外侧缰核星形胶质细胞对抑郁症发生时间窗的调控及其机制

Depression is a complex, heterogeneous psychiatric disorder and several neurotransmitter and neurohormonal pathways have been implicated in the pathophysiology of depression. The mechanisms underlying the pathogenesis of depression onset are not well understood. In recent years, habenula, a conserved brain structure that has critical roles in regulating stress response, aversive emotions and reward behaviors, has emerged as a major player in depression pathogenesis. Previous oberservations of our group discovered that Kir4.1, an astrocytic specific inward rectifying potassium channel, is overexpressed in the lateral habenula at symptomatic age of depression animal models. Moreover, many of antidepressants, such as fluoxetine, Despiramine, exert an antagonizing effect on Kir4.1 current, indicating Kir4.1 may involve in the depression onset. In this application we propose Kir4.1 overexpression leads to neuronal hyperactivity and depression onset. First we will test depression onset windows in both cLH rats and chronic restraint mice. We will also test if Kir4.1 is overexpressed in depression animals according to the depression onset windows. Secondly we will investigate astrocytic morphological and functional changes before and after depression, and its roles in regulating habenula’s neuronal activity. Finally we will test antidepressant effect on depression onset. By investigating habenula from behavior, cellular and subcellular levels, not only will we gain more comprehensive and deeper insights about habenula’s central roles in depression pathogenesis, but we will also provide highly valuable tools to benefit both basic and clinical depression research including new anti-depressant discovery.

抑郁症是一种非常常见且严重的精神障碍疾病，其临床症状主要表现为绝望行为、快感缺失，严重的有自杀倾向。近年来研究表明，抑郁症核心症状与外侧缰核的异常神经活动相关。外侧缰核在抑郁症中过度兴奋，提示其细胞在形态、功能上均处于不稳定的动态变化中，而星形胶质细胞在维持神经网络内稳态上起着不容忽视的重要作用。然而，长期以来神经元一直被认为是精神类疾病发病机制的核心，对于胶质细胞在抑郁症中所起的作用研究甚少。本实验室前期结果揭示，三月龄的抑郁症大鼠缰核胶质细胞内向整流性钾离子通道表达显著增高，缰核星形胶质细胞形态和功能发生改变，同时抑郁症产生表型。因此，本项目将针对先天抑郁及后天压力抑郁模型动物，探索星形胶质细胞在抑郁症早期发生中的调控机制，寻找抑郁症预防及早期诊断的分子靶点。

据WHO定量评价，截止2017年抑郁症致残率已超过癌症和心脏病，成为健康的头号杀手。目前的“单胺假说”认为，抑郁症是由于大脑内单胺递质水平失衡所导致。但这一理论存在的主要的问题在于，病人服药后大脑中单胺类递质水平会在几小时内恢复正常，但情绪改善往往要几周之后。这说明传统抗抑郁药物还未触及抑郁症核心机制。在抑郁症相关环路中，我们关注一个叫外侧缰核的核团，近年来发现它能介导一系列负面情绪，被称为大脑的“反奖赏中心”，它通过一个抑制性的中转核团，从而抑制“奖赏中心”单胺能脑区。脑成像实验中发现，在抑郁病人以及多种抑郁动物模型中，缰核是唯一代谢活动显著增高的脑区。2018年，本人以唯一第一作者和共同第一作者身份在Nature上发表背靠背原创性长文两篇，颠覆了以往假说，首次破译抑郁症密码-簇状放电；首次从神经编码层面揭示氯胺酮快速抗抑郁之谜；首次发现缰核胶质细胞-神经元互作新结构；首次发现缰核胶质细胞能调节神经元簇装放电从而调节抑郁。该研究为临床提供了新的分子靶点，目前申请专利六项。目前发表研究性论文2篇，综述3篇。