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Lasting Impact of Chronic Adolescent Stress and Glucocorticoid Receptor Selective Modulation in Male and Female Rats.

ABSTRACT: Adolescent animals are vulnerable to the effects of stress on brain development. We hypothesized that long-term effects of adolescent chronic stress are mediated by glucocorticoid receptor (GR) signaling. We used a specific GR modulator (CORT108297) to pharmacologically disrupt GR signaling in adolescent rats during exposure to chronic variable stress (CVS). Male and female rats received 30?mg/kg of drug during a 2-week CVS protocol starting at PND46. Emotional reactivity (open field) and coping behaviors (forced swim test (FST)) were then tested in adulthood, 5 weeks after the end of the CVS protocol. Blood samples were collected two days before FST and serial samples after the onset of the swim test to determine baseline and stress response levels of HPA hormones respectively. Our results support differential behavioral, physiological and stress circuit reactivity to adolescent chronic stress exposure in males and females, with variable involvement of GR signaling. In response to adolescent stress, males had heightened reactivity to novelty and exhibited marked reduction in neuronal excitation following swim stress in adulthood, whereas females developed a passive coping strategy in the FST and enhanced HPA axis stress reactivity. Only the latter effect was attenuated by treatment with the GR modulator C108297. In summary, our data suggest that adolescent stress differentially affects emotional behavior and circuit development in males and females, and that GR manipulation during stress can reverse at least some of these effects.

SUBMITTER: Cotella EM

PROVIDER: S-EPMC7391799 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Lasting Impact of Chronic Adolescent Stress and Glucocorticoid Receptor Selective Modulation in Male and Female Rats.

Cotella Evelin M EM Morano Rachel L RL Wulsin Aynara C AC Martelle Susan M SM Lemen Paige P Fitzgerald Maureen M Packard Benjamin A BA Moloney Rachel D RD Herman James P JP

Psychoneuroendocrinology 20191027

Adolescent animals are vulnerable to the effects of stress on brain development. We hypothesized that long-term effects of adolescent chronic stress are mediated by glucocorticoid receptor (GR) signaling. We used a specific GR modulator (CORT108297) to pharmacologically disrupt GR signaling in adolescent rats during exposure to chronic variable stress (CVS). Male and female rats received 30 mg/kg of drug during a 2-week CVS protocol starting at PND46. Emotional reactivity (open field) and coping ...[more]

PMID: 31786480

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Project description:Stress early in life can have a major impact on brain development, and there is increasing evidence that childhood stress confers vulnerability for later developing psychiatric disorders. In particular, during peri-adolescence, brain regions crucial for emotional regulation, such as the prefrontal cortex (PFC), amygdala (AMY) and hippocampus (HPC), are still developing and are highly sensitive to stress. Changes in myelin levels have been implicated in mental illnesses and stress effects on myelin and oligodendrocytes (OLs) are beginning to be explored as a novel and underappreciated mechanism underlying psychopathologies. Yet there is little research on the effects of acute stress on myelin during peri-adolescence, and even less work exploring sex-differences. Here, we used a rodent model to test the hypothesis that exposure to acute traumatic stress as a juvenile would induce changes in OLs and myelin content across limbic brain regions. Male and female juvenile rats underwent 3 h of restraint stress with exposure to a predator odor on postnatal day (p) 28. Acute stress induced a physiological response, increasing corticosterone release and reducing weight gain in stress-exposed animals. Brain sections containing the PFC, AMY and HPC were taken either in adolescence (p40), or in adulthood (p95) and stained for markers of OLs and myelin. We found that acute stress induced sex-specific changes in grey matter (GM) myelination and OLs in both the short- and long-term. Exposure to a single stressor as a juvenile increased GM myelin content in the AMY and HPC in p40 males, compared to the respective control group. At p40, corticosterone release during stress exposure was also positively correlated with GM myelin content in the AMY of male rats. Single exposure to juvenile stress also led to long-term effects exclusively in female rats. Compared to controls, stress-exposed females showed reduced GM myelin content in all three brain regions. Acute stress exposure decreased PFC and HPC OL density in p40 females, perhaps contributing towards this observed long-term decrease in myelin content. Overall, our findings suggest that the juvenile brain is vulnerable to exposure to a brief severe stressor. Exposure to a single short traumatic event during peri-adolescence produces long-lasting changes in GM myelin content in the adult brain of female, but not male, rats. These findings highlight myelin plasticity as a potential contributor to sex-specific sensitivity to perturbation during a critical window of development.

Project description:Anxiety disorders and nicotine use are significant contributors to global morbidity and mortality as independent and comorbid diseases. Early-life stress, potentially via stress-induced hypothalamic-pituitary-adrenal axis (HPA) dysregulation, can exacerbate both. However, little is known about the factors that predispose individuals to the development of both anxiety disorders and nicotine use. Here, we examined the relationship between anxiety-like behaviors and nicotine responses following adolescent stress. Adolescent male and female BALB/cJ mice were exposed to either chronic variable social stress (CVSS) or control conditions. CVSS consisted of repeated cycles of social isolation and social reorganization. In adulthood, anxiety-like behavior and social avoidance were measured using the elevated plus-maze (EPM) and social approach-avoidance test, respectively. Nicotine responses were assessed with acute effects on body temperature, corticosterone production, locomotor activity, and voluntary oral nicotine consumption. Adolescent stress had sex-dependent effects on nicotine responses and exploratory behavior, but did not affect anxiety-like behavior or social avoidance in males or females. Adult CVSS males exhibited less exploratory behavior, as indicated by reduced exploratory locomotion in the EPM and social approach-avoidance test, compared to controls. Adolescent stress did not affect nicotine-induced hypothermia in either sex, but CVSS males exhibited augmented nicotine-induced locomotion during late adolescence and voluntarily consumed less nicotine during adulthood. Stress effects on male nicotine-induced locomotion were associated with individual differences in exploratory locomotion in the EPM and social approach-avoidance test. Relative to controls, adult CVSS males and females also exhibited reduced corticosterone levels at baseline and adult male CVSS mice exhibited increased corticosterone levels following an acute nicotine injection. Results suggest that the altered nicotine responses observed in CVSS males may be associated with HPA dysregulation. Taken together, adolescent social stress influences later-life nicotine responses and exploratory behavior. However, there is little evidence of an association between nicotine responses and prototypical anxiety-like behavior or social avoidance in BALB/cJ mice.

Dataset Information

Lasting Impact of Chronic Adolescent Stress and Glucocorticoid Receptor Selective Modulation in Male and Female Rats.

Publications

Lasting Impact of Chronic Adolescent Stress and Glucocorticoid Receptor Selective Modulation in Male and Female Rats.

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