Patients suffering from chronic stress develop numerous symptoms, including emotional and cognitive deficits. The precise circuit mechanisms underlying different symptoms remain poorly understood. We identified two distinct basal forebrain cholinergic subpopulations in mice projecting to the dorsal hippocampus (dHPC) or ventral hippocampus (vHPC), which exhibited distinct input organizations, electrophysiological characteristics, transcriptomics, and responses to positive and negative valences of stimuli and were critical for cognitive and emotional modulation, respectively. Moreover, chronic stress induced elevated anxiety levels and cognitive deficits in mice, accompanied by enhanced vHPC but suppressed dHPC cholinergic projections. Chemogenetic activation of dHPC or inhibition of vHPC cholinergic projections alleviated stress-induced aberrant behaviors. Furthermore, we identified that the acetylcholinesterase inhibitor donepezil combined with blockade of muscarinic receptor 1–type muscarinic acetylcholine receptors in the vHPC rescued both stress-induced phenotypes. These data illuminated distinct septo-hippocampal cholinergic circuits mediated specific symptoms independently under stress, which may provide promising strategies for circuit-based treating of stress-related psychiatric disorders.

中文翻译：

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不同的鼻中隔-海马胆碱能投射分别介导压力诱导的情绪和认知缺陷


患有慢性压力的患者会出现许多症状，包括情绪和认知缺陷。不同症状背后的确切回路机制仍然知之甚少。我们在投射到背侧海马体 （dHPC） 或腹侧海马体 （vHPC） 的小鼠中鉴定了两个不同的基底前脑胆碱能亚群，它们表现出不同的输入组织、电生理特征、转录组学以及对刺激的正负价的反应，分别对认知和情绪调节至关重要。此外，慢性压力导致小鼠焦虑水平升高和认知缺陷，伴随着 vHPC 增强但抑制了 dHPC 胆碱能投射。dHPC 的化学遗传学激活或 vHPC 胆碱能投射的抑制减轻了压力诱导的异常行为。此外，我们发现乙酰胆碱酯酶抑制剂多奈哌齐联合阻断 vHPC 中的毒蕈碱受体 1 型毒蕈碱乙酰胆碱受体挽救了两种应激诱导的表型。这些数据阐明了不同的隔膜-海马胆碱能回路在压力下独立介导特定症状，这可能为基于回路的应激相关精神疾病治疗提供有前途的策略。