GABARAP介导的VTA多巴胺能神经元自噬/外泌体分泌在早年应激抑郁中的作用

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.

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。

早年应激是抑郁发生的高危因素，早年应激在抑郁发生发展的作用及其机制目前尚不十分明确。本项目从动物和细胞两个水平开展研究，通过建立早年应激抑郁动物模型，观察有和无早年应激的成年大鼠再次遭遇应激前后不同时间点行为的改变；检测有和无早年应激大鼠VTA内DA神经元GABARAP蛋白表达、自噬发生和外泌体水平变化，并结合体外细胞实验来探讨早年应激在成年大鼠抑郁发生发展中的作用及其GABARAP介导的分子机制。研究结果发现：（1）早年应激增加了成年大鼠快感缺失样行为的易感性，再次经历慢性应激后表现更早和更严重的快感缺失；（2）外周血DA浓度的降低可能是快感缺失行为表现的生物标志物；（3）有早年应激抑郁大鼠，其VTA 内GABARAP 蛋白表达或分布异常，从而导致自噬-溶酶体降解途径受阻，损伤多巴胺能神经元结构和功能，进而参与抑郁的发生。这些结果揭示早年应激抑郁发生的重要机制，为抑郁症病理机制的研究提供了有价值的客观数据；也为临床上抑郁症的诊断、个体化治疗及新药研发提供新思路和实验依据。