Development of food intake controls: Neuroendocrine and environmental regulation of food intake during early life

    Development of food intake controls: Neuroendocrine and environmental regulation of food intake during early life Erica J. Crespi, Margaret K. Unkefer PII: DOI: Reference:

S0018-506X(14)00062-2 doi: 10.1016/j.yhbeh.2014.04.004 YHBEH 3705

To appear in:

Hormones and Behavior

Received date: Revised date: Accepted date:

11 November 2013 1 April 2014 5 April 2014

Please cite this article as: Crespi, Erica J., Unkefer, Margaret K., Development of food intake controls: Neuroendocrine and environmental regulation of food intake during early life, Hormones and Behavior (2014), doi: 10.1016/j.yhbeh.2014.04.004

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Manuscript submitted as a review article in the special issue, “Comparative Approaches to the Study of Ingestive Behavior, Energy Balance, and Metabolic Control of Reproduction.”

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Development of food intake controls: Neuroendocrine and environmental regulation of food intake during early life

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Erica J. Crespi* and Margaret K. Unkefer

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School of Biological Sciences, Washington State University, Pullman, WA 99164

* Corresponding author PO Box 644236, Pullman WA 99164-4236 [email protected] Phone: 011-1-509-335-3833

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ACCEPTED MANUSCRIPT Abstract

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The development of neuroendocrine regulation of food intake during early life has been shaped by natural selection to allow for optimal growth and development rates needed for survival. In vertebrates, neonates or early larval forms typically exhibit “feeding drive,” characterized by a developmental delay in 1) responsiveness of the hypothalmus to satiety signals (e.g., leptin, melanocortins) and 2) sensitivity to environmental cues that suppress food intake. Homeostatic regulation of food intake develops once offspring transition to later life history stages when growth is slower, neuroendocrine systems are more mature, and appetite becomes more sensitive to environmental or social cues. Across vertebrate groups, there is a tremendous amount of developmental plasticity in both food intake regulation and stress responsiveness depending on the environmental conditions experienced during early life history stages or by pregnant/brooding mothers. This plasticity is mediated through the organizing effects of hormones acting on the food intake centers of the hypothalamus during development, which alter epigenetic expression of genes associated with ingestive behaviors. Research is still needed to reveal the mechanisms through which environmental conditions during development generate and maintain these epigenetic modifications within the lifespan or across generations. Furthermore, more research is needed to determine whether observed patterns of plasticity are adaptive or pathological. It is clear, however, that developmental programming of food intake has important effects on fitness, and therefore, has ecological and evolutionary implications.

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Keywords Appetite regulation, glucocorticoids, testosterone, leptin, hypothalamus, developmental plasticity, epigenetics, maternal effects

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ACCEPTED MANUSCRIPT Introduction: For most vertebrates, the diet and food intake patterns at the earliest developmental stages vary greatly from those of adults, especially in animals that are dependent on parental provisioning of

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food such as mammals and birds. This is also the case for frogs or fish that have larval or

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juvenile forms that inhabit a completely different environment from those inhabited by adults. In

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all of these situations, the regulation of food intake follows a developmental progression that is geared toward obtaining resources while optimizing growth and survival through these early life

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history stages.

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In this review we take a comparative approach to synthesize what is known about the development of neuroendocrine regulation of food intake across vertebrate groups. We do not

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extensively review all aspects of food intake regulation in each group, although we provide

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references of reviews and key papers for each; rather, we aim to highlight the developmental

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processes that affect food intake behaviors across groups. Food intake strategies also vary within the adult lifespan due to changes in activity across seasons, e.g., seasonal breeders, migratory species, or hibernators (Cornelius et al. 2013; Janos et al. 2011). While these transitions offer unique opportunities to explore how changes in food intake regulation is adapted to allow for successful life history transitions, here we focus on early life history stages and how the development of food intake controls can be altered by the environment. Because the brain is still developing during early stages, the environment experienced during this time can influence food intake regulation throughout the life of the animal (see reviews Grayson et al., 2010; Grove et al. 2005; Spencer, 2013). Therefore, we also review what is known developmental plasticity in food intake regulation across vertebrates, and the endocrine and epigenetic modifications that mediate this plasticity. We conclude by highlighting the ecological and evolutionary significance of developmental plasticity in food intake regulation and by providing a prospectus of future research directions in this field. 3

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Development of food intake controls in mammalian models Our understanding of the ontogeny of neuroendocrine mechanisms regulating food intake

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largely comes from studies of rodents, which serve as models to which developmental processes

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of other organisms can be compared. Neonatal rat and mice pups are born highly dependent on

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maternal care and resource provisioning, as many physiological, morphological and sensory systems are still developing and the accumulation of fat reserves is needed to survive. Not

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surprisingly, food intake regulation during the first few weeks of this neonatal period is

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characterized by an overriding drive to eat (Melnick et al., 2007). Instead of the adult homoestatic neuroendocrine model of food intake regulation, in which post-meal satiety signals

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regulate meal size and frequency (Schwartz et al., 2000), oral-sensory reflexes stimulate food

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intake right after birth (Grove, 2005; Smith, 2006). Signals reflecting hydration status are

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primarily used to determine the volume of milk to consume, as eating and drinking regulation is the same at this stage (Smith, 2006). The primary negative feedback that is associated with the cessation of suckling is driven by the extension of the stomach, which stimulates peripheral neurological and hormonal signals from the gastrointestinal tract to the hindbrain. There is no evidence to suggest that nutrition-related cues are used to regulate food intake within the first weeks of post-natal life; it appears that it is all about volume (Smith, 2006). During this neonatal period in rodents, neural circuits between the brainstem, the gut, and the hypothalamus are critical to the regulation of food intake behaviors. The brainstem is thought to be the integrator of hunger and satiety signals, as the hypothalamic feeding centers (e.g., arcuate nucleus, ARC, paraventricular nucleus, PVN, ventromedial and lateral hypothalamus) are not yet involved to a great extent in the regulation of food intake (Grove et al. 2003; 2005). Studies have shown that ARC neurons are not yet responsive to circulating hormones in the periphery, nor are they neurologically connected to other hypothalamic feeding centers (Grove et 4

ACCEPTED MANUSCRIPT al., 2003; 2005). For example, experimental administration of neuropeptide Y (NPY), one of the most potent orexigenic neuropeptides involved in hypothalamic regulation of appetite during later life stages, increases suckling behavior as early as postnatal day 2 (Capuano et al., 1993).

