Early life adversity reduces affiliative behavior with a stressed cagemate and leads to sex-specific alterations in corticosterone responses in adult mice.

Experiencing early life adversity (ELA) alters stress physiology and increases the risk for developing psychiatric disorders. The social environment can influence dynamics of stress responding and buffer and/or transfer stress across individuals. Yet, the impact of ELA on sensitivity to the stress of others and social behavior following stress is unknown. Here, to test the impact of ELA on social and physiological responses to stress, circulating blood corticosterone (CORT) and social behaviors were assessed in adult male and female mice reared under limited bedding and nesting (LBN) or control conditions. To induce stress, one cagemate of a pair-housed cage underwent a footshock paradigm and was then returned to their unshocked partner. CORT was measured in both groups of mice 20 or 90 min after stress exposure, and social behaviors were recorded and analyzed. ELA rearing influenced the CORT response to stress in a sex-specific manner. In males, both control and ELA-reared mice exhibited similar stress transfer to unshocked cagemates and similar CORT dynamics. In contrast, ELA females showed a heightened stress transfer to unshocked cagemates, and sustained elevation of CORT relative to controls, indicating enhanced stress contagion and a failure to terminate the stress response. Behaviorally, ELA females displayed decreased allogrooming and increased investigative behaviors, while ELA males showed reduced huddling. Together, these findings demonstrate that ELA influenced HPA axis dynamics, social stress contagion and social behavior. Further research is needed to unravel the underlying mechanisms and long-term consequences of ELA on stress systems and their impact on behavioral outcomes.

Elevated prenatal maternal sex hormones, but not placental aromatase, are associated with child neurodevelopment.

Fetal exposure to testosterone may contribute to vulnerability for autism spectrum disorder (ASD). It is hypothesized that placental aromatase prevents fetal exposure to maternal testosterone, however, this pathway and the implications for child neurodevelopment have not been fully explored. We examined the relationships between prenatal maternal testosterone and estradiol at 19.2 ± 1.3 weeks, cord blood testosterone and estradiol at birth, placental aromatase mRNA expression, and neurodevelopment using the Social Communication Questionnaire (SCQ), the Behavioral Assessment System for Children, 3rd Edition (BASC-3), and the Empathizing Quotient for Children (EQ-C) at 4.5-6.5 years of age in a sample of 270 Nulliparous-Mothers-to-be (nuMoM2b) study participants. Maternal testosterone levels were positively associated with SCQ scores, but the association was not significant after adjusting for maternal age at delivery, nor was there a significant interaction with sex. Maternal estradiol levels were negatively associated with BASC-3 Clinical Probability scores among males (n = 139). We report a significant interaction effect of cord blood testosterone and fetal sex on both total SCQ scores and t-scores on the Developmental Social Disorders subscale. Placental aromatase was not associated with any neurodevelopmental or hormone measure, but under conditions of low placental aromatase expression, high maternal testosterone was positively associated with SCQ scores in males (n = 46). No other associations between hormone levels and neurodevelopment were significant. Our findings provide a foundation for further investigation of the mechanisms through which maternal sex hormones and placental steroidogenesis may affect fetal hormone production and neurobehavior.

Age-dependent changes in hormonal stress reactivity following repeated restraint stress throughout adolescence in male rats.

Stress-related psychological dysfunctions show a marked increase during adolescence, yet the mechanisms that mediate these vulnerabilities are unknown. Notably, however, adolescence is associated with changes in hormonal stress reactivity mediated by the hypothalamic-pituitary-adrenal (HPA) axis, which might contribute to these dysfunctions. Specifically, pre-adolescent animals display prolonged stress-induced HPA responses compared to adults. Previous experience with stressors further modify these changes in stress reactivity, such that repeated exposure to the same stressor results in an augmented HPA response prior to adolescence, but a habituated response in adulthood. It is unclear when during adolescence the habituated, adult-like response develops to a repeated stressor. Using male rats at various ages that span adolescence (30-70 days of age), we show that by mid-adolescence (i.e. 42 days of age), animals show neither a facilitated nor a habituated HPA hormonal response following four days of repeated restraint stress (4RS) compared to a single restraint session (1RS). We also show that the habituated HPA response to 4RS develops between late-adolescence and young adulthood (i.e. between 56 and 70 days of age, respectively). Further, we find age- and experience-dependent changes in progesterone and testosterone secretion, indicating that the interaction between development and experience affects stress-induced hormonal responses outside of canonical HPA-related hormones. Despite these hormonal differences mediated by age and experience, repeated restraint stress resulted in decreased fecal boli production at all four ages, suggesting dissociation between hormonal and autonomic reactivity during adolescence. These data indicate that HPA plasticity is significantly affected by adolescence and that a habituated hormonal response to homotypic stress does not occur until young adulthood. A greater appreciation of these changes in stress reactivity will contribute to our understanding of the psychological vulnerabilities often associated with stressful adolescence.

