteal phase of the cycle.239,241–243 The absence of a dramatic withdrawal of circulating progesterone before parturition in humans is intriguing because when labor begins, there is both high circulating progesterone and the formidable onset of myometrial contractility. There is thought to be a functional “­progesterone block” that is alleviated prior to the onset of labor when the myometrial contractions are otherwise held in check by progesterone.244 Mechanisms for how progesterone’s function in the uterus is blocked during labor include a change in the dominant form of the genomic progesterone receptor, from the B to the A form, and subsequent release of myometrial contractility.245–247 Interestingly, nongenomic progesterone receptor activity may favor myometrial contractility rather than inhibit it.244 Adrenal steroids: Primarily due to the contributions by the fetus and placenta, cortisol levels rise substantially across human pregnancy, rising 30% in the first trimester and by nearly threefold in the last two trimesters.237,238,243 In the last trimester, plasma cortisol is nearly double that found in nonpregnant women.75 In a within-subject longitudinal study, it was found that cortisol fell to slightly higher than prepregnancy levels within 2 days postpartum,248 resulting in about half that seen during late pregnancy and labor,243 and that the levels remained there for at least part of the postpartum period.249 Walker and coworkers recently showed that the daily rhythm of cortisol returns to its normal circadian course and to nonpregnant levels in weeks 5–20 postpartum and that these

FIGURE 51.6  Schematic representation of circulating plasma levels of estradiol and progesterone across pregnancy and parturition in humans. Note that the levels of progesterone shown are divided by a factor of 10. For example, the immediate prepartum progesterone level is actually approximately 500 nmol/l. Source: Modified from Brett and Baxendale, 2001.749

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Hormones Most Significant for the Onset of Maternal Behavior in Rodents, Sheep, and Humans

levels are not altered by the mother’s parity or whether she breastfeeds or bottle feeds the infant.250,251 Prolactin and its family members: Plasma PRL levels rise about 10-fold during pregnancy, without significant changes in cerebrospinal fluid levels.75,238 As in other mammals, placental lactogens rise across pregnancy in humans to levels much higher than those of PRL itself. There have been no measures of PRL levels in the brain itself, but because PRL transporters are present in the choroid plexus, the human maternal brain is probably chronically exposed to high amounts of all PRL-type hormones from the periphery and may also be affected by PRL of purely central origin. The structurally similar placental growth hormone is also present at high levels in maternal blood, but less is understood about its access to her brain.252 Placental lactogen is involved in lactogenesis and steroidogenesis, but human pregnancy is fine without it, possibly due to compensation by the structurally similar growth hormone.252,253 However, data from mice deficient in growth hormone that are also lactogen resistant suggest that these hormones have distinct functions.254 Within a day after parturition in women, placental hormones disappear from the blood stream and PRL itself is thereafter the dominant hormone supporting lactation.236 Because PRL has a role in onset of maternal behavior in most animals examined, it seems possible that this is true for humans, but it has not been established in correlational studies. Whether such PRL effects would depend on peripheral PRL acting on the brain, or by PRL both made and acting within the brain, is a viable question. Correlations among circulating hormones and human maternal behavior: There is a positive relationship between the ratio of the levels of estrogens:progesterone in human mothers and higher levels of feelings of attachment in the peripartum period, as well as increased approach and appropriate contingent responsiveness to infant cues, further providing evidence that these hormones in nonhuman primate females are related to behaviors thought to typify a good mother.4,104,230,255 There is also work from psychologists and anthropologists supporting a role for circulating estrogens for maternal tendencies (i.e., interest in and desire to have children) and other features often associated with feminization.256 As discussed in detail in the section Hormones Most Significant for Paternal Behaviors, the first findings concerning testosterone and parental behavior were that lower circulating testosterone correlates with higher responsiveness in human fathers. A similar correlation has also been reported in women, with lower testosterone levels associated with motherhood and long-term social attachment such as that found in marriage,257,258 whereas lower scores on maternal interest and reproductive ambition were found in women with higher circulating testosterone.259 Circulating testosterone was not correlated with general career ambition,

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suggesting a restricted realm of influence for testosterone in women. Novel work from Fleming and colleagues demonstrates that, among the steroid hormones, adrenal steroids are the most highly and positively correlated to high maternal responsiveness in women.104,232 Specifically, mothers with higher levels of circulating cortisol interact more sensitively with their infants,260 are more sympathetic to cries,261 and are more attracted to and can better discriminate among infant odors (Figure 51.7).232,261 This may indicate that higher cortisol contributes to a level of arousal that is optimal for maternal responsiveness, although overarousal would presumably interfere with appropriate mothering. These data were obtained on a single afternoon (a circadian point of decreasing levels) in a hospital setting, which may itself increase basal cortisol, 2 days after delivery when cortisol would be expected to have fallen to a point somewhat above prepregnancy levels. In contrast to these results, Feldman et al. reported that higher cortisol levels were associated with lower maternal behavior in a population of both primiparous and multiparous women of diverse socioeconomic status.231 These findings were based on repeated measures taken in a clinical setting during the first and second trimesters and then 4 weeks postpartum (the time of day of cortisol sampling was not specified). Lactating women, like other mammals, have attenuated HPA axis responses to stressors.262 While some have reported reduced HPA axis responses to a social stressor immediately after nursing compared to women who simply held their infants,263,264 others find this only in multiparous women250 or if the time between feeding the

FIGURE 51.7  Correlation between salivary cortisol and the hedonic ratings (i.e., how pleasant or unpleasant) made by first-time mothers about the odor from their own infant’s shirt. Mothers with higher cortisol rated the odors as more pleasant. Source: Modified from Fleming et al., 1997.232

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infant and exposure to the stressor was relatively long.265 Furthermore, suckling by the infant exerts a shorter term restraint on the HPA axis in humans compared to the longer term effect lasting even a day or two after litter contact seen in laboratory rats.263 Differences among studies in the relationship between adrenal steroids and mothering or stress responsiveness in parturient women highlight how sensitive such results are to a myriad of factors. This includes when the hormones are measured, which is particularly relevant for adrenal steroids that show marked circadian rhythm and very dramatic changes across pregnancy, parturition, and the postpartum period. Further influences include socioeconomic status (which is inversely correlated with basal cortisol), cultural and social conditions, infant feeding choices, and parity.250,251 Also relevant is the potential for personality trait dependence of such findings, possibly including those underlying variations in basal and reactive cortisol responses.104,249 In any case, while the bases of the discrepant findings are unknown, they are worthy of further exploration. Among the peptides, OT has been the most studied for a relationship with human maternal care. OT released into the peripheral circulation has well-known roles for uterine contractions at parturition and postpartum milk letdown, with plasma levels of OT elevated during late pregnancy and in response to postpartum suckling.75,266 While a few findings suggest that peripherally available OT has the potential to alter human maternal behavior, these studies do not provide any mechanism by which these effects occur as OT cannot cross into the brain. Intranasally administered OT does substantially raise salivary OT levels, with a short-lived peak after administration, but more work needs to be done in humans to determine the relationship between naturally occurring brain and peripheral OT.267 Without being able to define whether brain or peripheral OT is involved, there appears to be a role for the extended OTergic system in maternal attachment and care of infants. Circulating OT levels across pregnancy and the postpartum period are higher in women who are the most attached to their infants, and these women also exhibit higher levels of some maternal behaviors.231 Additionally, mothers who are highly affectionate with their infants have higher circulating OT following an interaction with them compared to women rated as providing low levels of affectionate contact.200 Polymorphisms in the genes coding for the OT receptor or CD38 are also associated with mother–infant bonding,268 a finding reminiscent of the relationship between variation in OT receptor expression and some maternal behaviors in laboratory rats.208 Furthermore, 6–14-week postpartum mothers with the greatest increase in plasma OT in response to a play interaction with their infants score highest on orienting sensitivity and attention to the

mood, sensory cues, and emotions of their infants. Conversely, women who scored highest in trait measures of effortful control and focus on executive plans have lower levels of OT.233 These interesting results suggest that the quality of certain mother–infant interactions are related to OT even during the later postpartum period, and that stable personality traits may predict some of these interaction qualities and their relationship with OT release.

HORMONES MOST SIGNIFICANT FOR PATERNAL BEHAVIORS Paternal care is found across a large swath of the animal kingdom, from insects to humans. Birds are the most paternal vertebrates, with over 90% of species displaying biparental care, and the endocrinological basis of caregiving in avian fathers is quite well studied.269,270 Fathering in mammals is much rarer, seen in only approximately 5–10% of species,1,271 and is most commonly found in rodents, canines, and about 40% of primates. Laboratory studies of male rodents, such as laboratory rats, that are not parental in their natural environments reveal that the behavior can still be induced after manipulations that include early feminization by neonatal castration, treatment with very high doses of ovarian hormones during adulthood, and/or prolonged exposures to neonates.2,28 Thus, the conclusion can be made that many male brains contain the necessary substrates for expressing paternal behaviors, regardless of natural history, and that this latent system can be uncovered under precise laboratory conditions. Natural paternal involvement in caregiving is often coupled with a monogamous mating system and its associated increase in, but not absolute certainty of, paternity. Paternal involvement is also more likely expressed in relatively harsh environments in which food resources are sparse or temperatures are extreme, such that caregiving from two parents can greatly contribute to offspring survival and reproductive success.1,271 Fathers of biparental species can also provide additional protection and supervision of the offspring. Studies of the benefits of fathering within a laboratory setting probably underestimate its importance given the undemanding environment,28 although litter growth and survival have still been observed to be compromised in the absence of a sire even within the laboratory.272–275 In humans, many studies have shown that the absence of a biological father or a second highly invested caregiver can contribute to negative social, psychological, and physical health consequences for children.276 We here review the endocrinology of paternal behavior in some exemplar parental mammals, with a focus on species displaying obligate paternal behavior within their natural environments, meaning that paternal care is

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Hormones Most Significant for Paternal Behaviors

continually displayed by most sires of the species. This can be contrasted to the facultative fathering that is expressed more sporadically by sires in other species only during times of particular need and when mothering alone is inadequate.28 For example, with approaching winter temperatures, many typically nonpaternal meadow voles (Microtus pennsylvanicus) nest with females and interact positively with their pups.277 Such facultative fathering is not very often studied endocrinologically or neurobiologically, but is particularly intriguing because it requires the behavior to be switched on and off, sometimes repeatedly in the same individual across their lifespan. These transient plastic changes in the brain necessary for facultative fathering may involve the same systems necessary for paternal behavior in obligate fathers.278 It is also interesting to consider that the behaviors of these more flexible facultative fathers are more likely susceptible to environmental influences compared to the relatively hard-wired behavior of obligate fathers.279 Studies of the endocrinology of fathering have often followed the heuristic that changes in steroid and peptide hormones that compel males to act paternally are similar to those necessary for females to display the same behaviors (i.e., elevated E, PRL, and OT). It will be seen that this assumption is not always correct and that the hormonal profiles associated with fathering considerably differ across species, especially among rodents.28

California Mice The California mouse, P. californicus, is an important model system for investigating the hormonal control of paternal behavior. In contrast to most other socially monogamous species, including prairie voles,280 DNA fingerprinting and paternity analysis suggest that wild California mice have extremely low rates of extrapair fertilizations and are essentially strictly monogamous.281 Equivalent levels of caregiving behaviors are expressed by males and females, with the obvious exception of nursing,282,283 and offspring survival relies tremendously on the care provided by their father.284 Virgin male ­California mice are not particularly attracted to pups and often attack them, but they become more paternal in response to olfactory cues they receive while living with their pregnant mate and are very paternal after the pups are born.2 The hormones and neuropeptides studied for paternal behavior in California mice are numerous, with testosterone and its intraneuronal aromatization to estradiol receiving the greatest attention. There is a classical inverse relationship between circulating testosterone and parenting that was first established in paternal birds285 and that alters males’ time allocation to other reproductive endeavors, including aggression, attracting mates, mate guarding, and an

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increased focus on their mate.286 Further studies reveal plasticity in this hormone–behavior relationship, particularly when there is temporal overlap among mating, aggression, and paternal behaviors.282,287 For example, California mouse pairs mate during the postpartum estrus, but males need to coordinate this with mate guarding and behavior toward their young pups in the nest. Behavioral conflicts do arise, as in one case observed in which a male California mouse removed the pups from the nipples of his female mate and placed them in the corners of the cage prior to mating with her (Marler, unpublished data). As predicted from this classical perspective, testosterone levels in male P. californicus peak at courtship and significantly drop when they become fathers (Figure 51.8).288 However, there is a positive correlation between testosterone and huddling with and grooming of pups in experienced fathers, and this relationship is not seen in virgin males.289 A similar positive relationship between circulating testosterone and huddling with young pups has been found in another biparental male rodent, the Mexican volcano mouse (Neotomodon alstoni).290 This positive hormone–behavior association is further supported in California mice by the detrimental effects of castration on their paternal care and the resumption of fathering after reintroduction of testosterone.291,292 At first glance, it seems difficult to assimilate these seemingly contradictory findings, but there is an interesting evolutionary twist in male California mice because testosterone influences paternal behavior through activity of estrogen receptors rather than androgen receptors. Testosterone is aromatized into estradiol locally in specific brain regions to influence paternal behavior in California mice, as first suggested by the finding that implants of estradiol are as

FIGURE 51.8  Circulating testosterone (Mean +/- SEM) in male ­ alifornia mice before pairing with a female (Baseline), an hour C after pairing (Courtship), 3 weeks after pairing (Bonded), and 4 days after the birth of their pups (Paternal). Source: Modified from Gleason and Marler, 2010.288

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effective as testosterone in maintaining paternal behavior in castrated males.292 In addition, aromatase activity in the medial preoptic area (mPOA), a brain area critical for expression of most parental behaviors in all species studied (see the section Sensory Control of Maternal Care), is significantly elevated in fathers compared to mated males without pups.293 Evolutionarily, it is possible that P. californicus males have successfully co-opted some of the mechanisms used in maternal care while avoiding some of the high costs of testosterone. The relationships between glucocorticoids and the physiology and behavior of rodent mothers were reviewed above in the section Hormones Most Significant for the Onset of Maternal Behavior, but studies of male ­California mice indicate they may be mostly resistant to such glucocorticoid effects. This is suggested at a physiological level by their very high basal ­corticosterone levels, the inability of even moderate doses of dexamethasone to suppress this endogenous release, and the fact that several stressors are unable to further raise cortico­ sterone levels but instead lower them at the time of the high diurnal peak.294 Nonetheless, males’ ­corticosterone does increase in response to a predator odor at times during the day when corticosterone levels are naturally lower,294 as in response to social defeat at any time of day.295 With regard to a relationship between glucocorticoids and paternal behavior, the published data are conflicting. A single injection of corticosterone administered in a manner that mimics an acute stress response has no effect on males’ paternal behavior.296 However, a complex analysis that included corticosterone, dehydroepiandrosterone (DHEA), and interruption of ­ behavioral patterning in response to exposure to a novel object found greater levels of circulating corticosterone and DHEA but less behavioral disruption in fathers compared to sexually inexperienced males.297 Others have found no difference in basal circulating corticosterone among males assessed as virgins, mated but without pups, and fathers.298 In a study examining immediateearly gene activity of cells in the hypothalamic PVN that produce corticotropin-­releasing hormone (CRH), there was no difference between paternal and nonpaternal males in response to stress.299 Overall, male California mice appear to be resistant to stressors through both behavioral and HPA axis changes. What is unclear is whether this relates to the transition from being sexually inexperienced to becoming a father. Even if it does not, there may have been general selection for these males to respond less to stress because of the monogamous nature of their mating system. Males that mate for life and that have few offspring per litter are predicted to have buffers against stressors, unless a stressor strongly impacts the survival of the family unit or their ability to mate guard. Whether this also involves a change in emotional state in ­California mice is unclear because there are variable results regarding the effects of fatherhood on anxiety,

fear, and neophobic behaviors,297,299,300 even though fatherhood does appear to suppress activity in brain areas underlying these emotional behaviors.301 Correlational analyses of other plasma hormones in male California mice indicate little evidence that OT is important for paternal behavior. OT levels are high in males the day following mating, but then remain low throughout the mate’s pregnancy and later development of the offspring.302 More compelling are the findings that PRL rises within 2 days after the birth of a litter303 and that progesterone levels drop with the onset of paternal behavior.293 Exogenous PRL has been seen to rapidly induce paternal responding even in the typically nonpaternal male laboratory rat,304 but additional studies are needed to assess cause-and-effect relationships between PRL or progesterone and paternal behavior in P. californicus.

Wild House Mice Feral wild house mice live in extended social groups that often consist of an adult breeding male, several females and their litters, and a number of subordinate males.305 Similar to other rodents living under such conditions, the expression of paternal behavior is likely in their natural environment. In the laboratory environment, almost all virgin males are infanticidal but can be parentally sensitized, and after mating they will refrain from killing pups when tested early or late during their mate’s pregnancy.82,306 The stimuli capable of inhibiting infanticide in mated wild male house mice are numerous, and this inhibition can occur from copulation alone82 or by cohabitation with a pregnant female.306 Hormonal factors contributing to high infanticide in wild male house mice followed by its decrement after mating have not been examined in great detail, but they involve unusually high endogenous testosterone release during neonatal development and a later decrease in circulating testosterone after mating or cohabitation,82 the latter being similar to numerous other mammalian fathers.

