Introduction Deficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ GABA cells) are commonly reported in human studies of mood and anxiety disorder patients. A causal link between SST+ cell dysfunction and symptom-related behaviors has been proposed based on rodent studies showing that chronic stress, a major risk factor for mood and anxiety disorders, induces a low SST+ GABA cellular phenotype across corticolimbic brain regions; that lowering Sst, SST+ cell, or GABA functions induces depressive-/anxiety-like behaviors (a rodent behavioral construct collectively defined as “behavioral emotionality”); and that disinhibiting SST+ cells has antidepressant-like effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions, α5-GABAA receptor positive allosteric modulators (α5-PAMs), achieved antidepressant-like effects. Together, the evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in mood disorders and that rescuing SST+ cell function via α5-PAM may represent a targeted therapeutic strategy. Methods We developed a mouse model allowing chemogenetic manipulation of brain-wide SST+ cells and employed behavioral characterization 30 minutes after repeated acute silencing to identify contributions to symptom-related behaviors. We then assessed whether an α5-PAM, GL-II-73, could rescue behavioral deficits. Results Brain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant- and anxiolytic-like improvements among behavioral deficits induced by brain-wide SST+ cell silencing. Conclusion Our data validate SST+ cells as regulators of mood and cognitive functions and demonstrate that bypassing low SST+ cell function via α5-PAM represents a targeted therapeutic strategy.

中文翻译：

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由生长抑素阳性 GABA 神经元沉默引起的行为缺陷被 Alpha 5 GABA-A 受体增强所拯救

简介 生长抑素阳性 γ-氨基丁酸中间神经元（SST+ GABA 细胞）的缺陷在情绪和焦虑症患者的人体研究中很常见。啮齿类动物研究表明，慢性压力是情绪和焦虑症的主要危险因素，会导致皮质边缘脑区的 SST+ GABA 细胞表型降低。降低 Sst、SST+ 细胞或 GABA 功能会诱发抑郁/焦虑样行为（一种啮齿动物行为结构，统称为“行为情绪化”）；并且去抑制SST +细胞具有抗抑郁样作用。最近的研究发现，化合物优先增强介导 SST+ 细胞功能的受体，α5-GABAA 受体正变构调节剂 (α5-PAMs) 具有抗抑郁样作用。总之，证据表明 SST+ 细胞调节在情绪障碍中被破坏的情绪和认知功能，并且通过 α5-PAM 挽救 SST+ 细胞功能可能代表一种靶向治疗策略。方法 我们开发了一种小鼠模型，允许对全脑 SST+ 细胞进行化学遗传学操作，并在反复急性沉默 30 分钟后采用行为表征来确定对症状相关行为的贡献。然后，我们评估了 α5-PAM、GL-II-73 是否可以挽救行为缺陷。结果全脑 SST+ 细胞沉默诱导压力相关疾病的特征，包括神经元活动和血浆皮质酮水平升高，焦虑和快感缺乏样行为增加，和受损的短期记忆。GL-II-73 导致全脑 SST+ 细胞沉默引起的行为缺陷中的抗抑郁药和抗焦虑药样改善。结论我们的数据验证了 SST+ 细胞作为情绪和认知功能的调节剂，并证明通过 α5-PAM 绕过低 SST+ 细胞功能代表了一种靶向治疗策略。