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The amygdala is a heterogeneous group of nuclei that plays a role in emotional and social learning. As such, there has been increased interest in its development in adolescent animals, a period in which emotional/social learning increases dramatically. While many mechanisms of amygdala development have been studied, the role of cell proliferation during adolescence has received less attention. Using bromodeoxyuridine (BrdU) injections in adolescent and adult rats, we previously found an almost fivefold increase in BrdU-positive cells in the amygdala of adolescents compared to adults. Approximately one third of BrdU-labeled cells in the amygdala contained the putative neural marker doublecortin (DCX), suggesting a potential for neurogenesis. To further investigate this possibility in adolescents, we examined the proliferative dynamics of DCX/BrdU-labeled cells. Surprisingly, DCX/BrdU-positive cells were found to comprise a stable subpopulation of BrdU-containing cells across survivals up to 56 days, and there was no evidence of neural maturation by 28 days after BrdU injection. Additionally, we found that approximately 50% of BrdU+ cells within the adolescent amygdala contain neural-glial antigen (NG2) and are therefore presumptive oligodendrocyte precursors (OPCs). We next characterized the response to a short-lived stressor (3-day repeated variable stress, RVS). The total BrdU-labeled cell number decreased by ∼30% by 13 days following RVS (10 days post-BrdU injection) as assessed by stereologic counting methods, but the DCX/BrdU-labeled subpopulation was relatively resistant to RVS effects. In contrast, NG2/BrdU-labeled cells were strongly influenced by RVS. We conclude that typical neurogenesis is not a feature of the adolescent amygdala. These findings point to several possibilities, including the possibility that DCX/BrdU cells are late-developing neural precursors, or a unique subtype of NG2 cell that is relatively resistant to stress. In contrast, many proliferating OPCs are significantly impacted by a short-lived stressor, suggesting consequences for myelination in the developing amygdala., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Exposure to traumatic stressors typically causes lasting changes in emotionality and behavior. However, coping strategies have been shown to prevent and alleviate many stress consequences and the biological mechanisms that underlie coping are of great interest. Whereas the laboratory stressor inescapable tail-shock induces anxiety-like behaviors, here we demonstrate that permitting a rat to chew on a wooden dowel during administration of tail-shock prevented the development of anxiety like behaviors in the open field and juvenile social exploration tests. Uncontrollable stressors increase corticosterone and decrease thyroid hormone, and we hypothesized that coping would blunt these changes. While tail-shock did produce these effects, active coping did not alter hormone levels. The dissociation between behavioral resilience and circulating hormones is discussed with regard to the utility of these molecules as biomarkers for psychiatric disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Adolescence is a developmental time period marked by rapid changes in behavior and brain structure. Stress during adolescence has been shown to cause long-lasting behavioral changes, including increased anxiety- and depression-like behavior, in both rats and humans. These findings have led to the hypothesis that adolescence may be a particularly vulnerable or sensitive period for stress exposure. To investigate this hypothesis, we directly compared the effects of a 3-day stress exposure during either an adolescent (post natal day (PND) 27-29) or adult (PND 72-74) time window on exploratory behavior in male rats, measured 6 weeks post-stress (PND 72 or PND 117). Exploratory behavior was tested in both 'anxiogenic' and 'anxiolytic' environments, using the open field and novel object tests, respectively. We hypothesized that rats stressed as adolescents would show greater behavioral changes than rats stressed as adults. Contrary to our hypothesis, we found a decrease in exploratory behavior in the open-field test in both age groups. Furthermore, the magnitude of difference between stress and age-matched control animals was similar between age groups. In contrast, stress had no effect at either age in the novel object test, a more anxiolytic environment. Older adults showed decreased exploration in the novel object test compared to the younger adults, regardless of stress experience. These results suggest that adolescence is not a sensitive period for the effects of repeated variable stress on exploratory behavior in an anxiogenic environment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Thyroid hormones are essential regulators of growth, development and normal bodily function and their release is coordinated by the hypothalamic-pituitary-thyroid (HPT) axis. While the HPT axis has been established as an acutely stress-responsive neuroendocrine system, relatively little is known about the mechanisms of its stress regulation. The present study examined acute stress-induced changes in peripheral hormone levels [triiodothyronine (T3); thyroxine (T4), thyroid-stimulating hormone (TSH), reverse triiodothyronine (rT3)] and central mRNA levels of regulators of the HPT axis [thyrotropin-releasing hormone (TRH), somatostatin (SST), type II deiodinase (D2)] in response to an inescapable tail-shock, a rodent model of stress. Additionally, we examined whether individual differences in spontaneous exploratory behavior in an open field test predicted basal levels of TH or differential susceptibility to the effects of stress. The stress condition was associated with decreases in peripheral T3, T4 and TSH, but not rT3, when compared with controls. No changes were observed in TRH or SST mRNA levels, but there was a trend suggesting stress-related increases in D2 mRNA. We also found that an animal's exploratory behavior in an unfamiliar open field arena was positively related to peripheral thyroid hormone levels and predicted the magnitude of stress-induced changes. In conclusion, we found suggestive evidence for stress-induced decrease in central drive HPT axis, but the central mechanisms of its stress regulation remain to be elucidated. Additionally, we found that individual differences in animals' exploratory behavior were correlated with peripheral TH levels., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Understanding environmental effects on mouse brain development would allow us to take advantage of powerful genetic tools to determine the interaction between genetic and epigenetic factors governing brain development in C57BL/6 mice. Experiment 1 examined whether time of day for neonatal manipulations affects adult stress-induced hormone secretion. Three rearing groups were examined: early handled (EH; dam removed 10 min/day); maternal separated (MS; dam removed 180 min/day); and an animal facility raised (AFR) control. Separations occurred during either the first or last 3 h of the light phase. Corticosterone (CORT) secretion in response to 100 dB white noise was assessed in adulthood. Both EH and MS males separated during the last 3 h of the light phase exhibited blunted stress-induced CORT compared to all other groups. Experiment 2 varied time of behavior testing. A fourth group was also added: maternal isolated (MI; separated from dam and littermates 180 min/day). Adult male behavior was assessed in three different tests. EH males tested in the elevated zero maze (EZM) during the light phase and MS males tested in the EZM during the dark phase exhibited diminished anxiety-like behavior compared to the other groups. We conclude that the EH protocol is marginally effective in blunting stress-induced CORT secretion and anxiety-like behavior in C57BL/6 mice, and these early handling effects are influenced by time of day. We also conclude that the 3 h MS or MI protocol is not effective in exacerbating future adult stress-induced CORT secretion or anxiety-like behavior in C57BL/6 mice.

