Prefrontal representation of affective stimuli: importance of stress, sex, and context

Major depressive disorder diminishes health-related quality-of-life and disproportionality impacts females. Negative life events predict the onset of depressive symptoms including negative mood, anhedonia, and social withdrawal. While the neurobiology of affective illness is not completely understood, structural and functional changes in the ventromedial prefrontal cortex (vmPFC) associate with mood and anxiety disorders. Rodent studies have investigated the prefrontal impact of chronic stress, a preclinical model of mood disruption. However, ex vivo slice and postmortem histological studies have focused largely on males and yielded mixed results. Although genetically-defined recordings in behaving animals of both sexes have not been reported. Here, we hypothesized that chronic variable stress (CVS) would reduce the neural processing of affective stimuli in the infralimbic region of rodent vmPFC region. To test this hypothesis, we targeted expression of a fluorescent calcium indicator, GCaMP6s, to infralimbic pyramidal cells. In males, CVS reduced infralimbic responses to social interaction and restraint stress but increased responses to novel objects and food reward. In contrast, females did not have CVS-induced changes in infralimbic activity, which was partially dependent on ovarian status. Collectively, these results indicate that both male and female vmPFC pyramidal cells encode social, stress, and reward stimuli. However, chronic stress effects are sex-dependent and behavior-specific. Ultimately, these findings extend the understanding of chronic stress-induced prefrontal dysfunction and indicate that sex is a critical factor for cortical processing of affective stimuli. Significance Mood disorders are often preceded by stressful experiences and exhibit sex differences in prevalence. Further, affective illness is frequently accompanied by changes in prefrontal cortical function. However, the neurobiology that underlies sex-specific cortical processing of affective stimuli is poorly understood. Therefore, the current studies employ cell type-specific calcium photometry to determine the effects of chronic stress on ventromedial prefrontal cortex (vmPFC) activity in male and female rats. Our results indicate that chronic stress exposure differentially alters vmPFC encoding of social, stress, and reward stimuli. Moreover, the sex-specific effects of chronic stress are partially mediated by ovarian hormones. Ultimately, our results indicate that prolonged stress alters vmPFC function in a context-dependent and sex-specific manner, contributing to the biological bases for sex differences in emotional processing.