Sex-specific timelines for adaptations of prefrontal parvalbumin neurons in response to stress and changes in anxiety- and depressive-like behaviors.

Women are twice as likely as men to experience emotional dysregulation after stress, resulting in substantially higher psychopathology for equivalent lifetime stress exposure, yet mechanisms underlying this vulnerability remain unknown. Studies suggest changes in medial prefrontal cortex (mPFC) activity as a potential contributor. Whether maladaptive changes in inhibitory interneurons participate in this process, and whether adaptations in response to stress differ between men and women, producing sex-specific changes in emotional behaviors and mPFC activity, remained undetermined. This study examined whether unpredictable chronic mild stress (UCMS) in mice differentially alters behavior and mPFC parvalbumin (PV) interneuron activity by sex, and whether these neurons' activity drives sex-specific behavioral changes. Four weeks of UCMS increased anxiety- and depressive-like behaviors associated with FosB activation in mPFC PV neurons, particularly in females. After 8 weeks of UCMS, both sexes displayed these behavioral and neural changes. Chemogenetic activation of PV neurons in UCMS-exposed and non-stressed males induced significant changes in anxiety-like behaviors. Importantly, patch-clamp electrophysiology demonstrated altered excitability and basic neural properties on the same timeline as the emergence of behavioral effects: changes in females after 4 weeks and in males after 8 weeks of UCMS. These findings show, for the first time, that sex-specific changes in prefrontal PV neurons' excitability parallel the emergence of anxiety-like behavior, revealing a potential novel mechanism underlying the enhanced vulnerability of females to stress-induced psychopathology, and supporting further investigation of this neuronal population to identify new therapeutic targets for stress disorders. Significance Statement While adult women are more often diagnosed with a mood disorder after facing stressful events than men, the mechanisms responsible for this sex-specific vulnerability remain unknown. This study uses a mouse model of stress-induced anxiety- and depressive-like behaviors to show a novel mechanism, adaptation of prefrontal parvalbumin neurons, that may underlie the greater susceptibility of females to stress-related psychopathologies. Female parvalbumin neurons adapt after shorter periods of chronic stress than male neurons, paralleling earlier emergence of anxiety-like behaviors in females. We propose that prefrontal PV interneurons are an important contributor to female stress sensitivity that should be further investigated to identify new therapies for psychopathology related to stress.