There has been little research on effects of chronic stressors on neuroendocrine function in adolescence despite increasing evidence of enduring effects of stressors during this period on behaviour in adulthood. We previously reported that social stress (SS: daily 1 h isolation and new cage partner for 16 days) in adolescence altered locomotor responses to psychostimulants in adulthood. Here, we investigated neuroendocrine responses over the duration of the procedure that may underlie the enduring effects of SS. SS rats were compared to rats undergoing daily isolation only (ISO) and controls (CTL) to determine responses to acute and repeated isolation with and without social instability. At 30 days of age (first isolation), higher plasma corticosterone and corticotrophin-releasing hormone (CRH) mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus and in the central nucleus of the amygdala (CeA) were found in males caged with a new partner (SS) after isolation than those returned to their original partner (ISO). On day 45, SS males and females showed less habituation (higher bioactive levels of corticosterone based on plasma corticosterone and corticosteroid binding globulin levels) to the 16th episode of isolation than did ISO. SS and ISO had higher baseline expression of CRH mRNA in the PVN on day 45 than did CTL, and only CTL had increased levels after isolation. CRH mRNA expression in the CeA increased to a first isolation in CTL and to a 16th isolation in SS but not in ISO males. Modest differences in social interactions were observed between SS and ISO when returned to their cages after isolation. The results suggest that mild social stressors in adolescence impede neuroendocrine adaptation to homotypic stressors. The resultant increase in exposure to glucocorticoids over adolescence may alter ongoing brain development and increase vulnerability to psychopathology.

