气体信号分子硫化氢调控海马BDNF/TrkB通路-神经发生拮抗慢性应激性抑郁

Depression causes a great harm to our mental health. It is of great significance from a new perspective to explore the mechanisms and the targets for the prevention of depression. H2S is a novel gas-neuromodulator. Based on the literatures and our previous studies, we believe that the low level of endogenous H2S is closely related to depression and H2S can prevent depression by modulating hippocampal BDNF/TrkB pathway and neurogenesis. Based on our previous findings that H2S induces antidepressant-like effect in acute stress-induced depression, we will further reveal the relationship between endogenous H2S and depression and clarify the antidepressant effects of H2S using the model of chronic social defeat stress or chronic unpredictable mild stress by exploring the changs of endogenous H2S generation and its generation system, observing the antidepressant-like effect of enhancing the level of H2S in brain on chronic depression, and analyzing the role of decreasing the level of endogenous H2S in brain in promoting chronic depression.We will clarify the molecular mechanism of the antidepressant effect of H2S through exploring the role of BDNF/TrkB pathway and hippocampal neurogenesis in the antidepressant effect of H2S. Thus, the present work will reveal a novel mechanism of depression and provide novel targets and avenues for the treatment of depressive disorders from the new perspective of the gasotransmitters H2S.

抑郁症的危害性大，从新的视角探讨其发生机制和防治靶点具有重要意义。H2S是一种新颖的气体性神经调质，基于文献和前期研究，我们认为抑郁与低水平的内源性H2S密切相关，H2S可通过调制海马BDNF/TrkB通路及神经发生拮抗抑郁。我们已发现H2S对急性应激性抑郁具有拮抗作用，在此基础上，本项目拟进一步建立慢性社交失败应激或慢性非预期温和应激等慢性应激性抑郁模型，观察慢性抑郁状态时内源性H2S生成及其生成体系的变化情况，探讨增加脑内H2S水平对慢性应激性抑郁的拮抗作用以及降低脑内H2S水平对慢性应激性抑郁的促进作用，以揭示内源性H2S与抑郁的关系和阐明H2S的抗抑郁作用；探讨H2S对海马BDNF/TrkB通路和神经发生的调控作用，从海马BDNF/TrkB通路-神经发生的角度揭示H2S抗抑郁的神经分子机制。本项目的开展有望从气体信号分子H2S这一新视角揭示抑郁的新机制，为其防治提供新靶点和策略。

抑郁症已成为一个全球性的健康问题，但其发病机制仍不明确，现有临床应用的抗抑郁症药物的临床疗效均不尽人意。因此，从新的视角进一步研究抑郁症的发病机制和探索防治抑郁的新靶点是一个的重要研究课题。H2S是一种新颖的气体性神经调质，具有重要的神经生物学作用。本项目主要探讨其在防治抑郁症中的潜力及其作用机制。我们发现H2S对急性应激性抑郁和焦虑具有拮抗作用，海马内源性H2S的生成受阻可能在慢性应激引起抑郁中起至关重要的作用，而外源性给以H2S可显著减轻慢性应激所致的抑郁样行为，并降低慢性应激引起的海马内质网应激、氧化应激、凋亡以及神经再生障碍，表明H2S具有拮抗慢性应激性抑郁的作用，其机制可能与其促进海马神经再生、减轻海马神经损伤密切相关。同时，我们还证实BDNF-TrkB通路和Sirt-1通路对H2S抗慢性应激性抑郁具有介导作用。另外，我们还探讨了H2S对糖尿病性抑郁的影响，发现H2S还可通过减轻海马氧化应激而改善糖尿病性抑郁。本课题在急、慢性应激性抑郁模型上，首次明确了H2S的抗抑郁作用，这是一个全新的发现，为抑郁的发生机制的研究提供新的切入点，为其防治提供了新的靶点和策略。