P11调控DG-mPFC神经通路参与东莨菪碱抗抑郁作用的机制研究

The current antidepressants are facing various difficulties such as delayed onset, poor efficacy and resistance. To overcome the presented treatment barriers, seeking antidepressant with rapid action and understanding its mechanism has become a critical issue. Previous studies found that synaptic plasticity promoted antidepressant effects through activity-dependent brain-derived neurotrophic factor (BDNF) induced by Scopolamine with unclear mechanism. In addition, P11 (S100a10), as a key factor regulating BDNF activity, has not been carefully examined for its relationship with Scopolamine involved in this antidepressant process. We propose that Scopolamine inhibit the excitatory toxic effects of hippocampal dentate gyrus (DG) moss cells with abundant P11 expression, and it promotes releasing BDNF and regulating synaptic plasticity through DG-medial prefrontal cortex (mPFC) pathway. This study will focus on the DG and mPFC, the core area of the antidepressant effect. We aim to explore the relationship between e P11 expression in DG and antidepressant of Scopolamine by the optogenetics and nerve electrophysiology in vivo extensively. We hope it will add to the knowledge for the antidepressant effect and clinical application of Scopolamine.

抑郁症治疗面临起效慢，疗效差，治疗抵抗等诸多难题，因此寻找快速持续抗抑郁剂，并理解其作用机制，已成为抑郁症治疗领域亟待解决的关键科学问题。既往研究发现东莨菪碱可通过增加活性依赖的脑源性神经营养因子（BDNF）促进突触可塑发挥抗抑郁作用，而作为调节BDNF活性和抗抑郁治疗的关键因子P11（S100A10），在东莨菪碱抗抑郁作用中的机制不清。本研究创新性的提出东莨菪碱抑制高表达P11的海马齿状回（DG）苔状细胞的兴奋性毒性作用，并通过DG-内侧前额叶（mPFC）投射通路促进皮层脑区活性依赖的BDNF释放调节突触可塑，发挥快速持续抗抑郁作用。本课题将利用光遗传学、在体神经电生理等多项技术和手段，聚焦抗抑郁起效的核心脑区DG和mPFC，从神经通路水平，逐层探讨DG区P11表达参与东莨菪碱抗抑郁作用机制，为揭示东莨菪碱药理作用及临床推广应用提供理论依据。

抑郁症（MDD）治疗面临起效慢，疗效差，治疗抵抗等诸多难题，寻找快速持续抗抑郁剂，尤其理解其作用机制，已成为MDD治疗领域亟待解决的关键科学问题。本研究通过临床和基础研究两个层面证实东莨菪碱具有抗抑郁作用和P11参与东莨菪碱的抗抑郁作用机制。基础研究发现，慢性不可预见性温和应激（CUMS）抑郁模型鼠存在P11相关蛋白表达下降，给予东莨菪碱治疗后情绪相关脑区（前额叶、海马）脑源性神经营养因子（BDNF），磷酸化丝氨酸受体激酶（p-TrkB）和哺乳动物雷帕霉素靶蛋白（mTORC）表达升高。海马齿状回rAAV病毒敲减P11表达后表现出明显的抑郁样行为。临床研究发现外周血单核细胞和T淋巴细胞P11表达升高，尤其在女性患者中更常见。P11联合相关因子可以较好的对MDD进行判别。MDD患者P11基因甲基化水平显著增高，P11基因DNA甲基化水平和早年生活应激通过交互作用影响抗抑郁药物的短期疗效。以上研究结果为揭示P11参与MDD的发病机制及东莨菪碱的抗抑郁作用提供重要参考依据。