基于Glu/GluR2/Cyt-C通路介导的“线粒体自噬-凋亡对话”探讨糖尿病并发抑郁症海马突触微环境损伤机制及中药干预

糖尿病并发抑郁症（DD）发病隐匿、易反复、致死率高，属于中医药治疗优势突出但目前进展薄弱的病种。课题组前期在明确谷氨酸和海马神经元凋亡分别是诱发DD的关键信号和直接原因后，发现GluR2表达下调介导的自噬和凋亡与DD海马突触可塑性相关，但其调控突触可塑性的关键机制尚不清楚。最新研究认为，突触微环境的改变是影响突触可塑性的关键因素。为此，本项目突破现有思维瓶颈，将DD研究的视角从单一突触可塑性损伤转向海马突触微环境损伤，并提出“Glu/GluR2/Cyt-C通路介导‘线粒体自噬-凋亡对话’致海马突触微环境损伤继而诱发DD”的新假说。本项目拟通过体内与体外研究，运用高内涵、激光共聚焦等技术，系统探讨DD海马突触微环境损伤的内在特点、规律及其生物学机制，并采用“滋阴益气、化瘀解郁”立法方药干预反证，为丰富DD“虚、瘀、郁”中医病机的现代化科学内涵提供新视角，为DD发病机制和中医药防治提供新思路。

Diabetes-related depression（DD）is a concealed, relapsed and highly lethal disease. However, its research has been hampered although the advantages of traditional Chinese medicine treatment. Our previous studies have found that autophagy and apoptosis, triggered by GluR2 down-regulation, is associated with hippocampal synaptic plasticity after we defined that the glutamate and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes-related depression, respectively. Unfortunately, the crucial mechanism involved in its regulation of synaptic plasticity remains unclear. The latest researches show that altered synaptic microenvironment is the key factor leading to the impairment of synaptic plasticity. Hence, this research intends to break the existing thinking limitations and shift the impaired focus of the DD from single synaptic plasticity to hippocampal synaptic microenvironment. Furthermore, we hypothesized that diabetes-related depression might be related to damage of hippocampal synaptic microenvironment based on Glu/GluR2/Cyt-C pathway mediated crosstalk between mitophagy and apoptosis. To testify this hypothesis, this research is aimed at systematically exploring the intrinsic characteristics, rules and biological mechanisms of hippocampal synaptic microenvironment damage in DD on the aspects of in vivo-in vitro by the modern technologies of laser scanning confocal microscope and high content analysis etc..The theory of “enriching yin and nourishing qi, disperse blood stasis and resolve depression” was further applied to disproof and elucidate the pathology (asthenia, stasis and depression) of DD, which could provide a novel ideas for the research of its pathogenesis and traditional Chinese medicine intervention.