Laboratory Mice Paternal responding in virgin male laboratory mice is now very often studied, but as discussed earlier in this chapter for the study of female laboratory mice, levels of spontaneous paternal behavior strikingly vary among mouse strains.83 This indicates the tremendous importance of genetics on males’ responses to neonates, but does not make it easy to reach universal conclusions about the endocrine bases of fathering in laboratory mice. Early studies reported that individual differences in circulating testosterone do not correlate well with paternal responses in male Rockland Swiss albino mice,307 but infanticide is still reduced by castrating males with

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Hormones Most Significant for Paternal Behaviors

no prior killing experience.308 It has also been seen that neonatally castrated males are more likely than males not neonatally castrated to kill pups after being treated with testosterone as adults,309 suggesting that neonatal testicular hormones render the albino mouse brain to be less responsive to the infanticide-inducing effects of later androgens. Similar to wild house mice and gerbils (see the ­section Mongolian Gerbils), mating eventually reduces infanticide and increases paternal behaviors in numerous strains of male laboratory mice that are not already highly paternal as virgins. This effect is maximal soon before their mates give birth and is due to the stimuli associated with ejaculation during copulation. Cohabitation with the mate or another pregnant female is neither necessary nor sufficient for this increase in paternal responsiveness in some strains of mice,310,311 and in these cases the behavioral change appears to be based only on the number of light–dark cycles experienced by the male after ejaculating.312 In other strains of mice, both ejaculation and cohabitation with a pregnant female may be needed to promote fathering.313–315 The only genetic manipulations of neuroendocrine systems in male laboratory mice that provide information about their paternal behavior involve KO of the progesterone and PRL receptors. The fascinating findings from the PRKO model included a tremendous reduction in infanticide and increased parental behavior by the males, which are of a strain that is normally aggressive toward pups (Figure 51.9).316 Consistent with these results, wild-type male mice chronically treated with the PR antagonist RU486 are highly paternal,316 while a history of chronic exposure to exogenous progesterone increases the percentage of males that attack pups even without progesterone “on board” at the time of testing.317 Progesterone is a primary inhibitor of the onset of maternal behavior in female rats (see the ­section Hormones Most Significant for the Onset of Maternal

FIGURE 51.9  Percentage of male wild-type (C57BL/6) and progesterone receptor knockout (PRKO) mice committing infanticide after the birth of their first or second litters. PRKO mice do not attack pups. Source: Modified from Schneider et al., 2003.316

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Behavior), and this work suggested for the first time that PR activity can also interfere with paternal behavior in a male rodent. With regard to PRL, and in contrast to females, PRL signaling is expendable in male mice and the absence of the PRL receptor gene does not prevent males from interacting normally with pups. These males do not show the PRL-mediated neurogenesis necessary for later recognition of their own adult offspring, but the importance of such late offspring recognition in this species is also not obvious.318

Mongolian Gerbils Virgin male Mongolian gerbils are either spontaneously paternal319 or at least become less infanticidal soon after mating.320 Housing with a pregnant female promotes males’ interest in pups,319 making Mongolian gerbils similar to some laboratory mice and California mice. Like many paternal rodents, circulating testosterone rises in Mongolian gerbils after mating but drops dramatically after pups are born,321 which is functionally significant because castrating adult virgin males increases paternal behavior, and providing replacement testosterone reduces it.322 Circulating PRL in male Mongolian gerbils generally rises across their mate’s pregnancy and continues to rise as the pups age,321 although no manipulations of PRL have been conducted to determine any relevance of this change for paternal behavior.

Prairie Voles Prairie voles (M. ochrogaster) are socially monogamous rodents that form lifelong pair bonds after mating and display biparental behavior after the birth of pups. This has been inferred from field studies where both parents are found with offspring in the natal nest or directly observed within seminatural or laboratory environments.323–326 Plasma testosterone in male prairie voles increases in response to mating and cohabitation with a female,327,328 and males’ paternal behavior then increases across her pregnancy,328 but it is not known if these events are causally associated. Unlike unmated California mice, most virgin male prairie voles respond very positively to pups.329,330 The consequence of castration during adulthood on parenting in these virgin males is equivocal. One study found that half of virgin prairie voles castrated as adults were infanticidal and the remaining voles weakly parental,331 while a later study reported that castration had no significant effect on parental behavior when the virgin males were tested 4 or 8 weeks after surgery.330 Differences between the two prairie vole colonies studied in their basal paternal responsiveness (lower in the first study compared to the second) and the presence of a litter effect in the first study probably account for the discrepancy. However, gonadal hormones are not completely irrelevant for

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paternal behavior in male prairie voles, but they may be particularly important during early development. Neonatal castration reduces the percentage of virgin male prairie voles acting paternally during adulthood, even when testosterone is replaced weeks before testing.332 In addition, alloparenting by weanling male prairie voles is reduced by inhibiting aromatization of testosterone to estradiol with 1,4,6-androstatriene-3,17-dione (ATD), or blocking androgen receptors with flutamide, during the second week of life.333 Consistent with the study showing that adult castration has no effect on paternal behavior in male prairie voles,330 and very different from studies of male California mice, work by Cushing and colleagues has revealed that neural ERα expression and signaling (presumably from binding estradiol generated by the aromatization of testicular testosterone) has a negative relationship with paternal behavior in prairie voles (detailed in the section Brain Control of Maternal Behaviors). Preliminary data indicate that blockade of progesterone receptors with RU486 has no effect on prairie vole paternal behavior.2 The influence of exogenous glucocorticoids on prairie vole paternal behavior is unknown, but Bales et al.334 found that a single swim stress increases males’ later huddling with pups, possibly because males seek out pups as social buffers to dampen their elevated HPA axis activity. Relatedly, stimulation of CRH2 receptors by intraperitoneal injection of urocortin also increases huddling with pups in male prairie voles.335 A stressassociated increase in huddling with pups may help explain why RU486, which is also a glucocorticoid receptor antagonist, had no effect on pup-directed behavior in unstressed virgin male prairie voles from a colony that was highly paternal.2 Only a small amount of research has examined roles of peripheral peptides for paternal behavior in male prairie voles. Preliminary data indicate that their paternal behavior is unaffected by inhibiting pituitary PRL release with the dopamine receptor antagonist bromocryptine.2 OT is very quickly released into the general circulation when juvenile or adult male prairie voles interact with a pup.336 Whether this peripheral OT can cross the blood–brain barrier to facilitate ongoing paternal behavior, or is associated with concurrent OT release in the central nervous system, requires further study. Peripheral AVP levels are not affected by pup exposure and corticosterone release is blunted, again indicating that the presence of pups reduces stress.336

Dwarf Hamsters The endocrine basis of caregiving behavior displayed by a subspecies of dwarf hamster that is biparental and monogamous, P. campbelli, has been extensively studied. Male P. campbelli are transiently alloparental as juveniles

but become infanticidal as they age.337 Reproductively experienced males are unlikely to attack pups, though, and are very paternal by the time their pups are born. In fact, they even contribute to delivery by pulling pups from their mate’s vagina and by cleaning the pups of birth membranes and amniotic fluid.338 Unlike California mice that become more paternal in response to urinary cues from their pregnant mate,339 the suppression of infanticide and expression of midwifery in P. campbelli does not require that males receive any postcopulatory cues from their mates.340 Years of detailed work by Wynne-Edwards and colleagues have led to the conclusion that peripheral hormones do fluctuate in P. campbelli males across the transition to fatherhood, but that these hormones have very little if any role in regulating their paternal behavior. Correlational work reveals that males’ circulating testosterone increases after mating but precipitously drops in concert with a spike in PRL just before pups are born.341 Furthermore, expression of the long form of the PRL receptor in the choroid plexus falls and then rebounds in anticipation of the pups’ birth.342 Unlike most female mammals, circulating basal estradiol levels in male P. campbelli are consistently very high across the peripartum period, and their progesterone levels rise rather than fall associated with birth of a litter.343 Because testosterone has been thought to impede nurturant behavior,285 and high PRL and estradiol facilitate mothering in female rats, these patterns of endocrine changes could be reasonable facilitators of fathering in P. campbelli. Compellingly, none of these endocrine events occur after mating in the nonpaternal, but closely related, male Phodopus sungorus.344 While castrating male P. campbelli after mating reduces their circulating testosterone and estradiol to almost nondetectable levels, and reduces territorial aggression, it has no effect on retrieval of pups or viability of the litters.345 Similarly, chronic inhibition of males’ estradiol synthesis with the aromatase inhibitor, letrozol, beginning during their mate’s pregnancy also has no effect on paternal care.346 Experimental manipulations of PRL have revealed similar negative results—­dopamine D2 receptor antagonism that reduces circulating PRL a few days before and after the birth of pups has no consequence on paternal behavior in P. campbelli (Figure 51.10).347 In sum, there appears to be a pattern of low testosterone and high PRL in P. campbelli and many other rodent fathers, and these hormones can sometimes be correlated with particular aspects of their paternal behavior. These correlative relationships are not found in all rodent fathers, and the cause-and-effect relationships between circulating hormones and paternal behavior in some species remain to be examined.348,349 In species where experiments have been conducted to manipulate

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Hormones Most Significant for Paternal Behaviors

FIGURE 51.10  Percentage of male Djungarian hamsters that ever retrieved a pup, and their highest overall parental responsiveness score, after administration of vehicle or bromocryptine for the 3 days before birth of their pups via subcutaneous injection (top panels) or chronically via osmotic minipumps (bottom panels). Prolactin suppression had no effect on paternal responding. Source: Modified from Brooks and Wynne-Edwards, 2005.347

males’ endocrine status, paternal behavior may or may not be affected. Thus, there is no universal endocrine basis of fathering in paternal rodents, suggesting that the behavior has evolved numerous times via numerous endocrine and nonendocrine mechanisms.

Primates The small arboreal New World monkeys, the Callitrichids, are the best studied nonhuman primates for examining relationships between hormones and paternal behavior. They are cooperative breeders that live in family groups consisting of a monogamous male–female pair and their offspring of various ages, all of whom help care for the youngest infants in the family.350 Paternal involvement in some Callitrichids and other nonhuman primates is so impressive that fathers may be the primary nonnutritive caregiver and can be observed to carry their infants considerably more than the mothers!351,352 Testosterone and PRL were the first hormones examined for an association with paternal care in any primate. Dixson and George reported that most, but not all, male common marmosets (Callithrix jacchus) cohabitating with

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their mate and young offspring had lower circulating testosterone compared to males living with a nonpregnant or a pregnant female.353 This result was bolstered by later work showing lower testosterone in common marmoset fathers after the birth of the infants compared to beforehand and a drop in males’ testosterone during acute exposure to infant-related cues.354,355 Testosterone was also inversely associated with infant carrying in black tufted-ear marmoset fathers (Callithrix kuhlii).356 On the other hand, there is no significant relationship between circulating testosterone and paternal behavior in white-faced marmosets (Callithrix geoffroyi),357 although this does not eliminate the possibility that the relevant testosterone is converted to estradiol within the brain to influence their behavior.292 Along with their decreased testosterone, common marmoset fathers sometimes have tremendously high circulating PRL.353,354 PRL levels are elevated in these fathers only if they very recently carried an infant, and the levels are positively correlated with how long they carried the infant; these findings are not specific to fathers because they occur in male marmoset alloparental “helpers.”353,358–360 In contrast to marmosets, father Goeldi’s monkeys (Callimico goeldii) do not have higher PRL levels than their adult nonreproductive sons, but PRL in fathers rises after the birth of their neonates and drops after they begin expressing paternal behavior.361 Also different from marmosets are Pithecid fathers (Titi monkeys; Callicebus cupreus), which have higher urinary PRL compared to their nonreproductive sons a few weeks before the infants’ birth, but show no changes in urinary PRL from a few weeks prepartum to 3 weeks postpartum, even though they carry their infants almost exclusively.361 In rare experimental studies manipulating hormones in monkey fathers, it was found that suppressing pituitary PRL release reduced infant carrying by alloparental marmoset males,362 but that experienced fathers showed no such reduction in carrying after PRL suppression and were instead slightly more interested in infants compared to controls.363 In fact, experience is an important determinant of whether endocrine fluctuations even occur in some nonhuman primate fathers. For example, there is no prepartum to postpartum hormonal change in mated male cotton-top tamarins (Saguinus oedipus) that have no parenting experience, but experienced males undergo rises in estrogens (estradiol and estrone), androgens (testosterone and dihydrotestosterone), PRL, and cortisol as their mate’s pregnancy progresses, perhaps triggered by olfactory or other cues from the female.364 These hormonal changes in male fathers can have important peripheral effects, in addition to any central effects. This can be seen in male tamarins that experience a PRL-mediated increase in body weight across their mate’s pregnancy, which may be necessary for the metabolic demands of later infant carrying.354

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The only nonhuman apes that exhibit paternal care are members of the family Hylobatidae, which consists of the socially monogamous and pair-bonding “lesser apes,” commonly known as gibbons and siamangs. They provide an interesting comparison between closely related species because gibbons mostly ignore infants while siamangs readily carry their offspring.365 In a study involving small numbers of three species of paternally experienced Hylobatidae, fathers’ fecal androgen and estrogen metabolites did not significantly change from 1 month prepartum to 7 months postpartum in the nonpaternal gibbons, but androgen metabolite levels in the paternal siamangs rose across the mate’s pregnancy and decreased after she gave birth. Males’ estrogen metabolites also increased across pregnancy and were maintained at high levels through the postpartum period,365 which is reminiscent of changes in estrogenic activity in paternal California mice. It is probably unnecessary to state that many human fathers can be engaged and engrossed with their infants to the degree typically found in mothers.366 Intense paternal behavior is common in humans, but not ubiquitous, with fathers having moderate to high contact with young infants in about half of the cultures examined.367 As with naturally paternal rodents, high paternal involvement in humans is most likely to be found in cultures characterized by monogamy in which assurance of paternity is relatively high. It is also more likely to be found in cultures that conduct only small-game hunting and where animal husbandry is absent—the cultures perhaps with the least reliable food resources in which paternal assistance can have the greatest impact on offspring survival.367 Even so, paternal involvement in childrearing other than basic “breadwinning” is still highly variable within most cultures where fathering commonly exists.279 Furthermore, in societies where paternal interaction with infants is considered high, the average duration of time that fathers spend each day in physical contact with their infant or toddler can be quite small (15–90 min per day in the United States), even though fathers’ general availability to offspring is usually considerably higher.368 It is also true that human paternal behavior differs from maternal behavior in numerous ways, including that fathers are more arrhythmic in their interactions with infants, are more physically stimulating to them, respond more to infant motor cues than social cues, and are most likely to be touching their infants when play is occurring than during other types of interaction.366 Research on the endocrinology of human fathering has often hypothesized homology across species and between the sexes, and so predicts that fathers will have low circulating testosterone but high estradiol and PRL. In the first study of its kind in a now-burgeoning literature, Storey et al.369 used a longitudinal design to find that plasma testosterone levels in men did drop after their partners gave birth, and others soon thereafter

FIGURE 51.11  Plasma concentrations of testosterone, prolactin, and cortisol in human fathers before and after the birth of their infant. Different letters at base of bars indicate significant differences compared to the early prenatal group. Source: Modified from Storey et al., 2000.369

reported similar results (Figure 51.11).370 Later studies in numerous cultures indicate significantly or at least notably lower testosterone in partnered fathers compared to partnered nonfathers or unpartnered nonfathers370–375 and this difference is greatest when they are compared against the most involved fathers.372 Even though human fathers’ baseline testosterone is lower than that of n ­ onfathers, fathers respond acutely with a rise in ­testosterone after hearing infant cries, although this acute increase is less in men expressing the greatest sympathy and concern to those cries.369,371 In contrast, testosterone levels fall in fathers during a 30 min face-to-face interaction with their 2 year olds, but this depends on the context because it is only found in the fathers who spend more time interacting with the child during testing and

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whose partners spend less time interacting with their toddler during the test, and only if it is a day when fathers have already spent considerable time with their children.376 An important consideration for evaluating the results of these studies is that testosterone concentrations are stably lower in men who eventually pair bond than in single men who do not form such a relationship,377 so the longitudinal studies and the studies comparing partnered fathers with partnered childless men are particularly valuable for determining relationships between men’s testosterone and their fathering status or behavior. Estradiol also changes across fatherhood in men. A longitudinal study of men becoming fathers for the first time found that estradiol was more likely to be detected in their saliva samples than it was in samples from nonfathers. Fathers’ estradiol was also more likely detectable a month after the infant was born compared to a few weeks before the birth, even though absolute levels of estradiol did not significantly differ in men before and after their infant’s birth.370 PRL levels in men rise across their partner’s pregnancy,376 resulting in fathers having higher PRL than nonfathers, particularly for men who are first-time fathers or are fathers of very young children.371,378 Furthermore, PRL levels are correlated with paternal responsiveness, with greater PRL levels in men who report more alertness to and concern with recorded infant cries, as well as who show greater attention and coordination in their behavior with the infant.369,371,379,380 Levels of PRL drop while firsttime fathers interact with their child, though, indicating that not only do the most paternally sensitive men have the highest PRL but their hormones probably predict their upcoming behavior rather than are a result of it.371,376,379,381 An interesting parallel is found in male meerkats, where PRL levels predict which males are the most likely to initiate a bout of caregiving.382 Fascinatingly, PRL is also higher in fathers who report more couvade symptoms, the sympathetic somatic and emotional events characteristic of females’ pregnancy, further reflecting these men’s greater investment in the upcoming birth and higher sensitivity to their partner’s experience.369 There is no evidence that circulating or plasma OT is higher in fathers than nonfathers, which is also true for postpartum women who have not recently breastfed, but OT levels in fathers are associated with emotional synchrony, engagement, and positive communication with the infant.200,380 These men with high OT are prone to this type of social interaction because they also report greater attachment in social relationships throughout their lives, including with their parents and romantic partners.200 Perhaps related to apprehension about the upcoming birth of an infant, glucocorticoid levels rise in expectant fathers during their partner’s late pregnancy and peak the week before the delivery.369,370 Similar to PRL, these high glucocorticoid levels drop across time while fathers

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interact with their infants381 or toddlers.376 Fathers with showing the smallest drop while interacting with their toddler are the most attentive fathers,376 which is similar to the greater maternal responsiveness sometimes found in postpartum women with higher cortisol,232 again suggesting that elevated cortisol at reasonable levels can positively contribute to parental attention. Because glucocorticoids (and PRL) have a reactive component to their release, these studies can be difficult to interpret and depend on the environment in which the samples were taken and the possibility that interacting with an infant can itself be acutely stressful. In sum, unlike studies of rodents, the extant studies of primate fathers are generally consistent among each other, and the observed hormone profiles in these fathers generally support the hypothesis of homology between the sexes in their endocrine release before and during parenthood. This is particularly true for PRL. Given that, there are conflicting data regarding whether there are significant correlations between the hormone levels of individual father-and-mother pairs.200,369,383 As with our discussion about the relevance of the correlations between hormones and behavior in human mothers (see the section Hormones Most Significant for the Onset of Maternal Behavior), a greater understanding of how and how much these changes in circulating hormones affect paternal behaviors in primate fathers is a critical area of future research.

