Chronic restraint stress in adolescence differentially influences hypothalamic‐pituitary‐adrenal axis function and adult hippocampal neurogenesis in male and female rats

Abstract

Previous studies have shown a relationship between adversity in adolescence and health outcomes in adulthood in a sex-specific manner. Adolescence is characterized by major changes in stress-responsive regions of the brain, including the hippocampus, the site of ongoing neurogenesis throughout the lifespan. Prepubertal male and female rats exhibit different acute reactions to chronic stress compared to adults, but less is known about whether these stress-induced changes persist into adulthood. Therefore, in this study, we investigated the effects of chronic, intermittent stress during adolescence on basal corticosterone levels, dentate gyrus (DG) volume, and neurogenesis in the hippocampus of adult male and female Sprague-Dawley rats. Adolescent male and female rats were either restrained for 1 h every other day for 3 weeks from postnatal days (PDs) 30-52 at unpredictable times or left undisturbed. All rats received a single injection of bromodeoxyuridine (BrdU; 200 mg/kg) in adulthood on PD70 and were perfused 3 weeks later. Brains were processed for Ki67 (endogenous marker of cell proliferation) and BrdU (to estimate effects on cell survival). In addition, blood samples were taken during the restraint stress period and in adulthood. Results show that males and females exhibit different corticosterone responses to chronic stress during adolescence and that only adult female rats exposed to stress during adolescence show higher basal corticosterone levels compared to nonstressed controls. Furthermore, stressed females showed a reduced number of proliferating and surviving cells in the DG in adulthood compared to nonstressed same-sex controls. The majority of BrdU-labeled cells were co-labeled with NeuN, an endogenous marker of mature neurons, indicating that neurogenesis was decreased in the DG of adult female rats that had undergone chronic restraint stress in adolescence. Although male rats were more responsive to the chronic stress as adolescents showing higher corticosterone levels and reduced body weight, as adults they showed a slight increase in cell survival and no effect of adolescent stress on basal corticosterone levels. These results suggest that stress during adolescence can have effects on hypothalamic-pituitary-adrenal axis function and hippocampus plasticity in adulthood, particularly in female rats.

Chronic Corticosterone Exposure during Adolescence Reduces Impulsive Action but Increases Impulsive Choice and Sensitivity to Yohimbine in Male Sprague-Dawley Rats

“…Stress exposure during certain vulnerability periods, including adolescence, is known to alter how the HPA axis responds to future stressors (Barha et al, 2011;Burke et al, 2010;Isgor et al, 2004;Weintraub et al, 2010). Therefore, chronic high levels of the hormone corticosterone, which is released by the adrenal glands after HPA axis activation, could produce permanent changes in response to stressors long after the CORT exposure has ended.…”

“…However, the majority of differences in impulsivity observed here are unlikely to be explained by altered HPA axis function, but rather by long-lasting neuroplasticity in the circuits that regulate impulsive behavior and decision-making. Indeed, several studies involving adolescent stress exposure report that in adulthood the animals have no difference in baseline CORT levels, though they may have a reduction in peak CORT levels or faster negative feedback after an acute stressor (Weintraub et al, 2010;Burke et al, 2010;Barha et al, 2011).…”

“…For example, male rodents exposed to chronic restraint or unpredictable stress in adolescence do not show reductions in hippocampal neurogenesis, as is observed in adult animals exposed to chronic stress (Barha et al, 2011;Toth et al, 2008). However, female rodents exposed to chronic stress in either adolescence or adulthood show reductions in neurogenesis (Barha et al, 2011). In addition, chronic CORT exposure in both young (adolescent) and older adult monkeys decreases inhibitory control in a PFC-dependent test of behavioral flexibility (Lyons et al, 2000).…”

“…Interestingly, some of the effects of chronic CORT or stress exposure in adult animals do not appear to occur when the stress takes place during adolescence (Bourke and Neigh, 2011;Jankord et al, 2011;Xu et al, 2011). For example, male rodents exposed to chronic restraint or unpredictable stress in adolescence do not show reductions in hippocampal neurogenesis, as is observed in adult animals exposed to chronic stress (Barha et al, 2011;Toth et al, 2008). However, female rodents exposed to chronic stress in either adolescence or adulthood show reductions in neurogenesis (Barha et al, 2011).…”

Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats

“…In general, resting corticosterone levels and their responsiveness to additional stressors showed null or small effects (Giavanoli et al, 2013;Ilin and Richter-Levin, 2009;Jacobson-Pick et al, 2012;Maslova et al, 2002a;Sandi, 2007, 2011;Yee et al, 2011). Interestingly, there is some evidence for a stronger effect of stress during adolescence (prepubertal or posterior) on adult HPA reactivity to stress in females than in males (Barha et al, 2011;Bourke and Neigh, 2011;Jacobson-Pick et al, 2012;Pohl et al, 2007;Weathington et al, 2012), although these gender differences have not been found consistently McCormick et al, 2005McCormick et al, , 2008Toledo-Rodríguez and Sandi, 2007;Wright et al, 2008). The particular type of stressor may be one of the factors to account for those inconsistencies.…”