Prior stress followed by a novel stress challenge results in sex-specific deficits in behavioral flexibility and changes in gene expression in rat medial prefrontal cortex.

Chronic stress leads to sex-specific changes in the structure and function of rat medial prefrontal cortex (mPFC). Little is known about whether these effects persist following the cessation of chronic stress, or how these initial effects may impact responses to future stressors. Here we examined attentional set-shifting in male and female rats following chronic restraint stress, a post-chronic stress rest period, and an acute novel stress challenge. Chronic stress resulted in a reversible impairment in extradimensional set-shifting in males, but had no effect on attentional set-shifting in females. Surprisingly, chronically stressed female, but not male, rats had impaired extradimensional set-shifting following a novel stress challenge. Alterations in the balance of excitation and inhibition of mPFC have been implicated in behavioral deficits following chronic stress. Thus, in a separate group of rats, we examined changes in the expression of genes related to glutamatergic (NR1, NR2A, NR2B, GluR1) and GABAergic (Gad67, parvalbumin, somatostatin) neurotransmission in mPFC after acute and chronic stress, rest, and their combination. Stress significantly altered the expression of NR1, GluR1, Gad67, and parvalbumin. Notably, the pattern of stress effects on NR1, Gad67, and parvalbumin expression differed between males and females. In males, these genes were upregulated following the post-chronic stress rest period, while minimal changes were found in females. In contrast, both males and females had greater GluR1 expression following a rest period. These findings suggest that chronic stress leads to sex-specific stress adaptation mechanisms that may contribute to sex differences in response to subsequent stress exposure.