SENSORY CONTROL OF MATERNAL CARE Parents must accurately recognize infants at either short or long distances to initiate contact seeking and establish the physical proximity required for the execution of parental duties. As already noted in the Introduction, parenting is not a unitary process but is composed of numerous individual behaviors, and these behaviors differ in what sensory inputs elicit and maintain them. Studies of the sensory control of parenting traditionally focus on the senses involved in maternal recognition of young and contact-seeking behaviors, rather than the senses required to maintain or terminate physical proximity after its establishment. In laboratory rodents, the senses involved in maternal approach to offspring, followed by carrying them to the nest, are most often studied. Although retrieval is probably rare in undisturbed environments with young, mostly immobile pups, how rapidly dams approach offspring during a retrieval test can provide particularly valuable information about factors modulating maternal motivation to initiate contact with pups, as well as the ability to pick them up, hold them in the mouth while transporting them, and finally release them in the nest.

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In some of the earliest studies investigating the sensory requirements for retrieval in multiparous postpartum laboratory rats, Beach and Jaynes32 reinforced the important concept of “multisensory control” for how the senses act individually and together for a mother’s behavioral responding. Dams appeared to use both olfactory and visual cues to orient toward pups, but retrieval remained rapid after cauterizing the olfactory bulbs and was only slightly slowed by surgical removal of the eyes. Furthermore, loss of tactile input (i.e., anaptia) by severing any one of six sensory nerves subserving the face and head only slightly affected dams’ retrieval capabilities. A small number of animals tested after two desensitizations displayed somewhat greater impairment, and only after three desensitizations (blind–anosmic–anaptic) did performance notably suffer, even though some still retrieved a few pups. From these results, it was concluded that dams may normally use all available senses to fine-tune their behavior, but any individual sensory modality was mostly expendable as long as there was sufficient input from the other senses to compensate. More recent studies on this topic from primiparous laboratory rat and human mothers discussed below support many of Beach and Jaynes’s early conclusions.

Vision and Hearing Vision and hearing are still thought to be mostly unnecessary for maternal behavior in rats. Rats that are enucleated before giving birth or had their eyes temporarily sutured closed after parturition are competent mothers and raise healthy pups.384,385 Consistent with this, blind nulliparae are just as likely to become maternally sensitized as sighted ones,386 all of which may not be surprising for this nocturnal, burrowing rodent. With regard to sound, mother rats and mice can detect pup sonic and ultrasonic vocalizations, and can discriminate the sex of the pup based on their vocalizations,387 but will not use sound alone to guide their behavior.388,389 Dams also do not absolutely require sonic inputs, and deaf postpartum or Caesarean-sectioned rats still retrieve pups although do so more slowly compared to hearing females.15,384 Similarly, dams orient to and retrieve dead, chilled, or anesthetized pups but do so more slowly than when presented with active and vocalizing pups.390–392 Deaf postpartum rats also exhibit normal licking and nursing,385 and deaf virgins are just as likely to become maternally sensitized as hearing females, but are more likely to accidentally step on and injure a pup.386 The combination of blindness and deafness decreases nursing frequency in rats, but is not inconsistent with rearing viable pups.393 Diurnal ungulates living in large, mobile groups can also dispense with visual or auditory cues for maternal identification of or behavior toward their lambs.

Blindfolded ewes and beef cows can identify and accept their young,394,395 and ewes continue to prefer the vocalizations of their own lamb even if they cannot see them.396,397 This does not mean that auditory cues from the lamb are what is required for maternal identification, because ewes successfully find their lambs even after surgical removal of the ewe’s auditory canals394 or when the lambs are contained in a soundproof chamber.398 In both cases, the ewes may act by sight, although ewes are unable to readily learn to use photographs of their lamb’s faces as discriminative stimuli to gain access to their offspring.399 Importantly, when both vision and hearing are eliminated, ewes are much less likely to immediately choose their own lamb over alien lambs. Moreover, most ewes cannot find any lambs at all when the sense of smell is simultaneously impaired with vision and hearing.394 It was once thought that at short distances from the lamb, sound and sight have little role in ewe’s acceptance of the lamb at the udder and that olfaction was primarily responsible,394 but this has more recently been questioned after the finding that anosmic ewes do recognize their own lambs within hours after giving birth and later use the remaining available cues to selectively nurse them.400 How a lack of vision influences maternal care in human and nonhuman primates has rarely been studied. This is surprising because human mothers and infants are innately interested in each other’s faces, normally spend a tremendous amount of time looking at each other, use eye-to-eye contact and its disengagement to modify their interactions, and the foundation of their bonding usually involves face-to-face interactions.401,402 After spending as little as an average of 5 h with the neonate, mothers (as well as fathers) can accurately identify photographs of their infant’s face.403,404 These infant visual cues, including the infant’s physical attractiveness, are unconsciously associated with differential maternal responses to and attributes made about the infant.405 In the absence of vision, however, maternal interactions with infants appear to be normal, and blind mothers use a variety of flexible strategies to interact and communicate with their infant.406,407 Compared to the study of maternal vision, maternal hearing has received more investigation. Most human mothers distinguish between the cries of their own and other infants within 48–72 h after parturition, and many can do so even before then.408,409 Some analyses of deaf mothers interacting with their hearing infants indicate no differences,410 while others report that deaf mothers have less vocal interaction with their infants,411 and yet others find that deaf mothers vocalize more often than do hearing mothers during face-to-face interaction with their hearing infants.412 In the absence of incoming auditory cues, deaf mothers may compensate by briefly touching the infant and using hand gestures more often, which is thought to help maintain the connection with and attention by the infant.413,414

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Olfaction Over the past four decades, there has been a tremendous amount of research devoted to understanding the olfactory control of maternal behavior in rodents, consistent with the thought that olfaction is the primary sensory mediator of social information in nonprimate mammals.415 A distillation of this literature is that olfactory cues from rat pups are unattractive or even aversive to nonpregnant or nonparturient rats, and that a primary consequence of peripartum ovarian and pituitary hormones is to alleviate this olfactory aversion and permit attraction to the sensory cues from neonates. After hormones have completed this task, olfaction is thereafter mostly unnecessary for ongoing maternal care. These hypotheses were partly based on anecdotal observations of differences in behavior of parturient and nonparturient females after young pups are placed in their home cage.10,416 While mothers rapidly seek out and retrieve or lick the pups, nonparturient females exposed to pups for the first time approach and sniff them, but usually make a hasty retreat. Nulliparous females also actively avoid previously preferred parts of their home cage if pups are placed there,417 but such avoidant responses wane after a few days of exposure, and maternal responses often emerge thereafter. Early work from Fleming and colleagues provided further supporting evidence that olfaction inhibited mothering in rats. They found that virgin female rats exhibit a rapid onset of maternal behavior after being olfactory bulbectomized, with latencies of ∼2–3 days versus ∼7 days in controls.418 Moreover, 70% of bulbectomized responders were maternal within 24 h after their first exposure to pups. In subsequent studies, they further demonstrated that peripheral anosmia induced by irrigating the nasal cavity with zinc sulfate also elicited rapid mothering in most virgin females and that sectioning the vomeronasal nerve reduced sensitization latencies by 50%.419 Because combining vomeronasal section with olfactory bulb damage stimulated the behavior even faster (Figure 51.12),420 both pheromonal and volatile olfactory appeared to inhibit maternal responding. Similar hastening of caregiving behaviors in virgin rats occurs after destroying the medial amygdala (MeA), stria terminalis, or bed nucleus of the accessory olfactory tract,421,422 which transmits olfactory information to the hypothalamus and other areas of the basal forebrain. Disruption of olfactory paths even promotes maternal responding in virgin male rats,423,424 which are less positively disposed to pups than are virgin females.2 Although maternal responding in olfaction-disrupted nulliparous rats is impressively hastened, it is not the only inhibitor of mothering because administration of ovarian hormones makes anosmic females even more responsive to pups.425 A number of points are relevant for interpreting the literature on olfaction and mothering. First, the ability

FIGURE 51.12  Mean latency for nulliparous female rats to display maternal behavior after receiving cuts to the vomeronasal nerve (VN), olfactory bulb (OB), or both (VN–OB). Control animals received a sham section of the VN or OB. Note the particularly fast sensitization in the VN–OB females. Source: Modified from Fleming et al., 1979.420

of intranasal irrigation of zinc sulfate to produce anything other than a brief (<72 h) and incomplete anosmia in rats has long been questioned.426,427 In fact, one early study indicated that the loss of olfactory discrimination after intranasal zinc sulfate did not correspond well with maternal responding, given that most females were probably no longer anosmic 2 days after treatment but still exhibited very rapid onset of maternal behavior at that time.428 Second, the concept of segregated main and, accessory olfactory systems has been questioned because they functionally overlap more than is often considered. For example, both systems can respond to volatile odors and pheromones, and the difference between them is in their degree of responsiveness to particular odorants, rather than their ability to respond to them at all.429,430 Third, olfactory disruption in mammals broadly affects endocrine function, including thyroid, pineal, pituitary, gonadal, and adrenal hormones.431 Olfactory bulbectomy also increases the expression of estradiol receptors in the female rat MeA,432 which may contribute to faster sensitization; there is a relationship between ERα expression in numerous other brain areas and the propensity to sensitize in olfactory-intact virgin female rats.433 Whether or not such changes in hormone release or expression of their receptors occur in a time frame consistent with studies of maternal behavior that can initiate pup exposure days or weeks after a manipulation

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should be considered. Interestingly, Gonzales-Mariscal and colleagues found that disrupting main or accessory olfactory input dramatically hastens maternal responsiveness in virgin rabbits, but not if females were ovariectomized.434,435 A similar need for the ovaries is found for the facilitated maternal behavior after cell-body-specific chemical lesions of the MeA in nulliparous rats.436 Lastly, if olfaction is a primary inhibitor of maternal responding, it is surprising that sensitization is not necessarily hastened in nulliparous rats by habituating them to distal cues from pups encased in a wire mesh box and placed in the home cage before sensitization begins.437,438 On the other hand, female rats reared from birth to weaning in a colony room that housed other dams with pups do sensitize faster during adulthood than females raised without this exposure.439 This could indicate that exposure to distal pup cues, especially during early development, establishes a strong, long-lasting habituation to these cues compared to what can be achieved when exposure occurs during adulthood. It is also valuable to note that two studies sometimes cited as evidence that mothers are attracted to pup odors while nonmothers find them aversive did not demonstrate report data leading to that conclusion. Bauer reported that late-pregnant and early-postpartum rats preferred their own soiled bedding, or bedding soiled by other postpartum rats, over bedding soiled by virgins or clean bedding.440 Because peripartum females also equally preferred bedding of late-pregnant rats, the source of the preferred odor could very well be from mothers rather than from pups. Furthermore, nulliparous virgin females in this study did not have an aversion to soiled bedding from maternal nests, but rather had no preference for it over clean bedding. Similarly, Fleming et al. reported that steroid hormone–primed nulliparous rats had a strong preference for soiled nest material over clean bedding, but the control females given cholesterol did not show an aversion to the soiled bedding—if anything, they had a slight preference for it.441 Any need for olfaction during ongoing postpartum maternal behavior in rats is unclear. Most studies find little effect of olfactory bulbectomy performed before mating or during pregnancy, but a few have reported high pup mortality at parturition or impaired maternal behaviors thereafter (see Refs 442–444). Discrepancies might be explained by the nonsensory consequences of bulbectomy because neither peripheral anosmia nor vomeronasal nerve damage has much effect on postpartum pup care.442 In contrast to its inhibition of mothering in virgin rats and likely irrelevance in postpartum rats, olfaction is essential for maternal behavior in female mice. Because most strains of virgin laboratory female mice are spontaneously parental to varying degrees, it must be the case that no pup sensory cues invariably need to be overcome.

Both virgin and postpartum mice can use pup odor to find and retrieve them, and olfactory bulbectomized virgin mice show no maternal care and often cannibalize pups.389,445,446 Bulbectomy before mating, during pregnancy, or postpartum produces similar effects in parturient females.447–449 Less dramatic impairments in mothering are observed after peripheral anosmia with zinc sulfate,449 and maternal experience can mostly compensate for this peripherally induced loss of olfaction450 but it cannot overcome bulbectomy.447 Inducing general anosmia by deleting the SCN9A gene in olfactory sensory neurons, thereby eliminating the Nav1.7 voltage-gated sodium channel, abolishes retrieval but apparently does not induce cannibalism.451 This genetic manipulation helps clarify the effects of anosmia on mouse maternal care by avoiding the known side effects of surgical intervention or nasal irrigation with zinc sulfate. The importance of the main olfactory system in mouse mothering seems to also be supported by the severely impaired retrieval and nest building of virgin or postpartum mice with a targeted deletion of the adenylyl cyclase type 3 (AC3) gene,452 which is necessary for second-messenger cascades in main olfactory neurons, but presumably also in any of the brain sites underlying maternal behaviors. Vomeronasal organ removal in female mice leaves maternal behavior intact,453 as does eliminating a suite of putative pheromone receptor genes.454 However, deleting the Trpc2 gene that codes for an ion channel found in the vomeronasal organ deforms the accessory olfactory bulb, reduces the frequency of postpartum nest building and nursing,455 and results in an early decline in nest attendance as postpartum time ensues.456 Olfactory control of mothering in ewes involves a prepartum inhibition perhaps similar to rats, followed by a postpartum facilitation that differs in purpose from that found in mice. Amniotic fluid is aversive to nulliparous female sheep, but the aversion can be relieved by peripheral anosmia with zinc sulfate or, of course, by the hormonal milieu of pregnancy.457 Mothers’ strong attraction to amniotic fluid at parturition is observed even toward a bowl containing the liquid.458 Ewes reject and are even aggressive toward their own lambs if the offspring are washed immediately after delivery,459 and they are more prone to accept alien lambs wearing a jacket soaked in amniotic fluid.460 When examined immediately after parturition, the lack of olfaction produces small detriments to, but does not prevent, mothering in primiparous ewes and has no effect in multiparous ewes.461 Anosmic ewes do show indiscriminate mothering toward any lamb and461 anosmic postpartum goats are similarly indiscriminate.462 Severing the vomeronasal nerve does not produce such effects in ewes, so main olfactory cues are probably more relevant than pheromones for early maternal responding and identification of the lamb.461