The metamorphosis of adolescent hormonal stress reactivity: A focus on animal models.

As adolescents transition from childhood to adulthood, many physiological and neurobehavioral changes occur. Shifts in neuroendocrine function are one such change, including the hormonal systems that respond to stressors. This review will focus on these hormonal changes, with a particular emphasis on the pubertal and adolescent maturation of the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, this review will concentrate on studies using animal models, as these model systems have contributed a great deal to our mechanistic understanding of how factors such as sex and experience with stressors shape hormonal reactivity during development. Continued study of the maturation of stress reactivity will undoubtedly shed much needed light on the stress-related vulnerabilities often associated with adolescence as well as providing us with possible strategies to mitigate these vulnerabilities. This area of research may lead to discoveries that enhance the well-being of adolescents, ultimately providing them with greater opportunities to mature into healthy adults.

Sex Differences and Similarities in Hippocampal Cellular Proliferation and the Number of Immature Neurons during Adolescence in Rats.

Adolescence is associated with significant reductions in hippocampal cellular proliferation and neurogenesis, the physiological and behavioral implications of which are unclear. Though sex differences exist in these proliferative processes in adulthood, relatively little is known about the role sex plays in these adolescent-related changes. To address this gap, we examined cross-sectional area of the dentate gyrus and cellular proliferation, as measured by Ki-67 immunohistochemistry, in pre- (30 days), mid- (45 days), and post-adolescent (70 days) male and female rats. We also investigated the number of immature neurons using doublecortin (DCX) immunohistochemistry in pre- and post-adolescent males and females. Despite increases in the size of the dentate gyrus during adolescence, we found significant adolescent-related decreases in hippocampal proliferation in both males and females, with a more dramatic decrease in males, indicating both age- and sex-dependent changes in the dentate gyrus. We also found an adolescent-related decline in the number of immature neurons in the dentate gyrus of male rats and a female-biased sex difference in the number of immature neurons in adults. Given these significant changes in the dentate gyrus, these data suggest that this period in development might be particularly sensitive to internal and external factors known to modulate neurogenesis, with potential sex-specific neurobehavioral ramifications.

Dynamic changes in social dominance and mPOA GnRH expression in male mice following social opportunity.

Social competence - the ability of animals to dynamically adjust their social behavior dependent on the current social context - is fundamental to the successful establishment and maintenance of social relationships in group-living species. The social opportunity paradigm, where animals rapidly ascend a social hierarchy following the removal of more dominant individuals, is a well-established approach for studying the neural and neuroendocrine mechanisms underlying socially competent behavior. In the current study, we demonstrate that this paradigm can be successfully adapted for studying socially competent behavior in laboratory mice. Replicating our previous reports, we show that male laboratory mice housed in a semi-natural environment form stable linear social hierarchies. Novel to the current study, we find that subdominant male mice immediately respond to the removal of the alpha male from a hierarchy by initiating a dramatic increase in aggressive behavior towards more subordinate individuals. Consequently, subdominants assume the role of the alpha male. Analysis of brain gene expression in individuals 1h following social ascent indicates elevated gonadotropin-releasing hormone (GnRH) mRNA levels in the medial preoptic area (mPOA) of the hypothalamus compared to individuals that do not experience a social opportunity. Moreover, hormonal analyses indicate that subdominant individuals have increased circulating plasma testosterone levels compared to subordinate individuals. Our findings demonstrate that male mice are able to dynamically and rapidly adjust both behavior and neuroendocrine function in response to changes in social context. Further, we establish the social opportunity paradigm as an ethologically relevant approach for studying social competence and behavioral plasticity in mammals.

Stress-induced oxytocin release and oxytocin cell number and size in prepubertal and adult male and female rats.

