Long-term impact of chronic variable stress in adolescence versus adulthood

Abstract

Adolescence is a period of active development of stress regulatory neurocircuitry. As a consequence, mechanisms that control the responses to stress are not fully matured during this developmental period, which may result in vulnerability to chronic stress. We hypothesized that adolescent chronic stress would have negative consequences on stress adaptation later in life. Male Wistar rats (PND40) were subjected to chronic variable stress (CVS) for 2 weeks, with 2 daily stressors randomly presented and overnight social stressors twice a week. After five weeks, animals were evaluated during adulthood, using the elevated plus maze (EPM) and the forced swim test (FST). The hypothalamic-pituitary adrenal (HPA) axis response to a 30-min restraint was also assessed. Results are compared to those of adult rats tested 5 weeks following CVS cessation. Our results demonstrate that the long-term effects of CVS are specific to the age of application of the stress regime. We show how behavior and HPA axis response as well as hypothalamic paraventricular nucleus activation can differ with age, resulting in differential behavioral adaptations for animals stressed in adolescence and dysregulation of the HPA axis in the animals stressed in adulthood, These data underscore the importance of the adolescent period in determining resilience of the HPA axis and programming behavioral responses later in life.

Selective modulation of the glucocorticoid receptor with CORT108297 during chronic adolescent stress evokes sex-specific effects in adulthood

“…In the case of the coping behavior during the forced swim test, we replicated previous results of increased immobility in adult females previously subjected to adolescent CVS (Wulsin et al, 2016) but in the case of the males, we only observed a modest effect of adolescent CVS at the end of the test, which was also consistent with previous results (Cotella et al, 2019) but in a less marked way. Bourke and Neigh indicated that females but not males are vulnerable to the effects of adolescent stress on the forced swim test as adults (Bourke and Neigh, 2011), and another study fails to report effects in male rats (Toth et al, 2008), suggesting that females may be more sensitive to the impact of adolescent stress on selection of coping strategy It is notable that administration of C108297 did not block effects of CVS but did promote behavioral changes independent of stress.…”

“…The avoidance of the center area and reduced exploration in an open field is typically interpreted as an indicator of heightened emotional reactivity to the novel environment (Faraji et al, 2014). These data are consistent with prior findings from our group and others (Cotella et al, 2019;Green et al, 2013;Ilin and Richter-Levin, 2009;Jacobson-Pick and Richter-Levin, 2010;Luo et al, 2014;McCormick et al, 2008;Zhang and Rosenkranz, 2012), and suggest that prior stress reorganizes behavioral responses to potential danger in males.…”

“…This contrasts with lasting sensitization seen in adults receiving CVS and tested 5 weeks later (Cotella et al, 2019), suggesting that if anything, adolescence confers resilience to the longterm effect of stress on the HPA axis in males. Unlike males, adolescent stress sensitized HPA axis reactivity in adult females, suggesting a lasting impact on stress reactivity.…”

“…Exposure to adolescent CVS does not affect the magnitude of the male HPA axis responses to an acute novel stressor in adulthood (5 weeks later) (Cotella et al, 2019;Smith et al, 2018).…”

“…Prior data from our group indicates that chronic variable stress (CVS) during adolescence can evoke changes in anxiety like-behavior and coping style in both males and females. In the case of the HPA axis response to stress, females showed reduced stress responsivity and males were not affected (Cotella et al, 2019;Wulsin et al, 2016). To further understand the mechanisms behind these sex-specific enduring effects of adolescent stress, we tested the hypothesis that adolescent chronic stress causes life-long, sex-specific effects that are determined by the signaling through the glucocorticoid receptor (GR) during stress exposure.…”