Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210.
Department of Psychology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202.
eNeuro. 2023 Mar 2;10(3). doi: 10.1523/ENEURO.0300-22.2023. Print 2023 Mar.
Women are twice as likely as men to experience emotional dysregulation after stress, resulting in substantially higher psychopathology for equivalent lifetime stress exposure, yet the 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 the activity of these neurons drives sex-specific behavioral changes. Four weeks of UCMS increased anxiety-like 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 nonstressed 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 the excitability of prefrontal PV neurons 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.
女性在经历压力后出现情绪调节障碍的可能性是男性的两倍，导致在同等的终生压力暴露下出现更高的精神病理学，而这种脆弱性的潜在机制仍不清楚。研究表明，内侧前额叶皮层（mPFC）活动的变化可能是一个潜在的贡献因素。抑制性中间神经元的适应性变化是否参与了这一过程，以及应对压力的适应是否因性别而异，导致情绪行为和 mPFC 活动出现性别特异性变化，这些仍未确定。本研究检查了不可预测的慢性轻度应激（UCMS）是否会通过性别差异改变小鼠的行为和 mPFC 钙调蛋白结合蛋白（PV）中间神经元活动，以及这些神经元的活动是否会导致性别特异性的行为变化。四周的 UCMS 增加了焦虑样和抑郁样行为，与 mPFC PV 神经元中的 FosB 激活有关，特别是在雌性中。在 8 周的 UCMS 后，两性都显示出这些行为和神经变化。在 UCMS 暴露和非应激雄性中，通过化学遗传学激活 PV 神经元，诱导焦虑样行为发生显著变化。重要的是，膜片钳电生理学证明了兴奋性和基本神经特性的改变与行为效应的出现具有相同的时间轨迹：在 UCMS 后的 4 周和 8 周后，女性出现变化，男性出现变化。这些发现首次表明，前额叶 PV 神经元兴奋性的性别特异性变化与焦虑样行为的出现平行，揭示了女性对压力引起的精神病理学易感性增强的潜在新机制，并支持对该神经元群体的进一步研究，以确定应激障碍的新治疗靶点。
