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Stress and prefrontal cortical plasticity in the developing brain
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Cognitive Development
Stress and prefrontal cortical plasticity in the developing brain Bryan Kolb a,b,∗ , Allonna Harker a , Richelle Mychasiuk c , Silvana R. de Melo d , Robbin Gibb a a b c d
Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K 3M4 Canada Canadian Institute for Advanced Research, 180 Dundas St W, Toronto, ON, M5G 1Z8 Canada Alberta Children’s Hospital Research Institute, HMRB233,3330 Hospital Drive, Calgary, AB, T2N 4N1, Canada Department of C. Morfológicas – DCM, University of Estadual de Maringá, Maringá, Paraná, Brazil
a r t i c l e
i n f o
Article history: Received 30 April 2016 Received in revised form 31 October 2016 Accepted 5 January 2017 Available online xxx Keywords: Prefrontal cortex Cerebral development Stress Brain plasticity Epigenetics
a b s t r a c t There is a large literature showing that stress in adulthood induces the production of stress hormones leading to a modulation of brain function, which is accomplished, in part, by changing the structure of neurons, especially in the hippocampus and prefrontal cortex, and these changes are correlated with behavioral change. Here we review the effects of preconception, gestational, and bystander gestational stress, as well as maternal separation on prefrontal cortex and behavioral development, largely in animal models. The general conclusion is that developmental stressors modify the organization of the prefrontal cortex in adulthood with results varying according to age at stress and region measured. It is likely that all of these stress effects are mediated by (re)programming of later gene activity in the brains of the offspring. © 2017 Elsevier Inc. All rights reserved.
Contents 1.
2. 3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.1. Organization of the prefrontal cortex of rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.2. What are appropriate animal models of stress? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.3. How is PFC plasticity measured? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Effects of stress on adult PFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Effects of stress on the developing prefrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Gestational stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. Bystander gestational stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. Maternal separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.4. Preconception stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Summary of the effects of developmental stress on the PFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author at: Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K 3M4, Canada. E-mail address: [email protected] (B. Kolb). http://dx.doi.org/10.1016/j.cogdev.2017.01.001 0885-2014/© 2017 Elsevier Inc. All rights reserved.
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Fig. 1. The prefrontal cortex of the rat. Serial sections through a rat brain showing different cytoarchitectonic regions (Zilles, 1985, nomenclature). Dotted areas receive projections from MD; gray areas receive projections from the amygdala. Abbreviations: Cg1, cingulate area 1; Cg3, cingulate area 3; Fr2, frontal area 2 IL, infralimbic; AID, agranular insular; MO, medial orbital; PL, prelimbic; VLO, ventral lateral orbital; VO, ventral orbital, LO, lateral orbital. (Modified and adapted from Reep, 1984).
1. Introduction The modern idea that stress changes the body, including the brain, can be traced to Hans Selye in the 1930s. Selye, a physician, noticed that all of his patients, regardless of what they were hospitalized with, looked sick. He inferred that they must all be under physical stress that resulted in the release of stress hormones. This observation led him to search for a stress-processing mechanism, eventually leading to the concept of the hypothalamic-pituitary-adrenal system (HPA axis) (e.g., Harris, 1970; Selye, 1950, 1978). Although Selye’s focus was on physiological stressors it became clear that psychological factors could also stimulate the HPA axis to affect the body and brain. Further, over the past 60 years it has become evident that the effects of stress are not only dependent upon the HPA axis but involves a two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms (McEwen, 2006). One of the effects of stress hormones is a modulation of brain function, which is accomplished, in part, by changing the structure of neurons, especially in the hippocampus (CA3 and the dentate gyrus), amygdala, and prefrontal cortex (Chattarji, Tomar, Suvrathan, Ghosh, & Mohammed, 2015). This review provides an overview of the effects of stress on the developing prefrontal cortex, with an emphasis on the effects in laboratory rats, which is the most-studied model to date. Understanding the effects of stress on the PFC has become increasingly interesting owing to its vulnerability to stress and the realization that the PFC has a significant role in many neuropsychiatric disorders (McEwen & Morrison, 2013).
1.1. Organization of the prefrontal cortex of rodents In the 1960s the prefrontal cortex (PFC), which was often called the frontal granular cortex, was defined by both the frontal granular cell layer and the connections it made with the dorsomedial nucleus of the thalamus (MD) (Warren & Akert, 1964). Although these two definitions define a large region of overlap, the MD-projection cortex extends well beyond the frontal granular cortex of primates (Wise, 2008). Rodents do not have a frontal granular cortex but they do have an MDprojection area that was first described by Leonard (1969). This region does not include the frontal pole but rather includes regions along the anterior medial wall of the cerebral hemispheres as well as the ventral and lateral regions bordering the rhinal fissure (See Fig. 1). Later definitions of the rodent PFC expanded to include the connections with the amygdala and ventral tegmentum (Reep, 1984; Schoenbaum & Setlow, 2002) as well as the basal ganglia (Uylings, Groenewegen, & Kolb, 2003). The degree to which the rat and primate “prefrontal” regions are homologous has been controversial (e.g., Wise, 2008), but there are clearly areas of the rat PFC that sub-serve functions similar to those in the primate (Brown & Bowman, 2002; Kolb, 1984). For our purposes we will assume that the medial prefrontal cortex of the rat (mPFC), including anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices house many functions similar to the medial or dorsolateral regions of the primate, whereas the orbitofrontal region (OFC) including the ventral, ventral lateral, lateral orbital regions (VO, VLO, LO) and the ventral and dorsal and agranular insular regions (AID) house functions similar to the orbital region of the primate (Uylings et al., 2003). Although an extensive discussion of the behavioral functions associated with the PFC is beyond the scope of this review, it will be useful to describe the general functions of the prefrontal regions (see also Wise, 2008). At a general level the dorsolateral region of primates plays an important role in working memory, particularly as it relates to certain executive processes such as the monitoring, sequencing, and planning of behaviors, as well as directed attention to Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 2. Common models of stress in rodents. (Adapted from Chattarji et al., 2015).