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The enlarged cortex of primates has diminished the importance of olfactory communication to guide their behavior,229 resulting in only a small literature on olfaction and primate mothering. This is despite the fact that body odors can both convey and influence emotional states in humans and other primates,463 which helps set the stage for maternal caregiving (see the section ­Sensory Control of Maternal Care). It is well known that infant human and nonhuman primates are attracted to and can identify their mother by her olfactory cues alone, and use those cues to guide their contact-seeking behaviors.464,465 In the reverse direction, early postpartum human mothers find the odor of T-shirts worn by infants more attractive than nonmothers do, and this attraction is associated with individual differences in maternal behavior—mothers who rate their infant’s odor as highly attractive spend more time in close physical contact with their infant than do mothers who give lower ratings.466 Women can also use the sense of smell to selectively identify clothing worn by their infants even after surprisingly little interaction with them after parturition,467,468 but maternal recognition of her own odor profile, which may be inherited by infants, could contribute to this ability. It would be fascinating to study if the inability to detect infant odors disrupts human mothering, but anosmia in reproductive-aged women is uncommon conditions that do not otherwise compromise reproduction and parenting (e.g., Kallman syndrome, schizophrenia, and multiple sclerosis). There are no readily found studies of mothering by anosmic monkeys, and one might predict that the absence of olfaction would have little consequence.469

Taste It has not been examined in detail if taste influences any maternal behavior in any species, but anesthetizing the tongue significantly decreases maternal licking but does not affect retrieval.470 This finding is difficult to interpret because tongue anesthesia impairs both taste and somatosensory inputs, and may impede motor control of the tongue by the hypoglossal nerve in a way known to reduce other types of licking (i.e., nonpup).471

Somatosensation After being drawn to their offspring via distal cues, perioral and ventral somatosensory inputs that m ­ others receive from the pups are essential for the normal pattern of mothering to continue (Figure 51.13).73 Retrieval is inhibited if the texture of pups’ skin is altered by making it greasy or tough,32 or if the pups’ skin temperature is abnormally low,390 but not if it is too high.472 Dams detect these pressure and thermal skin qualities through

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the infraorbital branch of the trigeminal nerve—which mediates the tactile function of the snout, ­ whiskers, nose, and mucous membranes of the mouth—in order for the mouth-opening reflex that is needed for retrieval to occur. Reducing or eliminating tactile inputs to the perioral region by anesthetizing dams’ mystacial pads or severing the infraorbital nerve impairs or even abolishes retrieval and licking of pups.73,473 Such deficits are not observed after severing the mental nerve serving the chin and lower lip. Importantly, although dams with infraorbital denervation or anesthesia cannot retrieve, they still self-groom (and even do so more than controls), indicating differential sensory control of retrieving and some other oral behaviors.73 The mostly abolished retrieval and licking seen after perioral anesthesia or nerve cuts are greatly lessened if rats have pretreatment experience retrieving pups or trying to retrieve pups under previous lidocaine treatment,473,474 suggesting compensation by other sensory inputs. Indeed, experienced dams spend additional time sniffing pups between retrievals, perhaps to maximize the input from remaining sources of stimulation.474 The maternal experience of multiparous females could explain why early studies indicated little effect of sensory denervation of the snout or mouth on rat mothering.32 This is reminiscent of the effects of olfactory bulbectomy on postpartum behavior, which, when found, are diminished in multiparous compared to primiparous dams.475 Perhaps unexpectedly, Stern and colleagues found that perioral tactile inputs facilitate not only dams’ oral maternal behaviors, but also their quiescent nursing.470 Dams separated from their litters for 4–6 h and then subjected to perioral anesthesia shortly before reunion did not continually attempt to interact with pups but ignored the individual offspring scattered around the cage. Even if the litter was manually placed directly in the nest, periorally anesthetized animals still ignored the pups and rarely nursed them. Thus, just having the pups in a single location without tactile input to the dams’ snout is insufficient to maintain maternal interest or eventually lead to nursing of young pups. Because older and more motorically capable pups are persistent in seeking out their mother and can burrow under their periorally desensitized dam to search for a nipple, nursing can be elicited. Interestingly, if anaptic dams are deprived of contact with offspring for a rather long period of time before testing (∼24–36 h), mothers do remain with a young foster litter and nurse,476,477 suggesting that high maternal motivation overrides the lack of perioral inputs for nursing to occur. The skin of the snout is not the only tactile regulator of mothering in laboratory rats. Nursing behavior, involving cessation of motor activity and often kyphosis (crouched posture over pups), is closely tied to the

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FIGURE 51.13  Sensory events regulating maternal behavior in laboratory rats. In this dyadic interaction, distal cues from pups elicit maternal contact seeking, which then permits the mother to receive perioral tactile inputs required for retrieval. Perioral tactile cues that dams receive while in the nest, mostly obtained while licking the pups, maintain her interest in interacting with the litter and stimulate the litter to search for nipples. Once a sufficient number of pups attach to nipples and begin suckling, these ventral inputs that the dam receives elicit her to show prolonged bouts of quiescent nursing and eventually let down milk. Sated pups will detach from nipples, and the loss of suckling inputs will often result in either the dam resuming active maternal behaviors while hovering over the litter or the dam leaving the nest. Source: Modified from Stern, 1996.73

somatosensory inputs that dams receive to their ventrums while pups search for and suckle on a nipple. This requisite ventral stimulation must come from a relatively large number of active pups. Indeed, dams are unlikely to nurse if interacting with fewer than four pups or if the pups are immobilized by anesthesia, chilling, or warming.73 Furthermore, the pups must be not only active but also capable of suckling because normal nursing cannot occur if the pups’ mouths are closed shut or anesthetized, or if the dams cannot detect pup suckling because her ventrum is anesthetized or her nipples were surgically removed (a procedure termed thelectomy).390,478 In the absence of adequate ventral

stimulation and the quiescence it instills, mothers often continue to actively hover over the litter while exhibiting oral behaviors (licking, repositioning the pups within the nest, and self-grooming) until eventually lying flat on top of the litter without assuming kyphosis or simply leaving the nest. The termination of a nursing bout also depends on sensory inputs from the pups. The intensity and rhythm of pup suckling reflect their nutritional state, with hungry pups attaching to nipples faster, maintaining attachment longer, and sucking more vigorously and synchronously than do sated pups.479,480 Because pup suckling induces dams’ quiescence, more suckling

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results in longer nursing bouts. If hungry pups are suckling a dam that cannot provide milk because her nipples are ligated, or because she is treated with the PRL release inhibitor bromocryptine, nursing bouts are prolonged.73,481 Conversely, if pups are artificially fed through a gastric tube before interacting with their mother, nursing is truncated.386 Termination of nursing behavior in rabbits, which typically occurs once per day for only a few short minutes, is also at least in part controlled by suckling inputs from the young.59 Given the importance of suckling for the initiation and continuation of nursing bouts in lactating rats, it is surprising that some aspects of the nursing-like behaviors displayed by sensitized nulliparous rats (which are naïve to pregnancy’s endocrine influences on skin sensitivity and have no developed nipples upon which pups can suckle) are more similar to those of suckled postpartum dams than those of postpartum thelectomized rats.107 Perhaps once a postpartum female rat experiences suckling pups, the range of sensory inputs required for quiescence and nursing behaviors is narrowed, but maternal virgins without such experience remain responsive to nonsuckling inputs from the litter. A number of studies have revealed a critical role for somatosensation in establishing and maintaining maternal responsiveness more generally. One of the earliest events indicating upcoming successful maternal sensitization in nulliparous rats is not a sudden onset of retrieval, but females’ tolerance of physical contact with pups that had crawled to them.386,482 This is consistent with the unusually fast sensitization of virgin rats housed in small cages that do not allow her to avoid physical contact initiated by the pups.482 In mated female rats, if physical interaction with pups at parturition or relatively soon after a Caesarian delivery is prevented, the mothers are later unresponsive to pups even if they had earlier received distal cues from them.437,483,484 This early somatosensory input that establishes later interest in pups is diffuse and can be satisfied by either perioral or ventral inputs. If both sources are blocked during the initial interaction with pups, via perioral anesthesia combined with a “jacket” covering the trunk, females are as unresponsive to pups as Caesarian-sectioned females who have never before seen pups at all.477 Tactile sensitivity of the human breast, nipples, and areolae is higher during the first few days postpartum compared to during pregnancy.485 It is unknown if this is also true for other highly sensitive skin, such as the fingertips or face, but it is not found on the back of the hand.486 The power of this sensitivity is indicated by the ability of postpartum women to identify their own infant just by stroking the infant’s hand.487 Such changes in tactile sensitivity are surely the consequence of ovarian and other hormones,488,489 and are important for successful breastfeeding and perhaps early bonding between

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mothers and infants.490,491 Disorders associated with tactile hypersensitivity (e.g., fibromyalgia or chronic pain) or hyposensitivity (e.g., multiple sclerosis or spinal cord injury) may be expected to interfere with mother–infant interactions through both sensory and cognitive mechanisms, but this remains to be extensively studied. These findings about how the tactile senses are critical regulators of mothering in laboratory rats are not necessarily universal. For example, the inability to touch the lamb after parturition has little effect on ewes’ later maternal acceptance of them as long as they had been able to smell the lambs at a distance.492 Another possible example is related to the fact that rabbits do not retrieve displaced young and rarely lick them during their brief once-daily interaction,493 so presumably the absence of perioral sensations would have little or no effect on rabbit mothering.

BRAIN CONTROL OF MATERNAL BEHAVIORS Brain Control of Maternal Behaviors in Nonhuman Animals Most of what we know about the neurobiological mechanisms regulating maternal behaviors is derived from laboratory research investigating nonhuman mammals. Laboratory rats have traditionally been the model of choice, but other rodents (mice, voles, gerbils, and hamsters) as well as sheep, rabbits and monkeys have been invaluable additional models that provide essential comparative information. Because at least some of the sensory, motivational, and motor aspects of maternal behaviors are taxonomically conserved, converging evidence gathered across species has outlined a core neural network for mothering. Recent functional magnetic resonance imaging (fMRI) studies in humans have confirmed and extended much of what we originally gleaned from research on nonhuman animals. Studies on this topic in the recent past have often separately considered the functions of a handful of brain structures commonly associated with regulating maternal behavior. However, it needs to be emphasized that such structures belong to interacting neural networks that integrate many processes contributing to successful mothering. These include neurobiological systems involved in ­sensorimotor integration, motivation, arousal, emotional processing, attentional selection, decision making, learning and memory, and inhibitory control. Together, they orchestrate the effective expression of behaviors appropriate to the needs of both mother and young. Conceptualizations of the neurobiological underpinning of parental behaviors originally involved a single system that required a particular threshold of

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hormonal and/or sensory stimulation from neonates to be reached before an appropriate caregiving response could be triggered.416 Early detailed analyses of the behavior shown by female rats toward pups were not completely consistent with this conceptualization, though. Particularly inconsistent was that inexperienced nulliparous rats exposed to pups in a maternal sensitization paradigm are not simply neutral toward young and then spontaneously attracted to them a few days later, but instead exhibit what appear to be fearful responses and will actively avoid the offspring. As days of pup exposure progress, these females approach and investigate the pups more often without recoiling, tolerate physical contact from and even lick the pups, and then eventually seek them out. This can easily be contrasted with the wholly positive responses to pups displayed by almost all naturally parturient mothers. These observations led to an alternative “approach– avoidance model” of mothering.56,416 This model could be applied to any behavior involving a conflict between competing motivations and a shift in attraction to a social or even presumably nonsocial stimulus. Within this framework, the hormonal events of late pregnancy and parturition do act on the brain and peripheral sensory structures to shift the valence of pup sensory cues from negative to positive, but instead two distinct neurobiological systems are simultaneously modified for this to occur—an excitatory network promoting approach to and interaction with neonates, and an inhibitory system that promotes avoidance and withdrawal from them.4 The balance of activity in these networks resolves the conflict between avoidance and attraction to pups such that mothering can be expressed. As discussed in detail below, in an attempt to match this model to the known neural systems regulating maternal behavior, the mPOA and adjacent ventral bed nucleus of the stria terminalis (BSTv) have been considered the primary “excitatory” nuclei that project facilitatory information to the mesolimbic dopamine system for the execution of maternal behavior. The MeA and its connections with the dorsal hypothalamus–anterior hypothalamic area (DH/AHA) and ventromedial nucleus (VMN) of the hypothalamus have been suggested to be the primary “inhibitory” nuclei with respect to maternal behavior.4 In accordance with this model, the onset of maternal behavior is facilitated by a switch from functional dominance of the inhibitory MeA-to-DH/AHA–VMN system to the excitatory mPOA–BSTv-to-mesolimbic system. It will be seen that the approach–avoidance model has been a very useful heuristic for understanding the neurobiology of maternal behavior, but there are caveats that must first be mentioned. Most problematic is that some brain sites can promote as well as inhibit the behavior, depending on the subpopulation of cells involved or the context in which the behavior is being studied. Thus,

it is too simplistic to suggest that some neural sites or systems always promote maternal behavior while others inhibit such responses. Also, the evidence supporting this approach–avoidance model of mothering is heavily based on the inexperienced laboratory rat, in which avoidance of pups is very high and is alleviated by anosmia or sometimes continual exposure to their sensory cues. The model is not readily applied to other animals where parental behavior is spontaneously expressed at very high levels even by inexperienced members—they show no avoidance that needs to be overcome. Importantly, there is probably also no such avoidance that needs to be overcome in many mammals living in their natural environments. Many animals live in large social groups containing numerous reproducing females. Juveniles in such groups are usually extremely interested in neonates and often have the opportunity to interact with young siblings or nonsibling conspecifics.350 Similarly, in species like rats and other rodents with a postpartum estrus, lactating females living in natural environments commonly give birth to a subsequent litter before the older litter has reached the age of dispersal from the nest.54 In either case, juveniles gain parental experience that may permanently obviate most of the aversion to offspring because this experience produces long-term effects on the brain that enhance later parental responding.494–497 This early experience can affect later behavior to the point that, in its absence, some primate mothers are much more likely to kill or neglect their young.498 Even in humans, previous experience with infants is a strong predictor of a new mother’s positive responses to her own infant and feelings of maternal competency.499–501 Medial Preoptic Area (mPOA) The brain site most studied for an involvement in parenting behaviors in mammals is the mPOA of the ventral forebrain, which lies just rostral to the anterior hypothalamus and caudal to the diagonal band of Broca. As mentioned in the section Components of Parental Care, it has been known that the mPOA was involved in parental behaviors since Fisher’s work on ­ testosterone-infused male rats in 1956.44 A tremendous number of later studies from numerous laboratories have greatly expanded upon these findings by showing that a functional mPOA is essential for both the onset and early expression of maternal behavior. Premating, preparturitional, pre–Caesarean delivery, or postpartum destruction of the mPOA with electrolytic or excitotoxic lesions severely disrupts many components of maternal ­ behavior in female rats, especially retrieval of pups and nest building.3,4 A similar effect is produced by severing the dorsolateral axons coming to and emanating from the mPOA,502–504 or by pharmacologically inactivating

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the mPOA.505,506 Licking the pups has not always been quantified in these studies, but when it is, it appears to be less negatively affected by mPOA lesions or knife cuts than other oral maternal behaviors.504,507–509 The disrupted maternal behavior after mPOA lesioning is not due to endocrine disruption because such lesions impair the onset and expression of sensitized mothering in female and even male rats, whose maternal-like behavior is presumably independent of hormones.3,4 Electrically stimulating the mPOA promotes maternal responsiveness in maternally experienced rats and in virgin female rats,510 further supporting the idea that activity in the mPOA promotes mothering. Importantly, the behavioral effects of depressed mPOA activity are relatively specific, since it does not affect females’ locomotor activity, sexual behavior, ingestive behavior, and ability to carry pup-sized inanimate objects around their home cage. The importance of the mPOA for many components of maternal behavior is conserved across species and these include laboratory mice,511 California mice,509 hamsters,512 rabbits,110 and sheep.513 Most studies agree that interfering with the mPOA severely to completely disrupts the active oral components of maternal behavior, but only moderate or mild alterations are found in nursing behaviors.3,4 As discussed in the section Components of Parental Care, when deficits in nursing are found after mPOA manipulations, they may be secondary to the deficit in retrieval and the associated absence of a sufficient number of pups in the nest that can stimulate nursing. It is noteworthy in this context that mother rats with mPOA lesions or ­dorsolaterally severed axons approach and sniff pups in a manner similar to controls,502,504,507,514 indicating that the mothers remain interested in pups and initiate physical contact with them. Additional lines of research further support the notion that the mPOA is involved in motivational processes associated with mothering. For instance, in an operant procedure, bar pressing for access to pups in early postpartum females is substantially reduced after mPOA lesions, whereas food-reinforced bar pressing is unimpaired.508 Similarly, transient inactivation of the mPOA completely abolishes conditioned place preferences to pup-associated incentives.515 Relevant to understanding the role of the mPOA, or any other component of the brain’s maternal behavior network, is that mammalian maternal care is provided over a long period of time lasting from weeks to years depending on the species. Across this period, the mother’s responsiveness to her growing and maturing young changes to match their evolving needs. The temporal dynamics of mother–infant interactions have been described for numerous mammalian species,99,100 and it is typical for mothers to relax their care in accordance with the increasing physiological and behavioral independence of the young. Indeed, as weaning approaches,