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However, endogenous NPY may not be a signal that promotes food intake at this time, because it

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is expressed in very low levels in the ARC, and efferent projections of NPY neurons do not

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extend from the ARC to other hypothalamic nuclei until later in the post-natal period (Grove et al., 2003; Smith, 2006). In addition, three of the primary anorexigenic or satiety signals in adults,

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the hypothalamic neuropeptide α-melanocyte-stimulating hormone (α-MSH), the fat-secreted

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hormone leptin, and the gut-secreted hormone cholecystokinin, do not exert their inhibitory effects on food intake until after this 3-week period (Grove et al., 2003; Proulx et al., 2002,

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Rineman et al., 2003). The switch between hindbrain-driven food intake regulation to

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hypothalamic-driven regulation occurs during the weaning period when NPY and αMSH neurons

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in the ARC 1) become sensitive to orexigenic (e.g., stomach-secreted ghrelin) and anorexigenic signals (e.g., leptin) coming to the hypothalamus from the periphery, and 2) form connections to the PVN and other food intake centers of the brain, and (e.g., leptin; Melnick et al., 2007). In addition to the immaturity of hypothalamic homeostatic regulatory system, the feeding drive of the early neonatal period is also established due to the lack of physiological responsiveness to environmental perturbations displayed by rodent pups. The first two weeks after birth is often called the “stress hypo-responsive period,” and is characterized in part by a reduction in stress-induced inhibition of food intake relative to responses exhibited by older pups (Sapolsky and Meaney, 1986; Levine, 2002). During this period, the hypothalamo-pituitaryadrenal (HPA) axis has not fully developed; thus the responsiveness of corticotropin-releasing factor (CRF) neurons in the PVN to environmental stimuli is reduced, which also prevents the secretion of glucocorticoids in these conditions (Levine, 2002). Although this hypo-responsive period is thought to be an adaptation to minimize the negative effects of elevated glucocorticoids 5

ACCEPTED MANUSCRIPT on neurogenesis, cell proliferation of developing organ systems, and immune function (Levine, 2002), the suppression in secretion of CRF, a potent anorexigenic neuropeptide, also allows for the maximization of food intake and growth during the suckling period (Heinrichs and Richards,

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1999). As pups are weaned, the HPA axis matures and rat pups display a greater sensitivity to

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social or environmental conditions that prevent foraging in potentially adverse conditions

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(Sapolsky and Meany, 1986). The mechanisms that modulate the timing of maturation of hypothalamic CRF neurons and expression of CRF receptors, or lack of sensitivity of various

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sensory systems that detect potential stressors is an excellent point of focus for future research.

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By contrast to rodents, hypothalamic regulation of food intake develops in utero in precocial animals with longer gestation periods. In non-human primates and sheep, fibers

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containing both NPY and agouti-related protein (AgRP), another orexigenic neuropeptide, are

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found throughout the hypothalamus in the late second-trimester, and density of these projections

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increases in the third trimester as birth approaches (Grayson et al., 2006; Muhlhausler et al., 2004; 2006). In addition, neuronal connections between the brainstem and hypothalamic feeding centers are established in utero. For example, during late gestation in nonhuman primates, NPY neurons extend from the brainstem to the ARC during the late third trimester (these neurons extend to PVN in post-natal rodents), and there is an increase in NPY neurons extending from the ARC to the PVN during late gestation (Grayson et al., 2006). Connectivity of hypothalamic feeding centers also matures during late gestation in sheep, when experimental administration of NPY stimulates swallowing behavior in late gestation fetuses (El-Haddad et al., 2004a). Feeding drive (i.e., lack of response to satiety signals) appears to begin before birth in sheep, as leptin administration does not inhibit these in utero swallowing behaviors (El-Haddad et al., 2004b; Ross et al., 2003). Leptin levels are positively correlated with fat mass and growth in human infants during the first 90 days after birth (Akcurin et al., 2005; Karakosta et al., 2011), but to our knowledge there is no evidence to suggest that leptin acts as a physiological regulator of 6

ACCEPTED MANUSCRIPT meal size at this life stage in humans, primates or sheep. These findings suggest that like rodents, there is a delay in the development of neuroendocrine satiety signals during the earliest, rapid-

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growth life stages of mammals with extended gestation (Fig.1).

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Development of food intake controls in amphibians, fish, and birds

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Comparative studies have shown that the major neuropeptides and peripheral hormones known to affect food intake in mammals have similar roles in other vertebrate groups, such as fish,

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amphibians, and birds (Carr et al., 2002; Crespi et al., 2004; Hoskins and Volkoff, 2012;

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Kuenzel, 1994; Volkoff et al., 2005). In addition, the hypothalamus and hindbrain are important regulatory centers of food intake in the central nervous system of these vertebrates as in

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mammals, although other brain regions are studied in this context as well (e.g., pre-tectum/optic

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tectum in amphibians, Carr, 2013). Given the evolutionary conservation of food intake

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mechanisms and central nervous systems despite very different life histories, there are interesting parallels as well as novel contexts in the development of hypothalamic food intake controls between pre- and post-weaning rodents and those early life history stages of other vertebrates. Here we highlight the neuroendocrine regulation food intake regulation in early life history stages of birds, amphibians and fish and make comparisons to the developmental patterns in mammals described above.

Birds In precocial birds, the neonatal chicken has been the model in which the neuroendocrine controls of food intake have been studied. Experimental administration of orexigenic (e.g., NPY Jonaidi and Noori, 2012) and anorexigenic neuropeptides (α-MSH, Honda, et al. 2012; CRF, Ohgushi et al., 2001) stimulated and inhibited food intake in neonatal chicks and adults, respectively. Hypothalamic NPY mRNA expression is low at hatching and increases with age, suggesting that 7

ACCEPTED MANUSCRIPT endogenous NPY may not be playing a significant role in regulating food intake in the first days post-hatching (Cassy et al., 2004). Leptin administration inhibits food intake in adult chickens (Denbow et al., 2000, Cassy et al., 2004), but in neonatal chicks leptin treatment has been shown

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to cause a weaker reduction or no effect, depending on the study (Bungo et al., 1999; Cassy et

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al., 2004). Like rodents, the expression of leptin receptor in the hypothalamus of avian neonates

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is lower than that of 35-day old chicks (Cassy et al., 2004), which may explain the reduced actions of leptin during earlier life stages in chicks as seen in neonatal rodents. These results

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suggest at least one possible mechanism that mediates the similarities between post-hatching

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birds and neonatal rodents is their relative resistance to the action of satiety signals. However, little is known about the developmental expression patterns of hypothalamic neuropeptides

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involved in food intake during early stages of development beyond chickens. Comparative

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studies in other precocial birds or in altricial birds are needed to establish whether actions of

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hypothalamic satiety signals are generally delayed in early life stages of birds. In both precocial and altricial birds, there is evidence that hatchlings experience a hyporesponsive period associated with feeding drive as described in neonatal rats. In the broiler chicken, a strain selected for rapid growth and body size, neonatal chicks eat more (Cassy et al., 2004), exhibit less fearful behavior, and lower glucocorticoid responses to stressors and standardized CRF injections than those of chicks from slower growing strains (e.g., layers; Furuse, 2007). Broiler chicks also have higher amounts of other factors that suppress HPA axis responsiveness (e.g., melatonin, lipids, creatine) than other bird strains (Furuse, 2007). In altricial birds, a neonatal hypo-responsive period also has been proposed, as many species show a reduced stress-responsiveness to handling or other stressors during the early part of the nestling period (Wada and Breuner, 2010; Lynn et al., 2013). In white-crowned sparrows, the responsiveness of glucocorticoids to acute stressors is low right after hatching, but