objects, places, actions, and intentions. The orbital regions are involved in socio-emotional behaviors, inhibition of behaviors, associations between reward and external cues, and in certain types of olfactory and gustatory processing. Although the anatomical and functional details of the PFC must be unique in rodents and primates, they likely evolved from a common ancestor that had developed the prefrontal regions to solve common problems of all mammals (class common behaviors) and thus continue to have shared functions (Kolb, 2007). Thus, studying the effects of experience on the PFC in rodents should give us important clues to how the PFC regions in primates are also changed by experiences such as stress. 1.2. What are appropriate animal models of stress? Animal models focus on two different types of stressors, namely physical and psychological (see Chattarji et al., 2015) (see Fig. 2). Physical stress has common variations: immobilization in a bag or in a narrow tube and forced swimming in cold water. Psychological stress has many forms including predator odor, elevated platform, social defeat, living with a stressed cage mate (bystander stress), and maternal separation. In addition, some studies mix different stressors at different times to prevent (or reduce) habituation to the stressor. It is obviously difficult to compare stressors in humans to those in laboratory animals, but to the extent that both increase levels of corticosterone in rats (cortisol in humans) and activate the HPA axis, the animal models have generally been seen as good approximations to human conditions. 1.3. How is PFC plasticity measured? Neural plasticity can be measured at many levels of analysis, ranging from behavior to electrophysiologically-defined maps, to measures of neuronal morphology, and to molecular measures, such as gene expression. Most studies on the rodent PFC have focused on behavioral and morphological changes, and more recently on epigenetic changes in gene expression. Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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In adults, the largest behavioral changes have been seen in executive and motor functions although there are many other measures used in development, such as play behavior and ultrasonic vocalizations. Behavioral changes are correlated with morphological changes, both in individual neurons and circuits. It is important to emphasize that although there is a tendency to think that good experiences increase synapse numbers and poor experiences decrease synapse numbers, this is not the case. Rather, changes in synapse numbers reflect changes in neural networks and it is not uncommon for an experience such as stress to produce opposite changes in different subregions of the PFC (see below). The neurons in the PFC are largely excitatory (80–90%) and synapse on dendritic spines, while the remaining neurons are inhibitory GABAergic interneurons. Both excitatory and inhibitory neurons can be subdivided into many types but virtually nothing is known about how different subtypes differentially respond to experiences. One emerging field is related to understanding mechanisms that maintain an excitatory/inhibitory balance (E/I), which is likely central to understanding changes in neural networks (e.g., Kvitsiani et al., 2013; Yizhar et al., 2011). Most studies of neuronal morphology use some type of staining technique that makes it possible to measure the number of dendritic branches, the length of dendritic branches, and their spine density. Because most excitatory synapses are found on spines, by knowing the length of dendrites and the spine density, it is possible to estimate the number of synapses on neurons. Epigenetics refers to changes in gene expression that are not related to changes in the DNA. The genes expressed in a cell are influenced by factors within the cell and the cell’s environment. The cell’s environment determines which genes are expressed and thus how the cell functions, including its role in the nervous system. But the cell’s environment does not only include the chemicals that surround the cell within the body, but also the environment that an organism finds itself in throughout its lifespan. Thus, our experiences can influence expression of our genes. Epigenetic mechanisms can influence protein production either by blocking a gene to prevent transcription or by unlocking a gene so that it can be transcribed. Chromosomes are comprised of DNA wrapped around supporting molecules of a protein called histone, which allows many meters of DNA to be packaged in a small space. For any gene to be transcribed into messenger RNA, its DNA must be unspooled from the histones. Thus, one measure of changes in gene expression is histone modification through either methylation or acetylation. Methyl groups (CH3 ) or other molecules bind to the histones, either blocking them from opening or allowing them to unravel. Methylation can also occur in CpG islands (regions of DNA where a cytosine nucleotide is adjacent to a guanine nucleotide, separated only by a single phosphate) on the DNA that are usually located near promoter sites for genes. When methylation occurs at these sites gene transcription cannot proceed. Changes in the amount of methylation in a tissue thus can give an indirect estimate of the amount of gene expression. As a rule of thumb more methylation means fewer genes expressed whereas reduced methylation means more genes are expressed. Unfortunately, methylation levels do not tell us which genes are on or off, but methylation does provide a rough (and inexpensive) gauge as to whether there is a change in gene expression. 2. Effects of stress on adult PFC Historically, although most studies in the literature have emphasized the effect of stressful experiences on the hippocampus (HPC), there is a growing literature on the effects of adult stress on the prefrontal cortex, and the interactions between the HPC, mPFC, and OFC. Functionally, chronic stress has been associated with a multitude of cognitive, social, and physical symptoms that include deficits in emotional regulation, impaired motor function, impaired executive function including short-term memory, diminished self-regulatory behavior, and immunological impairment (e.g., Cohen, Janicki-Deverts, & Miller, 2007; McEwen, 2008; Metz, 2007; Segerstrom & Miller, 2004). It has been proposed that many of the cognitive symptoms, especially those related to cognitive functioning, are directly linked to dysfunctional connectivity between regions of the HPC, mPFC, and OFC (McEwen, 2007). Chronic stress decreases synaptic space and spine density in the mPFC, with an estimated drop of 30% of excitatory synapses but, in contrast, the pyramidal neurons in OFC show a stress-related increase in dendritic length and spine density (e.g., Liston et al., 2006; Fig. 3). The large drop in synapses in mPFC is dramatic but recovers quickly over 3 weeks in young animals, but this is not seen in older animals. It is unknown if the OFC changes persist. A few studies have looked at mPFC subregions separately and as of yet there is no consensus on the differences (Izquierdo, Wellman, & Holmes, 2006; Lin, Borders, Lundewall, & Wellman, 2015), which may be related to stress type and duration. There are also extensive epigenetic changes following chronic adult stress. Mychasiuk, Muhammad, and Kolb (2016) compared the mRNA gene expression in the mPFC, OFC, and HPC following 14 days of platform stress followed by a 14 day recovery period, and found areal differences in gene expression patterns. As in the morphological studies (Fig. 4) the mPFC and OFC exhibited contrasting effects in gene expression. Somewhat surprisingly, given that most previous studies of stress and PFC plasticity have been on the mPFC and HPC, it was the OFC that showed the most extensive changes in gene expression. Overall, this study found gene expression changes that are likely related to the changes in neuronal morphology and cognition associated with chronic stress. 3. Effects of stress on the developing prefrontal cortex Although there is a large literature showing the effects of stress on brain and behavior in adults, the role of perinatal stress is relatively unexplored. Nonetheless, is known that both gestational and infant stress predisposes individuals to a Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 3. Chronic stress in adult rats reduces dendritic length (and thus synaptic space) in the medial prefrontal cortex (left) but increases dendritic length in the orbital prefrontal cortex (right). (Based on McEwen & Morrison, 2013).
Fig. 4. Venn diagram outlining the number genes exhibiting significant expression level changes in the mPFC, OFC, and HPC for male and female exposed to chronic stress (Mychasiuk et al., 2016).
variety of maladaptive behaviors and psychopathologies. For example, prenatal stress is a risk factor in the development of schizophrenia, attention-deficit hyperactivity disorder (ADHD), depression, and drug addiction (e.g., Anda et al., 2006; Charil, Laplante, Vaillancourt, & King, 2010; Van den Bergh & Marcoen, 2004). Experimental studies with laboratory animals have confirmed these findings, with the overall result being that perinatal stress in rodents produces a range of behavioral abnormalities including an elevated and prolonged stress response, impaired learning and memory, deficits in attention, altered exploratory behavior, altered social and play behavior, and increased preference for alcohol (Weinstock, 2008). Although there are a lot of studies looking at changes in the organization of brain regions from early stress, until recently the data were focused on changes in the amygdala and hippocampus (for a review see Charil et al., 2010). Although early studies on the effects of perinatal stress tended to lump together stressors given at different times and of different types, it is becoming clear that stress during development has differing effects depending on the time period, ranging from preconception to gestation to the postnatal period (see Tables 1 and 2). We consider each time period separately. We begin with gestational stress because this is most studied model, followed by maternal separation, and then preconceptional stress.
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Table 1 Models of Developmental Stress in Laboratory Rodents. Time of Stressor
Basic Reference
Preconception Maternal Stress Preconception Paternal Stress Direct Gestational Stress Indirect Gestational Stress Maternal Separation (15 min) Maternal Separation (1–3 h) Paternal Separation
Bock et al. (2016) Mychasiuk et al. (2013) Bock et al. (2015) Mychasiuk, Gibb et al. (2011) and Mychasiuk, Ilnytskyy et al. (2011) Meaney et al. (1991) Huot, Thrivikraman, Meaney, and Plotsky (2001) Helmeke et al. (2009)
Table 2 Summary of the effects of stress on dendritic organization following gestational stress or maternal separation. Measure
GSP21
GSP110
Byst P21
MSP110
Brain weight
D
U
NA
D
CG3 Branch apical CG3 Length apical CG3 spines apical
U NS D
D U NS
NA NA NA
NS NS U
CG3 Branch basilar CG3 Length basilar CG3 spines basilar
NS NS D
NS U NS
U U U
U U U
AID Branch basilar AID Length basilar AID spines basilar
D D D
NS U U
NS U U
U U U
Proportion changed
7/10
6/10
5/6
8/10
Abbreviations: PCS, preconceptual stress; GSP21, gestational stress, Postnatal day 21 data; GSP110, gestational stress, Postnatal day 110 data; Byst P21, bystander stress, Postnatal day 21 data; prolonged maternal separation, MSP, postnatal day 110 data. NS = No significant effect; U = significant increase; D = significant decrease.