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mothers leave older young unattended more often and at greater distances, will reject their attempts for physical contact and nursing, and no longer restrain them from leaving the nest. Recent research has revealed that a substantial functional reorganization of the maternal circuitry occurs, probably sculpted by the continuous experience of interaction with the developing pups, to allow such changes in the mother’s behavior across the postpartum period that are attuned to the needs of her young. Specifically, Pereira and Morrell revealed that the mPOA is differentially engaged throughout the postpartum period to orchestrate maternal responses to the changing needs of the developing pups, from a necessary facilitatory role during early postpartum period to an inhibitory role during the late postpartum period.506,516 Transient inactivation of the mPOA with the anesthetic bupivacaine during the first week postpartum was found to produce the expected loss of maternal responding in rats (Figure 51.14). The same mPOA inactivation during late lactation did not, and instead it increased maternal responding during this time when responsiveness has waned (Figure 51.14).506,516 Fascinatingly, such changes in the mPOA could be occurring simultaneously with the demonstration of the full pattern of maternal behavior toward a new litter of pups born as a result of mating during the postpartum estrus,15,496 and may involve even a different pattern of activity in the mPOA and elsewhere to allow dams to both ignore the older litter while remaining interested in the recently born pups. There is also some evidence from immediate-early gene studies that some cells in the mPOA and also the BSTv respond to the aversive qualities of pups, possibly inhibiting maternal behavior, because nonmaternal nulliparous rats have almost as much Fos expression in the mPOA–BSTv after forced exposure to pups as do maternal rats in some studies.517 Another consideration for a more comprehensive view of the mPOA in mothering is that long after weaning of the litter, the female brain remains primed for future maternal responding, and experienced females are more resistant to sensory and neural insults compared to inexperienced females.418,508,513,518 Even nulliparous sensitized female rats are more likely to act maternally at a future date than inexperienced females, indicating that experiential effects do not require endocrine factors.519,520 The neural basis of this may be related to the finding that second-time mothers have more glial fibrillary acidic protein (GFAP)-immunoreactive cells (i.e., astrocytes) in the mPOA compared to virgins or first-time mothers, and this parity difference requires that females maternally interact with pups after parturition.521 The functional implications of an increased number of astrocytes are unknown, but perhaps they contribute to a mother’s long-term interest in pups by modulating the adjacent

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FIGURE 51.14  Frequencies of maternal behaviors (Median ± SIQR) shown by female rats tested early postpartum (days 7 and 8) or late postpartum (days 13 and 14) after transient inactivation of the mPOA with 2% bupivacaine or no inactivation by infusing saline. The behavioral control group received no stereotaxic surgery or infusion. Inactivating the mPOA disrupted all measures of active maternal behavior when performed early postpartum, but facilitated the same behaviors when performed late postpartum, indicating the differing role of the mPOA for maternal behavior across the postpartum period. Source: Modified from Pereira and Morrell, 2009.506

preoptic area neurons necessary for maternal motivation or behavior. Other types of structural plasticity in the mPOA, such as changes in the size of its somata and the number of basal dendritic branches, occur across pregnancy and in response to exogenous ovarian hormones but are not permanent,522,523 so they are more likely involved in the onset of maternal behavior rather than long-term experience effects. Numerous neurotransmitters are released in the intact mPOA to promote or inhibit maternal behaviors. Compared to nonmaternal nulliparous rats, mother rats have greater dopaminergic and serotonergic activity in the mPOA,524,525 and when they interact with their offspring, AVP is locally released at high levels.526 In ewes, the release of dopamine, gamma aminobutyric acid (GABA), and OT increases in the mPOA during interaction with the lamb, but there is no change in serotonin release.227 Infusion of pharmacological agents that mimic or block the activity of a number of neurochemicals alters maternal behaviors. For example, various aspects of maternal behavior are disrupted by mPOA administration of a GABAA or GABAB receptor agonist,505 D1 or D2 receptor antagonists or a dopamine reuptake inhibitor,527–530 α2-autoreceptor antagonists that increase norepinephrine release,531 and a nitric oxide synthesis inhibitor that could blunt the release of a number of neurotransmitters.532 Serotoninergic signaling is essential for maternal behavior in rodents,533,534 but the effect of serotonin receptor modulation specifically in the mPOA has not yet been investigated. While most of the research on the mPOA shows little effect on nursing, does the mPOA really have nothing to do with this essential component of mammalian maternal behavior? A subset (∼5%) of mPOA cells that express Fos

during maternal behavior project to the midbrain periaqueductal gray (PAG),535 and this projection has been proposed to regulate nursing behavior in postpartum rats.536 Neurons in the ventrocaudal PAG uniquely show very high Fos expression in response to suckling inputs from pups,537,538 and lesioning this site greatly interferes with kyphosis while leaving nursing in other postures and appetitive maternal behaviors such as retrieval intact.537,539 Kyphosis is tonically inhibited by GABA release in the ventrocaudal PAG, but the posture is disinhibited by suckling inputs impinging on PAG cells that are involved in postural control.540 Because dams cannot simultaneously show immobile nursing and active maternal behaviors, it has been proposed that inhibitory reciprocal projections between the mPOA and ventrocaudal PAG ensure the suppression of inappropriate maternal responses depending on the presence or absence of pup suckling.537

Immediate-Early Gene Expression Studies using expression of the immediate-early genes c-fos, FosB, and Egr-1 as markers for cellular modulation in response to cues from pups or behavioral interactions with them have helped confirm and further explicate the role of the mPOA in mothering behaviors. Very large increases in immediate early-gene expression are found in the mPOA when sensitized virgin or postpartum female rats interact with pups,443,541–545 and this increased expression can persist for many hours (Figure 51.15).546 If postpartum females are only distally exposed to pups at testing, however, Fos is not increased in the mPOA compared to unexposed controls.443,542 The same is true for virgin and postpartum laboratory mice,547,548 but postpartum rabbits require only distal

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FIGURE

51.15  Schematic representation of frontal sections through the postpartum rat medial preoptic area (mPOA) and ventral bed nucleus of the stria terminalis (BSTv) showing the location of Fos-immunoreactive (left) and FosB-immunoreactive (right) cells after no interaction with pups (left half of each panel) and after an interaction with pups and the display of maternal behavior (right half of each panel). Ac: anterior commissure; oc: optic chiasm. Source: Modified from Numan et al., 2006.4

cues from pups for peak Fos expression.549 The importance of the behavioral interaction with offspring rather than their distal cues in rats is further supported by the inability of olfactory bulbectomy, peripheral ­anosmia, thelectomy, or general ventral anesthesia to reduce Fos-immunoreactive cells in the mPOA as long as the females behave maternally.443,444,544 Nonetheless, the development of fMRI for use in live rodents has revealed that even when postpartum rats are restrained and cannot actively interact with pups, the maternal mPOA still exhibits positive blood oxygenation level–dependent activation (often thought to reflect the increased blood flow and metabolism associated with elevated cellular activity) in response to pups’ ventral probing and suckling.550 In multiparous sheep, the vaginocervical stimulation associated with parturition induces Fos in the mPOA, but Fos is not further increased by the presence of the lamb.551,552 This could indicate little involvement of the mPOA in response to lamb ­ cues or the expression of maternal behavior soon after parturition, but a more reasonable interpretation is that parturition generates a ceiling effect in Fos-immunoreactive cells in the ewes’ mPOA. This is reasonable because inactivation of the mPOA during parturition with the anesthetic lidocaine does prevent the onset of maternal behavior in primiparous ewes. Lidocaine in ewes’ mPOA also reduces some aspects of ongoing mothering when infusions begin hours after parturition.513 This immediate-early gene activity in the maternal mPOA is a convenient marker for genomic activity in response to offspring cues or the expression of parenting, but the specific function of these Fos-immunoreactive cells in the mPOA remains an important question. Half to 75% of the mPOA cells expressing Fos after postpartum rats and mice interact with pups also express glutamate decarboxylase 1 (GAD67), so these cells are likely GABAergic.511,553 Activation of so many potentially inhibitory cells in the maternal mPOA could reflect the removal of tonic inhibition on downstream cell groups necessary for maternal behavior, or that activation of these GABAergic cells is suppressing other cell groups that would otherwise interfere with the behavior.553 A

recent anatomically refined study found that the subregional location of the densest Fos in the mPOA after the display of maternal behavior by postpartum mice was not the same mPOA subregion where maternal behaviors were the most disrupted by excitotoxic lesions, suggesting that many of the mPOA cells are responding to maternal interaction with pups for some other behavioral or physiological purpose.511 A major limitation of these immediate-early gene studies is that this approach has little temporal resolution. Progress in understanding maternal behavior is hindered by the lack of understanding of the real-time events and the coordinated and sequenced activity across neural components necessary for mothering. Particularly useful would be functional circuit analysis with electrophysiological approaches and continued use of fMRI in mother laboratory rats. Some insight into the role of the immediate-early genes themselves in maternal behavior, other than just being convenient markers for cellular modulation, comes from virgin female mice with a targeted deletion of the FosB gene. These mice are less likely to spontaneously retrieve pups as virgins, and even after mating and giving birth to healthy pups still will not care for them; most pups die within days after birth.554,555 Inhibiting phosphorylation of the extracellular signal-regulated kinase protein (ERK), which is part of the intracellular cascade triggered by growth factors and necessary for FosB transcription, also inhibits spontaneous retrieval in inexperienced virgin female mice, but does not do so in experienced postpartum mothers.556 Because FosB knockout mice are hyperactive, impulsive, and possibly hyperemotional, and their brains contain markers of neuropathology, the relationship between FosB and maternal behavior may be nonspecific.555

Relationship of the mPOA with the BSTv The cells relevant for maternal behavior extend out of the cytoarchitectorally defined borders of the mPOA and into the adjacent BSTv (including parts of the dorsomedial, dorsolateral, magnocellular, and anteroventral subnuclei of the BST). Because of the close proximity of

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the two sites, many mPOA lesion and hormone infusion studies have probably also affected cells of the BSTv,557 and the mPOA and BSTv have sometimes been presented as a common functional unit for maternal behavior because distinguishing their individual roles is difficult.3,557 Nonetheless, it has been observed that whereas retrieval does not recover after mPOA lesions,514,558 it does reemerge in some postpartum rats with neurotoxic lesions of the BSTv.557 Similarly, in primiparous sheep, the onset of maternal behavior at parturition is almost completely prevented by temporary inactivation of the mPOA, while almost no deficits are seen after BSTv inactivation.513 Differences between the function of the mPOA and BSTv are also indicated by the findings that retrieval is more greatly impaired after mPOA than BSTv infusion of idazoxan (an α2-autoreceptor antagonist that increases norepinephrine release)531 and that dampening AVP V1a receptor activity in the mPOA reduces retrieval and nursing in postpartum rats while having no effect in the BSTv.526,559 These results distinguishing between the two sites are probably related to the different projections of mPOA and BSTv cells that are stimulated during the performance of maternal behavior. The termination sites of almost half of all Fos-expressing neurons in the mPOA and BSTv of maternally acting female rats have been identified and involve just six brain areas—the lateral septum, ventromedial hypothalamus, lateral habenula, retrorubral field, ventral tegmental area (VTA), and lateral PAG. While most of the identified mPOA Fos-containing cells projected to the two forebrain sites (the ventromedial hypothalamus and lateral septum), the identified BSTv Fos-containing cells projected more widely to the six targets.535 This functional and anatomical information could suggest that mPOA output primarily modulates activity in brain sites that would otherwise inhibit maternal behaviors, including the ventromedial hypothalamus and lateral septum, whereas the BSTv functions more to activate midbrain motor and motivation systems necessary for maternal behaviors to be displayed.

mPOA as a Site for Hormone-Sensory Integration The mPOA is an essential component of the maternal behavior network, in part because it is perfectly situated to integrate an animals’ endocrine state with incoming sensory cues from young, and then transmit this information to motivation and motor effector pathways that orchestrate the expression of maternal behaviors. Indeed, the mPOA is exquisitely sensitive to ovarian and pituitary hormones and a primary neural site for their effects on the onset of maternal behavior. It contains very high densities of receptors for ER, PR, PRL, and OT, all of which fluctuate in their expression near the end of

pregnancy and in the early postpartum period in many animals.110,131,180,560–562 When estradiol is implanted or repeatedly infused into the mPOA of nulliparous rats, the onset of retrieving is rapid, although other maternal behaviors are not necessarily so quickly established.205,563,564 In rabbits, which do not retrieve young, estradiol implanted into or very near the mPOA stimulates components of maternal nest-building behavior.565 Even though estradiol in the mPOA stimulates components of maternal behavior in virgin animals, implanting the selective ER modulator tamoxifen (often traditionally used as an estrogen receptor antagonist in the brain) into the mPOA 2 days before parturition does not prevent the onset of maternal behavior.566 Tamoxifen implants into the mPOA do somewhat reduce the percentage of females showing maternal care (by ∼33%) if litters are delivered by Caesarian section,566 suggesting that the experience of parturition and release of its hormones may override the need for late-pregnancy estrogenic activity in the mPOA. Recently, this question was re-examined by studying the maternal behavior of female laboratory mice after mPOA delivery of a short hairpin RNA (shRNA) that interferes with the mRNA for ERα. When testing began 4 days after parturition, these females displayed rather severe deficits in almost all maternal behaviors.141 Unfortunately, it remains unknown how soon after parturition maternal behavior began to be impaired, if these mothers were lactating normally, or what the mothers were doing in the absence of spending time with the litter. Once ER signaling in the mPOA helps establish maternal behavior, it may continue to help maintain the behavior even in the absence of estrogen. A large percentage (∼33%) of the mPOA cells expressing Fos during the display of postpartum maternal behavior also contain ERα,567 and in the absence of high levels of circulating estrogen during lactation, activation of ERα in these cells may instead occur through a ligand-independent mechanism involving stimulation of the receptors by classic neurotransmitters.568 The sites where PRL acts to hasten maternal behavior are certainly within the central nervous system, as daily intracerebroventricular infusion of PRL or placental lactogens facilitated the behavior in steroidprimed females.188 Bakowska and Morrell presented similar conclusions from pregnant female rats that were hysterectomized and ovariectomized on day 16 of pregnancy.569 Conversely, a PRL receptor antagonist delivered into the cerebral ventricles delays the onset of mothering in parturient rats.570 The mPOA is one site mediating these effects. Similar to ventricular infusion, PRL or placental lactogens infused into the mPOA can act along with ovarian hormones to hasten the onset of maternal behavior in nulliparous rats;188,571 antagonism of PRL receptors in the mPOA delays the onset of

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mothering in nulliparous steroid-treated rats.572 Other brain sites where PRL acts to promote maternal behavior are unknown. The mPOA is also a target for the effects of OT and its receptor antagonist on maternal behavior,207 and fMRI activity in the POA is blunted by pretreating mother rats with an OT receptor antagonist before exposing them to pups.550 Surprisingly, OT release in the mPOA does not increase during mother–infant interactions,526 even though OT acts there to promote maternal behavior and individual differences in OT receptor expression in the mPOA are associated with the frequency of postpartum maternal licking.208 Other forebrain sites where OT promotes mothering are mostly unknown, but maternal behavior can be stimulated by infusing OT into the olfactory bulb573 and impaired by OT receptor antagonism in the VTA.207 It was noted in the section Hormones Most Significant for the Onset of Maternal Behavior, that reducing OT signaling to the mPOA and elsewhere by lesioning the PVN of the hypothalamus, the major source of OTergic projections in the brain, disrupts the onset of maternal behavior at parturition but has little effect on its maintenance.198,199,574 Other neuropeptides or their receptor antagonists that can influence maternal behavior after mPOA infusion include AVP,207,559 endogenous opioids,575 cholecystokinin,576 and melanin-concentrating hormone.577 Progesterone is a strong inhibitor of maternal behavior (see the section Hormones Most Significant for the Onset of Maternal Behavior), and the mPOA has been studied as its target for this effect, but hysterectomized and ovariectomized pregnant female rats with progesterone implanted in the mPOA at the time of surgery are still rapidly maternal.578 Perhaps progesterone acts elsewhere or on multiple sites simultaneously to produce its inhibitory effects on maternal behavior, but Sheehan and Numan did find that progesterone prevented the increase in Fos expression in the mPOA (and BSTv) of hysterectomized and ovariectomized pregnant female rats given an injection of estradiol that would have rapidly stimulated maternal behavior.579 Circulating progesterone levels begin to rise a few days after parturition and remain very high through the second week of lactation in rats (see the section Hormones Most Significant for the Onset of Maternal Behavior), but it is unknown why this endogenous progesterone acting in the mPOA or elsewhere does not interfere with the maintenance of maternal behavior. Maybe this can be avoided because basal progesterone receptor expression is very low in the postpartum mPOA,560,580 rendering it insensitive to progesterone’s potential inhibitory effects on mothering. With regard to sensory inputs from pups, the mPOA receives converging information from virtually all sensory modalities and sends input back to those sources. Olfactory information from the main and accessory

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olfactory bulbs reaches the mPOA via the MeA,581,582 and the mPOA receives ventral trunk somatosensory inputs directly from the peripeduncular nucleus of the lateral midbrain582 and perioral tactile inputs through a direct trigeminohypothalamic projection583 and indirectly via brainstem relay nuclei.582 Gustatory input can reach the BST,584 which, in turn, is densely interconnected with the mPOA. Moreover, olfactory, gustatory, somatosensory, auditory, and visual regions within the insular cortex project to several limbic and sensorimotor regions and densely to the infralimbic region of the medial prefrontal cortext (mPFC), which, in turn, also projects to the mPOA.582