Studies indicate that adolescent exposure to stress is a potent environmental factor that contributes to psychological and physiological disorders, though the mechanisms that mediate these dysfunctions are not well understood. Periadolescent animals display greater stress-induced hypothalamic-pituitary-adrenal (HPA) axis responses than adults, which may contribute to these vulnerabilities. In addition to the HPA axis, the hypothalamo-neurohypophyseal tract (HNT) is also activated in response to stress. In adults, stress activates this system resulting in secretion of oxytocin from neurons in the supraoptic (SON) and paraventricular (PVN) nuclei. However, it is currently unknown whether a similar or different response occurs in prepubertal animals. Given the influence of these hormones on a variety of emotional behaviors and physiological systems known to change as an animal transitions into adulthood, we investigated stress-induced HPA and HNT hormonal responses before and after stress, as well as the number and size of oxytocin-containing cells in the SON and PVN of prepubertal (30d) and adult (70d) male and female rats. Though we found the well-established protracted adrenocorticotropic hormone and corticosterone response in prepubertal males and females, only adult males and prepubertal females showed a significant stress-induced increase in plasma oxytocin levels. Moreover, though we found no pubertal changes in the number of oxytocin cells, we did find a pubertal-related increase in oxytocin somal size in both the SON and PVN of males and females. Taken together, these data indicate that neuroendocrine systems can show different patterns of stress reactivity before and after adolescent development and that these responses can be further modified by sex. Given the impact of these hormones on a variety of systems, it will be imperative to further explore these changes in hormonal stress reactivity and their role in adolescent health.

On the causes of early life experience effects: evaluating the role of mom.

Early life experiences are thought to have long-lasting effects on cognitive, emotional, and social function during adulthood. Changes in neuroendocrine function, particularly the hypothalamic-pituitary-adrenal (HPA) axis, contribute to these systems-level behavioral effects. In searching for causal mechanisms underlying these early experience effects, pioneering research has demonstrated an important role for maternal care in offspring development, and this has led to two persistent ideas that permeate current research and thinking: first, environmental impact on the developing infant is mediated through maternal care behavior; second, the more care that a mother provides, the better off her offspring. While a good beginning, the reality is likely more complex. In this review, we critically examine these ideas and propose a computationally-motivated theoretical framework, and within this framework, we consider evidence supporting a hypothesis of maternal modulation. These findings may inform policy decisions in the context of child health and development.

Maternal modulation of novelty effects on physical development.

Familiarity to the mother and the novelty afforded by the postnatal environment are two contrasting sources of neonatal influence. One hypothesis regarding their relationship is the maternal modulation hypothesis, which predicts that the same neonatal stimulation may have different effects depending on the maternal context. Here we tested this hypothesis using physical development, indexed by body weight, as an endpoint and found that, among offspring of mothers with a high initial swim-stress-induced corticosterone (CORT) response, neonatal novelty exposure induced an enhancement in early growth, and among offspring with mothers of a low initial CORT response, the same neonatal stimulation induced an impairment. At an older age, a novelty-induced increase in body weight was also found among offspring of mothers with high postnatal care reliability and a novelty-induced reduction found among offspring of mothers with low care reliability. These results support a maternal modulation of early stimulation effects on physical development and demonstrate that the maternal influence originates from multiple instead of any singular sources. These results (i) significantly extend the findings of maternal modulation from the domain of cognitive development to the domain of physical development; (ii) offer a unifying explanation for a previously inconsistent literature regarding early stimulation effects on body weight; and (iii) highlight the notion that the early experience effect involves no causal primacy but higher order interactions among the initial triggering events and subsequent events involving a multitude of maternal and nonmaternal influences.

Shifts in hormonal stress reactivity during adolescence are not associated with changes in glucocorticoid receptor levels in the brain and pituitary of male rats.

Preadolescent animals display protracted hormonal stress responses mediated by the hypothalamic-pituitary-adrenal (HPA) axis compared to adults. Though the mechanisms that underlie this shift in stress reactivity are unknown, reduced glucocorticoid-dependent negative feedback on the HPA axis has been posited to contribute to this differential responsiveness. As the glucocorticoid receptors (GRs) are integral to this feedback response, we hypothesize that prior to puberty there will be fewer GRs in the neural-pituitary network that mediate negative feedback. To test this hypothesis we measured GR protein levels in the brains of preadolescent (28 days old), midadolescent (40 days old) and adult (77 days old) male rats via immunohistochemistry. Additionally, we assessed stress-induced plasma adrenocorticotropic hormone and corticosterone in prepubertal (30 days old) and adult (70 days old) male rats and examined GR protein levels via Western blot in the brain and pituitary. We found that despite substantial adolescent-related changes in hormonal responsiveness, no significant differences were found between these ages in GR protein levels in regions that are important in negative feedback, including the medial prefrontal cortex, paraventricular nucleus of the hypothalamus, hippocampal formation, and pituitary. These data indicate that the extended hormonal stress response exhibited by preadolescent animals is independent of significant pubertal changes in GR protein levels.

