作为最常见、疾病负担最重的精神疾病，抑郁症是神经生物学研究的重大课题。缰核是大脑中对压力和负面情绪反应具有重要调控作用的脑区，近年来在抑郁症中的重要性逐渐显现。本课题组发现βCaMKII基因在外侧缰核中的过量表达显著提高缰核的神经活动进而诱发抑郁症，为深入揭示缰核在抑郁症中的作用提供了基础。本项目将系统地研究缰核功能异常导致抑郁症的机制。我们将利用分子遗传手段构建新型的啮齿类抑郁模型。利用这些和已知的模型，我们将研究缰核中胶质细胞在抑郁症前后在形态和功能上的变化及其对缰核神经活动的调控。最后我们将追踪以缰核为中心的神经环路，鉴定外侧缰核内不同区域与其他脑区（如杏仁核）的连接以研究这些区域在抑郁症中的功能。通过在细胞、环路和行为水平上对缰核功能的研究，我们不仅将能够全面地认识缰核在情绪调控和抑郁症病理中的作用，而且将为基础和临床上对抑郁症的研究提供具有高度应用价值的工具。

Depression is among the most common and most burdensome mental disorders today and has been a major research topic in neurosciences. In recent years, habenula, a brain structure that has critical roles in regulating stress response, aversive emotions and reward behaviors, has emerged as a major player in depression pathogenesis. Our group discovered that βCaMKII’s overexpression in lateral habenula significantly elevates habenula’s neuronal activity and consequently causes depression. These findings provided foundations for further investigations to fully uncover habenula’s roles in depression. In this application we will conduct a systematical interrogation on mechanisms through which habenula malfunction leads to depression. First we will develop novel molecular genetics-based techniques to establish new rodent models for depression research. Secondly we will use these new models, as well as previously established models, to investigate habenula glia cells about their morphological and functional changes before and after depression, and their roles in regulating habenula’s neuronal activity. Finally we will map habenula-centric neuronal circuits to identify and differentiate neuronal connectivity from sub-regions of lateral habenula to other brain structures (including amygdala). In doing so we will understand these sub-regions’ distinct roles in depression. By investigating habenula from behavior, circuit and cellular levels, not only will we gain comprehensive insights about habenula’s central roles in emotion regulation and depression pathogenesis, but we will also provide highly valuable tools to benefit both basic and clinical depression research.

抑郁症是一种常见且严重的精神障碍疾病，给社会和家庭造成了巨大的经济和精神心理负担。缰核是大脑奖赏环路中的中继核团，近年来在抑郁症中的作用受到越来越多的关注。本课题组发现βCaMKII基因在外侧缰核中的过量表达显著提高缰核的神经活动进而诱发抑郁症，为深入揭示缰核在抑郁症中的作用提供了基础。为进一步探索缰核在抑郁症中的作用。本课题进行了以下三个方面的研究。第一，新型抑郁动物模型的构建。通过在大鼠或小鼠的外侧缰核过量表达βCaMKII，构建了一个能很好的模拟临床上患者的病症、病因和治疗情况的抑郁动物模型，为新型抗抑郁药物的筛选提供了一个理想的动物模型；第二，缰核胶质细胞在抑郁症的调节作用，缰核星形胶质细胞表达的外向整流型钾通道Kir4.1，是另一个高通量蛋白质谱筛选出的在抑郁动物缰核高表达的蛋白，以紧密包绕神经元胞体的方式，调节胞外空间钾离子浓度，调节神经元静息膜电位和神经元簇状放电比例，进而调节抑郁症的产生，可作为一种潜在的抗抑郁药物分子靶点；第三，氯胺酮快速抗抑郁的缰核机制，外侧缰核中氯胺酮通过抑制NMDA受体和低电压敏感的钙通道（T-VSCCs）依赖的簇状放电，产生快速抗抑郁作用。外侧缰核局部抑制NMDAR或T-VSCCs均可产生快速抗抑郁作用，同时光遗传诱导外侧缰核产生簇状放电可诱发抑郁表型。揭示外侧缰核簇状放电在快速抗抑郁中的重要作用，为快速抗抑郁药物的研发提供新的思路和方向。在项目执行的3年期间，本课题组在世界知名学术期刊中发表研究论文2篇和研究综述2篇。这些期刊包括Science, Nature Protocols, Trends in Neurosciences, Current opinion in Neurobiology。此外项目负责人胡海岚教授，也多次获得了重要奖励。