Chronic stress produces enduring sex- and region-specific alterations in novel stress-induced c-Fos expression

Abstract

Prolonged or repeated exposure to stress increases risk for a variety of psychological disorders, many of which are marked by dysfunction of corticolimbic brain regions. Notably, women are more likely than men to be diagnosed with these disorders, especially when onset of symptoms follows stressful life events. Using rodent models, investigators have recently begun to elucidate sex-specific changes in the brain and behavior that occur immediately following chronic stress. However, little is known regarding the lasting sequelae of chronic stress, as well as how potential changes may impact responsivity to future stressors. We recently demonstrated that male and female rats show different patterns of dendritic reorganization in medial prefrontal cortex in the days following chronic stress. Here, we examined the immediate and lasting effects of chronic restraint stress (CRS; 3 h/day, 10 days) on neuronal activation, across several corticolimbic brain regions, induced by novel acute stress exposure. Chronically stressed male and female rats were exposed to acute elevated platform stress (EPS) either 1 (CRS-EPS) or 7 (CRS-Rest-EPS) days after CRS. Compared to rats exposed to EPS only, significant reductions in acute stress-induced c-Fos expression were observed in the medial prefrontal cortex, hippocampus, and paraventricular nucleus of the hypothalamus (PVN) in CRS-EPS male rats, some of which persisted to 7 days post-stress. In contrast, we found little modulation of novel stress-induced c-Fos expression in CRS-EPS female rats. However, CRS-Rest-EPS female rats exhibited a significant enhancement of acute stress-induced neuronal activity in the PVN. Together, these data show that prior chronic stress produces sex- and region-specific alterations in novel stress-induced neuronal activation, which are dependent on the presence or absence of a rest period following chronic stress. These findings suggest that the post-stress rest period may give rise to sex-specific neuroadaptations to stress, which may underlie sex differences in stress susceptibility versus resilience.

Social instability in adolescence differentially alters dendritic morphology in the medial prefrontal cortex and its response to stress in adult male and female rats

“…Consistent with previous studies in stress‐naïve rats (Baran, Armstrong, Niren, Hanna, & Conrad, ; Bollinger et al, ; Garrett & Wellman, ; Moench et al, ), chronic stress attenuated weight gain and increased adrenal‐to‐body weight ratios in male and female rats that were stressed in adolescence. However, unlike in our previous study (Moench & Wellman, ), in males the increased adrenal weight was maintained after 7 days of rest.…”

“…This suggests that while both sexes show apical dendritic retraction immediately following adolescent stress, further remodeling occurs in males—but not females. This suggests that, as in adults (Moench et al, ; Moench & Wellman, ), adolescent males and females show differential patterns of prefrontal plasticity in the extended period after stress.…”

“…Stress in adulthood consisted of chronic restraint stress (3 hr/day for 10 days) in which rats were placed in a semi‐cylindrical Plexiglas tube (male: 16 cm × 6.5 cm × 5 cm; female: 15 cm × 6 cm × 4.5 cm, modified so the tail piece locks into place; Braintree Scientific, Braintree, MA). This procedure increases adrenal weights and attenuates weight gain in males and females (Bollinger, Collins, Patel, & Wellman, ; Moench et al, ).…”

“…Therefore, we also characterized dendritric morphology at 7 days poststress. For simplicity and consistency with previous studies (Moench, Breach, & Wellman, ; Ortiz & Conrad, ), we will refer to this undisturbed interval as “rest” hereafter.…”

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…Supporting the hypothesis that females are more susceptible to a "second hit" of stress, chronically stressed female rats given a rest period show enhanced activity in limbic brain regions following a novel acute stressor compared to their unstressed counterparts. By contrast, male rats showed blunted activity in the PFC and limbic brain regions under the same conditions (Moench et al, 2019). This research implies that plasticity of the PFC following stress is important for resilience and recovery, and that chronic or repeated stress may impair prefrontal plasticity especially in females.…”