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ACCEPTED MANUSCRIPT corticosteroid-binding globulins keep free levels of glucocorticoids low through 7-9 days of the nestling period (Wada et al., 2007). Regulation of feeding behavior in the nestling stage also involves corticosterone and

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testosterone signaling in altricial birds, although the direction of the effects of these hormones is

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not consistent across species or contexts (reviewed in Henriksen et al., 2011). The level of

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competition for food is intense among siblings within the nestling stage, and factors that increase begging behaviors or vocalizations typically yield greater amounts of food obtained from

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parents. Transient increases in glucocorticoids during the nestling stage have been shown to

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inhibit begging behaviors and reduced growth in white-crowned sparrows (Wada and Breuner, 2008). By contrast, in the context of increased glucocorticoids in times of food shortages,

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Kitaysky et al. (2001) showed that experimentally increasing corticosterone in black legged

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kittiwake nestlings increased begging behavior, although it did not stimulate increased feeding

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rates from parents. Several studies also showed that circulating testosterone levels in nestlings correlates positively with begging behaviors, growth, and fledgling success of offspring within and between nests (Groothuis et al., 2005; Goodship and Buchanan, 2006). Variation in corticosterone and testosterone levels in offspring has been associated with environmental conditions of the parents, such as higher population densities (Bentz et al., 2013) or low food availability (Kitaysky et al., 2001). Elevated circulating concentrations of these hormones in maternal circulation allows for excess allocation of corticosterone and/or testosterone into egg yolks and developing embryos (corticosterone: Hayward and Wingfield, 2004; Hayward et al. 2005; Kitaysky, 2001; testosterone: Groothuis et al., 2005; Schwabl, 1996). Although the frequency of begging behaviors resulting from elevated corticosterone or testosterone increases fitness in some studies, there also can be negative effects on growth and development rates (Kilner 2001; Kitaysky 2003; Wada and Breuner, 2008). Together these findings show that

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ACCEPTED MANUSCRIPT glucocorticoids and testosterone influence growth and ingestive behaviors in newly hatched birds, but there is much work to do to distinguish between correlation vs. causation.

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Amphibians

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In anuran amphibians, there have been several studies examining the roles of NPY, CRF,

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and α-MSH, glucocorticoids (corticosterone), and leptin in the regulation of food intake in larval and post-metamorphic frogs (see Table 1). Early in larval development (i.e., premetamorphic

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stage), elevations in corticosterone (experimental or stress-induced) inhibit growth in several

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species (e.g., Glennemeier and Denver, 2002; Ledon-Rettig et al., 2009), although food intake per se was not observed. Administration of CRF in the tadpole brain inhibits food intake in all

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stages of development, which suggests elevations in CRF secretion causes stress-induced

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anorexia in tadpoles that have been observed throughout the larval period (Crespi and Denver,

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2004). These results are consistent with those in many species suggesting that stress-induced CRF is accompanied by the inhibition of food intake; however, we do not know if orexigenic neuropeptides are needed to stimulate food intake at this stage. More complex hypothalamic regulation of food intake by inhibitory factors develops during prometamorphic larval stage (see Table 1), which is a time when other neuroendocrine systems mature prior to metamorphosis. Crespi and Denver (2004) showed that icv injection of a general CRF receptor antagonist had no effect on food intake during premetamorphic stages, but it caused a dramatic elevation in food intake in prometamorphic tadpoles and juveniles. Therefore, only during later tadpoles stages does CRF regulate food intake by tonic inhibition (in non-stressed animals). These findings also show that CRF as a dual role in amphibians as seen in other animals. It can inhibit food intake in stress and non-stressful situations, an effect with can be reversed by treatment with a CRF antagonist.

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ACCEPTED MANUSCRIPT Leptin also inhibits ingestive behaviors in amphibian tadpoles, but there is a similar developmental shift in its action as seen with CRF. During premetamorphic stages icv leptin injection does not affect food intake behaviors, but after the prometamorphic transition leptin

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inhibits food intake in a dose-dependent manner as it does in post-memamorphic frogs (Crespi

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and Denver, 2006). Given that leptin exerts its anorexic effect partially via CRF stimulation in

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mammals (Uehara et al., 1998), it is possible that these developmental shifts in CRF and leptin actions are functionally linked. This greater regulation of food intake by inhibitory signals during

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later tadpole stages is associated with an overall greater sensitivity to environmental conditions

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as metamorphosis approaches. Many anuran frogs exhibit plasticity in growth and developmental timing according to environmental conditions in the pond; when conditions become adverse, the

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timing of metamorphosis can be accelerated in many anuran species by activation of the

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hypothalamo-pituitary-interrenal (HPI, analog to HPA in amphibians and fish) axis (Denver,

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1997). Once metamorphic climax is attained rapid morphological changes ensue, including a reformation of the gut; anorexia is associated with this process (Crespi and Denver, 2004, Matsuda et al., 2010). An increase in the actions of anorexigenic factors in the hypothalamus at this time would allow for this cessation of feeding. Another developmental shift in the actions of neuropeptides related to food intake occurs as metamorphosis approaches. In contrast to the effects of NPY in other vertebrates and in postmetamorphic frog, icv injection of NPY inhibits food intake in prometamorphic tadpoles (Crespi and Denver, 2012, in spadefoot toads, Spea hammondii; Crespi and Kucera in Xenopus, unpublished data). This developmental reversal in the effect of NPY may be due to differential expression of NPY receptors during this life history transition, with the inhibitory actions mediated through the Y2 receptor in tadpoles. Alternatively, NPY may stimulate CRF neurons to cause anorexia and elevations in NPY may serve as a cue for HPI activation of metamorphosis. NPY also increases with cortisol levels during late gestation in sheep, and this connection has 11

ACCEPTED MANUSCRIPT been proposed to precipitate birth in response to high energy demand as would be indicated by high fetal NPY levels (Warnes et al., 1998). Developmental reversals in neuropeptide actions also have been observed in mammals (Melnick et al. 2007), and future research on NPY

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regulation of food intake through the tadpole-metamorph transition in spadefoot toads will add to

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our understanding of the molecular mechanisms that underlie the differences in ingestive

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behaviors over the life history of animals.

In contrast to the inhibitory effects of NPY in spadefoot toad tadpoles, Shimizu et al.

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(2013) found that NPY injections stimulated food intake in bullfrog tadpoles (Rana catesbeiana),

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and this effect was blocked by the Y1 receptor antagonist. These findings are similar to those of Crespi and Denver (unpublished data) that showed that a general NPY receptor antagonist

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reduced food intake in prometamorphic bullfrog tadpoles (although icv NPY injections did not

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increase food intake). Given that bullfrogs are in a different genus and remain in the tadpole

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stage for 2-3 years, while spadefoot toad tadpoles metamorphose within weeks-months, it is possible that the development of food intake controls vary phylogenetically and/or with life history within amphibians as they do across different mammals groups with different gestation times (see above).

