内侧前额叶皮层星形胶质细胞调控抑郁样行为的神经环路机制研究

Depression is a common psychiatric disorder that affects over 120 million people worldwide. The neuronal monoamine systems have long been the focus of depression research. However, the monoamine-based antidepressants have some disadvantages, such as the delayed clinical effect and the side effect. Thus, there is now a tendency that mechanism research in depression move beyond the neuronal systems and the monoamine systems. Astrocyte function and neural circuits function have emerged as a vibrant area to research in depression. However, there is little evidence studying the mutual effect and the mechanism of both in depression. Our preliminary experimental results showed that astrocyte mediated the GABAergic transmission deficiency of the mPFC-LHb projecting neurons in depression, which may be mediated by astrocyte-released ATP and the deficiency of mPFC-LHb neural circuit functions. The present project will further determine ①the mechanism of astrocyte-released ATP on regulating GABAergic transmission in mPFC; ②the role of mPFC-LHb neural circuit in regulating depression; ③the involvement of astrocyte-released ATP in depressive behavior regulated by mPFC-LHb neural circuits. The project will help to uncover a new neural circuit mechanism of the mPFC astrocyte regulated depression and may be provide a new strategy for the therapeutic treatments of depression.

抑郁症，作为最常见的精神障碍，影响全球逾1.2亿人。抑郁症的研究长期聚焦在神经元单胺系统领域，而基于此开发的药物治疗方法，仍有着起效时间较长、副作用大等劣势。因此，非神经元、非单胺系统领域成为抑郁研究的焦点。其中，星形胶质细胞和神经环路研究领域在近年来成为了抑郁症机制研究的新热点，然而鲜有研究对上述二者在抑郁症病理过程的相互关系及机制进行阐明。我们预实验结果发现，抑郁样行为中星形胶质细胞介导mPFC-LHb投射神经元的抑制性突触传递功能障碍，其机制可能与ATP及mPFC-LHb神经环路功能障碍有关。本项目将进一步①阐明星形胶质细胞ATP调控mPFC抑制性突触传递的作用及其机理；②明确mPFC-LHb神经环路在抑郁行为中的改变及机理；③证明星胶细胞ATP介导了mPFC-LHb神经环路对抑郁样行为的调控。本项目将揭示mPFC星形胶质细胞ATP调控抑郁的神经环路机制，并可能为抑郁症治疗提供新策略。

抑郁症(Depression)，作为最常见的一种精神障碍，影响全球逾1.2亿人，其高发病率、高复发率以及自杀倾向，已经成为一个严重危害人类生命与健康的公共卫生问题。目前抑郁症防治的关键科学问题是阐明其发病机制，进而寻找治疗新靶点。近年来报道内侧前额叶皮层星形胶质细胞ATP参与了抑郁症的病理生理过程。然而，内侧前额叶皮层ATP调节抑郁行为的细胞及神经环路机制仍不清楚。在本项目中，1.我们发现抑郁模型小鼠细胞外ATP缺陷导致其向外侧缰核（LHb）投射的mPFC神经元（mPFC→LHb）的抑制性突触传入降低且神经元兴奋性升高，而不影响向中缝背核（DRN）投射的mPFC神经元（mPFC→DRN）。进一步的机制研究表明，mPFC抑制性中间神经元P2X2受体介导了ATP对mPFC→LHb神经元功能及抑郁样行为的调节。该研究从细胞及神经环路水平阐明了mPFC中ATP对抑郁样行为的调节机制，为抑郁症及ATP的抗抑郁作用提供了理论基础。2.我们发现发现mPFC中Nrf2可以直接与BDNF启动子1结合，促进BDNF的转录进而增加BDNF的表达水平，进而调控抑郁样行为。3. 我们发现LHb中小胶质细胞对LHb神经元兴奋性的调节作用，并阐述了相关机制。总而言之，本项目阐明了内侧前额叶皮层-外侧缰核通路在抑郁症的发生发展中的重要作用，为后续进一步开展基于该神经环路介导抑郁样行为的分子及细胞机制挖掘工作奠定了坚实的理论基础，也为后续基于该神经环路的药物研发工作成为可能。