3.1. Gestational stress Maternal exposure to stressful life events during pregnancy is known to affect the cognitive skills of the offspring. These include attention difficulties, verbal and spatial working memory, as well as general cognitive development (e.g., Bergman, Sarkar, O’Connor, Modi, & Glover, 2007; Laplante et al., 2004; Plamondon et al., 2015; Tarabulsy et al., 2014). Although there is little doubt that the resultant offspring of women stressed while pregnant may suffer from significant cognitive sequelae, no studies have been able to relate the stressors to effects on specific brain regions. Recent studies of natural disasters may shed light on this. Perhaps the most extensive prospective study is on the effects of the Quebec, Canada, Ice Storm of 1998. This storm was the largest natural disaster in Canadian history as power was knocked out for up to 6 weeks, affecting approximately 2 million people, during the coldest month of the year. Many women were pregnant at different stages of gestation and had varying levels of hardship ranging from severe to none. There are now several prospective studies on the children of a large cohort of women beginning shortly after the storm and still continuing today. Overall, the results show that the offspring of the women exposed to high levels of objective stress show significant developmental delays in language, cognition (IQ), motor skills, and play (e.g., King, Dancause, Turcotte-Tremblay, Veru, & Laplante, 2012). This is correlated with widespread effects on DNA methylation across the entire genome of their children, detectable during adolescence (Cao-Lei et al., 2015). There is an ongoing study of structural MRIs of these children, although no results are yet available. Nonetheless, when the MRI data are available this study promises to provide clues of how gestational stress affects brain, especially hippocampus, amygdala, and prefrontal cortex, and the relationship to behavior. One additional study is relevant here. Buss, Davis, Muftuler, Head, & Sandman (2010) examined the effects of gestational anxiety (measured at 19, 25, and 31 weeks of gestation) on the structural MRIs of the offspring’s brains at 6–9 years of age. The results showed a reduction in gray matter density in prefrontal, premotor, medial temporal, lateral temporal, the fusiform gyrus, and cerebellum of children whose mothers experienced pregnancy anxiety at 19 but not 25 or 31 weeks of gestation. At about 19 weeks of gestation, neurogenesis is nearly complete but neuronal migration is at its peak and neuronal differentiation is well underway. This corresponds to about the 3rd week of gestation (of a total of 3 weeks) for rats and mice. Despite the paucity of studies showing localized synaptic changes in prefrontal cortex following gestational stress, there is direct evidence of both behavioral and neuronal changes in laboratory rodents. Thus, gestational stress in embryonic days 12–16 (roughly second trimester in humans) has been shown to produce increased anxiety in males, disrupted play behavior in males and females, and impaired performance on fine motor skills in adult offspring (e.g., Muhammad & Kolb, 2011b). In addition, some studies have shown impairment in spatial learning for male rats (Halliwell, 2011; Lemaire, Koehl, LeMoal, & Abrous, 2000). Brain analysis of such animals has shown a reduction in brain weight in males, reduced spine density in mPFC in both sexes, reduced spine density in the VL and LO (males only), but not the AID region, of OFC (Muhammad & Kolb, 2011b; Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 5. Levels of global DNA methylation shown as a percentage of methylated CpG sites in frontal cortex of offspring at postnatal day 21 (*p < 0.0001).
Murmu et al., 2006; Mychasiuk, Gibb, & Kolb, 2012b). The sex difference in both behavioral and anatomical effects (bigger in both domains in males) is consistent with two previous studies showing that prenatal stress reduces general cortical thickness in the right, but left, hemispheres of males but not females (Fleming, Anderson, Rhees, Kinghorn, & Bakaitis, 1986; Stewart & Kolb, 1988). In addition to the dendritic changes Mychasiuk et al. (2012b) also found sexually-dimorphic changes in gene expression in frontal cortex of gestationally-stressed rats. The studies reviewed above did not all use the same stress model but the results are strikingly consistent, suggesting similar stress levels, but this may not be so. Mychasiuk, Ilnytskyy et al. (2011) placed pregnant dams on an elevated Plexiglas platform twice daily from gestational day 12 (E12) to E16. One cohort of dams was on the platform for 10-min sessions whereas another cohort was there for 30-min sessions. The authors expected a linear relationship between stress severity and outcomes but as shown in Fig. 5, the effects of stress at the two durations were strikingly different: the shorter stress session led to an increase in global methylation whereas the longer stress session produced a decrease, resulting in about a 20% difference between the offspring of the two groups. In addition, the authors found that the brain and body weights of the offspring of the shorter duration stressed dams were significantly reduced relative to the control and longer duration animals, whereas the longer stress increased brain weight in the female offspring. This surprising result calls for further study. We noted earlier that adult stress (15 min sessions) leads to decreased gene expression in both the mPFC and OFC, which is similar to the short duration stress in the gestational studies. It would be interesting to determine if the effects of more intense stress in adults parallels the infant response. 3.2. Bystander gestational stress Although most studies of gestational stress involve studying the offspring of dams directly exposed to a stressor, stressors can also be indirect. One example is what has been called bystander stress: a situation in which one individual is exposed to another stressed individual. Mychasiuk, Gibb et al. (2011) generated a model of prenatal “bystander stress” by housing a pregnant mother with a female cage-mate who experienced daily chronic stress from E12–E16. The authors then examined the effects on the offspring of the bystander stress on pre-weaning behavior, global methylation patterns, gene expression profiles, and cerebral morphology of the offspring. Similarly, in a parallel study pregnant mothers were housed with stressed males and behavior and cerebral morphology of the offspring was examined. As infants, the offspring of bystander-stressed animals exhibited altered behavioral development, whereas animals killed at weaning (postnatal day 21, P21) exhibited an increase in global methylation in the frontal cortex and hippocampus (Mychasiuk, Schmold et al., 2011). Behavioral observations in neonates (P9, P10) showed that brain development was delayed in the bystander-stressed offspring. Gene microarray analysis revealed significant gene expression level changes in 558 different genes, of which only 10 exhibited overlap between males and females or brain areas. When measured at P21 there was no effect of stress on brain weight, although female offspring had lower body weights than unstressed controls. Analysis of Cg3 and AID neurons showed an increase in dendritic branching and spine density in both regions (see Table 2). Using stereological procedures the number of neurons and glia were determined in littermates in whom the brains were processed differently (cresyl violet to allow neuron counting) than the Golgi-stained brains. There were significantly more neurons in the Cg3 of female, but fewer in male, offspring. AID was unaffected in either sex. By combining the Golgi and stereological results the authors determined that the number of estimated synapses was therefore dramatically increased in females in mPFC (nearly double) but unchanged in males. One other interesting result was that when the stressed females were returned to their home cage analysis of ultrasonic vocalizations showed high levels of low frequency distress calling Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 6. Average number of low (top) and high (bottom) frequency ultrasonic vocalizations recorded over 10 post-stress sessions. (After Mychasiuk, Gibb et al., 2011).
(22 kHz) whereas the bystander female responded with high levels of high frequency singing (55 kHz) (see Fig. 6). It is unknown how this difference in ultrasonic vocalizations may have influenced the unborn offspring. In sum, bystander stress had large effects on behavioral development, neuronal morphology, and gene expression relative to control animals. Analysis of the effects on offspring of the stressed sire included both neonatal behavior as well as adult behavioral measures. As in the bystander-stressed female experiments described above, behavioral development was delayed by a day in neonates. In adults, there was a large increase in time (nearly double) in the open arms of an elevated plus maze, indicating a reduction in anxiety in the male-stressed offspring. As in the Harker experiments analysis of brain weight showed no stress effect but in contrast to the Harker studies, there was also no effect on body weight. Analysis of cortical thickness and dendritic morphology is still in progress (E. Fraunberger, R. Gibb, & B. Kolb, unpublished observations, April 2016). In summary, the data show that prenatal stress does not have to be experienced directly by the mother herself to influence offspring brain development. Furthermore, this type of ‘indirect’ prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior. Thus, both forms of gestational stress (direct and bystander) altered brain development but in different ways (Table 2). It is unknown if this reflects a difference in the intensity of the stress or some other factor. 