The influence of poststress social factors on hormonal reactivity in prepubertal male rats.

Following a variety of stressors, prepubertal animals display significantly longer hormonal stress responses than adults. Although the mechanisms that mediate this pubertal-related difference in stress reactivity are unclear, previous studies have shown that social interactions are differentially affected by stress in animals before and after puberty. Given the influence of social factors on stress reactivity, we hypothesize the protracted stress-induced hormonal response in prepubertal animals may be in part mediated by aspects of their poststress social environment. We explored this hypothesis by measuring plasma ACTH and corticosterone in prepubertal male rats 15, 30, and 45 min after a 30 min session of restraint stress exposed to one of three social conditions: recovering in the presence of a stressed cage mate; recovering in the presence of a nonstressed cage mate; and recovering in the absence of a cage mate. We report here that although prepubertal and adult animals display different hormonal responses following restraint, the presence or absence of stressed cage mates has little impact on the poststress hormonal response in prepubertal males. We do, however, show that social factors can alter HPA reactivity in prepubertal animals, in that significant hormonal responses are evoked in nonstressed animals exposed to a stressed cage mate, an effect not found in adults. Collectively, these data indicate that although the poststress social environment does not play a role in mediating the protracted hormonal response in prepubertal animals, the social context can significantly influence HPA activation in otherwise unstressed animals prior to puberty.

Changes in hypothalamic-pituitary-adrenal stress responsiveness before and after puberty in rats.

This article is part of a Special Issue "Puberty and Adolescence". Many endocrine changes are associated with pubertal and adolescent development. One such change is the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to physical and/or psychological stressors. Recent human and non-human animal studies have shown that hormonal stress reactivity increases significantly throughout puberty and adolescence. Specifically, exposure to various stressors results in greater adrenocorticotropic hormone (ACTH) and glucocorticoid responses in peripubertal compared to adult animals. This review will focus on how stress reactivity changes throughout puberty and adolescence, as well as potential mechanisms that mediate these changes in stress responsiveness. Though the implications of these pubertal shifts in stress responsiveness are not fully understood, the significant increase in stress-related mental and physical dysfunctions during this stage of development highlights the importance of studying pubertal and adolescent maturation of HPA function and its reactivity to stress.

Metabolic dysfunctions following chronic oral corticosterone are modified by adolescence and sex in mice.

Adolescence is a period of development in which shifts in responses to glucocorticoids is well-documented. Obesity and metabolic syndrome are substantial health issues whose rates continue to rise in both adult and adolescent populations. Though many interacting factors contribute to these dysfunctions, how these shifts in glucocorticoid responses may be related remain unknown. Using a model of oral corticosterone (CORT) exposure in male and female mice, we demonstrate differential responses during adolescence (30-58 days of age) or adulthood (70-98 day of age) in endpoints relevant to metabolic function. Our data indicate that CORT resulted in significant weight gain in adult- and adolescent-exposed females and adult-exposed males, but not adolescent-exposed males. Despite this difference, all animals treated with high levels of CORT showed significant increases in white adipose tissue, indicating a dissociation between weight gain and adiposity in adolescent-treated males. Similarly, all experimental groups showed significant increases in plasma insulin, leptin, and triglyceride levels, further suggesting potential disconnects between overt weight gain, and underlying metabolic dysregulation. Finally, we found age- and dose-dependent changes in the expression of hepatic genes important in glucocorticoid receptor and lipid regulation, which showed different patterns in males and females. Thus, altered transcriptional pathways in the liver might be contributing differentially to the similar metabolic phenotype observed among these experimental groups. We also show that despite little CORT-induced changes in the hypothalamic levels of orexin-A and NPY, we found that food and fluid intake were elevated in adolescent-treated males and females. These data indicate chronic exposure to elevated glucocorticoid levels results in metabolic dysfunction in both males and females, which can be further modulated by developmental stage.

Early life adversity reduces affiliative behavior towards a distressed cagemate and leads to sex-specific alterations in corticosterone responses.

