ANA-12与7, 8-DHF在不同神经环路抗抑郁作用的神经可塑性机制研究

Major depressive disorder (MDD) is a common, recurrent mental illness that affects millions of people worldwide. Accumulating evidence suggests that the neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathogenesis and treatment of this disease. Our preliminary studies showed both TrkB antagonist ANA-12 and TrkB agonist 7, 8- dihydroxyflavone (7, 8-DHF), two novel therapeutic compounds, exerted antidepressant effects. Based on this contradiction, we hypothesized the changes of neural plasticity on different neural circuits (VTA-NAc/hippocampus-PFC) induced by ANA-12 and 7, 8-DHF respectively are different. In order to test our hypothesis, we will carry out experiments on unpredictable chronic mild stress (UCMS) mice model with ANA-12, 7, 8-DHF, and traditional antidepressants imipramine, fluoxetine. We hope this study will benefit unravelling the pathophysiology of MDD, and also provide a promising path to develop new antidepressants.

重性抑郁障碍（MDD）病因和发病机制目前仍不完全清楚。研究表明脑源性神经营养因子（BDNF）及其受体TrkB已被作为MDD病理生理的关键中介因子。已有文献及本课题小组的预实验发现新近报导的TrkB受体拮抗剂ANA-12与TrkB受体激动剂7,8-DHF均具有抗抑郁作用，但其内在的机制尚不清楚。本研究正是从这一表面矛盾的结果出发，提出理论假设:MDD的不同神经环路（VTA-NAc、海马-PFC）上BDNF受体拮抗剂和受体激动剂的神经可塑性改变（突触可塑性、神经发生、结构可塑性、神经可塑性分子表达及其信号通路等）不同。本研究采用本课题小组已经成功建立的最接近临床真实的不可预期慢性温和应激（UCMS）小鼠抑郁模型对这一假说进行验证，并对比传统抗抑郁剂丙咪嗪和氟西汀，以期从神经环路角度寻求MDD发病机制的新突破。

重性抑郁障碍（MDD）病因和发病机制目前仍不完全清楚。研究表明脑源性神经营养因子（BDNF）及其受体 TrkB 已被作为 MDD 病理生理的关键中介因子。已有文献及本课题小组的预实验发现新近报导的 TrkB 受体拮抗剂 ANA-12 与 TrkB 受体激动剂 7,8-DHF 均具有抗抑郁作用，但其内在的机制尚不清楚。本研究采用了小鼠社会挫败（SD）抑郁模型，母体免疫激活（MIA）模型和 不可预期慢性温和应激（UCMS） 模型对其表观效度（抑郁样行为）、预测效度（采用ANA-12，7, 8-DHF干预）进行确证；研究发现在SD模型中ANA-12可能是通过降低NAC的GluA1，7,8-DHF通过上调PFC、DG和CA3的PSD-95, GluA1表达发挥其抗抑郁效果；在UCMS模型中，ANA-12和7,8DHF可能是上调PFC和HIP中BDNF，TrkB和PSD95表达发挥其抗抑郁作用。本研究结果为抑郁症的发病机制以及抗抑郁新药的研发提供新思路。