Connections of the mPOA for the Elicitation of Maternal Behaviors Motivation Systems Primary efferents from the mPOA traveling through the lateral hypothalamus allow it to interact with components of the mesolimbic dopamine (DA) system for the motivational aspects of maternal responsiveness to pups. The mesolimbic DA system, which is composed of DA cell bodies in the midbrain VTA that project to the nucleus accumbens (NA) in the forebrain, has been recognized for its central role in several behavioral functions related to motivation.585,586 The NA receives converging excitatory inputs from most cortical and limbic structures, and hence has long been considered an interface linking those corticolimbic structures to behavioral output systems, under the modulatory influence of DAergic inputs from the VTA.587 Neurophysiological and neuroanatomical studies suggest that DA in the NA may select and integrate the effects of limbic and cortical afferents, thus influencing the transmission of information to output areas, and ultimately modulating goaldirected behaviors.586,588 Anatomically and functionally, the NA can be divided into two distinct regions, the core and the shell.589,590 Each receives different but overlapping excitatory glutamatergic projections from corticolimbic structures, including the basolateral amygdala (BLA), hippocampus, and prefrontal cortex (PFC).589,591 The core and shell also differ in their downstream targets. The NA core projects primarily to the dorsolateral portion of the ventral pallidum, the substantia nigra pars reticulata, and the subthalamic nucleus.590,592 Projections from these targets travel to the motor thalamus and then to cortical motor areas for the execution of behavior. The NA shell, in contrast, sends projections mainly to the ventromedial ventral pallidum, substantia innominata, mPOA, several hypothalamic nuclei, substantia nigra pars compacta, VTA, and PAG.592–595 In the context of maternal behavior, several pieces of evidence indicate that DA released in the NA shell and core

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participates in activating maternal behavior. For instance, many laboratories have used microdialysis to find that DA release in both the core and shell of postpartum mother rats is enhanced during interactions with pups.596–599 It appears that the hormones associated with pregnancy and parturition bias the mesolimbic DA system to respond to pups by reducing mother’s basal DA levels in the NA shell. As a result, the magnitude of pupevoked DA release is more striking.596,600 In a very recent study, DA responses in the NA were further characterized during a fine-grained analysis of mother–pup interactions across the postpartum period. It was found that during the early postpartum period, the presentation of pups behind a screen that elicited maternal pup-seeking behavior resulted in a robust increase in DA release in the NA core, which was further augmented during active but not passive maternal interaction with pups. Although this pattern of DA release was also found in late-postpartum females, the magnitude of release was considerably attenuated in those mothers.601 Finer temporal analysis using in vivo voltammetry has also revealed that the DA signaling in the NA shell and core increases with the initial presentation of pups after a brief separation, and also immediately before as well as during active maternal behaviors such as pup retrieval

and licking (Figure 51.16).597,602 Furthermore, the magnitude of DA release is related to individual variation in maternal licking, such that high-licking mothers show a greater increase in DA release before or during a licking bout compared to low-licking mothers.597 Levels of DA receptor expression in the NA are also positively correlated, and DA transporter levels negatively correlated, with mothers’ levels of licking.597 Together, these studies suggest that changes in NA DA activity associated with mother–pup interactions may serve as a neural substrate for the dynamic motivational aspects of maternal behavior among individuals and across postpartum time. Interfering with this DA neurotransmission by electrolytic or DA-depleting lesions of the VTA, pharmacological manipulation of VTA activity, or core or shell administration of D1 or D2 receptor antagonists each selectively and severely disrupt most active maternal behaviors in early-postpartum rats.529,603–609 The amount of time these mothers spend with the pups is normal, indicating that they remain interested in approaching the pups and maintaining physical contact with them. Indeed, these VTA or NA manipulations can even facilitate nursing behavior if pups are manually placed in the nest,536 which is consistent with studies showing that manipulating accumbens DA selectively influences

FIGURE 51.16  Changes in dopamine (DA) signaling in the shell of the nucleus accumbens of two representative high-licking and low-licking postpartum rats before, during, and after a bout of licking their pups. The gray bar indicates the duration of the licking bout. Note the greater increase in high-licking rats and that the rise in DA signaling begins to occur before licking is exhibited. Source: Modified from Champagne et al., 2004.597

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the activational or effort-related aspects of motivated behaviors, while leaving the directional aspects relatively intact.586,610 The disruptive effects of DA receptor antagonism on active maternal behaviors are not exclusive to rats and occur in both sexes of the biparental prairie vole.611 Consistent with these studies, D1 receptor stimulation of the NA promotes the onset of maternal behavior in hysterectomized, pregnant female rats.530 Of course, DA in the NA does not activate maternal behaviors in chemical isolation and the purine nucleoside, adenosine, and the adenosine A2A receptor have been found to modulate DA-mediated maternal behavior.612 The nature of the impairments seen after interfering with DAergic activity is thought to mostly reflect deficits in maternal motivation, which is demonstrated by the fact that the deficits can be overridden if dams are separated from pups for 3–12 h605,613 or if the motivational salience of the pups is increased by presenting mothers with hungry, demanding pups.614 In both cases, active components of maternal behavior are restored to levels characteristic of control dams. Also, if postpartum rats are muzzled so they cannot retrieve pups, they spend considerable time pushing at the pups with their snouts and handling them with their paws, but such compensatory behaviors are not displayed if mesolimbic DA transmission is reduced.615 Furthermore, DA release in the NA contributes to the rewarding aspect of the pups, as mothers can form a conditioned place preference for an environment in which they interacted with pups, but not if DA release in the NA is impaired.599,607,616 Given the results of the studies described immediately above, it is probably surprising to read that lesioning the NA produces no deleterious effects on maternal behaviors in rats.508,617 To reconcile this, it is essential to consider prevailing models of how the NA is involved in basal ganglia function. These models propose that the NA consists of distinct populations of medium spiny GABAergic projection neurons that selectively express either D1 or D2 receptors.618 These neurons respectively project directly or indirectly to basal ganglia output nuclei, namely, the substantia nigra pars reticulata and pedunculopontine tegmental nucleus.619,620 Through these opposing direct and indirect output pathways, NA neurons are proposed to select appropriate behavioral responses while inhibiting competing ones. Manipulations that interfere with DA neurotransmission in the NA (inactivating the VTA, intra-NA DA receptor antagonism, and depletion of DA within the NA) all result in a marked impairment in behavioral responding to pups and related stimuli. By contrast, transient inactivation or permanent cell body lesions of the NA uniformly inhibit all its neurons, regardless of the medium spiny neuron subtypes or their efferent destination, and have virtually no effect on motivated behaviors. Given the distinct populations of medium spiny neurons within the NA,

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eliminating all NA activity might produce effects that negate each other at the level of basal ganglia output, with no net change in behavior. In an elegant series of studies, Numan and collaborators have provided substantial evidence supporting the idea that activation of hormonally primed and offspringstimulated mPOA projections to the VTA and NA promotes maternal behavior.621 The mPOA can influence NA function through a direct projection to it and indirectly through projections to the VTA.622,623 The mPOA projections to DAergic neurons in the VTA include OT-expressing cells,624 providing a neuroanatomical substrate for how OT modulates maternal behavior.207 Moreover, infusion of OT into the VTA can trigger DA release into the NA,625 and this promotes the onset of maternal behavior and probably influences its ongoing display.207 Intact bilateral connections between the mPOA and the VTA and NA are essential for maternal behavior in rats. In a study using an asymmetrical lesion design,606,626 unilateral mPOA lesion paired with a contralateral lesion of the VTA severely disrupted maternal retrieval of pups, while various control lesions were relatively ineffective. Consistent with these results, the NA shows increased Fos expression during the display of maternal behavior in rats,542 but not if the ipsilateral mPOA is lesioned.627 After hormone and pup sensory information has reached the NA via the mPOA, and probably to a minor degree via the basolateral amygdala,628,629,630 this information is transmitted to the ventral pallidum. The ventral pallidum is reciprocally connected via GABAergic neurons to the NA and responds to the pleasurable qualities of stimuli such as pups.588 The ventral pallidum also projects to motor networks necessary for the execution of behavior.631 Lesioning or infusing a GABAA receptor agonist into the ventral pallidum causes a dramatic disruption in maternal responsiveness,558,617 as does a unilateral lesion of mPOA paired with a contralateral lesion of the ventral pallidum.617 Together, these studies demonstrate the importance of the mPOA interactions with the VTA–NA–ventral pallidum circuitry in the activational aspects of maternal motivation and behavior.

Emotion Regulation Systems The approach–avoidance model of maternal behavior in rats suggests that neophobia of pup-related cues is a primary impediment to maternal responding in inexperienced rats, theoretically by high neural activity in brain sites involved in aversion or negative emotional reactivity that do not allow the mPOA and its connection to the brain’s maternal motivation systems to dominate.416 Because the odors of pups have traditionally been thought to be the basis of this neophobia, the locus of inhibitory control of mothering has been on the MeA,

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which receives projections from both the main and accessory olfactory bulbs.581 The MeA very densely and reciprocally innervates the mPOA, and each site can inhibit or excite the other. Estradiol reduces excitatory input from the mPOA to the MeA, which may be the basis of how estradiol regulates this projection to facilitate mothering.632 Similar to the effects of anosmia, nulliparous or ­pregnancy-terminated female rats sustaining electrolytic or cell body–specific lesions of the MeA, and sometimes also the cortical amygdala, are faster to act maternally than unlesioned controls.422,436,633 These lesioned females do not actively avoid pups placed in their nest and are more tolerant of contact with them even if not yet expressing maternal behavior.422 An intact mPOA is required for this facilitation, suggesting that the absence of the MeA does not alone promote maternal behavior but instead removes an inhibitory input to sites that do.634 The onset of maternal behavior in MeA-lesioned animals can still take a few days, so it is not as effective as peripheral anosmia, suggesting that some olfactory inputs inhibiting maternal behavior are transmitted elsewhere in the brain. As opposed to the positive effects of MeA lesions in nulliparous rats, repeated kindling-like electrical stimulation of the MeA inhibits the future resumption of mothering in experienced postpartum rats. Furthermore, MeA kindling also somewhat reduces the preference for pup-related cues by inexperienced nulliparous rats, but it does not further affect their already low maternal responding in a sensitization procedure.510 Nulliparous ewes also find offspring olfactory cues aversive, but it remains unknown if deactivating the MeA elicits

FIGURE 51.17  Percentage of ewes that selectively interacted with their lamb after 2, 4, or 8 h of inactivation of the cortical (Co), medial (Me), or basolateral (Bl) amygdala with lidocaine beginning at parturition. Inactivation of the cortical or medial nuclei, but not the basolateral nucleus, disrupted selectivity for the lamb. Source: Modified from Keller et al., 2004.635

maternal behavior. It is known that temporary chemical inactivation of the MeA or nearby cortical amygdala (but not the basolateral amygdala) beginning at parturition does not affect the onset of maternal behavior, but it does render ewes non-selectively maternal when tested hours later. Later MeA inactivation in already-selective ewes does not produce this effect, indicating that the MeA must process cues necessary for establishing an olfactory memory of the lamb (Figure 51.17).635 Note that in animals requiring olfaction for the expression of maternal behavior, such as voles and mice, MeA lesions could be expected to produce blunted interest in pups, but this has not been examined in female voles, and lesion studies in mice have not targeted the MeA.49,636,637 Another consideration regarding the MeA mentioned earlier in this chapter is that cell body–specific lesions of the MeA are incapable of promoting maternal responding in nulliparous female rats if their ovaries had been removed,436 suggesting that the endocrine events involved with pseudopregnancy that can be induced after some types of MeA lesions are responsible for the effects on maternal behavior. In support, pharmacologically inhibiting pituitary PRL release prevents the facilitation of maternal behavior after excitotoxic MeA lesions. In addition, by delaying testing until well after postlesion pseudopregnancy has terminated, there is only a modest facilitation of maternal responding.436 Such results might suggest that the negative influence of the MeA on maternal behavior in rats has been overemphasized, although it is interesting that in another series of studies using ovariectomized nulliparae tested 5 days after receiving electrolytic MeA lesions, there was still a dramatic onset of mothering compared to controls.422 This apparent inconsistency could be related to differences between the studies in the neuroanatomical extent of the lesions or the lesion methods used (electrolytic versus excitotoxic).638 The MeA not only projects heavily to the mPOA but also provides major efferent projections to the DH/AHA and VMN of the hypothalamus, which are thought to partly mediate the MeA inhibition of maternal behavior. The DH/AHA and VMN are more generally components of the neural network mediating aversive and defensive behaviors,639 and electrical stimulation of at least the VMN inhibits the firing of many mPOA neurons.640 Aversive pup stimuli do not elicit Fos in the VMN of nonmaternal rats, but they do in the DH/AHA,517 and MeA neurons that are activated in nonmaternal rats by aversive pup stimuli project to both hypothalamic regions.633 Important direct evidence for the inhibitory role of these sites is that excitotoxic lesions of the DH/AHA or VMN stimulate maternal responding in steroid-primed nulliparous rats.641 An indirect route through which AHA–VMN output may regulate avoidance of pups in nonmaternal rats is through projections to parts of the midbrain PAG involved in defensive responses. It would be valuable to

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Brain Control of Maternal Behaviors

determine if lesioning any subregion of the PAG can alter defensive responding and promote maternal behavior in nulliparous rats. Ventrocaudal PAG lesions do reduce anxiety in postpartum rats,74 and destruction of the rostral lateral PAG reorients the focus onto pups in morphinetreated postpartum rats that would rather hunt than mother.642 Other brain sites, including the septum, central amygdala, mammillary region, and midbrain raphe serotonin system, could also interact with the MeA, DH/ AHA, and VMN to instill aversion to pups in nonmaternal rats.4,643 Of particular mention in this context is the lateral habenula, which regulates midbrain raphe cells to elicit or suppress aversive responses,644 and is known to be necessary for the onset but not maintenance of natural or sensitized maternal behavior in rats.645,646 The function of the MeA has been suggested to switch after female rats give birth, by acting at that point to transmit olfactory inputs to the mPOA to increase attraction to pups and maternal behaviors.4 There is little experimental support for this; on the contrary, olfaction is not needed for postpartum maternal behavior in rats (see the section Components of Parental Care), and increasing inhibitory tone in the MeA with the GABAA receptor agonist muscimol has no effect on postpartum mothering.629 The MeA regulates innate fear responses to olfactory stimuli,647 which is consistent with the promotion of maternal responsiveness after MeA lesioning, but these lesions also reduce emotional reactivity unassociated with social odors. Female rats with corticomedial amygdala lesions not only are more maternal but also spend more time in the center of an open field, indicative of reduced general anxiety.422 A regimen of exogenous ovarian hormones that presumably acts in part on the MeA to induce maternal behavior also increases time in the center of an open field.441 Conversely, nulliparous female rats that received kindling-like electrical stimulation of the MeA spend less time in the center of the open field, indicative of higher anxiety.510 The question arises whether MeA lesions promote maternal behavior by removing the ability to process aversive pup odors, or because of a more general dampening of emotional reactivity. It seems that for the onset of maternal behavior in laboratory rats, the olfactory modification is the most relevant. This is supported by data indicating that maternal interest increases in the final few days of pregnancy in female rats,89 but their general anxiety-related behaviors in an open field or an elevated plus-maze are not lower than those of cycling females.648,649 Second, if a general reduction in emotional reactivity was necessary for the onset of maternal behavior, treating rats with anxiolytics would be predicted to hasten maternal sensitization in nulliparous rats, but it does not.650 Third, olfactory bulbectomy or peripheral anosmia very quickly induces maternal behavior, but does not in all studies reduce anxiety-related behaviors.651,652

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Lastly, nulliparous female rats that had juvenile experience with pups show very low adult anxiety-related behavior, meeting the low levels found in most postpartum rats. These adult nulliparae still avoid pups, though, and require a days of exposure to young before acting maternally, although they do sensitize faster than females not exposed to pups during juvenile life.497 A generalized reduction in anxiety or other aspects of emotional reactivity may not critically contribute to the natural onset of maternal behavior in laboratory rats, but there is such a reduction in anxiety after females have given birth. Lower anxiety behavior can be found in many behavioral paradigms within 24 h after parturition, lasts for about 1 week postpartum, and requires recent physical contact with the litter but not their suckling.50 This mitigated reactivity to anxiogenic stimuli in maternal animals that have recent litter contact is reflected by lower Fos expression in some brain areas traditionally associated with emotional regulation.653 The effectiveness of mother–offspring touch to suppress anxiety or other negative affective behaviors is further seen by the blunted reactivity of nulliparous, maternally sensitized female rats.654–656 This blunted anxiety accompanying motherhood in rats also occurs in women,50 but mother rhesus monkeys appear to be more anxious when they have infants to care for.657 As discussed elsewhere,3,50 this general reduction in anxiety may affect numerous other postpartum behaviors. A suppression of anxiety could reduce dams’ reactivity to intruders to the nest site in a way that is permissive for maternal aggression, although some data do not support this.52 Low anxiety may also help maintain maternal attention to pups under mildly threatening conditions, but this suggestion is complicated by the findings that mother rats genetically selected for high anxiety spend more time with pups under undisturbed conditions and are faster to retrieve them under either undisturbed or challenging conditions compared to low-anxiety dams.658 Others have found no relationship between “trait” anxiety in female laboratory mice and their later maternal behavior.659 It has also been reported that noradrenergic manipulations in the BSTv, long associated with anxiety-related behaviors in addition to maternal behaviors, can impair mothering but not necessarily alter anxiety in postpartum rats.531 It may be the case that within a natural environment, low postpartum anxiety is most important for achieving the metabolic demands of lactation, by allowing dams to forage further from the nest and take greater risks to obtain food. The more time that the dam spends away from the nest would lead to a gradual loss of the sensory “trace” instilled by pups that is needed for her low anxiety, and the resultant rise in anxiety could drive her to return to the familiar environs of the nest where she would then reunite with the pups.660

