外侧缰核钙通透AMPA受体在经颅直流电刺激（tDCS）调节帕金森病抑郁中的作用及机制研究

Depression commonly occurs in Parkinson’s disease (PD) and severely affect quality of life and treatment compliance. Current treatment approaches in PD-related depression are limited and the pathogenesis is poorly understood. The lateral habenular nuclerus(LHb) is an epithalamic region with a crucial role in the regulation of monoaminergic systems in the brain. The balance between excitatory and inhibitory transmission in the LHb plays an important role in the depression. Our previous studies found that unilateral lesions of the medial forebrain bundle in rats induced depressive-like behaviors, led to a more burst-firing activity of LHb glutamate neurons, and decreased dopamine levels in the striatum, medial prefrontal cortex, LHb, hippocampus and amygdala compared to sham-operated rats.Transcranial direct current stimulation (tDCS) can regulate the activity of monoaminergic systems in the brain by calcium-permeable AMPA receptors (CP-AMPARs), suggesting that tDCS might be a novel therapeutic strategy for PD-related depression by regulating LHb CP-AMPARs. In this project, we will investigate: (1) The effect of tDCS on depression behavior in rats with 6-hydroxydopamine lesions of the medial forebrain bundle by using behavioral approaches; (2) The effect of tDCS on CP-AMPARs, activity of LHb glutamate neurons and monoaminergic neurotransmitter release in LHb-related brain regions by using molecular biological, electrophysiological, and morphological approaches; (3) After downregulating, upregulating and inhibiting of CP-AMPARs in the LHb, the effect of tDCS on depressive behavior, activity of LHb glutamate neurons and monoaminergic neurotransmitter release in LHb-related brain regions.This study is expected to explore the effects and mechanisms of tDCS in regulating PD-related depression, and we hope that these findings will provide experimental evidences that tDCS is feasible for PD-related depression.

抑郁是帕金森病（PD）常见的非运动系统症状，其发病机制不清，治疗手段有限。外侧缰核（LHb）是调节脑内单胺能神经递质活动的关键核团，并表达丰富的钙通透AMPA受体（CP-AMPARs）。我们前期研究发现，PD状态下LHb内神经元电活动增强，其相关脑区中单胺能神经递质含量降低。因此提出假设：经颅直流电刺激（tDCS）通过调节LHb内CP-AMPARs调节PD相关抑郁行为。本项目以PD相关抑郁模型大鼠为对象，采用tDCS干预，观察：（1）tDCS对PD相关抑郁行为的作用；（2）tDCS对LHb内CP-AMPARs、神经元电活动及相关脑区中单胺能神经递质释放的作用；（3）上调、下调LHb内CP-AMPARs的表达及抑制其功能后，tDCS对PD大鼠抑郁行为、LHb内神经元电活动及相关脑区中单胺能神经递质释放的作用。本研究有望阐明tDCS在调节PD相关抑郁中的机制，为探索PD相关抑郁新疗法奠定基础。

抑郁及认知障碍是常见的帕金森病（PD）非运动系统症状，严重影响患者的生活质量及治疗依从性，目前其治疗手段有限。经颅直流电刺激（tDCS）作为非侵入性神经调控模式，对抑郁等情绪障碍及认知行为均具有调控作用，提示tDCS极有可能是PD非运动症状的新治疗模式。为明确tDCS对PD非运动症状的作用及机制，本研究以成功建立的PD大鼠模型为对象，综合采用行为学、分子生物学、电生理学及形态学方法，观察了tDCS对PD运动、抑郁及认知障碍的作用，并进一步观察了tDCS对外侧缰（LHb）、前额叶皮层（mPFC）、缝核（RN）等相关脑区电活动、c-Fos表达的影响。研究结果显示：tDCS可显著改善PD模型大鼠的运动行为、抑郁症状，产生抗抑郁样效应；tDCS显著增加LHb、PrL、RN的c-Fos密度；tDCS显著降低了PD模型大鼠LHb内神经元的放电频率。上述结果提示：tDCS对PD抑郁症状及工作记忆具有改善作用，这一作用与LHb、PrL、RN区域的激活及LHb神经元电活动的调控相关。本研究为探讨tDCS治疗PD抑郁症状的可行性提供了实验依据。