抑郁症模型及大脑深处刺激在前额叶皮质的突触传递及可能的分子机制

Recently , the treatment for depression and it's causes have been widely focusing on, however, what is the related pathway and mechanism is needed to go deep. In this project, we want to examine synaptic circuitry underlie the model of depression and DBS-treated depression using the method of electrophysiology. Three major points would be investigated in this study. 1) The effect of agonist of D1 and D2 receptors on classic K+ channel (KCNQ and Trek) using the method of whole cell clam patch. 2) Examine the property of synaptic circuitry in PFC in the depressive animals. First, the evoked potentials in PFC are induced by the stimulation of VTA. The technique of CSD allows us to know the laminar profile and figure out which layer is the VTA-input layer. Second, the EPSCs of VTA-projecting neurons in PFC are recorded. And the EPSCs of layer Ⅴ pyramidal neurons are recorded induced by the stimulation of surface layer to examine the changes of the introcortical synaptic circuitry. Finally, the effect of two opamine receptor subunits on EPSCs are examined to know it's potential mechanism. 3) examine whether the behavioral performances could be recovered in depressive animals induced by deep brain stimulation in SCC. Also, the EPSCs of VTA-projecting neurons and layer Ⅴ neurons evoked by the stimulation of VTA and surface layer, respectively.

目前对于抑郁症的治疗和患病机制的研究倍受关注，但是对其相关通路和调控机制的研究还有待深入。本项目拟通过电生理的方法，探讨抑郁症模型动物及DBS调控抑郁症突触环路的细胞机制。主要通过三个方面展开研究：（1）通过全细胞膜片钳的方法，分别研究D1和D2受体激活后对KCNQ和Trek钾离子通道的影响。（2）考察抑郁症模型动物PFC内突触环路的生理特征：采用CSD技术，电刺激VTA，考察抑郁症模型动物中脑皮层通路在PFC各层的诱发电位；在体标记VTA投射到PFC的细胞，考察标记细胞的EPSCs；并电刺激PFC的表层，记录第Ⅴ锥体细胞的EPSCs,了解皮层内突触连接的变化；最后考察不同多巴胺受体亚型对EPSCs的影响及可能的分子机制。（3）脑深处刺激SCC，通过行为测试观察该刺激是否可以使抑郁动物得到恢复，并考察VTA投射到PFC标记细胞的EPSCs和皮层表层投射到第Ⅴ层锥体细胞的EPSCs。

重症抑郁是精神疾病中常见的一种疾病, 由于目前对于重症抑郁的治疗方法普遍存在起效慢、疗效差和副作用强等缺点, 需要我们进一步探索抑郁症的发病机制和发现新治疗方案。近年来，深部脑刺激（DBS）用于治疗重度抑郁症备受关注, 但是对其抗抑郁作用的神经生物学机制尚不明确。本项目通过建立抑郁动物模型，从前额叶神经递质传递和突触可塑性的角度，探讨抑郁症的致病机理、评估DBS治疗抑郁症的疗效以及其作用的机制。研究结果提示应激造成兴奋性突触传递的功能受损，包括突触前谷氨酸神经递质释放减少和突触后受体信号传导功能的异常，是产生抑郁症的重要机制之一。该研究的另一个重要发现是通过胼胝体下扣带回高频刺激可以快速的逆转应激造成的抑郁表型，其作用的机理与增强兴奋型突触传递和提高神经突触可塑性相关；而mTOR信号通路的激活能快速的提高突触相关蛋白的表达(如GluR1、PSD 95等)，起到有效且快速的抗抑郁作用。由于临床对于DBS的评价不一，该成果在动物模型上明确DBS具有显著的快速抗抑郁作用，且对其机制的研究，能为难治性型和重度抑郁症的应用提供理论支持，也为临床评价该治疗方案提供理论依据。