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Interestingly, some of the emotional consequences of motherhood persist long after lactation, and anxiety can be lower in mothers tested many months after weaning of the litter.661,662 This depends on when previous mothers are tested because cycling, primiparous female rats are less anxious than nulliparous females during the afternoon of proestrus but not during other phases of the estrous cycle.662 This suppression of anxiety is clearly not due to recent contact with pups but instead due to the enduring neuroendocrine effects of parity, including lower PRL and estrogen release in previous mothers compared to nonmothers, but enhanced sensitivity to estradiol from greater ERα expression in the pituitary gland and brain—including in the mPOA.663 Cognitive Systems Maternal behaviors emerge once the mPOA–mesolimbic pathway is activated and the MeA–DH/AHA–VMN inhibitory pathway is deactivated, but caregiving and its associated behaviors can be further improved by finetuning other neurobiological systems, including those underlying cognitive functioning. New parents must plan and be organized, but also prepared to respond to sudden change. That is, environmental cues need to be freshly evaluated, attended to, and efficiently processed so that the parent’s behavior can be rapidly initiated or inhibited. New types of social interactions and physical features in the environment must be remembered to best guide future activities. Many such cognitive skills are enhanced in parental animals, and this involves a “resculpting” of their brain. This resculpting occurs to an impressive degree. For example, on a gross structural level, total brain volume shrinks by over 5% in pregnant women and this is accompanied by a 30% increase in the size of their ventricles.664 These measures revert to prepregnancy values within 6 months after parturition, and at the same time the volume of women’s gray matter in the prefrontal cortex and parietal lobe selectively increases.665 Research by Kinsley and Lambert was the first to discover that mothering enhances female rats’ spatial memory, which is now known to involve striking hippocampal neuroplasticity. In an eight-arm radial maze, maternally experienced rats who had weaned their pups learned the location of baited arms after fewer trails than nulliparous females, and in a dry-land analog of the Morris Water Maze, the experienced females more rapidly reached a baited food well. The mothering experience, rather than pregnancy and lactation, is responsible for this benefit because nulliparous-sensitized females also show enhanced spatial memory.666,667 Amazingly, these cognitive benefits of previous motherhood in rats can last for years.668 Later work by Pawluski and colleagues extended this memory improvement in rats to current motherhood and found that it requires at least some contact with pups after parturition.669,670 Similar behavioral

results have been found in postpartum laboratory mice, and brain OT is one regulator of these effects in this species.671 There is evidence that reproductive and maternal experience improves some memory capabilities in women,672 and spatial memory improvements can also be found in rodent fathers.673 These results suggest that parental interactions with offspring, and in some cases exposure to hormones, induce plasticity in brain sites associated with learning and memory. Studies in rodents have focused on the hippocampus. One aspect of hippocampal plasticity in the maternal brain involves changes in the proliferation of new cells, including neurons. Cell birth in the brain was once thought to occur only during early development in mammals, but it is now well established in many adults, and altered cell proliferation is particularly common during times of hormone-mediated neurobehavioral flux, such as parenthood.674 New brain cells are often visualized with the use of the cell birth date marker bromodeoxyuridine (BrdU), a thymidine analog readily incorporated into cells that are synthesizing DNA in preparation for mitosis. One of the traditional areas for cell proliferation in the adult brain in many models is the granule cell layer of the hippocampal dentate gyrus (DG). Cell proliferation in the DG decreases during the middle and end of pregnancy in mice,675,676 and during the first week postpartum in laboratory rats; the latter is a result of suckling-induced corticosterone release.677–679 A similar decrease in DG cell proliferation is observed in parturient and maternal sheep.680 The hormone dependence of this phenomenon is demonstrated by the finding that mothering experience alone in sensitized rats without the endocrine consequences of lactation increases cell proliferation in the DG (Figure 51.18).678 A similar decrease in cell genesis during the first week postpartum also occurs in the midbrain dorsal raphe of laboratory rats,643 which may be related to changes in serotonin output necessary for maternal behavior and lactation. In forebrain sites more traditionally studied for roles in maternal behavior, increased numbers of BrdUlabeled cells are found in the dorsal BST and shell of the NA of postpartum rats that had brief maternal experience with pups compared to those without experience,681 but females of various reproductive states do not differ in the number of BrdU-labeled cells in these sites or in their mPOA, ventral BST, or shell and core of the NA.643 If new cells in these forebrain sites are not generated locally, they likely have migrated from the other classic neurogenic region, the subventricular zone (SVZ). The rodent SVZ shows pregnancy and early-postpartum changes in the number of BrdU-labeled cells, and this is a result of high circulating PRL.682,683 In contrast, neurogenesis in the SVZ of sheep decreases after parturition and interaction with the lamb, which might somehow reflect differences between species in their need for

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Brain Control of Maternal Behaviors

FIGURE 51.18  Number (Mean ± SEM) of BrdU-immunoreactive cells in the granule cell layer of the dentate gyrus of female rats measured 21 days after BrdU injection. Primiparous rats were injected with BrdU on postpartum day 1 and had fewer new cells surviving 21 days later compared to nulliparous control females. However, maternally sensitized nulliparous females had more new cells surviving 21 days after the beginning of pup exposure compared to controls. Groups did not differ in BrdU-immunoreactive cells in the hilus of the dentate gyrus. a = significantly different from nulliparous control females; b = significantly different from all other groups. Source: Modified from Pawluski and Galea, 2007.678

individual recognition of the offspring.680 Many of these newly born cells in the SVZ of mice appear to migrate to the olfactory bulb, suggesting a role in the olfactory control of maternal behavior, but suppressing endogenous PRL during early pregnancy to block this neurogenesis impairs maternal behavior only when mice are tested under novel conditions, suggesting a nonsensory effect. Anxiety is increased in these PRL-suppressed dams, which may offer an explanation.184 The plasticity of the maternal hippocampus also involves structural changes in neuronal dendrites. CA1 pyramidal cells of late-pregnant and early-postpartum rats have a higher density of apical dendritic spines compared to that found in virgins, but, by the time of weaning, mothers have shorter CA1 and CA1 apical dendrite length and a lower number of branch points than virgins. This increase in apical dendrite spines depends on ovarian hormones,684,685 and the later reductions in dendrite length and branch points may depend on adrenal corticosterone as it is not observed in multiparous females, which have lower circulating glucocorticoids compared to first-time mothers.685 These results and the postpartum

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decrease in hippocampal cell proliferation discussed here might appear inconsistent with the improvement in short-term memory during lactation, but even regressive events in the brain could indicate an enhancement or refining of the neural circuitry involved in memory, and warn against a “more brain equals more behavior” type of logic. The functional significance of hippocampal plasticity may relate to maternal behavior toward pups. Lesioning the hippocampus before mating results in poor nest building, disorganized retrieval, and fewer pups surviving to weaning.42 Similarly, mother rats with lesions of the fimbria, one of the major output paths of the hippocampus, build multiple small nests and retrieve some pups to each of them.686 Unmated female rhesus monkeys that received hippocampal lesions during infancy, however, are normally affiliative toward unrelated infants,687 which could reflect a species difference in the need for an intact hippocampus for mothering-like behavior or that other neural systems could eventually compensate for its loss in female monkeys. Peripartum hippocampal plasticity could also be involved in other functions in the females, including their altered negative feedback of the HPA axis response to stress.167 The cerebral cortex also exhibits peripartum plasticity, and cortical involvement in maternal behavior has recently received increased attention. Lactating rats have a thicker somatosensory cortex than cycling rats,688 and twice as much somatosensory cortex is devoted to dams’ representation of the skin of their ventral trunk, which is probably related to their enhanced sensitivity to pup probing and suckling.689 This expansion of the somatosensory cortex requires physical contact with pups, and within 2 weeks after weaning its size reverts back to a prepartum state.690 First-time mothers also have greater GFAP immunoreactivity in the cingulate cortex, a change that appears within hours of parturition if females are allowed to interact with pups, and this lasts through lactation.691 Virgin female rats that are given exogenous hormones and interact with pups have a similar increase in cingulate GFAP immunoreactivity.692 In addition, mother rats have a greater number of dendritic spines in the mPFC, an effect that coincides with their enhanced behavioral flexibility.693 Research on primates following lesions of the PFC or the anterior temporal cortex in postpartum rhesus monkeys demonstrated severe maternal behavior deficits, including an absence of contact seeking with infants, lack of retrieval from threatening situations, and only passive tolerance or active rejection if contact was infant initiated.694,695 As discussed in the section Components of Parental Care, early work incorrectly suggested that no one area of the cortex was crucial for the expression of maternal behavior in rats but that the size of the cortical lesion was most relevant. We now know that specific regions of the PFC are activated by offspring cues and expression of parenting behaviors in rodents628,696,697 and

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that lesions of the medial PFC have profound effects on maternal behavior.516,698,699 The PFC receives polymodal sensory input and has been implicated in stimulus recognition and executive functions contributing to attentional selection, optimal organization and planning, flexibility, and decision making in relation to complex goal-directed behaviors. The mPFC receives DA input from the VTA and has reciprocal connections with several subcortical structures, including many involved in maternal behavior such as the mPOA, BST, VTA, NA, and PAG. Thus, the mPFC can initiate a descending cascade though which the behavioral expression of a motivated or rewarding response results from outflow of the mPOA and limbic structures via the ventral pallidum and mesencephalic locomotor regions of the brain.569 The rodent mPFC can be functionally and anatomically subdivided into three distinct subregions—anterior cingulate (ACC), prelimbic (PrL), and infralimbic (IL)— each with distinct and dissociable contributions to the expression of maternal behavior across the postpartum period.516 Permanent lesions and transient inactivation of the dorsal mPFC or ACC affect the organizational aspects of maternal behavior during both early- and late-postpartum periods, likely by inducing deficits in attention and behavioral inhibition processes, although mother rats remain very interested in pups.41,43,49,516,698 Other studies have shown that depression of ventral mPFC activity severely disrupts maternal behaviors.516,699 Specifically, transient inactivation of the infralimbic cortex, the most ventral part of the mPFC, severely disrupted all components of early postpartum maternal behavior, whereas inactivation of the prelimbic subregion did not.516 It is worth noting that IL–mPFC inactivation, unlike mPOA inactivation that produced selective disruption of active maternal behaviors, resulted in females not directing their behavior toward pups at all but instead engaging in other activities such as eating, drinking, and resting. The IL–mPFC was also necessary for the dams’ choice of pups over competing alternative conditioned incentives.516 Together, it is tempting to speculate that the IL– mPFC is in a nodal position to integrate exteroceptive pup-related information with interoceptive information related to the maternal state, and to exert executive control to guarantee behavioral allocation toward pups and associated stimuli. By contrast, the mPOA is more a key component in motivational processing of pups and related incentive stimuli. Pereira and Morrell further demonstrated that, as the postpartum period progresses, the necessary facilitatory role of the IL–mPFC wanes, whereas the PrL–mPFC then contributed to the expression of late-postpartum maternal behavior.516 This role transfer within subregions of the mPFC across lactation might be related to the transition from goal directed to habitual responding that probably occurs over time when dams continually interact with pups.

In summary of this subsection, the mPOA has a multifaceted role in promoting as well as inhibiting maternal behaviors. The mPOA is one of the most sensitive brain sites to ovarian and pituitary hormones and has reciprocal connections with neural sites processing all five sensory systems. It has dense connections with areas for the brain involved in motivated behaviors, emotion regulation, and cognition. The mPOA is perfectly situated to act as an integration site for the hormonal and sensory inputs required for the triggering or inhibiting of maternal interest, and then communicates that information with the motor, motivation, and cognitive systems necessary for the planning and performance of maternal behaviors (Figure 51.19).

Brain Control of Maternal Behaviors in Humans Advances in fMRI to assess subregional changes in metabolic activity in the human brain have resulted in a small, but fascinating, collection of studies of how the postpartum human brain responds to infant-related auditory or visual cues. Because of the physical constraints involved with fMRI imaging, these studies do not reveal changes in brain activity during maternal behavior per se, but more about the perception and integration of sensory cues from infants and their rewarding or aversive properties. As discussed earlier in this chapter, heightened immediate-early gene expression in most brain sites involved in rodent mothering requires behavioral execution rather than distal stimulation from infants.542,543,628 Evaluating the human brain response to infants in the absence of the ability to behave maternally

FIGURE 51.19  Hypothetical neural model for the stimulation of active maternal behaviors. The hormones of pregnancy and sensory cues of offspring suppress inhibitory input from the MeA–DH/ AHA–VMN to the mPOA–BSTv while simultaneously stimulating mPOA–BSTv output to the VTA. This elicits dopamine release in the NA, PFC, and BLA. DA release in the NA inhibits VP output, thereby promoting the active components of maternal behavior. The NA, VP, PFC, and BLA can modulate this pathway by their connections to the MPOA–vBST or NA. AHA: anterior hypothalamic area; BLA: basolateral amygdala; BSTv: ventral bed nucleus of the stria terminalis; DH: dorsal hypothalamus; DA: dopamine; MeA: medial amygdala; mPOA: medial preoptic area; NA: nucleus accumbens; PFC: prefrontal cortex; VP: ventral pallidum; VTA: ventral tegmental area. Lines ending in arrows: excitatory input; lines ending in vertical bars: inhibitory input; lines ending in circles: DAergic signaling. Source: Modified from Olazabal et al., 2013.750

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is nonetheless particularly appropriate because human parenting involves more higher-order cognitive and emotional integration compared to that required for the parental behavior of rodents and other subprimates.229 Experiments exposing mothers to the cries of their own infant or the cries of an unfamiliar infant reveal widespread cortical and subcortical activation. Reliability about what brain regions are activated by infant cries will increase as more studies emerge, but the sites most frequently reported across studies to be activated by infant cries are areas involved in sensory perception and processing (the thalamus and superior temporal and auditory cortex), those involved in reward (the striatum and nucleus accumbens), and numerous regions of the cortex involved in emotion and cognition (the insular, orbitofrontal–inferior frontal, medial frontal, temporoparietal, and fusiform cortices).700 A smaller number of studies have reported activation in response to a familiar or unfamiliar infant cry in the anterior cingulate and ventral prefrontal cortices, amygdala, hypothalamus, hippocampus, and septum–preoptic area.700 Other series of experiments using infant photographs or videos as stimuli have most often reported greater activation to one’s own infant over an unfamiliar infant in many of the same areas activated by cries (e.g., the thalamus, striatum and nucleus accumbens, orbitofrontal and inferior frontal, and fusiform cortices). Activation in response to infant visual stimuli is also sometimes found in the insular and temporoparietal cortices, lentiform nucleus–globus pallidus, midbrain, and cerebellum. Thus, regardless of the modality of the distal infant cue, there is considerable overlap in the sites of the maternal brain that respond to these cues, and this may reflect the core neural network necessary for the sensory, emotional, reward, and cognitive processing involved in human mothering. Metabolic deactivation is rarely found in the maternal brain during exposure to infant cues, but two groups have each reported deactivation of the medial frontal gyrus when subjects are exposed to the cry of their own infant when compared to the cry of an unfamiliar infant or when comparing the response to an infant cry and infant laughter.700,701 Interestingly, lower activation of the medial frontal gyrus is also found when mothers view

