早年应激是抑郁发生的高危因素，有早年应激的抑郁以快感缺失和多巴胺（DA）奖赏环路受损为其主要特征；而中脑腹侧被盖区（VTA）内DA神经元异常可诱发快感缺失样行为，但分子机制尚不明确。GABA A型受体相关蛋白（GABARAP）可通过自噬调节神经元结构和功能；DA神经元自噬-溶酶体降解途径异常可增加其外泌体分泌，促进DA神经元对邻近细胞的损伤。但VTA内DA神经元自噬异常和外泌体分泌增加是否参与早年应激抑郁的发生，其机制是否由GABARAP蛋白所介导有待研究证实。本项目拟建立早年应激抑郁动物模型，检测不同时间点大鼠行为及VTA内DA神经元GABARAP蛋白表达、自噬发生和外泌体水平变化，并结合体外实验研究VTA内DA神经元自噬和外泌体分泌在早年应激抑郁中的作用及GABARAP介导的调控机制，以期阐明早年应激抑郁发生的分子机制，为临床上抑郁症的精准治疗及新药研发提供新思路和实验依据。

Early life stress (ELS) is a risk factor of depression. Anhedonia and impairments of dopaminergic (DAergic) reward circuit are the main characteristics of depression with ELS. The dysfunction of DAergic neurons in the ventral tegmental area (VTA) can induce anhedonia, but the mechanisms remain unknown. The γ-aminobutyric acid A receptor-associated protein (GABARAP) can regulate autophagy and subsequent affect the structures and functions of neurons. The abnormality of autophagy-lysosomal degradation pathway can increase exosome secretion, which subsequently cause injury of the nearby cells. However, whether the abnormality of autophagy and increase of exosome secretion in VTA DA neurons are involved in the ELS-induced depression and whether it is mediated by GABARAP protein need evidence. The proposed study will establish ELS-induced depression animal models and further investigate the expression of GABARAP protein, autophagy and exosome secretion level in VTA DAergic neurons, and behaviors in rats at different time points after stress. Combining with in vitro experimental study, we will explore the role of autophagy and exosome secretion of VTA DA neurons in ESL-induced depression and the GABARAP-mediated regulatory mechanisms. We will anticipant to elucidate the molecular mechanism of early stress depression and provide new ideas and experimental basis for the precise treatment of depression and development of new therapeutic agents.