Changes in peripheral thyroid hormone levels are associated with changes in human affective disorders, particularly depression. In the current study we used an animal stress paradigm, proposed to be an animal model of depression, to examine peripheral T(3) levels during and after escapable or inescapable stress in adult male rats. In this model, one animal can control the termination of foot-shock stress by performing a lever press, and therefore experiences escapable stress. His lever press also terminates the shock for his yoked partner, who has no control over the stressor, and therefore experiences inescapable stress. In three separate experiments, blood samples were collected during and after one or two sessions of escapable/inescapable stress. We found that exposure to inescapable stress, but not escapable stress, caused a decrease in T(3) levels 120 min post-stress initiation. Peripheral T(3) levels were not significantly altered in animals exposed to escapable stress. In sum, these results add to a large body of previous data indicating that psychological coping can prevent the effects of physical stress on many diverse systems.

Previous work has indicated that acute and repeated stress can alter thyroid hormone secretion. Corticosterone, the end product of hypothalamic-pituitary-adrenal (HPA) axis activation and strongly regulated by stress, has been suggested to play a role in hypothalamic-pituitary-thyroid (HPT) axis regulation. In the current study, we sought to further characterize HPT axis activity after repeated exposure to inescapable foot-shock stress (FS), and to examine changes in proposed regulators of the HPT axis, including plasma corticosterone and hypothalamic arcuate nucleus agouti-related protein (AGRP) mRNA levels. Adult male Sprague-Dawley rats were subjected to one daily session of inescapable FS for 14 days. Plasma corticosterone levels were determined during and after the stress on days 1 and 14. Animals were killed on day 15, and trunk blood and brains were collected for measurement of hormone and mRNA levels. Repeated exposure to FS led to a significant decrease in serum levels of 3,5,3'-triiodothyronine (T3) and 3,5,3',5'-tetraiodothyronine (T4). Stress-induced plasma corticosterone levels were not altered by repeated exposure to the stress. Despite the decrease in peripheral hormone levels, thyrotropin-releasing hormone (TRH) mRNA levels within the paraventricular nucleus of the hypothalamus were not altered by the stress paradigm. Arcuate nucleus AGRP mRNA levels were significantly increased in the animals exposed to repeated FS. Additionally, we noted significant correlations between stress-induced plasma corticosterone levels and components of the HPT axis, including TRH mRNA levels and free T4 levels. Additionally, there was a significant correlation between AGRP mRNA levels and total T3 levels. Changes in body weight were also correlated with peripheral corticosterone and TRH mRNA levels. These results suggest that repeated exposure to mild-electric foot-shock causes a decrease in peripheral thyroid hormone levels, and that components of the HPA axis and hypothalamic AGRP may be involved in stress regulation of the HPT., ((c) 2005 S. Karger AG, Basel)

This study investigated the effects of neonatal handling and maternal separation on the development of anxiety behavior and the hypothalamic-pituitary-adrenal axis of C57BL/6 mice. We hypothesized short periods of neonatal handling would diminish anxiety and secretion of corticosterone, while longer periods of maternal separation would elevate anxiety and plasma corticosterone compared to a nonhandled group. Mice were bred and reared as follows. After birth, each litter was assigned to one of four groups: mother and pups removed from the home cage for 10 min (group 1) or 180 min a day (group 2); mother only removed from home cage 180 min a day (group 3); and no handling until weaning (group 4). All separation occurred on the first 10 days of life. Juvenile males that experienced 10 min of separation/day exhibited decreased anxiety behavior compared to all other mice. A second group of litters were bred and reared according to groups 1, 2, and 4 as described above. Upon adulthood, anxiety behavior was assessed in males, and the corticosterone response to an acoustic stressor was quantified. No effect of differential rearing was observed on behavior, but there was a marked effect on plasma corticosterone secretion between the groups. Adult male mice neonatally handled for 10 min/day exhibited a blunted corticosterone response, and mice that experienced 180 min of maternal separation exhibited a prolonged corticosterone response to the acoustic stimulus compared to the nonhandled group. These results demonstrate the development of the mouse's hypothalamic-pituitary-adrenal axis can be modified by neonatal rearing conditions, and suggest that the mouse could be a viable animal model to determine the genetic-environmental interactions governing brain development.

