深部脑刺激治疗抑郁症模型大鼠的作用机制研究

项目名称： 深部脑刺激治疗抑郁症模型大鼠的作用机制研究

项目编号： No.81471378

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 马辛

作者单位： 首都医科大学

项目金额： 70万元

中文摘要： 难治性抑郁症（TRD）的治疗是临床工作中亟待解决的问题。多项临床研究表明在不同脑区进行深部脑刺激（DBS）均能有效改善TRD患者的抑郁症状，但相关机制尚不清楚。BDNF广泛参与神经元的存活、分化以及突触可塑性的调节，以往研究表明海马或腹侧被盖区（VTA）-伏隔核（NAc）的BDNF-TrkB信号通路异常可导致抑郁的发生。据此，我们推测DBS可能通过调节上述脑区的BDNF-TrkB信号通路发挥疗效，不同刺激部位影响的靶区不同，而最终途径可能是增强了海马的成体神经再生。为验证上述假说，本研究拟采用慢性不可预知性应激大鼠抑郁模型，选取临床实验已证实有效的刺激部位腹内侧前额叶皮层和NAc分别进行DBS治疗，并利用慢病毒载体分别对海马和VTA进行BDNF过表达或敲减，通过行为学、形态学、分子生物学等手段阐明BDNF-TrkB信号通路在DBS治疗抑郁症中的作用，为DBS的临床应用奠定理论基础。

中文关键词： 抑郁症；深部脑刺激；脑源性神经营养因子；信号通路；神经再生

英文摘要： It is important to find safe and effective treatment for treatment-resistant depression (TRD). Many clinical trials have proven deep brain stimulation (DBS) at several different brain targets in TRD patients can effectively relieve depressive symptoms. However, its mechanism of action remains unknown. BDNF plays critical roles in the neuronal survival, differentiation and synaptic plasticity. Previous studies have shown that abnormalities of BDNF-TrkB signaling pathway in the hippocampus and ventral tegmental area (VTA)-nucleus accumbens (NAc) may contribute to the development of depression. Accordingly, we hypothesize that DBS may exert their therapeutic effects through regulating BDNF-TrkB signaling pathway in the hippocampus or VTA-NAc, which is associated with the brain region that electrodes are implanted, and finally result in increased adult hippocampal neurogenesis. To verify this hypothesis, the present study will use DBS to treat chronic unpredictable stress (CUS)-induced depression model rats at two proven effective brain targets in TRD patients, ventromedial prefrontal cortex (vmPFC) and NAc, respectively. We will also use in vivo knockdown or overexpression of BDNF in the hippocampus and VTA to directly explore the role of BDNF-TrkB signaling pathway in antidepressant effects of DBS and related mechanisms. This study will provide the experimental theory for clinic application of DBS to treat depression.

英文关键词： depression;deep brain stimulation;BDNF;signaling pathway;neurogenesis