Experiencing early life adversity (ELA) alters stress physiology and increases the risk for developing psychiatric disorders. The social environment can influence dynamics of stress responding and buffer and/or transfer stress across individuals. Yet, the impact of ELA on sensitivity to the stress of others and social behavior following stress is unknown. Here, to test the impact of ELA on social and physiological responses to stress, circulating blood corticosterone (CORT) and social behaviors were assessed in adult male and female mice reared under limited bedding and nesting (LBN) or control conditions. To induce stress, one cagemate of a pair-housed cage underwent a footshock paradigm and was then returned to their unshocked partner. CORT was measured in both mice 20 or 90 minutes after stress exposure, and social behaviors were recorded and analyzed. ELA rearing influenced the CORT response to stress in a sex-specific manner. In males, both control and ELA-reared mice exhibited similar stress transfer to unshocked cagemates and similar CORT dynamics. In contrast, ELA females showed a heightened stress transfer to unshocked cagemates, and sustained elevation of CORT relative to controls, indicating enhanced stress contagion and a failure to terminate the stress response. Behaviorally, ELA females displayed decreased allogrooming and increased investigative behaviors, while ELA males showed reduced huddling. Together, these findings demonstrate that ELA influenced HPA axis dynamics, social stress contagion and social behavior. Further research is needed to unravel the underlying mechanisms and long-term consequences of ELA on stress systems and their impact on behavioral outcomes.

Neonatal novelty-induced persistent enhancement in offspring spatial memory and the modulatory role of maternal self-stress regulation.

Development of spatial memory in the rat is influenced by both maternal and nonmaternal aspects of the postnatal environment. Yet it remains poorly understood how these two aspects of the postnatal environment interact to program offspring cognitive development. By considering the joint influence of neonatal environmental novelty and maternal self-stress regulation on the development of spatial memory function in Long-Evans hooded rats, we show a persistent neonatal novelty-induced enhancement in spatial reference and working memory functions among the same individual offspring from juvenility to adulthood and a contrasting transient maternal modulatory influence on this novelty-related enhancement present during only juvenility. Specifically, at and only at juvenility, for mothers with good self-stress regulation as indexed by a low circulating basal corticosterone level, offspring showed a novelty-induced enhancement in spatial memory function, whereas for mothers with poor self-stress regulation, indexed by a high basal corticosterone level, offspring showed little enhancement or even small impairments. These findings indicate that maternal and nonmaternal postnatal environments exert separate but interacting influences on offspring cognitive development and support a maternal modulation model of cognitive development that considers maternal self-stress regulation as an important factor among the multitude of maternal influences.

The role of testicular hormones and luteinizing hormone in spatial memory in adult male rats.

Attempts to determine the influence of testicular hormones on learning and memory in males have yielded contradictory results. The present studies examined whether testicular hormones are important for maximal levels of spatial memory in young adult male rats. To minimize any effect of stress, we used the Object Location Task which is a spatial working memory task that does not involve food or water deprivation or aversive stimuli for motivation. In Experiment 1 sham gonadectomized male rats demonstrated robust spatial memory, but gonadectomized males showed diminished spatial memory. In Experiment 2 subcutaneous testosterone (T) capsules restored spatial memory performance in gonadectomized male rats, while rats with blank capsules demonstrated compromised spatial memory. In Experiment 3, gonadectomized male rats implanted with blank capsules again showed compromised spatial memory, while those with T, dihydrotestosterone (DHT), or estradiol (E) capsules demonstrated robust spatial memory, indicating that T's effects may be mediated by its conversion to E or to DHT. Gonadectomized male rats injected with Antide, a gonadotropin-releasing hormone receptor antagonist which lowers luteinizing hormone levels, also demonstrated spatial memory, comparable to that shown by T-, E-, or DHT-treated males. These data indicate that testicular androgens are important for maximal levels of spatial working memory in male rats, that testosterone may be converted to E and/or DHT to exert its effects, and that some of the effects of these steroid hormones may occur via negative feedback effects on LH.

An undergraduate laboratory exercise examining the psychomotor stimulant effects of caffeine in laboratory rats.