After metamorphosis, most frogs transition from a grazing or filter-feeding feeding strategy as tadpoles to a predatory, sit-and-wait feeding strategy, and this shift is associated with differences in their neuroendocrine regulation of food intake. The earliest studies of the regulation of food intake in frogs showed that stomach distention is a primary signal for shortterm satiety after a meal, as shown by reductions in food intake on subsequent days after frogs were fed a big meal or given glass beads (reviewed in Larsen, 1992). However, neuroendocrine factors are likely involved in driving the motivation to eat (Table 1). As in tadpoles, experiments have shown that CRF has inhibitory actions on food intake in frogs both in stressed and nonstressed conditions (Crespi and Denver, 2004, 2005); however, unlike its effect in tadpoles, NPY 12

ACCEPTED MANUSCRIPT stimulates food intake, striking, and increases visual sensitivity to prey in frogs (Crespi and Denver, 2012). Carr and colleagues showed that CRF, as well as α-MSH, increase habituation to an artificial prey stimulus, another dimension of food intake behavior (see references in Table 1).

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Because frogs rely on visual cues to stimulate striking at prey, stimulation of visual circuits is

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directly tied to the regulation of ingestive behaviors, and both CRF and NPY are important

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factors that regulate excitation of optic tectum via pre-tectal circuits (Carr et al., 2013; Ewert et al., 2001; Funke and Ewert, 2006). The actions of neuropeptides involved in the regulation of

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food intake behaviors are rarely studied in optic circuits in other groups of animals, but future

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research of the actions of orexigenic or anorexigenic peptides in these brain regions could yield

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interesting insights into the neurological basis of visual-stimulation of ingestive behaviors.

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Fishes

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The most information about the development of food intake regulation across early life stages in fishes can be found in salmonid fishes. In Atlantic salmon, which has an anadromous life cycle, food intake regulation varies across early life history stages in association with differences in stress responsiveness and growth. A study by Pankhurst et al. (2007) demonstrated that food intake is not interrupted by handling stress during the parr stage just prior to smoltification (the switch from freshwater to salt water). By contrast, fish in the smolt stage show a modest inhibition to food intake, and fish in the post-smolts showed the greatest inhibition of food intake (Pankhurst et al., 2007). These changes in food intake paralleled the responsiveness of the HPI axis, as post-smolt fish show the greatest increase in cortisol after 1 hr acute confinement stress and parr fish exibit the least. Cortisol response to acute stressors also was blunted during the first few weeks of larval development in rainbow trout (Oncorhynchus mykiss, Barry et al., 1995). This lack of sensitivity to environmental stress is similar to the postnatal non-responsive period associated with the rodent pups during the suckling stage and 13

ACCEPTED MANUSCRIPT immediate post-hatching period in birds (as described above), and may be an adaptation allowing for maximal growth during this life history stage and survival during the subsequent transition from fresh to salt water during smoltification.

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Similar to the anorexia exhibited by anuran tadpoles as they reach metamorphic climax,

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anadromous fish undergo a period of anorexia prior to smoltification. Depending on the species,

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food intake is reduced for up to 30 days upon exposure to salt water (e.g., Arctic charr, steelhead trout, Atlantic salmon; Pankhurst et al., 2007; Pirhonen, et al., 2003). This reduction in food

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intake could be specifically associated with the physiological changes that occur in response to

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the increase in salinity experienced during this life history stage (Pankhurst et al., 2007). As fish go into smoltification, endocrine factors, such as growth hormone, insulin-like growth factor and

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cortisol, are elevated to stimulate the preparatory development of seawater tolerance in

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osmoregulatory tissues (McCormick et al., 1998). It seems that an activation of the

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neuroendocrine stress axis is often associated with morphological and physiological changes involved in early life history transitions (see Crespi et al., 2013), which through elevated CRF secretion or chronic glucocorticoid secretion causes reduced food intake during these transitions.

Summary

Although there is great variation in life histories among the animal groups described above, we see a generalized pattern in the development of neuroendocrine regulators of food intake (Fig. 1). In each of these animal groups, there is a period after birth in which growth rate is maximized by delays in both the expression or reception of inhibitory neuropeptides and the formation of food intake circuits in the hypothalamus and brainstem. During this “feeding drive” stage, gastric filling appears to be the dominant regulator of meal size and frequency overriding a drive to eat. In addition, animals maximize growth rate during this time via a reduction in sensitivity to environmental stimuli that would normally inhibit food intake in other life history 14

ACCEPTED MANUSCRIPT stages (e.g., non-responsive neonatal period in rats, parr stage in salmon, premetamorphic period

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in anuran tadpoles).

Effects of the environment during development of food intake controls

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While there are phylogenetically determined differences in the development of food intake

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behaviors across vertebrate groups, likely the result of selection on growth rates at different stages of development within the life history of the animal (see Kingsolver and Gomulkiewicz,

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2003), the environment experienced during early life stages can alter the development of food

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intake controls (Fig. 2). Both correlative and experimental studies in humans, animal models, and wildlife have shown that variation in environment conditions experienced during oocyte

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development or during early post-natal/hatching development can predispose individuals toward

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different patterns in food intake during later life stages. Variation in factors such as food

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availability, hypoxia, clutch size, density, and maternal care during early developmental stages across species have been shown to affect food intake, as well as anxiety-related behaviors, growth, glucose regulation, and predispositions to late-onset diseases such as type II diabetes and obesity (reviewed in Crespi and Warne, 2013; Khulan and Drake, 2012; Koletzko et al., 2011; Spencer, 2013).

Developmental plasticity in food intake behaviors has been shown to result from environmentally induced alterations in the development of hypothalamic circuitry, such that homeostatic regulation of food intake functions differently throughout life (Grayson et al., 2006) But because the timing of hypothalamic maturation varies across species, the critical periods during which the environment will have the greatest effects on food intake also varies across species (see Fig. 2). In rodents, conditions in utero and during the neonatal period are important, as variation in nutrition, parental care and sibling interactions have been shown to affect food intake behaviors later in life (Jones and Friedman, 1982; Levine, 2002; Meaney, 2001). For 15

ACCEPTED MANUSCRIPT example, offspring of diabetic and hyperglycemic mothers often show hyperphagia and increased weight gain associated with more neurons expressing orexigenic neuropeptides such as NPY and ArGP in the ventromedial hypothalamus and ARC that suppress anorexigenic α-MSH neurons

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(Franke et al., 2005), although maternal food restriction during pregnancy could also cause

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hyperphagia in offspring (Jones and Friedman, 1982).

