脂联素上调BDNF在运动改善压力应激小鼠皮层树突棘发育和记忆缺陷中的机制研究

Stress can cause abnormal development of neuron dendritic spines, further affecting memory or cognitive functions. Exercise effectively relieves stress-induced memory dysfunction via modulating neurogenesis and neural development or synaptic plasticity. Our previous study demonstrated that adipocyte-derived adiponectin induced mouse hippocampal neurogenesis after physical exercise, and improved depression-like behavior. We recently found that exercise could protect cortical dendritic spines against elimination and rescued stress-induced memory dysfunction, via up-regulating brain-derived neurotropic factor (BDNF). However, little has been known regarding the mechanism of exercise-related spine development. Based on previous knowledge, we hypothesized that exercise alleviated stress-induced spine development deficit and memory dysfunction, by enhancing BDNF expression under the governance of peripheral adiponectin. This study aimed to investigate the role of peripheral adiponectin in exercise induced BDNF expression, and the role of adiponectin-dependent BDNF up-regulation in the improvement of dendritic spine development and behavioral paradigms, on an adiponectin gene knockout mouse model. Results of this study may provide evidences for both the knowledge of spine development and clinical intervention of stress disorder using exercise paradigm.

压力应激可导致神经元树突棘发育异常进而影响记忆认知功能，运动作为一种非药物干预手段可有效缓解压力触发的记忆障碍，并促进神经元发生发育和突触可塑性过程。申请人既往研究证实外周脂肪组织分泌的脂联素在运动后，通过诱导小鼠海马体神经元发生，从而缓解抑郁样行为。我们近期发现运动可以通过上调脑源性神经营养因子（BDNF）的表达，有效保护小鼠皮层树突棘消减，进而改善压力引发的记忆障碍。然而目前国内外对于运动改善皮层树突棘发育的外周因子和中枢机制尚不了解。因此，我们假定运动通过外周脂联素上调皮层内BDNF表达进而缓解压力应激导致的树突棘发育和记忆功能异常。本项目拟运用脂联素敲除小鼠模型和双光子皮层在体成像手段，重点研究运动诱导的外周脂联素对皮层BDNF表达的促进作用，以及上调的BDNF在促进皮层树突棘发育和行为改善中的机制。本项目可为深入了解树突棘发育提供理论依据，并为临床运动干预提供指导。

运动是一种有效改善认知和情感障碍的非药物干预手段，其疗效得到了诸多人群研究的支持；然而目前针对运动相关的神经生物学机制研究还多数局限在神经营养因子和成体神经发生领域，对于更为精细的神经突触结构在运动后的改变缺少较为系统的研究，特别是在体实验数据的支持。本项目在申请人前期成果揭示了脂联素介导运动抗抑郁效果基础上，进一步研究脂联素下游神经营养因子BDNF介导的突触发生及结构-功能可塑性，并解析其可能的分子机制。通过结合双光子在体成像、分子生物学、行为学等手段，研究发现，运动可有效增加小鼠皮层锥体神经元顶树突棘的发生和维持，并显著增强皮层神经网络的钙活动性；进一步的分子解析显示，运动通过激活皮层内mTOR信号通路，从而有效改善突触发生、钙活动性和轴突髓鞘化，从而促进皮层相关的复杂运动学习障碍。这些成果进一步拓展了运动改善认知功能的神经生物生物学机制，并为在大规模人群中科学合理评估运动疗效，乃至未来开发运动增效或部分替代性药物提供了理论依据。