投射特异性VTA多巴胺能神经元兴奋性调控机制及在抑郁行为中的作用

The dopaminergic (DA) neurons in the ventral tegmental area (VTA) of middle brain play important role in emotion related behaviour, and the alteration of excitability of VTA DA neurons are believed to be the key determinants in behaviours of depression and drug addictions. The excitability of VTA DA neurons controls the release of DA in the projection fiber terminals thus controls the function of VTA DA neurons. After many years hard work, we begin to understand how the excitability of VTA DA neurons are regulated, but these achievements are far from satisfactory. Furthermore, with recent progress and realization that property of VTA DA neurons, against the classical view that VTA DA neurons are homogeneous population, are distinctly different, thus the accumulated limited knowledge on the mechanism of excitability modulation of VTA DA neurons is especially short of expectation. The most outstanding indications of the heterogeneity of VTA DA neurons are represented by the distinctly different electrophysiological properties among VTA DA neurons projecting to different brain regions. However the underlying mechanism is not clear. In this application we plan to investigate the underlying mechanism determining the distinct excitability of VTA DA neurons projecting to the cortical and the limbic regions of the brain. The main focus of the study will be on the intrinsic ion channels and the related modulation mechanism of VTA DA neuron excitability. On the basis of this we will further study the mechanism which underlie alteration of excitability of VTA DA neurons in condition of depression state, and still further the related depression behaviour.

中脑腹侧背盖区（VTA）多巴胺（DA）神经元在情绪相关行为中发挥重要作用，其兴奋性异常与抑郁、药物成瘾等行为紧密相连。VTA DA神经元的兴奋性是控制DA神经元投射纤维释放DA进而控制其功能的关键环节。经多年的研究对调控VTA DA神经元的兴奋性的机制有了初步的了解，但还远远不够，尤其是随着近年来认识到VTA DA神经元并不是之前认为的那样是特质相同的一类神经元，而是存在特征性的异质性，我们之前所积累的对VTA DA神经元兴奋性调控机制有限的知识就更显的尤为不足。VTA DA神经元的异质性以其基于投射特异性的电生理（兴奋性）异质性为最显著的表现，但其机制不清。因此，本项目拟对投射到皮层及边缘系统的VTA DA神经元的兴奋性调控机制展开对比研究，主要研究决定这些神经元兴奋性的内在离子通道机制及相关的调控机制，在此基础上探讨在抑郁状态下VTA DA神经元兴奋性改变的机制，以及与抑郁行为的关系。

中脑多巴胺神经元参与众多生理功能包括奖赏行为等，其功能异常是包括PD、抑郁症等神经精神疾病的发病机制之一。多巴胺神经元功能表现的主要方式是其特征性的放电，并由此通过投射到不同脑区的通路影响众多脑区/核团功能。中脑多巴胺神经元具有高异质性特点，且这种异质性与其不同脑区的投射相关。这种基于不同投射的多巴胺神经元异质性有重要的生理学和病理学意义。投射特异性多巴胺神经元的异质性的具体表现之一是其电生理特性的异质性，但对其分子机制尚不清楚。本项目聚焦于此，重点了解投射到前额皮层、伏隔阂、外侧杏仁核的多胺神经元不同放电特征的细胞和分子基础，以及在此基础上与抑郁等情绪行为发生的关系。主要的研究内容包括：一、投射特异性的VTA DA 神经元转录组学分类及关联的电生理/兴奋性分类；二、投射特异性VTA DA 神经元兴奋性调控的离子通道机制；三、投射特异性VTA DA 神经元自调控/GPCR 受体调控机制；四、不同抑郁模型中投射特异性VTA DA 神经元兴奋性改变的机制。项目执行取得重要进展，主要在下列研究方向取得成果：一，投射特异性中脑多巴胺（ DA）神经元与兴奋性相关的离子通道及受体基因表达特征；二，投射特异性中脑多巴胺（ DA）神经元放电特征及去极化电流的离子通道机制；三，PI4K在调控VTA DA神经元兴奋性中的作用及其在抑郁和成瘾行为中的作用。已发表标注本基金的SCI论文6篇，另有2篇在投稿中；培养博士生及硕士生8名。本项目研究结果为了解中脑多巴胺神经元投射特异性兴奋性的细胞和分子机制提供了新的实验证据，为了解与VTA DA神经元兴奋性相关的药物成瘾、抑郁症等行为和疾病的发生机制提供新的视野，为发现新的相关治疗靶点及药物提供新的证据。