慢性应激可影响前额叶谷氨酸能突触传递，损害前额叶依赖的认知功能，是抑郁症等精神疾病的重要诱发因素。认知功能损害是抑郁症患者常见的残留症状，而目前尚缺乏有效的治疗。最新研究结果提示，痕量胺相关受体1（TAAR1）可调节前额叶谷氨酸NMDA受体的功能，且TAAR1激动剂有促认知和抗抑郁作用，提示TAAR1是神经精神疾病新的潜在治疗靶点。然而，TAAR1是否参与了慢性应激所致的负面效应尚未明确。本项目拟采用慢性社会挫败应激小鼠模型，以前额叶谷氨酸递质系统为切入点，探讨慢性应激对前额叶依赖认知功能及其TAAR1信号系统的影响。随后，结合离体和在体实验，利用分子生物学、电生理、药理学方法和转基因技术，深入探讨TAAR1调控慢性应激负性影响的分子机制。本研究预期初步阐明TAAR1在慢性应激对前额叶功能不良影响中的作用，这对于深入理解抑郁症的病理机制、探索治疗抑郁症认知功能损害的新靶点具有重要意义。

Chronic stress may suppress glutamatergic transmission in prefrontal cortex (PFC) and impair PFC-dependent cognitive function. Stressful life events are a key environmental risk factor to develop stress-related psychiatric disorders such as major depressive disorder (MDD). Cognitive dysfunction is a frequent residual manifestation in MDD patients, which may impede functional recovery including workforce performance. However, treatments targeting cognition dysfunction are lacking. Recent findings indicate that trace amine-assoicated receptor 1（TAAR1） modulates cortical glutamate NMDA receptor function, moreover, TAAR1 agonists show pro-cognitive and antidepressant-like properties in rodent and primate models. Accumulating evidences suggest that TAAR1 is a new promising target for neuropsychiatric disorders. However, the roles of TAAR1 in mediating the negative outcomes induced by chronic stress remain unknown. Based on glutamate receptor function in PFC and using the chronic social defeat stress paradigm in mice, in this study, we examine the effects of chronic stress on PFC-dependent cognitive tasks and TAAR1 signaling in PFC. Furthermore, using molecular biology, electrophysiology, pharmacology and transgenic techniques, the molecular mechanisms of TAAR1 in modulating chronic social defeat-induced abnormalities will be investigated via in vitro and in vivo experiments. Our finding may elucidate the essential role of TAAR1 in the adverse effects of chronic stress on PFC function and shed light on the pathophysiology of MDD and new treatment targets for cognitive impairment in MDD.