Stress decreases sexual activity. However, emerging research suggests that the psychological aspect of control prevents the detrimental effects of stress on male mating behaviour. The present study examined the effects of chronic escapable/inescapable stress on mating behaviour in the male Syrian hamster. Additionally, the ability of the antidepressant clomipramine to prevent the adverse effects of stress on mating behaviour was explored. In this paradigm, two groups received the same electric footshock stress, but differed in the psychological aspect of control. Cohorts were divided into two groups. One group received clomipramine via a sugar water solution while the other received plain sugar water. Mating behaviour was quantified before and after 12 consecutive days of stress. The morning following the final stress and behaviour session, trunk blood and brains were collected to assess: (i) plasma concentrations of testosterone and glucocorticoids and (ii) corticotropin-releasing hormone (CRH) mRNA expression within the paraventricular nucleus of the hypothalamus (PVN). In the drug-free groups, several aspects of mating behaviour were disrupted by inescapable but not escapable stress, including anogenital investigation before the first ejaculation and time of first ejaculation. Additionally, both escapable and inescapable stress caused a decrease in total hit rate compared to the no-stress control group. Unlike the sugar-water treated animals, hamsters in either stress condition receiving clomipramine showed no differences in anogenital investigation, time of first ejaculation, hit rate, or any other aspect of mating behaviour measured, compared to the clomipramine no-stress control males. The stress-induced inhibition of mating behaviour could not be explained by changes in baseline plasma concentrations of testosterone or total glucocorticoids; these values did not vary between any of the six treatment groups. It was found that clomipramine lowers CRH mRNA expression in the PVN by 74%, regardless of stressor conditions. The results of the present study have broad implications for understanding the relationships between stress, depression and reproduction, and for the treatment of people and animals suffering from the adverse effects of stress.

Stress decreases sexual activity, but it is uncertain which aspects of stress are detrimental to reproduction. This study used an escapable/inescapable stress paradigm to attempt to dissociate physical from psychological components of stress, and assess each component's impact on reproductive behavior in the male Syrian hamster (Mesocricetus auratus). Two experiments were completed using this protocol where two animals receive the same physical stressor (an electric footshock) but differ in the psychological aspect of control. One group (executive) could terminate the shock for themselves as well as a second group (yoked) by pressing a bar. Experiment 1 demonstrated a significant increase in plasma glucocorticoids at the end of a single 90-min stress session with no difference in glucocorticoid levels between the executive and yoked groups at any time point. Experiment 2 quantified male reproductive behavior prior to and immediately following 12 days of escapable or inescapable stress in executive, yoked, and no-stress control hamsters (n = 12/group). Repeated-measures analysis of variance revealed a number of significant changes in reproductive behavior before and after stress in the three treatment groups. The most striking difference was a decrease in hit rate observed only in the animals that could not control their stress (yoked group). Hit rate in the executive males that received the exact same physical stressor but could terminate the shock by pressing a bar was nearly identical to control animals that never received any foot shock. Therefore, we conclude that coping or control can ameliorate the negative effects of stress on male reproductive behavior.

The goal of this article is to describe some of the central nervous system circuits involved in the regulation of the hypothalamopituitary-adrenocortical (HPA) axis, with an emphasis on animal models believed to mimic the human experience of emotional stress. First, the basic constitutive elements of the HPA axis that control glucocorticoid secretion are reviewed. A description of the neural systems assumed to regulate the activity of the HPA axis, both anatomically and functionally, follows. It is argued that hypothalamic, septal and bed nucleus of the stria terminalis neurons are involved in the regulation of the HPA axis by situations eliciting emotional responses.

States of chronic undernutrition can cause a profound suppression of reproductive function. To begin to determine the time course and the nature of the mechanism by which undernutrition suppresses the activity of the reproductive axis we have examined the effects of brief periods of fasting on reproductive hormone secretion in men and male rhesus monkeys. In monkeys there is a significant suppression of pulsatile luteinizing hormone (LH) and testosterone secretion after a single day of fasting, that is apparent within the first 4 h after a meal is missed. The suppression of pulsatile LH secretion on a day of fasting does not appear to be caused by the psychological stress experienced when monkeys are deprived of their daily meal in that monkeys who are maintained in a metabolically fed state (by feeding a large excess of food on the day prior to fasting), but are deprived of a meal and displayed behavioural agitation associated with fasting, have no suppression of LH secretion. The suppression of LH secretion on a day of fasting cannot be reversed by naloxone infusion, indicating that increased secretion of opioid peptides is not the primary mechanism causing the decrease in the central drive to the reproductive axis during fasting.(ABSTRACT TRUNCATED AT 250 WORDS)