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In animals with long gestation periods, environmental conditions experienced during late gestation can have significant effects on the development of food intake control centers in the

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brain. In humans and sheep, babies experiencing intrauterine growth retardation (IUGR) or that

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were small for gestational age (which can be caused by either maternal obesity or undernutrition) are more likely to become obese later in life, in part due to hyperphagia (resulting in catch-up

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growth) during the neonatal period (Cianfarani et al., 2002; Li et al., 2013; Edwards and

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McMillen, 2002). There is still debate as to whether IUGR or the post-natal catch-up growth is

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more important in establishing a hyperphagic phenotype throughout life; but in general, these trajectories of nutrient intake and growth are thought to enhance survival during early life history stages at the cost of a higher probability of the onset of later-life obesity and metabolic disease (Hales and Barker, 1992).

In amphibians, environmental conditions during the larval stage (e.g., high conspecific density, low food resources) have been shown to affect post-metamorphic food intake behaviors associated with compensatory growth (Hu et al., 2008; Morey and Reznick, 2001). In birds, the environmental conditions of parents prior to egg laying and during nesting have been shown to affect food intake displayed by hatchlings (Hayward and Wingfield, 2004; Henriksen et al., 2011). For example, high conspecific density (Bentz et al., 2013) and reduced food availability (Kitaysky et al., 2001). It is clear that across such phylogenetic diversity, the developmental plasticity in food intake behaviors is a common feature in vertebrates that has important physiological, ecological and evolutionary implications (Monaghan, 2008). 16

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Endocrine mediators of developmental plasticity in food intake The organizing effects of hormones, both developing offspring and in mothers, have been linked

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to the plasticity of food intake phenotypes that vary across environmental conditions. Studies

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initially conducted in mammals have shown that elevated levels of glucocorticoids in response to

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adverse environmental conditions during early developmental stages mediate these long-term effects on phenotype (Khulan and Drake, 2012; Seckl and Meaney, 2004; Spencer, 2013).

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Glucocorticoid-mediated developmental programming is also seen in birds and frogs, suggesting

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that this form of programming is an evolutionarily conserved mechanism of phenotypic plasticity across vertebrates (Hayward and Wingfield, 2004; Hu et al., 2008; Spencer and Verhulst, 2007;

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Spencer et al., 2009).

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An example of how exposure to corticosteroids during early development can affect later-

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life behavior and health is illustrated by the influence of reduced resources (i.e., maternal malnutrition) during fetal/larval stages on food intake behavior. In mammals, maternal nutritional restriction causes increases in basal CRF content in the PVN and circulating glucocorticoid concentration of the fetus/neonate, reduced glucocorticoid receptor-mediated negative feedback, and and is often associated with hyperphagia and ‘‘catch-up growth’’ (Cianfarani et al., 2002; Vickers et al., 2000). Although there are many factors associated with catch-up growth, if pre- or neonatal stress programs basal plasma glucocorticoid concentration to a higher homeostatic set point, then daily food intake is expected to be higher in these individuals given the orexigenic actions of glucocorticoids (Dallman et al., 2004). Interestingly, the same long-term effects of nutrient restriction during early life can be seen in diverse taxa including amphibians: reduced food availability or high conspecific density in the tadpole stage is associated with increased food intake, compensatory growth, and elevated circulating

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ACCEPTED MANUSCRIPT glucocorticoid levels in juvenile frogs, particularly when in high food conditions (Morey and Reznick, 2001; Hu et al., 2008). By contrast, several studies have shown that elevations in glucocorticoids experienced

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during embryonic development reduce food intake and growth later in life. In yellow-legged

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gulls, Rubolini et al. (2005) showed that offspring hatching from eggs that were treated with

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corticosterone showed reduced begging and calling behavior of nestlings, although body sizes did not vary between treated and the control groups. Hayward and Wingfield (2004) showed that

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maternal implantation with corticosterone resulted in eggs with higher circulating corticosterone

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levels, which was associated with slower growth of hatchlings (although food intake behavior was not measured in this study).

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In wood frogs, Crespi and Warne (2013) showed that the post-metamorphic effects of

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precocial elevations in corticosteorne at the end of the larval period depended on food resources

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available to tadpoles. When tadpoles are reared in high food environments, early pond drying caused animals to metamorphose at a smaller size, but they caught-up in body size to those not experiencing pond drying by 10 weeks after metamorphosis. By contrast, when tadpoles were reared in low food environments, early pond drying also caused a reduction in body size, but animals had slower growth after metamorphosis, and a blunted glucocorticoid response to handling stress at 10 weeks. This result and others suggest that glucocorticoid-mediated longterm effects of early life stress depend on the severity of the stressor in context with the overall condition of the animal. Another hormone that more recently has been hypothesized to have organizational effects during development is leptin, although much less is known about the developmental effects of leptin during early life (reviewed in Granado et al. 2012; Vickers and Sloboda, 2012). In rodent and sheep models, energy balance homeostasis and metabolism disorders associated with intrauterine growth retardation (IUGR), or other causes of leptin deficiency during early life, can 18

ACCEPTED MANUSCRIPT be at least partially reversed with leptin treatment during the neonatal period, but not at any other period (Attig et al., 2008; Bouret et al., 2004). There is evidence that the rise in leptin levels during late-gestation or towards the end of the suckling period allows for proper development of

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neuronal projections from the ARC to other hypothalamic nuclei involved in the regulation of

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food intake, including NPY, ArRP, and proopiomelanocortin neurons (Simerly 2005). In

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addition, the timing and size of this leptin surge can vary with maternal nutrition, and this variance has been associated with differential onset of leptin resistance later in life (Yura et al.,

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2005). Much of this work has been done in rodent models, so much more research is needed to

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clarify leptin’s specific roles in developmental programming, including whether it mediates epigenetic changes in genes transcription (e.g., changes are DNA methylation and histone

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modification) that could affect later life physiological function (see Gluckman et al., 2007).

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Interestingly, glucocorticoids and leptin may have opposing actions during early

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development (Spencer, 2013). For example, elevation in glucocorticoids caused by prenatally experienced stressors, such as undernutitrion or hypoxia, induces apoptosis in the brain, reduces synaptic connectivity and transmission of neurons (Fuxe et al., 1996; Khulan and Drake, 2012; Levy and Tasker, 2012), and alters epigenetic regulation of gene expression (Szyf et al., 2005; Weaver et al., 2005; Harris and Seckl 2011). Leptin, which circulates at greater concentrations when animals are in good nutritional condition, has been shown to rescue cells from apoptosis (Folch et al., 2012; Takahashi et al., 1999; Shin et al., 2009; Zhang et al., 2012) and enhance dendritic morphology or synapse formation (Harvey et al., 2007) in the face of stress. The antagonism between leptin and glucocorticoids appears to be driven by indirect interactions of downstream signaling effects of these hormones on target cells, although there are studies that show inhibitory effects of leptin on the HPA axis at the level of brain (Heiman et al., 1997) and adrenal gland (Pralong et al., 1998). Although much more research is needed to understand the interactions between leptin and glucocorticoids, these findings support the hypothesis variation 19

ACCEPTED MANUSCRIPT in circulating leptin levels during stressful events could mediate condition-dependent effects of early life stress.

