Sex-Specific Timelines for Adaptations of Prefrontal Parvalbumin Neurons in Response to Stress and Changes in Anxiety- and Depressive-Like Behaviors

Abstract

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 StatementWhile 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.

Cortical–brainstem circuitry attenuates physiological stress reactivity

“…Additionally, vmPFC grey matter and functional activity are frequently altered in depression and other stress‐related disorders that disproportionately burden females (Drevets et al., 2008; Riecher‐Rössler, 2017). Accordingly, rodent studies have examined the vmPFC to identify neural substrates contributing to sex‐specific vulnerability (Hurley & Carelli, 2020; van der Zee et al., 2022; Woodward et al., 2023). In vivo monitoring of vmPFC projection neurons also revealed that sex and stress history interact to shape neural activity in response to both appetitive and aversive stimuli (Wallace & Myers, 2023).…”

Cortical-brainstem circuitry attenuates physiological stress reactivity

“…Additionally, vmPFC gray matter and functional activity are frequently altered in depression and other stress-related disorders that disproportionately burden females (Drevets et al, 2008; Riecher-Rössler, 2017). Accordingly, rodent studies have examined the vmPFC to identify neural substrates contributing to sex-specific vulnerability (Hurley & Carelli, 2020; van der Zee et al, 2022; Woodward et al, 2023). In vivo monitoring of vmPFC projection neurons also revealed that sex and stress history interact to shape neural activity in response to both appetitive and aversive stimuli (Wallace & Myers, 2023).…”

Interaction of Vasopressin with Hormones of the Hypothalamo-Pituitary-Adrenal Axis: Significance for Therapeutic Strategies in Cardiovascular and Metabolic Diseases

“…It is well known that there are sex differences in tolerance of stress, and in predisposition to anxiety, and depression, and that they may at least partly result from different regulation of the HPA axis [244][245]. Experimental studies demonstrated that the female rats respond with larger increases of ACTH to neurogenic stress than the male rats and suggested that during the neurogenic stress the gonadal steroids involved in the regulation of sexual behavior and reproduction may have a potential impact on the pituitary secretion of ACTH [246].…”

“…It is likely that one of the reasons of differences in sex-related susceptibility to stress results from functional heterogeneity of GR and MR in the brains of females and males, because higher expression of MR was found in the brain of the male mice than in the brain of female mice manifesting depressive behavior [248]. Research performed by Woodward et al (2023) on female and male mice, subjected to the UCMS procedure showed that female mice show anxiety and depressive behavior associated with FosB activation in neurons of the medial prefrontal cortex (mPFC) expressing parvalbumin after 4 weeks of exposure, while in male mice the behavioral and biochemical alterations is observed not earlier than after 8 weeks of UCMS. Furthermore, the use of patch-clamp electrophysiology allowed to demonstrate that there were time-corresponding sex-specific differences in altered neuronal excitability of the mPFC cells after 4 and 8 weeks of the exposure [245].…”

“…Research performed by Woodward et al (2023) on female and male mice, subjected to the UCMS procedure showed that female mice show anxiety and depressive behavior associated with FosB activation in neurons of the medial prefrontal cortex (mPFC) expressing parvalbumin after 4 weeks of exposure, while in male mice the behavioral and biochemical alterations is observed not earlier than after 8 weeks of UCMS. Furthermore, the use of patch-clamp electrophysiology allowed to demonstrate that there were time-corresponding sex-specific differences in altered neuronal excitability of the mPFC cells after 4 and 8 weeks of the exposure [245]. Rosinger et al (2019) using a corticotropin-releasing factor 1 receptor (CRFR1) reporter mouse line, demonstrated that male mice showed a significantly higher distribution of cells expressing CRFR1 in the PVN compared to females, however it should be noted that this relationship was age-related, because it was observed only in older (20-24-month) mice, and not in mice during the early post-natal life.…”