Jiang Tong, Feng Mengyang, Hutsell Alexander, Lüscher Bernhard
Department of Biology, Pennsylvania State University, University Park, PA, USA.
Center for Molecular Investigation of Neurological Disorders (CMIND), The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA.
Mol Psychiatry. 2025 Jun;30(6):2297-2308. doi: 10.1038/s41380-024-02835-8. Epub 2024 Nov 16.
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 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应激相关精神障碍易感性的关键因素。相反，小鼠中SST神经元的去抑制作用可使其对慢性应激的行为影响产生恢复力。在此，我们建立了一种低剂量慢性化学遗传学方案，以将这些正向和负向动机行为的变化映射到特定脑区。腺相关病毒-hM3Dq介导的前边缘皮层（PLC）中SST神经元的慢性激活对雄性而非雌性小鼠的焦虑样和快感缺失样动机行为具有抗抑郁药物样作用。对腹侧海马体（vHPC）进行类似操作对雌性而非雄性小鼠有此类作用。此外，雄性小鼠PLC和雌性小鼠vHPC中SST神经元的激活导致应激恢复力。激活雄性小鼠PLC中的SST神经元可逆转先前慢性应激诱导的动机行为缺陷，但对雌性无效。相反，激活雌性小鼠vHPC中的SST神经元可逆转慢性应激诱导的行为改变，但对雄性无效。对慢性应激暴露小鼠中c-Fos和FosB神经元的定量分析表明，SST神经元的慢性激活导致锥体细胞活性出现反常增加。总体而言，这些数据表明，由树突靶向中间神经元驱动的GABA能微回路可实现性别和脑区特异性神经可塑性，从而促进应激恢复力并逆转应激诱导的焦虑样和快感缺失样动机行为。这些数据为苯二氮䓬类药物缺乏抗抑郁疗效以及树突靶向、低效GABA受体激动剂具有更高疗效提供了理论依据，且与性别无关，尽管相关脑底物存在显著的性别差异。
