Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLA neurons’ NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders.

中文翻译：

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星形胶质细胞介导的 BLAWFS1 神经元调节可减轻 DISC1-N 小鼠的风险评估缺陷


评估和应对威胁在日常生活中至关重要。不幸的是，许多精神疾病涉及风险评估受损，影响患者、家庭和社会。这些行为背后的大脑过程尚不清楚。我们开发了一种转基因小鼠模型（精神分裂症中断 1 [DISC1]-N），其在危险环境中的回避反应被中断。我们的研究利用单核 RNA 测序和路径钳耦合与实时 RT-PCR 来揭示基底外侧杏仁核 (BLA) 中先前未描述的一组以 Wolfram 综合征 1 (WFS1) 表达为标志的谷氨酸能神经元，其活性受到调节由邻近的星形胶质细胞。 DISC1-N 小鼠中的这些神经元表现出放电能力减弱以及与星形胶质细胞的通讯受损。值得注意的是，这些星形胶质细胞的光遗传学激活通过作用于 BLA 神经元 NMDA 受体的 D-丝氨酸恢复了神经元兴奋性，从而改善了 DISC1-N 小鼠的风险评估行为。我们的研究结果表明 BLA 星形胶质细胞是治疗精神障碍风险评估功能障碍的有希望的靶点。