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Variation in sex steroid hormone exposure during early development may also affect food intake patterns in offspring by altering the composition, morphology and function of neural

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networks in the brain (e.g., Culbert et al., 2013; Klump et al., 2006; Nohara et al., 2011;

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Sheppard et al., 2011). Just as these hormones organize developmental processes in the brain that

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lead to post-natally expressed sex-specific behaviors, variation in the exposure of these hormones during critical windows of development can cause permanent changes in the limbic-

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hypothalamic circuits associated with food intake within and between sexes (Simerly, 2005). Similar to the effects of excess in utero exposure to glucocorticoids and leptin described above,

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elevations in testosterone exposure during fetal development results in IUGR and post-natal

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catch-up growth, which is associated with altered insulin and insulin-like growth factor

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physiology (Crespi et al., 2006); however, increased food intake during the catch-up growth stage has not been reported.

In altricial birds, elevations in testosterone during embryonic development, resulting from elevated testosterone concentrations in eggs (either from maternal transfer or experimental manipulations) increases in food intake by enhancing the competitive ability of nestlings to acquire resources from parents in birds. Schwabl (1996) was the first to show that variation in maternal allocation of testosterone in the yolk of eggs enhances growth in canary hatchlings primarily by enhancing the frequency of begging behaviors relative to other hatchlings in the nest, and this enhanced post-natal growth through fledging. Subsequent studies in several species have shown similar effects of elevated in ovo maternal transfer of testosterone on nestling behavior, growth, and survival (reviewed in Groothuis et al., 2005; Boncoraglio et al., 2006; Goodship and Buchanon, 2006). Furthermore, increased maternal transfer of testosterone to eggs

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ACCEPTED MANUSCRIPT is associated with elevations circulating testosterone levels in nestlings displaying increased begging and growth (Bentz et al., 2013; Hinde et al., 2009). Given that these high-T nestlings attain larger body sizes and greater probability of survival through fledging, the maternal transfer

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of testosterone to offspring is considered to be adaptive, although fitness trade-offs have been

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reported (Groothuis et al., 2005; Kilner, 2001). Relevant to the topic of this paper, however, it is

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not known the long-term effects of elevated testosterone on feeding behaviors per se, although increases in aggression, territoriality and social dominance have been shown to persist (reviewed

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in Bentz et al., 2013).

Epigenetic modifications and developmental plasticity

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Studies primarily in rodents have shown that developmental plasticity in feeding behavior

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phenotypes result from epigenetic modifications (primarily DNA methylation) in gene

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expression. Early work in this area showed that differences in maternal behaviors (e.g., licking, grooming of young) could affect methylation patterns of offspring in rats (Weaver et al., 2004), thus environmental conditions during early development could alter behaviors and physiology throughout life via epigenetic mechanisms. These maternally induced epigenetic effects in offspring are mediated by elevations in glucocorticoids caused by reduced maternal behaviors (Weaver, 2009). Subsequently, other factors such as maternal diet during pregnancy have been shown to significantly alter the epigenome of the fetus, creating a predisposition for certain metabolic profiles in the offspring that can be further altered by postnatal feeding behavior (Canani et al., 2011; Drummond and Gibney, 2013; Martinez et al., 2012). In mammalian systems, highfat/carbohydrate diets have the ability to modify placental nutrient transfer and gene expression, resulting in differential phenotypes in the offspring (Sferruzzi-Perri et al., 2013). Rats that experience a prenatal low-protein diet show reduced food intake behavior, but demonstrate 21

ACCEPTED MANUSCRIPT dramatic growth in adipose tissue when fed a postnatal high-fat diet. These changes were associated with increased methylation of insulin-like growth factor 2 (IGF-2) in adipose tissue (Claycombe et al., 2013). The fetuses of Japanese macaques fed high-fat diets demonstrated a

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three-fold increase in liver triglycerides and significant acetylation of H3 histones in hepatic

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tissue (Aagard-Tillery et al., 2008). These findings are supported in human systems; Drake et al.

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(2012) analyzed DNA methylation of key metabolic genes (associated with glucocorticoid actions) in the adult children of women who were involved in an unbalanced dietary study during

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pregnancy. Methylation at specific sites regulating 11ß-hydroxysteroid dehydrogenase 2,

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glucocorticoid receptor, and IGF-2 were associated with increased adult adiposity and elevated blood pressure in these offspring (Drake et al., 2012).

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While epigenetic regulation of specific food intake behaviors has yet to be well

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described, alterations in the chromatin structure of offspring resulting from variation in adult diet

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have been documented. The hypothalamus and ventral tegmental area of mice with post-weaning diet-induced obesity show altered gene expression and methylation patterns within the dopamine reward pathway, demonstrating the ability of certain diets to alter food intake behavior (Vucetic et al., 2012). In comparisons of obese mice fed either high-fat or high-carbohydrate diets, subjects receiving higher carbohydrates showed increased methylation of the stearoyl-CoA gene, which was correlated with increased expression of leptin levels and decreased levels of ghrelin (Schwenk et al., 2013). Some diet-induced epigenetic modifications appear to be labile, as the diet in later life stages could reverse such modification. Rats raised on an obseogenic diet show differential methylation of leptin promoters, but these effects reverted to normal levels after 10 weeks of feeding on a standard diet (Uriarte et al., 2013). Supplementation to poor diets can also alter methylation patterns. For example, rats fed high-fat-sucrose diets demonstrated differential methylation of fatty acid synthase promoter in the liver and high levels of triglycerides; however,

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ACCEPTED MANUSCRIPT supplementation of the same diet with methyl donors (such as folate) can modify methylation to a more normal state and reduce hepatic triglyceride accumulation (Cordero et al., 2012). More recently, the diet of parents, particularly obesogenic diets, have been shown to alter

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epigenetic signatures of the parental germ line such that the effects of diets can persist through

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generations. A recent study in rats found metabolic effects in the offspring of obese fathers

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related to altered methylation and microRNA expression in the F0 offspring’s germ line (Fullston et al., 2013). In addition, transgenerational epigenetic modifications in offspring through the F3

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generation have been caused by exposure to endocrine disruptors, such as the pro-estrogenic

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compounds diethylstilbestrol (DES, reviewed in Rosenfeld 2010), bisphenol A (Dolinoy et al. 2007), and genistein (Dolinoy et al. 2006), as well as the anti-androgenic vinclozolin (Skinner et

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al., 2012; 2013). In these studies, maternal or paternal exposure to these compounds increases

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risk of reproductive disorders and cancers, altered mating preference and social recognition

