社会失败抑郁模型的行为学变化及参与其发病或治疗的中枢神经机制

In the face of increasingly serious depressive disorders induced by social stress, this study will focus on the social defeat depression model. We study the behavioral changes induced by social defeat stress and the corresponding central neural changes, and explore the central mechanisms involved in its pathogenesis and treatment. Moreover, we will confirm the possible mechanisms through drug intervention and indicate the preventive methods and therapeutic drugs. To investigate the behavioral changes: social interaction tests will be applied to probe into social avoidance; elevated plus maze and open field test will be used to observe the anxiety-like behaviors; Morris water maze and Y maze will be utilized to assess the learning and memory changes. In addition, in vivo hippocampal field potential will be recorded to investigate the changes in long-term potentiation or depression induced by social defeat. Moreover, we will study the differences of susceptibility to social defeat stress that last different periods. Then, we will probe into some workable signaling pathways that mediate social defeat stress (planning: Purine receptors which mediate the ATP excitotoxity, or glia activation which affect the neuronal synaptic plasticity). Finally, antidepressants, as well as purine receptor antagonists, will be employed to evaluate their behavioral effects of anti social defeat, based on which we will explore the potential means and drugs for alleviating the symptoms of depression.

鉴于社会应激导致的抑郁症日益严重，本课题拟利用社会失败抑郁模型，研究遭受社会失败应激的小鼠行为学改变及中枢神经系统的变化，并揭示社会失败诱导抑郁症的中枢机制，继而通过药物干预加以证实，最后提出潜在针对社会失败抑郁症的预防手段与治疗药物。在行为学方面，拟通过社交测试观察社会失败模型小鼠的社交行为变化，通过高架十字迷宫及旷场测试观察焦虑样行为，通过水迷宫、Y迷宫等测试观察学习记忆的变化。利用在体海马场电位记录实验观察社会失败模型动物是否存在长时程增强或抑制的突触可塑性改变。并且，将探索不同的应激时间所造成的社交失败易感性的差异。继而，拟寻找一种可能介导社会失败应激导致抑郁症的神经系统信号途径（拟尝试嘌呤类受体介导的ATP信号途径及胶质细胞活化后影响神经元突触可塑性的途径）。最后，通过抗抑郁药或嘌呤类受体拮抗剂等，观察对抗社会失败的行为学效果，探索缓解社会应激诱导的抑郁症的手段与药物。

本项目利用小鼠社交挫败抑郁模型，观察了社交挫败应激所致的社交回避、焦虑、抑郁等行为学缺陷；并深度分析了社交挫败动物对应激源及同种鼠的社交水平变化及社交率受季节影响的规律；观察了社交挫败动物的海马神经电生理变化；研究了社交挫败过程中杏仁核PKA活化现象作为机体自身对抗焦虑的机理，提出了抗抑郁药缓解社交挫败模型焦虑行为的脑区和分子机制；不但如此，本课题在国际上首次发现并全面详尽地（从全面的学习记忆测试评估、及中期和长期等不同应激时间段）证实了社交挫败抑郁模型在致抑郁焦虑之外，可显著提升学习记忆能力的功能，并从海马新生神经元增高、海马二三级树突棘密度提升、血浆皮质酮水平提升加以佐证，进一步，揭示了社交挫败提升学习记忆通过了海马NR2B和SNAP25的介导的分子机理，并通过各类分子、病毒工具手段，描绘了社会应激→SNAP25提升→NR2B水平提升→学习记忆增强这一上下游流程。此外，借助社交挫败类似的造模方式，国际上首创了利用异性接触并隔离的全新社会应激抑郁模型，且通过各类行为学与脑区分子变化加以验证。以上实验不但为揭示社会应激致焦虑抑郁的病理过程提供了明确数据，为治疗社会应激所致焦虑提供了潜在靶点，清晰阐释了抗抑郁药的部分治疗机理，同时，从学习记忆增强的层面，为更全面理解应激对脑功能的影响补充了视角，甚至提供了新颖、潜在的促学习记忆的社会策略。

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