This paper describes an exercise in a Systems and Behavioral Neuroscience with Laboratory class, an introductory laboratory class taken by Barnard College students majoring in a wide range of academic topics. The study took place over three weeks, allowing students to assess the effects of caffeine on motor stimulation in laboratory rats. The within-subject design involved injecting rats with three different caffeine doses and measuring five different motor outputs in a standard open field. Students completed four different assignments related to this study, demonstrating acquisition of the stated learning goals. This lab exercise allowed students to learn about basal ganglia neural circuitry and stimulant pharmacology, to work directly with an animal model, and to generate enough data to perform statistical analyses. Course evaluations suggest that students liked learning about caffeine, a stimulant many of them have personal experience consuming. They also expressed appreciation for working with rats and for learning how to analyze data. This study can easily be implemented at most undergraduate institutions under minimal cost. The wide-ranging effects of caffeine also permit for flexibility in experimental design, allowing instructors and students options for different avenues of investigation.

Pubertal changes in the pituitary and adrenal glands of male and female rats: Relevance to stress reactivity.

The hormonal stress response mediated by the hypothalamic-pituitary-adrenal (HPA) axis changes significantly during puberty in a variety of species, including humans. For example, stress-induced adrenocorticotropic hormone (ACTH) and corticosterone responses are greater in prepubertal compared to adult rats, yet the mechanisms that mediate these age-related differences are unclear. It is possible that the pituitary and adrenal glands have higher hormonal concentrations prior to puberty, thus enabling a greater hormonal response if a stressor were to occur. Thus, we tested the hypothesis that resting levels of ACTH, and its precursor, proopiomelanocortin (POMC), are higher in the pituitary, and corticosterone levels are higher in the adrenals, of prepubertal compared to adult rats. Furthermore, to investigate any potential sex differences in these parameters, both males and females were assessed. Here we report that despite similar circulating plasma ACTH and corticosterone levels, prepubertal males and females have greater ACTH levels in the pituitary and greater corticosterone concentrations in the adrenals compared to adult males and females. Moreover, we show that POMC protein levels are significantly greater in the pituitary gland of prepubertal than adult rats, particularly in prepubertal females. These data suggest that increased glandular production of ACTH and corticosterone during puberty in part mediate pubertal differences in hormonal stress reactivity and highlight how each node of the HPA axis may contribute to these developmental changes. Given the dramatic increase in stress-related dysfunctions during puberty, continued study of all parts of the HPA axis will be imperative.

Hypertensive disorders during pregnancy and polycystic ovary syndrome are associated with child communication and social skills in a sex-specific and androgen-dependent manner.

Prenatal exposure to testosterone is implicated in the etiology of autism spectrum disorder (ASD). Hypertensive disorders of pregnancy and polycystic ovary syndrome are associated with both hyperandrogenism and increased risk for ASD. We examined whether increased maternal testosterone mediates the relationship between these hyperandrogenic disorders (HDs) during pregnancy and child communication and social skills. Maternal plasma was collected during the second trimester and parent-report measures of child communication and social skills were obtained at 4.5-6.5 years of age from 270 participants enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). Our retrospective frequency-matched cohort study design identified 58 mothers with one or both of the HDs and 58 matched controls. Women diagnosed with an HD who carried a female had higher testosterone levels compared to those carrying a male (t(56) = -2.70, p = 0.01). Compared to females controls, females born to women with an HD had significantly higher scores on the Social Communication Questionnaire (t(114) = -2.82, p =0.01). Maternal testosterone partially mediated the relationship between a diagnosis of an HD and SCQ scores among females. These findings point to sex-specific associations of two HDs - hypertensive disorders of pregnancy and polycystic ovary syndrome - on child communication and social skills and a mediating effect of maternal testosterone during pregnancy. Further research is needed to understand placental-mediated effects of maternal testosterone on child brain development and neurodevelopmental outcomes.

Pubertal maturation and programming of hypothalamic-pituitary-adrenal reactivity.

Modifications in neuroendocrine function are a hallmark of pubertal development. These changes have many short- and long-term implications for the physiological and neurobehavioral function of an individual. The purpose of the present review is to discuss our current understanding of how pubertal development and stress interact to affect the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine axis that controls the hormonal stress response. A growing body of literature indicates that puberty is marked by dramatic transitions in stress reactivity. Moreover, recent studies indicate that exposure to stressors during pubertal maturation may result in enduring changes in HPA responsiveness in adulthood. As puberty is marked by a substantial increase in many stress-related psychological and physiological disorders (e.g., depression, anxiety, drug abuse), it is essential to understand the factors that regulate and modulate HPA function during this crucial period of development.