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(Crews et al., 2007; Wolstenholme et al., 2013), as well as stress responsiveness and anxiety related behaviors (Skinner et al. 2008; Crews et al. 2012). Whether these transgenerational effects can be mediated by exposure to different environmental conditions across generations is still in question, and in some cases epigenetic phentoypes in offspring have been reversed by dietary supplements of folic acid or genestein (Dolinoy et al. 2007). An element of complexity associated with studies of developmental plasticity of food intake behaviors is that there are significant sex differences in plastic phenotypes, which seems to be more the rule than the exception. Sex-specific effects of environmental conditions or exposures to hormones on growth and feeding behaviors have been reported in mammals (Jones and Friedman, 1982; Simerly, 2005; Spencer, 2013; Schneider et al. 2014) birds, (Hayward et al., 2006; Sockman et al. 2008; de Coster et al., 2011), and amphibians (Morey and Reznick, 2001). The same holds for studies examining environmental epigenetic modifications (e.g., Culbert et al., 2013; Fullston et al., 2013). Given that there could be interactive actions glucocorticoids and 23

ACCEPTED MANUSCRIPT leptin with sex steroids during early developmental periods when sexual differentiation is patterned, it is not surprising that effects of early environmental conditions on food intake behaviors vary with sex (Spencer, 2013; Schneider et al. 2014). While epigenetic modification of

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gene expression and brain development is associated with sex-specific effects on behavior (e.g.,

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Crews et al., 2007; Wolstenholme et al., 2012), many of the developmental mechanisms are not

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understood, and the variance in the behavioral effects do not seem consistent and cannot be predicted at this time. Understanding these mechanisms not only will advance our fundamental

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knowledge about the ways in which the environment shapes behaviors, but it will also help us to

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predict significant effects of environmental change on population and evolutionary dynamics.

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Future research directions: Integration of development, behavior, ecology and evolution

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Because the study of the developmental origins of food intake behaviors has been studied

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in multiple vertebrate groups, cross-group comparisons of processes add to a greater understanding of the common features that exist in the development of behaviors in general. Within many groups, however, the number of animals studied is limited, and there is a greater diversity of life histories in which the development of food intake behaviors could be studied. Furthermore, most of the studies showing developmental plasticity in food intake controls reviewed thus far have been conducted within the laboratory or in controlled settings, which is often necessary to a) to minimize variance in environments when first identifying developmental mechanisms associated with food intake behaviors, and b) to conduct experiments testing causal links between environmental conditions and behavioral phenotypes. However, we have little understanding about the nature of developmental plasticity in food intake behaviors or their endocrine or epigenetic bases in the complexity of natural populations (see Ledon-Rettig, 2013). Studying environmental effects on the development of offspring food intake behaviors in the natural context allows for complete integration of ecology, developmental biology, behavior, 24

ACCEPTED MANUSCRIPT and evolution. In an extensive study of red squirrels, which cycle in population density with the fluctuation in availability of food resources, offspring produced by females in high density conditions showed increased growth rates compared with those of mothers in low densities with

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no access to additional resources (Dantzer et al., 2013). This increase in growth rate was

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associated with elevated fecal glucocorticoids in mothers and offspring (also produced when

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pups were fed glucocorticoid supplements (Dantzer et al., 2013). These authors argue that this environment-determined maternal programming of offspring growth is an adaptive adjustment to

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anticipated conspecific density conditions that typically cycle with availability of food resources

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(white spruce seeds).

In populations of snowshoe hares that undergo 10-year episodic cycles that vary with

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predation threat, maternal and offspring glucocorticoid levels are elevated in years of higher

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predation, and offspring experiencing these elevations in glucocorticoids had decreased fecal

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glucocorticoid concentrations but greater HPA responsiveness (Sheriff et al., 2010). These authors suggest that this transgenerational effect on HPA axis is associated with reduced reproductive rates observed in these offspring of mothers from the peak in predation levels that contribute to predator-prey population cycling. Note that the argument for the adaptive nature of these maternally-transmitted phenotypic effects on offspring is that these population cycles are predictable, and therefore selection can act to increase patterns in developmental plasticity that optimize fitness in these species. Many more questions exist in both the red squirrel and snowshoe hare populations, including how this transgenerational plasticity specifically relates to offspring behaviors (e.g., do behaviors resulting from glucocorticoid programming allow offspring to more efficiently forage for food in high density conditions or show greater abilities to evade predators). Given the depth of knowledge about the ecology of this system, hypotheses about the adaptive nature of developmental plasticity of behaviors can be tested in these systems.

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ACCEPTED MANUSCRIPT These systems are ideal to test the basic hypothesis promoted by laboratory studies: dietor endocrine-mediated epigenetic modifications resulting from environmental stimuli cause developmental plasticity of offspring physiology and behaviors. We already know that

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environmentally induced elevations in glucocorticoids or testosterone during pregnancy in

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mammals, during egg formation in birds, and during the larval period in amphibians, alter

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offspring behaviors and physiology (as described above), but the epigenetic mechanisms associated with these effects are largely not known. With increased sequencing of genomes in

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non-model organisms and molecular approaches to uncovering epigenetic patterns, future

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research will likely reveal additional patterns of environmentally induced epigenetic inheritance of phenotypes, including ingestive behaviors (see Ledon-Rettig 2013; Schrey et al., 2013).

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A common evolutionary framework within which developmental plasticity is studied in

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both biomedical and ecological contexts is the “thrifty phenotype hypothesis,” which is an

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ultimate explanation used to describe either 1) adaptive effects of maternal diet on offspring food intake behaviors and resource allocation, or 2) pathological effects of post-natal patterns of diet and food intake (see Wells, 2009 for review). According to this hypothesis, the fetus should develop a metabolic physiological system that aligns with the amount of resources forecasted by its maternal nutrient supply for its post-natal environment. In times of low or unpredictable food availability, for example, offspring should opportunistically acquire as much food as possible, and store excess resources as fat that can be tapped into when resources are scarce. The thrifty phenotype hypothesis has been invoked to explain the adaptive nature of post-natal catch-up growth after intrauterine nutrient restriction. But because the adaptive nature of this phenotype requires a match between maternal and neonatal environments, it also has been used to explain the higher probability of obesity and metabolic disorders later in life when IUGR individuals experience an abundance of food after birth (but see critique in Speakman, 2008; Wells, 2007; 2009). However, other models exist that predict long-term responses to early life stress and 26

ACCEPTED MANUSCRIPT don’t require matching of parental and offspring environments, such as the “silver spoon” (Monaghan 2008) or “best of bad lot” hypotheses (Whitehead, 1994), which may be more parsimonious since the correlation between parental and offspring environments is often loosely

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applied or other hypotheses are not explicitly tested.