3.3. Maternal separation The first studies on maternal separation were conducted by Seymour Levine (e.g., Levine & Lewis, 1959). He designed a simple study using three groups of rats. One group simply stayed with their mothers in a cage. A second group was removed from the mother at P1-14 for 3 min and exposed to a mild electric shock, which was thought to be a model of early trauma. A third group was removed from the mother but not shocked, a so-called “handled group.” Thus, Levine could compare a sheltered infancy with a stressful one. As the animals developed Levine conducted various behavioral tests. In one, the animals were placed in a box on a grid that became the source of a mild electric shock. The animals could escape the shock simply by running away. To Levine’s surprise the sheltered animals were slow to learn to escape the shock whereas the animals in the other groups displayed less fear and quickly learned to escape the shock. In another test, the rats were placed alone in large enclosure studded with toys to explore. Once again, the sheltered animals showed intense fear and showed little exploration. The handled and early stressed rats were bolder and explored more extensively. It was remarkable that a single 180-s experience in development Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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could have such profound consequences on later adult behavior. This led to many similar studies by others with the most common paradigm being removal from the mothers for 10–15 min per day from birth to P21. A clue to how the handling could have such profound effects came from later studies by Michael Meaney and his colleagues who showed that the early handling altered the hypothalamic-pituitary axis (HPA), making it more efficient allowing better recovery from stress (Meaney, Aitken, Bodnoff, Iny, & Sapolsky, 1985). Later studies showed that removal of the pups led to increased mothering (licking and grooming) by the dams, which influenced the development of central systems that serve to activate or inhibit the expression of behavioral and endocrine responses to stress (see review by Caldji, Diorio, & Meaney, 2000). The increased licking and grooming of the pups also alters gene expression in the infants, which in turn, alters brain and behavior in adulthood. Meaney et al. (1991) also showed that brief maternal separation attenuated the effects of aging on both hippocampal cell number and spatial learning. We are unaware of similar studies on PFC but stereological analyses of PFC regions in parallel studies would seem warranted. Gibb and Kolb (2005) examined the effect of 15 min handling 3X daily from P5 until weaning at P21 on behavior and brain. They found no behavioral effects on either a skilled reaching task or spatial learning. They did show an increase in cortical thickness in frontal cortex, although also found no effect on cortical thickness in prefrontal cortex. Although they did not measure dendritic effects in PFC they did measure parietal cortex and found decreased dendritic branching in handled animals but no effect on spine density. This study needs to be repeated with an analysis of PFC neurons. But clearly there must be a limit to the intensity of maternal separation that is beneficial. Indeed there is. Unfortunately the data are somewhat complex because the daily hours of separation and the number of days of separation is different in every study. The most intense separation was 3 h per day from P3-P21 (Muhammad & Kolb, 2011a; Muhammad, Carroll, & Kolb, 2012). The authors found increased anxiety in adult male offspring, disrupted play behavior in both sexes (albeit differently in each sex), decreased brain weight in males but not females, increased spine density in both Cg3 and AID, and increased dendritic length and branching in the basilar fields in both Cg3 and AID. A similar result was seen in Cg3 of degus who were separated for an hour three times a day for 21 days (Helmeke, Ovtscharoff, Poeggel, & Braun, 2001; Helmeke, Poeggel, & Braun, 2001). Other studies reported dendritic remodeling dependent upon factors such as the duration and separation procedure (e.g., separation vs. isolation). For instance, Bock, Gruss, Becker, and Braun (2005) reported an increase in basilar dendritic length in the Cg3 in rats maternally separated during P5–7 or 14–16 whereas a decrease in apical length was observed in rats separated during P1–3. Maternal separation for 3 h daily from P4-P12 led to no change in spine density if Cg3 but a decrease in AID in rats, which was correlated with increased anxiety in adulthood (S. de Milo, S. Hossain, C. Antoniazzi, & B. Kolb, unpublished results, July 2016). Monroy, Hernandez-Torres, and Flores (2010) also showed a drop in spine density in Cg3 when animals were separated for 2 h per day but unfortunately the authors do not say when this happened or for how long, although given the Bock et al. results we would not be surprised if it was just for the first few days. Taken together the studies on maternal separation show a goldilocks effect, whereby brief periods of daily separation are beneficial to later behavior, including response to adult stressors, as well as to the aging brain. In contrast, more extended periods of maternal separation (hours rather than minutes) have effects that vary with timing and duration. Maternal separation in just the first few days of life leads to reduced synapse numbers in the PFC whereas later separation or prolonged separation from birth to weaning appears to have the opposite effect. Although not yet studied, it seems likely that the differential effects of maternal separation are correlated with differential epigenetic effects, although this remains to be shown. 3.4. Preconception stress As reviewed above, there is a rich literature looking at the effects of maternal stress during gestation on the offspring. Much less is known about the effects of preconception maternal or paternal stress on the offspring. Bock et al. (2016) gave females moderate stress for a week and then either mated them the following day or 15 days later. The brains of the offspring were collected in late adolescence (P65). Analysis of the dendritic complexity and spine density in AC, PL, and OFC found no effect in the animals whose dams were mated immediately after the stress whereas those mated 2 weeks later showed increased dendritic complexity and spine density in AC and PL but not in OFC. As in the males experiencing gestational stress the effects in males were larger in the left hemisphere. The authors speculated that either a change in the maternal behavior or some type of epigenetic change in the dams or the offspring led to the delayed effects (see also Bock, Weinstock, Braun, & Segal, 2015). A more extensive series of experiments has examined the effect of preconception paternal stress (Harker, Raza, Williamson, Kolb, & Gibb, 2015; Harker, Carroll, Raza, Kolb, & Gibb, 2016; Mychasiuk, Harker, Ilnytskyy, & Gibb, 2013). In these studies male rats were stressed for 30 min, twice per day, for 27 consecutive days, and then mated with control female rats. The offspring’s brains were collected either at P21 or P110. Behavioral, epigenetic, and neuroanatomical analyses showed large effects of the preconceptional stress. For example, when tested at P33 or P61, both male and female offspring showed increased anxiety in an elevated plus maze and when tested in a skilled reaching task at P100 they were impaired (see Fig. 4). Epigenetic analysis of littermates killed at P21 showed significantly decreased methylation in frontal cortex (mPFC and adjacent motor cortex) in female but not male rats, and increased methylation in the hippocampus of both sexes. Thus, not only was there an areal difference (frontal cortex versus hippocampus), there was a sex difference in the frontal Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Table 3 Summary of the effects of preconceptual stress on dendritic morphology in animals killed at P21 or P110. P21 Brains
P110 Brains
Brain weight
D
U
CG3 Branch apical CG3 Length apical CG3 spines apical
U NS D
D U NS
CG3 Branch basilar CG3 Length basilar CG3 spines basilar
NS NS D
NS U NS
AID Branch basilar AID Length basilar AID spines basilar
D D D
NS U U
(Data from Harker et al., 2015, 2016). Abbreviations: NS = No significant effect; U = significant increase; D = significant decrease.
cortex. Anatomical analyses showed changes in all PFC regions but the effects differed with the age of the animals at analysis (see Table 2). Thus, surprisingly, the effects on brain weight were opposite at P21 (lighter) and P110 (heavier), even though there was no effect on body weight at either age. The increased brain weight was completely unexpected, as this has not been found in several gestational or maternal separation studies conducted in our laboratories (e.g., Mychasiuk, Gibb, & Kolb, 2011; Mychasiuk, Gibb, & Kolb, 2012a; Muhammad & Kolb, 2011a). The changes in dendritic complexity and spine density were also primarily opposite at the two ages, as there was a general reduction in dendritic complexity and spine density at P21 but an increase at P110. It is clearly difficult to compare the effects of preconceptional stress in females and males given that the effects differ with the age of analysis of the brains, the duration of the stress, and the “stress recovery time”. The simplest conclusion is that preconceptional stress in either sex has effects on the offspring and although the Bock study did not analyze behavior or epigenetics, in the context of our studies it seems likely that maternal stress would also affect both the behavior and epigenenome of the offspring. 4. Summary of the effects of developmental stress on the PFC Preconception, gestational, and neonatal stress all influence spine density in the adult offspring but the effects vary with age and which parent was stressed. Many of the aforementioned studies also examined dendritic branching and length and although the details of the changes are slightly different than the spine results, the general point is the same: these developmental stressors modify the organization of the PFC in adulthood (see Tables 2 and 3), with results varying according to age at stress and region measured. It is likely that all of these stress effects are mediated by (re)programming of later gene activity in the brains of the offspring. Although we have not emphasized sex differences, and many studies have used only males, there are clear sex differences with a general rule of thumb being that the effects of developmental stress appear to be larger in males. But we must note that there are sex differences in many measures of PFC anatomy in “control” animals (e.g., Kolb & Stewart 1991; Koss, Lloyd, Sadowski, Wise, & Juraska, 2015; Stewart & Kolb, 1988; Willing & Juraska, 2015) so we may be seeing an interaction between baseline and stress effects in the sex-related differences. There is a significant literature looking at the effects of postnatal stressors on the brain morphology in children (see review by Carrion & Wong, 2012) but we are unaware of any human studies examining the effects of preconceptional stress on this measure. Overall, the research demonstrates that children with severe early postnatal stress show significant changes in volume and activity in both the prefrontal cortex and hippocampus, a result consistent with the rodent studies discussed above. Human MRI studies examining children who have experienced preconceptional, gestational, or postnatal stress would be revealing. Acknowledgement The authors thank Natural Science and Engineering Research Council of Canada grants to BK and RG and a Canadian Institute for Advanced Research grant to BK. References Anda, R. F., Felitti, V. J., Bremmer, J. D., Walker, J. D., Whitfield, C., Perry, B. D., et al. (2006). The enduring effects of abuse and related adverse experiencesin childhood: A convergence of evidence from neurobiology and epidemiology. European Archives of Psychiatry and Clinical Neuroscience, 256, 174–186. Bergman, K., Sarkar, P., O’Connor, T. G., Modi, N., & Glover, V. (2007). Maternal stress during pregnancy predicts cognitive ability and fearfulness in infancy. Journal of the American Academy of Child and Adolscent Psychiatry, 46, 1454–1463. Bock, J., Gruss, M., Becker, S., & Braun, K. (2005). Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: Correlation with developmental time windows. Cerebral Cortex, 15, 802–808.
