Analyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive, dendrite-targeting GABAergic interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons (induced by Cre-mediated deletion of the γ2 GABA_A receptor subunit gene selectively from SST neurons, SSTCre:γ2^f/f mice) results in stress resilience. Similarly, chronic chemogenetic activation of SST neurons in the medial prefrontal cortex (mPFC) results in stress resilience but only in male and not in female mice. Here, we used RNA sequencing of the mPFC of SSTCre:γ2^f/f mice to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female SSTCre:γ2^f/f mice is characterized by resilience to chronic stress-induced transcriptome changes in the mPFC. Interestingly, the transcriptome of non-stressed SSTCre:γ2^f/f (stress-resilient) male mice resembled that of chronic stress-exposed SSTCre (stress-vulnerable) mice. However, the behavior and the serum corticosterone levels of non-stressed SSTCre:γ2^f/f mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of SSTCre:γ2^f/f mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes suggesting stress-induced enhancement of mRNA translation. Behaviorally, the SSTCre:γ2^f/f mice were not only resilient to chronic stress-induced anhedonia — they also showed an inversed, anxiolytic-like behavioral response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in the expression of putative stress resilience genes, through a sex-specific brain substrate.

对死后人脑的分析和对啮齿动物的临床前研究已经确定，生长抑素 （SST） 阳性、树突靶向 GABA 能中间神经元是调节对压力相关精神疾病脆弱性的关键因素。相反，遗传诱导的 SST 神经元去抑制（由 Cre 介导的 SST 神经元 SSTCre：γ2^f/f 小鼠的 γ2 GABA_A 受体亚基基因选择性缺失诱导）导致应激恢复力。同样，内侧前额叶皮层 （mPFC） 中 SST 神经元的慢性化疗发生学激活导致应激恢复力，但仅在雄性小鼠中，在雌性小鼠中不然。在这里，我们使用 SSTCre：γ2^f/f 小鼠 mPFC 的 RNA 测序来表征 GABA 能控制应激恢复力的转录组变化。我们发现雄性而非雌性 SSTCre：γ2^f/f 小鼠的应激恢复力的特点是对 mPFC 中慢性应激诱导的转录组变化的恢复力。有趣的是，非应激 SSTCre：γ2^f/f （应激抗逆性） 雄性小鼠的转录组类似于慢性应激暴露的 SSTCre （应激脆弱性） 小鼠的转录组。然而，非应激 SSTCre：γ2^f/f 小鼠的行为和血清皮质酮水平没有表现出生理应激的迹象。最引人注目的是，SSTCre：γ2^f/f 小鼠的慢性应激暴露与其慢性应激样转录组特征的几乎完全逆转有关，同时通路变化表明应激诱导的 mRNA 翻译增强。 在行为上，SSTCre：γ2^f/f 小鼠不仅对慢性应激诱导的快感缺乏具有弹性——它们还对慢性应激暴露表现出反向的、抗焦虑样的行为反应，这反映了慢性应激诱导的慢性应激样转录组特征的逆转。我们得出结论，SST 神经元对行为脆弱性和对慢性压力暴露的恢复力施加双向控制，这反映在推定的压力恢复基因表达的双向变化中，通过性别特异性的脑基质。