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In another perspective, the development of food intake behaviors can be viewed within

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the development of personalities (or behavioral syndromes, Sih et al., 2004), defined as suites of correlated behaviors that are consistent across time and contexts that develop throughout the life

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of the animal depending on experience (Stamps and Groothuis, 2010). In this view, food intake

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behaviors are associated with other behavioral phenotypes such as aggression, exploratory activity, or anxiousness, all of which should be considered simultaneously when assessing the

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adaptive nature of behavioral plasticity. These authors emphasize that personalities can change

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through space and time due to variation in experiences, and the ongoing nature of this

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developmental process is necessary to consider when examining variation in animal personalities across ecological and evolutionary time scales (Stamps and Groothuis, 2010). This form of developmental plasticity can be adaptive, for example, if the variation created allows individuals in the population to partition space or differentially utilize resources in a way that enhances individual fitness.

Whichever the context or the specific mechanisms involved, the accumulation of studies have shown significant developmental plasticity in food intake behaviors resulting from environmental variation during early development when the neuroendocrine controls of food intake are first established. The extent to which the neuroendocrine controls of food intake behavior are ecologically flexible may relate to the evolutionary capacity of vertebrates to facilitate adaptive divergence in body sizes and diet specializations (West-Eberhard, 1989). For example, in the sexually dimorphic house finch, the larger size of adult males relative to females is due to faster growth rates in males during the nestling period; thus, selection on adult body 27

ACCEPTED MANUSCRIPT size manifests in adaptations relating to the regulation of food intake behaviors during early life (Badyeav et al., 2001, 2002; Isaaksson et al., 2010). Similarly, changes in the sensitivity of the hypothalamus to anorexigenic factors (e.g., α,β-MSH) during the post-hatching stage have been

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associated with selection for larger body size between broiler and layer chicken strain (Furuse,

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2007; Honda et al. 2012). Further examination of developmental plasticity, local adaptation of

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food intake behaviors, and growth within and between populations and species will contribute

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significantly to an integrated understanding of the ecology and evolution of behavior in general.

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Acknowledgements

We thank Jill Schneider for the invitation to contribute this review for this special issue, and the

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suggestions of the anonymous reviewers who greatly improved the manuscript. Work reported in

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this review was funded by NSF IOS 0818212 to EJ Crespi.

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Whiteman, H.H. 1994. Evolution of facultative paedomorphosis in salamanders. Quart. Rev. Biol. 69, 205-221. Wolstenholme, J.T., Goldsby, J.A., Rissman, E.F. 2013. Transgenerational effects of prenatal bisphenol A on social recognition. Horm. Behav. Nov;64, 833-839. Yura S., Itoh, H., Sagawa, N., Yamamoto, H., Masuzaki, H., Nakao, K., Kawamura, M., Takemura, M., Kakui, K., Ogawa, Y., Fugii, S. 2005. Role of premature leptin surge in obesity resulting from intrauterine undernutrition. Cell Metab. 1, 371-378. Zhang, J.Y. Jr, Si, Y.L., Liao, J., Yan, G.T., Deng, Z.H., Xue, H., Wang, L.H., Zhang, K. 2012. Leptin administration alleviates ischemic brain injury in mice by reducing oxidative stress and subsequent neuronal apoptosis. J Trauma Acute Care Surg. 72, 982-91.

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Figure 1. Schematic representation of the two generalized stages of food intake during early development in vertebrates. During early life stages (e.g., neonatal mammals, premetamorphic tadpoles), growth is maximized to rapidly attain a critical body size for survival, thus this stage is characterized by a feeding drive. During the switch to homeostatic regulation of food intake (e.g., weaning, prometmorphic stage of anuran tadpoles), growth rate tapers off as hypothalamic satiety and hunger centers mature and food intake is more highly influenced by environmental or social cues during later developmental stages. (Illustrations by M.K. Unkefer)

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Figure 2. Environmental conditions experienced during early development can alter food intake behaviors throughout life. Animals have different critical windows of exposure, depending on when maturation of hypothalamic and brainstem food intake centers occurs; but it is clear that environmental conditions experienced by individuals during these early life stages can alter levels of organizing hormones, which in turn can alter the development of neuroanatomy to produce permanent food intake phenotypes and predispositions throughout life. Neuropeptide Y (NPY), agouti-related peptide (AgRP), α-melanocyte-stimulating hormone (αMSH), corticotropin-releasing factor (CRF). (Illustrations by M.K. Unkefer)

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Figure 1

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Figure 2

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Graphical abstract

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Prometamorphic

Location

Detritivore/Omnivore

Various nuclei in diencephalon including preoptic area, dorsal & ventral thalamus

Higher levels in diencephalon including preoptic area, dorsal & ventral thalamus

Pre-tectal thalamus, ventral hypothalamus, optic tectum7

• Stimulates food intake

• Regulates food intake

• Stimulates food intake

Xenopus laevis1, Rana esculenta2, R. arenarum3

Spea hammondii5, X. laevis6

R. catesbeiana4

• Inhibits food intake S. hammondii5

• Stimulates food intake R. catesbeiana4

Posterior telencephalon

Activity

CORT

Activity

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Location

Fibers in median eminence R. catesbeiana

• Stress-induced anorexia14

• Stress-induced reduction of growth rate R. pipiens , Scaphiopus Couchii20, S. bombifrons20 19

Leptin

Activity

R. esculenta10

R. esculenta10

Activity

CRF

Anterior pre-optic area

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• No effect on foraging behavior S. hammondii21

Predator

X. laevis1, R. esculenta2, R. arenarum 3

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Table 1. Development of evolutionarily conserved neuroendocrine regulators of food intake in anurans, with neuroanatomical and behaviors associated with each factor across early life history stages. NPY = neuropeptide Y, αMSH = alpha melanocyte-stimulating hormone, CRF = corticotropin-releasing factor, CORT = corticosterone.

S. hammondii5, X. laevis6

• Inhibits visuomotor circuits in optic tectum Bombina orientalis8,9

Pre-optic area, pre-tectum, optic tectum & ventral telecephalon11 • Reduced orienting behavior Bufo cognitus12, B speciosus13

Increased fiber density in median eminence

Pre-optic area, ventral hypothalamus, optic tectum

• Regulation of food intake

• Inhibits food intake

R. catesbeiana14

S. hammondii15

• Stress-induced anorexia

S. hammondii15, R. catesbeiana16

S. hammondii17, X. laevis5, R. catesbeiana16, B. speciosus13

• Inhibits visual prey cues B. speciosus

• Stress-induced anorexia X. laevis6, S. hammondii15, R. perezi18

• Regulates food intake S. hammondii15

• Increases foraging behavior S. hammondii15

• Inhibits foraging behavior S. hammondii15

• Repeated injections lead to weight loss X. laevis22

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• Exposure increased meal size X. laevis6

• Reduced orienting behavior B. marinus12

• Inhibits foraging behavior21

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Highlights: • Developmental patterns of food intake regulation were compared across vertebrates

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• Vertebrates experience “feeding drive” during early development

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• Development of food intake controls are highly plastic

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• Feeding drive results from delayed hypothalamic sensitivity to anorexigenic factors

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• Steroid hormones are conserved mediators of developmental plasticity in food intake

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