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Contents lists available at ScienceDirect
Cognitive Development
Stress and prefrontal cortical plasticity in the developing brain Bryan Kolb a,b,∗ , Allonna Harker a , Richelle Mychasiuk c , Silvana R. de Melo d , Robbin Gibb a a b c d
Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K 3M4 Canada Canadian Institute for Advanced Research, 180 Dundas St W, Toronto, ON, M5G 1Z8 Canada Alberta Children’s Hospital Research Institute, HMRB233,3330 Hospital Drive, Calgary, AB, T2N 4N1, Canada Department of C. Morfológicas – DCM, University of Estadual de Maringá, Maringá, Paraná, Brazil
a r t i c l e
i n f o
Article history: Received 30 April 2016 Received in revised form 31 October 2016 Accepted 5 January 2017 Available online xxx Keywords: Prefrontal cortex Cerebral development Stress Brain plasticity Epigenetics
a b s t r a c t There is a large literature showing that stress in adulthood induces the production of stress hormones leading to a modulation of brain function, which is accomplished, in part, by changing the structure of neurons, especially in the hippocampus and prefrontal cortex, and these changes are correlated with behavioral change. Here we review the effects of preconception, gestational, and bystander gestational stress, as well as maternal separation on prefrontal cortex and behavioral development, largely in animal models. The general conclusion is that developmental stressors modify the organization of the prefrontal cortex in adulthood with results varying according to age at stress and region measured. It is likely that all of these stress effects are mediated by (re)programming of later gene activity in the brains of the offspring. © 2017 Elsevier Inc. All rights reserved.
Contents 1.
2. 3.
4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.1. Organization of the prefrontal cortex of rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.2. What are appropriate animal models of stress? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.3. How is PFC plasticity measured? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Effects of stress on adult PFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Effects of stress on the developing prefrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Gestational stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.2. Bystander gestational stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.3. Maternal separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.4. Preconception stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Summary of the effects of developmental stress on the PFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author at: Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K 3M4, Canada. E-mail address: [email protected] (B. Kolb). http://dx.doi.org/10.1016/j.cogdev.2017.01.001 0885-2014/© 2017 Elsevier Inc. All rights reserved.
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Fig. 1. The prefrontal cortex of the rat. Serial sections through a rat brain showing different cytoarchitectonic regions (Zilles, 1985, nomenclature). Dotted areas receive projections from MD; gray areas receive projections from the amygdala. Abbreviations: Cg1, cingulate area 1; Cg3, cingulate area 3; Fr2, frontal area 2 IL, infralimbic; AID, agranular insular; MO, medial orbital; PL, prelimbic; VLO, ventral lateral orbital; VO, ventral orbital, LO, lateral orbital. (Modified and adapted from Reep, 1984).
1. Introduction The modern idea that stress changes the body, including the brain, can be traced to Hans Selye in the 1930s. Selye, a physician, noticed that all of his patients, regardless of what they were hospitalized with, looked sick. He inferred that they must all be under physical stress that resulted in the release of stress hormones. This observation led him to search for a stress-processing mechanism, eventually leading to the concept of the hypothalamic-pituitary-adrenal system (HPA axis) (e.g., Harris, 1970; Selye, 1950, 1978). Although Selye’s focus was on physiological stressors it became clear that psychological factors could also stimulate the HPA axis to affect the body and brain. Further, over the past 60 years it has become evident that the effects of stress are not only dependent upon the HPA axis but involves a two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms (McEwen, 2006). One of the effects of stress hormones is a modulation of brain function, which is accomplished, in part, by changing the structure of neurons, especially in the hippocampus (CA3 and the dentate gyrus), amygdala, and prefrontal cortex (Chattarji, Tomar, Suvrathan, Ghosh, & Mohammed, 2015). This review provides an overview of the effects of stress on the developing prefrontal cortex, with an emphasis on the effects in laboratory rats, which is the most-studied model to date. Understanding the effects of stress on the PFC has become increasingly interesting owing to its vulnerability to stress and the realization that the PFC has a significant role in many neuropsychiatric disorders (McEwen & Morrison, 2013).
1.1. Organization of the prefrontal cortex of rodents In the 1960s the prefrontal cortex (PFC), which was often called the frontal granular cortex, was defined by both the frontal granular cell layer and the connections it made with the dorsomedial nucleus of the thalamus (MD) (Warren & Akert, 1964). Although these two definitions define a large region of overlap, the MD-projection cortex extends well beyond the frontal granular cortex of primates (Wise, 2008). Rodents do not have a frontal granular cortex but they do have an MDprojection area that was first described by Leonard (1969). This region does not include the frontal pole but rather includes regions along the anterior medial wall of the cerebral hemispheres as well as the ventral and lateral regions bordering the rhinal fissure (See Fig. 1). Later definitions of the rodent PFC expanded to include the connections with the amygdala and ventral tegmentum (Reep, 1984; Schoenbaum & Setlow, 2002) as well as the basal ganglia (Uylings, Groenewegen, & Kolb, 2003). The degree to which the rat and primate “prefrontal” regions are homologous has been controversial (e.g., Wise, 2008), but there are clearly areas of the rat PFC that sub-serve functions similar to those in the primate (Brown & Bowman, 2002; Kolb, 1984). For our purposes we will assume that the medial prefrontal cortex of the rat (mPFC), including anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices house many functions similar to the medial or dorsolateral regions of the primate, whereas the orbitofrontal region (OFC) including the ventral, ventral lateral, lateral orbital regions (VO, VLO, LO) and the ventral and dorsal and agranular insular regions (AID) house functions similar to the orbital region of the primate (Uylings et al., 2003). Although an extensive discussion of the behavioral functions associated with the PFC is beyond the scope of this review, it will be useful to describe the general functions of the prefrontal regions (see also Wise, 2008). At a general level the dorsolateral region of primates plays an important role in working memory, particularly as it relates to certain executive processes such as the monitoring, sequencing, and planning of behaviors, as well as directed attention to Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 2. Common models of stress in rodents. (Adapted from Chattarji et al., 2015).
objects, places, actions, and intentions. The orbital regions are involved in socio-emotional behaviors, inhibition of behaviors, associations between reward and external cues, and in certain types of olfactory and gustatory processing. Although the anatomical and functional details of the PFC must be unique in rodents and primates, they likely evolved from a common ancestor that had developed the prefrontal regions to solve common problems of all mammals (class common behaviors) and thus continue to have shared functions (Kolb, 2007). Thus, studying the effects of experience on the PFC in rodents should give us important clues to how the PFC regions in primates are also changed by experiences such as stress. 1.2. What are appropriate animal models of stress? Animal models focus on two different types of stressors, namely physical and psychological (see Chattarji et al., 2015) (see Fig. 2). Physical stress has common variations: immobilization in a bag or in a narrow tube and forced swimming in cold water. Psychological stress has many forms including predator odor, elevated platform, social defeat, living with a stressed cage mate (bystander stress), and maternal separation. In addition, some studies mix different stressors at different times to prevent (or reduce) habituation to the stressor. It is obviously difficult to compare stressors in humans to those in laboratory animals, but to the extent that both increase levels of corticosterone in rats (cortisol in humans) and activate the HPA axis, the animal models have generally been seen as good approximations to human conditions. 1.3. How is PFC plasticity measured? Neural plasticity can be measured at many levels of analysis, ranging from behavior to electrophysiologically-defined maps, to measures of neuronal morphology, and to molecular measures, such as gene expression. Most studies on the rodent PFC have focused on behavioral and morphological changes, and more recently on epigenetic changes in gene expression. Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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In adults, the largest behavioral changes have been seen in executive and motor functions although there are many other measures used in development, such as play behavior and ultrasonic vocalizations. Behavioral changes are correlated with morphological changes, both in individual neurons and circuits. It is important to emphasize that although there is a tendency to think that good experiences increase synapse numbers and poor experiences decrease synapse numbers, this is not the case. Rather, changes in synapse numbers reflect changes in neural networks and it is not uncommon for an experience such as stress to produce opposite changes in different subregions of the PFC (see below). The neurons in the PFC are largely excitatory (80–90%) and synapse on dendritic spines, while the remaining neurons are inhibitory GABAergic interneurons. Both excitatory and inhibitory neurons can be subdivided into many types but virtually nothing is known about how different subtypes differentially respond to experiences. One emerging field is related to understanding mechanisms that maintain an excitatory/inhibitory balance (E/I), which is likely central to understanding changes in neural networks (e.g., Kvitsiani et al., 2013; Yizhar et al., 2011). Most studies of neuronal morphology use some type of staining technique that makes it possible to measure the number of dendritic branches, the length of dendritic branches, and their spine density. Because most excitatory synapses are found on spines, by knowing the length of dendrites and the spine density, it is possible to estimate the number of synapses on neurons. Epigenetics refers to changes in gene expression that are not related to changes in the DNA. The genes expressed in a cell are influenced by factors within the cell and the cell’s environment. The cell’s environment determines which genes are expressed and thus how the cell functions, including its role in the nervous system. But the cell’s environment does not only include the chemicals that surround the cell within the body, but also the environment that an organism finds itself in throughout its lifespan. Thus, our experiences can influence expression of our genes. Epigenetic mechanisms can influence protein production either by blocking a gene to prevent transcription or by unlocking a gene so that it can be transcribed. Chromosomes are comprised of DNA wrapped around supporting molecules of a protein called histone, which allows many meters of DNA to be packaged in a small space. For any gene to be transcribed into messenger RNA, its DNA must be unspooled from the histones. Thus, one measure of changes in gene expression is histone modification through either methylation or acetylation. Methyl groups (CH3 ) or other molecules bind to the histones, either blocking them from opening or allowing them to unravel. Methylation can also occur in CpG islands (regions of DNA where a cytosine nucleotide is adjacent to a guanine nucleotide, separated only by a single phosphate) on the DNA that are usually located near promoter sites for genes. When methylation occurs at these sites gene transcription cannot proceed. Changes in the amount of methylation in a tissue thus can give an indirect estimate of the amount of gene expression. As a rule of thumb more methylation means fewer genes expressed whereas reduced methylation means more genes are expressed. Unfortunately, methylation levels do not tell us which genes are on or off, but methylation does provide a rough (and inexpensive) gauge as to whether there is a change in gene expression. 2. Effects of stress on adult PFC Historically, although most studies in the literature have emphasized the effect of stressful experiences on the hippocampus (HPC), there is a growing literature on the effects of adult stress on the prefrontal cortex, and the interactions between the HPC, mPFC, and OFC. Functionally, chronic stress has been associated with a multitude of cognitive, social, and physical symptoms that include deficits in emotional regulation, impaired motor function, impaired executive function including short-term memory, diminished self-regulatory behavior, and immunological impairment (e.g., Cohen, Janicki-Deverts, & Miller, 2007; McEwen, 2008; Metz, 2007; Segerstrom & Miller, 2004). It has been proposed that many of the cognitive symptoms, especially those related to cognitive functioning, are directly linked to dysfunctional connectivity between regions of the HPC, mPFC, and OFC (McEwen, 2007). Chronic stress decreases synaptic space and spine density in the mPFC, with an estimated drop of 30% of excitatory synapses but, in contrast, the pyramidal neurons in OFC show a stress-related increase in dendritic length and spine density (e.g., Liston et al., 2006; Fig. 3). The large drop in synapses in mPFC is dramatic but recovers quickly over 3 weeks in young animals, but this is not seen in older animals. It is unknown if the OFC changes persist. A few studies have looked at mPFC subregions separately and as of yet there is no consensus on the differences (Izquierdo, Wellman, & Holmes, 2006; Lin, Borders, Lundewall, & Wellman, 2015), which may be related to stress type and duration. There are also extensive epigenetic changes following chronic adult stress. Mychasiuk, Muhammad, and Kolb (2016) compared the mRNA gene expression in the mPFC, OFC, and HPC following 14 days of platform stress followed by a 14 day recovery period, and found areal differences in gene expression patterns. As in the morphological studies (Fig. 4) the mPFC and OFC exhibited contrasting effects in gene expression. Somewhat surprisingly, given that most previous studies of stress and PFC plasticity have been on the mPFC and HPC, it was the OFC that showed the most extensive changes in gene expression. Overall, this study found gene expression changes that are likely related to the changes in neuronal morphology and cognition associated with chronic stress. 3. Effects of stress on the developing prefrontal cortex Although there is a large literature showing the effects of stress on brain and behavior in adults, the role of perinatal stress is relatively unexplored. Nonetheless, is known that both gestational and infant stress predisposes individuals to a Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 3. Chronic stress in adult rats reduces dendritic length (and thus synaptic space) in the medial prefrontal cortex (left) but increases dendritic length in the orbital prefrontal cortex (right). (Based on McEwen & Morrison, 2013).
Fig. 4. Venn diagram outlining the number genes exhibiting significant expression level changes in the mPFC, OFC, and HPC for male and female exposed to chronic stress (Mychasiuk et al., 2016).
variety of maladaptive behaviors and psychopathologies. For example, prenatal stress is a risk factor in the development of schizophrenia, attention-deficit hyperactivity disorder (ADHD), depression, and drug addiction (e.g., Anda et al., 2006; Charil, Laplante, Vaillancourt, & King, 2010; Van den Bergh & Marcoen, 2004). Experimental studies with laboratory animals have confirmed these findings, with the overall result being that perinatal stress in rodents produces a range of behavioral abnormalities including an elevated and prolonged stress response, impaired learning and memory, deficits in attention, altered exploratory behavior, altered social and play behavior, and increased preference for alcohol (Weinstock, 2008). Although there are a lot of studies looking at changes in the organization of brain regions from early stress, until recently the data were focused on changes in the amygdala and hippocampus (for a review see Charil et al., 2010). Although early studies on the effects of perinatal stress tended to lump together stressors given at different times and of different types, it is becoming clear that stress during development has differing effects depending on the time period, ranging from preconception to gestation to the postnatal period (see Tables 1 and 2). We consider each time period separately. We begin with gestational stress because this is most studied model, followed by maternal separation, and then preconceptional stress.
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Table 1 Models of Developmental Stress in Laboratory Rodents. Time of Stressor
Basic Reference
Preconception Maternal Stress Preconception Paternal Stress Direct Gestational Stress Indirect Gestational Stress Maternal Separation (15 min) Maternal Separation (1–3 h) Paternal Separation
Bock et al. (2016) Mychasiuk et al. (2013) Bock et al. (2015) Mychasiuk, Gibb et al. (2011) and Mychasiuk, Ilnytskyy et al. (2011) Meaney et al. (1991) Huot, Thrivikraman, Meaney, and Plotsky (2001) Helmeke et al. (2009)
Table 2 Summary of the effects of stress on dendritic organization following gestational stress or maternal separation. Measure
GSP21
GSP110
Byst P21
MSP110
Brain weight
D
U
NA
D
CG3 Branch apical CG3 Length apical CG3 spines apical
U NS D
D U NS
NA NA NA
NS NS U
CG3 Branch basilar CG3 Length basilar CG3 spines basilar
NS NS D
NS U NS
U U U
U U U
AID Branch basilar AID Length basilar AID spines basilar
D D D
NS U U
NS U U
U U U
Proportion changed
7/10
6/10
5/6
8/10
Abbreviations: PCS, preconceptual stress; GSP21, gestational stress, Postnatal day 21 data; GSP110, gestational stress, Postnatal day 110 data; Byst P21, bystander stress, Postnatal day 21 data; prolonged maternal separation, MSP, postnatal day 110 data. NS = No significant effect; U = significant increase; D = significant decrease.
