Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as critical elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here, we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq-mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-like motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, the activation of SST neurons in the PLC of male mice and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos⁺ and FosB⁺ neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. The data provide a rationale for the lack of antidepressant efficacy of benzodiazepines and superior efficacy of dendrite-targeting, low-potency GABA_A receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

临床和临床前研究已确定生长抑素 （SST） 阳性中间神经元是调节对压力相关精神疾病脆弱性的关键元素。相反，小鼠中 SST 神经元的去抑制导致对慢性压力的行为影响具有恢复力。在这里，我们建立了一个低剂量慢性化疗遗传学方案，以将这些积极和消极动机行为的变化映射到特定的大脑区域。AAV-hM3Dq 介导的边缘前皮层 （PLC） 中 SST 神经元的慢性激活对雄性而非雌性小鼠的焦虑和快感缺乏样动机行为具有抗抑郁药样作用。腹侧海马体 （vHPC） 的类似操作对雌性小鼠但没有这种影响。此外，雄性小鼠 PLC 中 SST 神经元的激活和雌性小鼠的 vHPC 导致应激恢复力。PLC 中 SST 神经元的激活逆转了先前慢性应激诱导的雄性动机行为缺陷，但对雌性无效。相反，vHPC 中 SST 神经元的激活逆转了慢性压力诱导的雌性行为改变，但未逆转雄性。慢性应激暴露小鼠中 c-Fos ⁺ 和 FosB ⁺ 神经元的定量显示，SST 神经元的慢性激活导致锥体细胞活性的反常增加。总的来说，这些数据表明，由树突靶向中间神经元驱动的 GABA 能微电路实现了性和大脑区域特异性的神经可塑性，从而促进压力恢复力并逆转压力诱导的焦虑和快感缺乏样动机行为。 这些数据为苯二氮卓类药物缺乏抗抑郁疗效和树突靶向、低效 GABA_A 受体激动剂的卓越疗效提供了理由，与性别无关，尽管相关脑底物存在显着的性别差异。