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their own infant versus another infant.702 The medial frontal gyrus is implicated in functions that include mood regulation,703 ­self-referential ­processing,704 and behavioral decision making.705 In psychologically healthy and motivated mothers, this deactivation in response to cues from their own children could be associated with suppressing negative affect and the intention of providing to provide selfless caregiving to their infant. Unfortunately, not all human mothers are healthy and motivated, and women are heterogeneous in their emotional and cognitive appraisals of infants. This is reflected by their fMRI activity. For example, mothers who are more sensitive have greater activity in their anterior prefrontal cortex, inferior and superior frontal cortex, and amygdala while hearing their own infant’s cry compared to that seen in less sensitive mothers.706,707 Studies examining how maternal mental health influences fMRI activity in response to infant cues demonstrate that poor maternal mood and high distress, which impair mother–infant interactions and bonding, are associated with lower amygdalar activity when mothers are viewing their infant’s face.708 Mothers with posttraumatic stress disorder, which is also associated with impaired bonding and interaction with infants, show limbic hyperactivity and lower prefrontal cortex activity than controls when watching videos of their children in a stressful situation.709 Similarly, reduced prefrontal cortex activity is found in substance-using mothers exposed to infant pictures or cries.710 Maternal brain activation in response to the cry of one’s own infant compared to those from other infants is also lower in multiple cortical regions (superior and middle temporal, superior frontal, medial fusiform, and superior parietal) and in the caudate, thalamus, hypothalamus, and amygdala in women who deliver via Caesarian section rather than vaginally (Figure 51.20).98 Interestingly, breastfeeding is associated with greater fMRI activity in some of these same regions (superior frontal cortex and amygdala) compared to the activation seen in mothers who bottle feed their infants,707 and these differences have been proposed to reflect the neuroendocrine consequences of vaginal delivery and suckling, as well as differences in maternal sensitivity to the infant.711 FIGURE 51.20  Sites of the maternal brain where fMRI activity was higher (indicated by red) in mothers who delivered vaginally compared to via Caesarean section while listening to their own infant crying. This figure is reproduced in color in the color plate section. Source: Modified from Swain et al., 2008.98

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BRAIN CONTROL OF PATERNAL BEHAVIORS Brain Control of Paternal Behaviors in Nonhuman Animals Fathers in most biparental species show the same repertoire of caregiving behaviors as their female mates, including nursing-like postures, even though suckling by pups and milk letdown cannot occur.326 Thus, it is parsimonious to think that brain networks controlling these behaviors are homologous to those in females, and immediate-early gene studies in prairie voles and California mice suggest this is mostly true. There has been no direct comparison of the immediate-early gene expression between female and male parents in either species, but patterns of immediate-early gene expression in parentally inexperienced virgin male and noninfanticidal virgin female prairie voles are very similar to those found in postpartum female rats and mice. For example, exposure to a single pup increases Fos expression in both the male and female prairie vole mPOA, BST, MeA, and lateral septum compared to the expression found after exposure to candy.712 In California mouse fathers, Fos expression is elevated in the mPOA after exposure to just the distal cues from a pup.713,714 With regard to sex differences in Fos response, the magnitude of the increase in Fos expression in the prairie vole mPOA after exposure to a pup is much higher in virgin males than in virgin females, possibly reflecting the higher spontaneous parental responsiveness in males found in most studies.330,715 Additionally, the paraventricular thalamus expresses Fos in paternally acting virgin male prairie voles, but it does not in females.712 The relevance of this sex difference in prairie voles is unknown, but the paraventricular thalamus also expresses high Fos in postpartum mother rats,542 and it could be related to sex differences in the role of the paraventricular thalamus in reward seeking716 or HPA axis regulation.717 There have been relatively few studies manipulating the paternal rodent brain. Excitotoxic lesions of the virgin male prairie vole MeA and surrounding region slightly reduced sniffing and licking of pups, but greatly reduced huddling over and lying next to them. The effects were specific in that side-by-side contact with a familiar female was not affected by the lesions.636 The role of the MeA in these males’ behavior must be more complex than just processing olfactory stimuli from pups because olfactory bulbectomy produced much more dramatic deficits that included infanticide and disruption of other social and nonsocial behaviors.718 In male California mice, electrolytic lesions of the mPOA produce results somewhat similar to those found in mPOA-lesioned female rats, including longer latencies to retrieve pups, less licking, and less time spent near offspring.509,637

The neurochemicals released from or acting in these sites in the paternal brain are surely numerous, but mostly unknown. In paternally experienced California mice, Fos is expressed in some serotonergic cells of the dorsal raphe.714 A small number of the Fos-expressing cells in the BST and MeA of virgin male prairie voles contain tyrosine– hydroxylase and may release l-DOPA or dopamine to modulate their paternal behavior.719 Fos is also expressed in the paternal prairie vole PVN, and quite a few of these cells synthesize OT or AVP.336 In fact, numerous studies have focused on the role of AVP in paternal behavior. It has long been recognized that male prairie voles differ from nonpaternal species of voles in the density of V1a receptor binding in many areas of the forebrain, including having greater expression in their accessory olfactory bulb, cingulate cortex, BSTv, VP, central amygdala, and paraventricular thalamus but lower V1a binding in their lateral septum, lateral habenula, and PAG.720 Correlational studies supporting a role for intracerebral AVP in fathering include that male prairie voles have plexuses of AVP-immunoreactive fibers in their lateral septum and lateral habenula (sites implicated in maternal behavior rats; see the section Components of Parental Care) that decrease in density after males cohabitate and mate with a female, and this decrease somewhat parallels the increase in their paternal responding. No changes were observed after mating in the AVP fiber plexuses of the nonpaternal male meadow vole.328,721 Because mating increases AVP mRNA in the male prairie vole BST, which is the source of this fiber innervation, this drop in fiber density probably reflects increased AVP release.327 Any causal link between this mating-induced change in AVP content and behavior is unclear because long-term castration of male prairie voles almost eliminates AVP synthesis in this system, but in some studies castration has no effect on their paternal behavior.330 Studies examining direct manipulations of central AVP on the paternal behavior of prairie voles have produced mixed results. Infusion of AVP into the border of the lateral and medial septum has been reported to increase males’ time spent in contact with pups compared to saline-infused controls, while infusion of a V1a receptor antagonist reduced pup licking.722 Some of these results could not later be reproduced,723 and intracerebroventricular infusion of a V1a receptor antagonist has also been seen to have little effect on pup licking or other paternal behaviors,724 but this latter null finding may be due to the nontargeted infusion. Even so, males receiving simultaneous intracerebroventricular infusion of a V1a receptor antagonist along with an OT receptor antagonist did display greater infanticide and reduced huddling over pups.724 The effectiveness of the combined treatment may be related to the greater OT receptor expression in the frontal cortex, nucleus accumbens, BST, and paraventricular thalamus of prairie voles

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Brain Control of Paternal Behaviors

compared to species of nonpaternal voles.725 Lastly, intracerebral administration of AVP increases licking and huddling with pups and decreases pup-directed aggression in male meadow voles, which suggests that changes in central AVP are involved in switching on and off their facultative paternal behavior.278 Several correlations suggest that AVP is also associated with paternal behavior in male California mice. Within the hypothalamic PVN, there is a positive association between levels of AVP mRNA and males’ approach toward a pup, but not other paternal behaviors.726 Moreover, California mouse fathers have more AVP-ir cells and fibers in the PVN and supraoptic nucleus (SON) than do fathers of a nonpaternal Peromyscus species, P. maniculatus.301 Within California mice, fathers that retrieve their pups more often have higher levels of AVP-ir in the SON.727 There is also a transgenerational relationship between AVP and paternal behavior, with offspring raised by castrated fathers that display less huddling and grooming toward them later expressing higher AVP in the PVN.728 These offspring raised by castrated fathers also display less huddling and grooming toward their own pups.729 Together, these results from California mice suggest that AVP in the PVN is involved in adult and developmental plasticity of paternal behavior, perhaps related to the hypothalamic systems involved in stress. Several lines of evidence also link AVP in the BST with developmental plasticity in paternal behavior. Cross-­fostering litters between the more paternal California mouse and the less paternal and promiscuous white-footed mouse, Peromyscus leucopus, produce male ­offspring that are more similar to their foster parents with respect to pup retrieval.730 AVP immunoreactivity in the offspring BST is positively correlated with the frequency of paternal retrievals that these cross-fostered male young had received and with their fathers’ huddling, grooming, and time spent in the nest.727 When retrieval by their fathers was increased by purposely displacing the litters from their nests, these offspring later retrieved their own pups more frequently (Becker and Marler, unpublished data) and also displayed higher paternal aggression after becoming fathers.728 These male offspring that were retrieved more often by their own fathers also had more AVP immunoreactivity in the dorsal fiber tracts of the BST.728 Moreover, there is a potential link between these results and testosterone because pups have an acute rise in testosterone when they are retrieved by their fathers,731 and this could influence both their AVP system and future paternal behavior as adults. Paternal behavior in P. californicus, therefore, appears to mediate the behavioral transmission of both paternal retrieval behavior and aggression and may do so via plasticity of numerous central AVP pathways. Central estrogen synthesis and presumably estrogen receptor signaling are required for paternal behavior in

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male California mice,292 but estrogenic activity instead inhibits fathering in male prairie voles and possibly some other rodents. Correlational studies show that the paternal pine vole (Microtus pinetorum) has lower ERα expression in areas of the brain involved in paternal behaviors, including the MeA and BST, compared to the polygamous and nonparental montane vole (M. montanus).732 Similarly, the highly parental male Djungarian hamster (Phodopus sungorus) has lower ERα expression in the BST compared to the less parental male Siberian hamster.732 In prairie voles, regional populations of males that are more alloparental have lower ERα expression in numerous brain regions, including the mPOA, BST, and VMN, compared to populations of less alloparental males.733 These differences in ERα expression in the MeA are functionally relevant for parenting because male prairie voles with viral vector-mediated overexpression of ERα in the MeA, but not in the BST, are much less likely to act paternally than controls.734,735 This negative relationship between paternal behavior and ERα is specific to this steroid receptor because there are no associations between the brain distribution and/or density of androgen receptors733 or progesterone receptors736 and paternal behavior in adult male prairie voles.

Brain Control of Paternal Behaviors in Primates The handful of studies of the paternal monkey brain have focused on neuropeptides, and the relationship between OT and maternal behavior in rodents appears to extend to male common marmoset fathers. OT levels released from hypothalamic explants of paternally experienced male common marmosets is significantly higher compared to those of inexperienced males,737 and intracerebroventricular infusions of OT decreases the number of refusals that fathers made for food transfers to their offspring.738 There are two studies associating central AVP with paternal behavior in common marmosets. One did not identify any changes in AVP release from hypothalamic explants based on paternal experience,737 and the other found that fathers have a greater number of AVP V1a receptors in their prefrontal cortex, that they have a greater density of dendritic spines on pyramidal neurons in the prefrontal cortex, and that more of these spines contained V1a receptors compared to paternally inexperienced males.739 Because human fathers are more variable in their parental involvement and interact differently with infants than do mothers, the three published studies of fMRI activity in the paternal brain during infant cue exposure are an important contribution to the human parental brain literature (see the section Brain Control of Maternal Behaviors). Seifritz and colleagues found no specific sites activated in fathers compared to mothers listening to infant laughing or crying, but they did

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FIGURE 51.21  Sites in the parental brain where mothers (left) or fathers (right) showed greater fMRI activity in response to their own infant video compared to viewing an unfamiliar infant. This figure is reproduced in color in the color plate section. Mothers showed greater activity in the right amygdala and temporal, occipital, and parietal cortices compared to fathers, while fathers had greater activity in the dorsal prefrontal cortex (dPFC). Source: Modified from Atzil et al., 2012.711

discover a few overall sex differences in activity, with women (mothers or nonmothers) showing deactivation of the anterior cingulate cortex and mesial prefrontal cortex during cue exposure, whereas men (fathers or nonfathers) showed no such change.701 The authors attributed the findings to sex differences in how these cortical areas control sensory gating and worrying or anxiety. They also found that compared to nonparents, parents of both sexes exhibited greater activation to infant crying in the amygdala; the cingulate, ventral prefrontal, and insular cortices; and the temporoparietal junction—all perhaps related to socioemotional regulation. A recent study comparing fMRI activity while fathers viewed video clips of a doll or their own infant’s emotionally neutral face found greater activation to the infant in a host of cortical regions that are also often activated in mothers (orbitofrontal, lateral frontal, superior parietal, and midtemporal). Some cortical regions (orbitofrontal, inferior and superior frontal, supramarginal, and midtemporal) were also more metabolically active when fathers viewed their own versus an unfamiliar infant.740 By imaging both mothers and fathers watching the same videos of their infant playing alone or a previous interaction with them, Atzil et al. found that functional activity was correlated between fatherand-mother pairs in numerous cortical areas involved in empathy and social information processing (anterior cingulate, inferior frontal, inferior parietal, medial and lateral prefrontal, and insula).711 Unlike the findings of Seifritz et al. indicating no father–mother differences in fMRI activity in response to infant vocalizations,701 Atzil and colleagues further found that mothers showed higher activation to their own infants’ visual cues than did fathers in areas of the cortex (temporal, postcentral, and fusiform), caudate, and amygdala (Figure 51.21).711 Also only in mothers, activity of the amygdala, cingulate cortex, and nucleus accumbens was positively

correlated with their plasma OT levels. Paternal plasma OT was instead negatively correlated with activation in cognitive cortical regions (dorsolateral PFC, dorsal ACC, IPC, and precentral gyrus),711 and these results could possibly be related to sex differences in limbic and cognitive control of parenting.

CONCLUSION A substantial amount of information clearly exists regarding the endocrine, neuroendocrine, sensory, and neural substrates necessary for the onset and maintenance of parental behaviors in rodents, sheep, and primates. We believe there are still numerous broad and specific areas for future research, and a few points to consider about the existing literature, that would improve the understanding of the physiology of parental care. Specifically, these might include:

  

• I ncreased investigation of the involvement of some steroid hormones in mothering. There is a very notable gap in our comprehension of how and where in the brain progesterone inhibits or facilitates caregiving behaviors. Since the early studies by Numan,578 in which progesterone implanted into none of the hypothalamic or midbrain sites examined could delay the onset of mothering, there has been no direct investigation of this question. Studies using targeted implants of progesterone into brain sites not examined in that study, or brain site–specific knockout of PR, would be informative. There is also almost nothing known about any behavioral implications of the very high androgen secretion during pregnancy or where in the brain androgen receptor activity might influence the onset of mothering.

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References

• A  more informed perspective is needed on the redundancy existing among the endocrine factors underlying parenting. As discussed in this chapter, knockout models in which parental behaviors are unaffected or less impaired than expected suggest that such redundancy exists and provide insight into the systems most valuable for further analysis of this question. • The neurobiological mechanisms involved in how parental behaviors are maintained by pup sensory cues after the endocrine effects have waned have not been well studied. Are the cells that were affected by hormones the same cells that are later responding to pup sensory cues? How is the physiology of these cells altered by hormones to assume this function? A somewhat similar question arises regarding how the multiparous brain differs mechanistically from the primiparous brain. The neural systems involved in mothering have been permanently altered to require reduced or no hormone exposure and less sensory input to elicit maternal behavior, but additional research into how this occurs would be tremendously valuable. • We and many others have reviewed the scientific literature on the numerous neural systems involved in the suite of behavioral alterations that are necessary for successful parenting, but how these systems interact as a larger neural network for seamlessly integrated behavioral responding is not well understood. Furthermore, because these systems are involved in almost every social behavior,6,741 it would be important to know how they selectively respond to offspring. Are different populations of cells within these structures involved in particular behaviors? How do the unique endocrine events of pregnancy versus other endocrine events involving the exact same ovarian and pituitary hormones (e.g., the estrous cycle) affect cells in ways that determine what social cues are responded to and what cues are ignored? • As translating information from nonhuman animals to humans continues to become an important goal of the field studying maternal behavior, animal models must be chosen wisely. For example, while studying nonhuman female primates is admirable, it is obviously difficult or impossible for most researchers. A cogent argument has been made that one of the animal models closest to humans in their peripartum endocrinology, delivery of a small number of precocious offspring, mother–offspring communication, and social attachment is the now rarely studied guinea pig.742–744 • Carefully consider the existing and future literature in the context of the natural display of parenting behavior. Beginning with some of the foundational

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work in this field on laboratory rats15,32,37 there has sometimes been an emphasis on retrieval of offspring as the most relevant, or sometimes the only, outcome measure. Retrieval is convenient to assess because it is usually rapid and clearly displayed by a subject or not, but it is problematic for a more holistic understanding of parenting because retrieval is uncorrelated with other parental behaviors of the same animals after retrieval has concluded or when the subjects are observed under undisturbed conditions.745,746 It is also problematic because this type of long-distance carrying of young is probably rare in nature unless the nest site is disturbed.747 Importantly, because parenting is not a unitary process, but instead involves a collection of individual behaviors with different sensory, endocrine, and neurobiological determinants, factors influencing retrieval will not translate to all other components of offspring care. • With few exceptions,661,678,748 we as a field focus on first-time parents with no previous experience with young. As discussed in part in this chapter, this is unnatural because most adult mammals are unlikely to approach parturition with no previous parenting experience because they would have received it during juvenile alloparenting and/or had given birth multiple times before. Under natural conditions, therefore, the relevant endocrine and sensory cues most often act upon an already heightened baseline to promote maternal behavior. Thus, laboratory studies may reveal how powerfully hormones, pup sensory cues, and other factors can influence parenting, but their importance for the majority of mothers and fathers living in natural environments is probably overemphasized in a literature that is mostly based on laboratory studies of inexperienced animals.   

Parental behaviors directed toward offspring can tremendously help or materially harm the young, and can do so with lifelong consequences. As researchers who benefit from and struggle with the advantages and limitations of our models, we must not lose sight of the idea that our knowledge obtained from nonhuman models of parental behavior is both incredibly useful in its own right for a comparative perspective about social–behavioral endocrinology, and also informs the human condition in ways that can immensely benefit both parents and offspring during this critical phase of mammalian reproduction.

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