3.1. Gestational stress Maternal exposure to stressful life events during pregnancy is known to affect the cognitive skills of the offspring. These include attention difficulties, verbal and spatial working memory, as well as general cognitive development (e.g., Bergman, Sarkar, O’Connor, Modi, & Glover, 2007; Laplante et al., 2004; Plamondon et al., 2015; Tarabulsy et al., 2014). Although there is little doubt that the resultant offspring of women stressed while pregnant may suffer from significant cognitive sequelae, no studies have been able to relate the stressors to effects on specific brain regions. Recent studies of natural disasters may shed light on this. Perhaps the most extensive prospective study is on the effects of the Quebec, Canada, Ice Storm of 1998. This storm was the largest natural disaster in Canadian history as power was knocked out for up to 6 weeks, affecting approximately 2 million people, during the coldest month of the year. Many women were pregnant at different stages of gestation and had varying levels of hardship ranging from severe to none. There are now several prospective studies on the children of a large cohort of women beginning shortly after the storm and still continuing today. Overall, the results show that the offspring of the women exposed to high levels of objective stress show significant developmental delays in language, cognition (IQ), motor skills, and play (e.g., King, Dancause, Turcotte-Tremblay, Veru, & Laplante, 2012). This is correlated with widespread effects on DNA methylation across the entire genome of their children, detectable during adolescence (Cao-Lei et al., 2015). There is an ongoing study of structural MRIs of these children, although no results are yet available. Nonetheless, when the MRI data are available this study promises to provide clues of how gestational stress affects brain, especially hippocampus, amygdala, and prefrontal cortex, and the relationship to behavior. One additional study is relevant here. Buss, Davis, Muftuler, Head, & Sandman (2010) examined the effects of gestational anxiety (measured at 19, 25, and 31 weeks of gestation) on the structural MRIs of the offspring’s brains at 6–9 years of age. The results showed a reduction in gray matter density in prefrontal, premotor, medial temporal, lateral temporal, the fusiform gyrus, and cerebellum of children whose mothers experienced pregnancy anxiety at 19 but not 25 or 31 weeks of gestation. At about 19 weeks of gestation, neurogenesis is nearly complete but neuronal migration is at its peak and neuronal differentiation is well underway. This corresponds to about the 3rd week of gestation (of a total of 3 weeks) for rats and mice. Despite the paucity of studies showing localized synaptic changes in prefrontal cortex following gestational stress, there is direct evidence of both behavioral and neuronal changes in laboratory rodents. Thus, gestational stress in embryonic days 12–16 (roughly second trimester in humans) has been shown to produce increased anxiety in males, disrupted play behavior in males and females, and impaired performance on fine motor skills in adult offspring (e.g., Muhammad & Kolb, 2011b). In addition, some studies have shown impairment in spatial learning for male rats (Halliwell, 2011; Lemaire, Koehl, LeMoal, & Abrous, 2000). Brain analysis of such animals has shown a reduction in brain weight in males, reduced spine density in mPFC in both sexes, reduced spine density in the VL and LO (males only), but not the AID region, of OFC (Muhammad & Kolb, 2011b; Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 5. Levels of global DNA methylation shown as a percentage of methylated CpG sites in frontal cortex of offspring at postnatal day 21 (*p < 0.0001).
Murmu et al., 2006; Mychasiuk, Gibb, & Kolb, 2012b). The sex difference in both behavioral and anatomical effects (bigger in both domains in males) is consistent with two previous studies showing that prenatal stress reduces general cortical thickness in the right, but left, hemispheres of males but not females (Fleming, Anderson, Rhees, Kinghorn, & Bakaitis, 1986; Stewart & Kolb, 1988). In addition to the dendritic changes Mychasiuk et al. (2012b) also found sexually-dimorphic changes in gene expression in frontal cortex of gestationally-stressed rats. The studies reviewed above did not all use the same stress model but the results are strikingly consistent, suggesting similar stress levels, but this may not be so. Mychasiuk, Ilnytskyy et al. (2011) placed pregnant dams on an elevated Plexiglas platform twice daily from gestational day 12 (E12) to E16. One cohort of dams was on the platform for 10-min sessions whereas another cohort was there for 30-min sessions. The authors expected a linear relationship between stress severity and outcomes but as shown in Fig. 5, the effects of stress at the two durations were strikingly different: the shorter stress session led to an increase in global methylation whereas the longer stress session produced a decrease, resulting in about a 20% difference between the offspring of the two groups. In addition, the authors found that the brain and body weights of the offspring of the shorter duration stressed dams were significantly reduced relative to the control and longer duration animals, whereas the longer stress increased brain weight in the female offspring. This surprising result calls for further study. We noted earlier that adult stress (15 min sessions) leads to decreased gene expression in both the mPFC and OFC, which is similar to the short duration stress in the gestational studies. It would be interesting to determine if the effects of more intense stress in adults parallels the infant response. 3.2. Bystander gestational stress Although most studies of gestational stress involve studying the offspring of dams directly exposed to a stressor, stressors can also be indirect. One example is what has been called bystander stress: a situation in which one individual is exposed to another stressed individual. Mychasiuk, Gibb et al. (2011) generated a model of prenatal “bystander stress” by housing a pregnant mother with a female cage-mate who experienced daily chronic stress from E12–E16. The authors then examined the effects on the offspring of the bystander stress on pre-weaning behavior, global methylation patterns, gene expression profiles, and cerebral morphology of the offspring. Similarly, in a parallel study pregnant mothers were housed with stressed males and behavior and cerebral morphology of the offspring was examined. As infants, the offspring of bystander-stressed animals exhibited altered behavioral development, whereas animals killed at weaning (postnatal day 21, P21) exhibited an increase in global methylation in the frontal cortex and hippocampus (Mychasiuk, Schmold et al., 2011). Behavioral observations in neonates (P9, P10) showed that brain development was delayed in the bystander-stressed offspring. Gene microarray analysis revealed significant gene expression level changes in 558 different genes, of which only 10 exhibited overlap between males and females or brain areas. When measured at P21 there was no effect of stress on brain weight, although female offspring had lower body weights than unstressed controls. Analysis of Cg3 and AID neurons showed an increase in dendritic branching and spine density in both regions (see Table 2). Using stereological procedures the number of neurons and glia were determined in littermates in whom the brains were processed differently (cresyl violet to allow neuron counting) than the Golgi-stained brains. There were significantly more neurons in the Cg3 of female, but fewer in male, offspring. AID was unaffected in either sex. By combining the Golgi and stereological results the authors determined that the number of estimated synapses was therefore dramatically increased in females in mPFC (nearly double) but unchanged in males. One other interesting result was that when the stressed females were returned to their home cage analysis of ultrasonic vocalizations showed high levels of low frequency distress calling Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Fig. 6. Average number of low (top) and high (bottom) frequency ultrasonic vocalizations recorded over 10 post-stress sessions. (After Mychasiuk, Gibb et al., 2011).
(22 kHz) whereas the bystander female responded with high levels of high frequency singing (55 kHz) (see Fig. 6). It is unknown how this difference in ultrasonic vocalizations may have influenced the unborn offspring. In sum, bystander stress had large effects on behavioral development, neuronal morphology, and gene expression relative to control animals. Analysis of the effects on offspring of the stressed sire included both neonatal behavior as well as adult behavioral measures. As in the bystander-stressed female experiments described above, behavioral development was delayed by a day in neonates. In adults, there was a large increase in time (nearly double) in the open arms of an elevated plus maze, indicating a reduction in anxiety in the male-stressed offspring. As in the Harker experiments analysis of brain weight showed no stress effect but in contrast to the Harker studies, there was also no effect on body weight. Analysis of cortical thickness and dendritic morphology is still in progress (E. Fraunberger, R. Gibb, & B. Kolb, unpublished observations, April 2016). In summary, the data show that prenatal stress does not have to be experienced directly by the mother herself to influence offspring brain development. Furthermore, this type of ‘indirect’ prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior. Thus, both forms of gestational stress (direct and bystander) altered brain development but in different ways (Table 2). It is unknown if this reflects a difference in the intensity of the stress or some other factor. 3.3. Maternal separation The first studies on maternal separation were conducted by Seymour Levine (e.g., Levine & Lewis, 1959). He designed a simple study using three groups of rats. One group simply stayed with their mothers in a cage. A second group was removed from the mother at P1-14 for 3 min and exposed to a mild electric shock, which was thought to be a model of early trauma. A third group was removed from the mother but not shocked, a so-called “handled group.” Thus, Levine could compare a sheltered infancy with a stressful one. As the animals developed Levine conducted various behavioral tests. In one, the animals were placed in a box on a grid that became the source of a mild electric shock. The animals could escape the shock simply by running away. To Levine’s surprise the sheltered animals were slow to learn to escape the shock whereas the animals in the other groups displayed less fear and quickly learned to escape the shock. In another test, the rats were placed alone in large enclosure studded with toys to explore. Once again, the sheltered animals showed intense fear and showed little exploration. The handled and early stressed rats were bolder and explored more extensively. It was remarkable that a single 180-s experience in development Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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could have such profound consequences on later adult behavior. This led to many similar studies by others with the most common paradigm being removal from the mothers for 10–15 min per day from birth to P21. A clue to how the handling could have such profound effects came from later studies by Michael Meaney and his colleagues who showed that the early handling altered the hypothalamic-pituitary axis (HPA), making it more efficient allowing better recovery from stress (Meaney, Aitken, Bodnoff, Iny, & Sapolsky, 1985). Later studies showed that removal of the pups led to increased mothering (licking and grooming) by the dams, which influenced the development of central systems that serve to activate or inhibit the expression of behavioral and endocrine responses to stress (see review by Caldji, Diorio, & Meaney, 2000). The increased licking and grooming of the pups also alters gene expression in the infants, which in turn, alters brain and behavior in adulthood. Meaney et al. (1991) also showed that brief maternal separation attenuated the effects of aging on both hippocampal cell number and spatial learning. We are unaware of similar studies on PFC but stereological analyses of PFC regions in parallel studies would seem warranted. Gibb and Kolb (2005) examined the effect of 15 min handling 3X daily from P5 until weaning at P21 on behavior and brain. They found no behavioral effects on either a skilled reaching task or spatial learning. They did show an increase in cortical thickness in frontal cortex, although also found no effect on cortical thickness in prefrontal cortex. Although they did not measure dendritic effects in PFC they did measure parietal cortex and found decreased dendritic branching in handled animals but no effect on spine density. This study needs to be repeated with an analysis of PFC neurons. But clearly there must be a limit to the intensity of maternal separation that is beneficial. Indeed there is. Unfortunately the data are somewhat complex because the daily hours of separation and the number of days of separation is different in every study. The most intense separation was 3 h per day from P3-P21 (Muhammad & Kolb, 2011a; Muhammad, Carroll, & Kolb, 2012). The authors found increased anxiety in adult male offspring, disrupted play behavior in both sexes (albeit differently in each sex), decreased brain weight in males but not females, increased spine density in both Cg3 and AID, and increased dendritic length and branching in the basilar fields in both Cg3 and AID. A similar result was seen in Cg3 of degus who were separated for an hour three times a day for 21 days (Helmeke, Ovtscharoff, Poeggel, & Braun, 2001; Helmeke, Poeggel, & Braun, 2001). Other studies reported dendritic remodeling dependent upon factors such as the duration and separation procedure (e.g., separation vs. isolation). For instance, Bock, Gruss, Becker, and Braun (2005) reported an increase in basilar dendritic length in the Cg3 in rats maternally separated during P5–7 or 14–16 whereas a decrease in apical length was observed in rats separated during P1–3. Maternal separation for 3 h daily from P4-P12 led to no change in spine density if Cg3 but a decrease in AID in rats, which was correlated with increased anxiety in adulthood (S. de Milo, S. Hossain, C. Antoniazzi, & B. Kolb, unpublished results, July 2016). Monroy, Hernandez-Torres, and Flores (2010) also showed a drop in spine density in Cg3 when animals were separated for 2 h per day but unfortunately the authors do not say when this happened or for how long, although given the Bock et al. results we would not be surprised if it was just for the first few days. Taken together the studies on maternal separation show a goldilocks effect, whereby brief periods of daily separation are beneficial to later behavior, including response to adult stressors, as well as to the aging brain. In contrast, more extended periods of maternal separation (hours rather than minutes) have effects that vary with timing and duration. Maternal separation in just the first few days of life leads to reduced synapse numbers in the PFC whereas later separation or prolonged separation from birth to weaning appears to have the opposite effect. Although not yet studied, it seems likely that the differential effects of maternal separation are correlated with differential epigenetic effects, although this remains to be shown. 3.4. Preconception stress As reviewed above, there is a rich literature looking at the effects of maternal stress during gestation on the offspring. Much less is known about the effects of preconception maternal or paternal stress on the offspring. Bock et al. (2016) gave females moderate stress for a week and then either mated them the following day or 15 days later. The brains of the offspring were collected in late adolescence (P65). Analysis of the dendritic complexity and spine density in AC, PL, and OFC found no effect in the animals whose dams were mated immediately after the stress whereas those mated 2 weeks later showed increased dendritic complexity and spine density in AC and PL but not in OFC. As in the males experiencing gestational stress the effects in males were larger in the left hemisphere. The authors speculated that either a change in the maternal behavior or some type of epigenetic change in the dams or the offspring led to the delayed effects (see also Bock, Weinstock, Braun, & Segal, 2015). A more extensive series of experiments has examined the effect of preconception paternal stress (Harker, Raza, Williamson, Kolb, & Gibb, 2015; Harker, Carroll, Raza, Kolb, & Gibb, 2016; Mychasiuk, Harker, Ilnytskyy, & Gibb, 2013). In these studies male rats were stressed for 30 min, twice per day, for 27 consecutive days, and then mated with control female rats. The offspring’s brains were collected either at P21 or P110. Behavioral, epigenetic, and neuroanatomical analyses showed large effects of the preconceptional stress. For example, when tested at P33 or P61, both male and female offspring showed increased anxiety in an elevated plus maze and when tested in a skilled reaching task at P100 they were impaired (see Fig. 4). Epigenetic analysis of littermates killed at P21 showed significantly decreased methylation in frontal cortex (mPFC and adjacent motor cortex) in female but not male rats, and increased methylation in the hippocampus of both sexes. Thus, not only was there an areal difference (frontal cortex versus hippocampus), there was a sex difference in the frontal Please cite this article in press as: Kolb, B., et al. Stress and prefrontal cortical plasticity in the developing brain. Cognitive Development (2017), http://dx.doi.org/10.1016/j.cogdev.2017.01.001
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Table 3 Summary of the effects of preconceptual stress on dendritic morphology in animals killed at P21 or P110. P21 Brains
P110 Brains
Brain weight
D
U
CG3 Branch apical CG3 Length apical CG3 spines apical
U NS D
D U NS
CG3 Branch basilar CG3 Length basilar CG3 spines basilar
NS NS D
NS U NS
AID Branch basilar AID Length basilar AID spines basilar
D D D
NS U U
(Data from Harker et al., 2015, 2016). Abbreviations: NS = No significant effect; U = significant increase; D = significant decrease.
cortex. Anatomical analyses showed changes in all PFC regions but the effects differed with the age of the animals at analysis (see Table 2). Thus, surprisingly, the effects on brain weight were opposite at P21 (lighter) and P110 (heavier), even though there was no effect on body weight at either age. The increased brain weight was completely unexpected, as this has not been found in several gestational or maternal separation studies conducted in our laboratories (e.g., Mychasiuk, Gibb, & Kolb, 2011; Mychasiuk, Gibb, & Kolb, 2012a; Muhammad & Kolb, 2011a). The changes in dendritic complexity and spine density were also primarily opposite at the two ages, as there was a general reduction in dendritic complexity and spine density at P21 but an increase at P110. It is clearly difficult to compare the effects of preconceptional stress in females and males given that the effects differ with the age of analysis of the brains, the duration of the stress, and the “stress recovery time”. The simplest conclusion is that preconceptional stress in either sex has effects on the offspring and although the Bock study did not analyze behavior or epigenetics, in the context of our studies it seems likely that maternal stress would also affect both the behavior and epigenenome of the offspring. 4. Summary of the effects of developmental stress on the PFC Preconception, gestational, and neonatal stress all influence spine density in the adult offspring but the effects vary with age and which parent was stressed. Many of the aforementioned studies also examined dendritic branching and length and although the details of the changes are slightly different than the spine results, the general point is the same: these developmental stressors modify the organization of the PFC in adulthood (see Tables 2 and 3), with results varying according to age at stress and region measured. It is likely that all of these stress effects are mediated by (re)programming of later gene activity in the brains of the offspring. Although we have not emphasized sex differences, and many studies have used only males, there are clear sex differences with a general rule of thumb being that the effects of developmental stress appear to be larger in males. But we must note that there are sex differences in many measures of PFC anatomy in “control” animals (e.g., Kolb & Stewart 1991; Koss, Lloyd, Sadowski, Wise, & Juraska, 2015; Stewart & Kolb, 1988; Willing & Juraska, 2015) so we may be seeing an interaction between baseline and stress effects in the sex-related differences. There is a significant literature looking at the effects of postnatal stressors on the brain morphology in children (see review by Carrion & Wong, 2012) but we are unaware of any human studies examining the effects of preconceptional stress on this measure. Overall, the research demonstrates that children with severe early postnatal stress show significant changes in volume and activity in both the prefrontal cortex and hippocampus, a result consistent with the rodent studies discussed above. Human MRI studies examining children who have experienced preconceptional, gestational, or postnatal stress would be revealing. Acknowledgement The authors thank Natural Science and Engineering Research Council of Canada grants to BK and RG and a Canadian Institute for Advanced Research grant to BK. References Anda, R. F., Felitti, V. J., Bremmer, J. D., Walker, J. D., Whitfield, C., Perry, B. D., et al. (2006). The enduring effects of abuse and related adverse experiencesin childhood: A convergence of evidence from neurobiology and epidemiology. European Archives of Psychiatry and Clinical Neuroscience, 256, 174–186. Bergman, K., Sarkar, P., O’Connor, T. G., Modi, N., & Glover, V. (2007). Maternal stress during pregnancy predicts cognitive ability and fearfulness in infancy. Journal of the American Academy of Child and Adolscent Psychiatry, 46, 1454–1463. Bock, J., Gruss, M., Becker, S., & Braun, K. (2005). Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: Correlation with developmental time windows. Cerebral Cortex, 15, 802–808.
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