内源性大麻素介导自主运动增强学习记忆及其机制

It is established that voluntary exercise enhances learning and memory, while endogenous cannabinoids play essential roles in learning and memory. Nevertheless, the underlying mechanisms remain elusive. Exercise is reported to regulate synaptic plasticity via upregulation of brain-derived neurotrophic factor (BDNF), and our previous study revealed the involvement of cannabinoid receptor CB1R of astroglial cells in exercise-induced BDNF production. In addition, we found that exercise increased eCB levels and promoted eCB-mediated depolarization-induced suppression of inhibition (DSI) in the GABAergic input of hippocampal CA1 region. Therefore, we propose that exercise induces learning and memory-related synaptic plasticity in the hippocampus via 2 eCB-dependent approaches: 1)it enhances DSI in GABAergic synapse in the CA1 region to minimize its inhibitory effect; 2) it triggers the release of eCB which subsequently binds CB1R of astroglial cells, increases the secretion of BDNF, and promote the transmission of excitatory synapses. In the present study, by using conventional and conditional CB1R knockout mouse models and combining electrophysiological, behavioral and molecular biology methods, we attempt to elucidate the role of eCB and the synaptic plasticity mechanisms in the enhancement of learning and memory by voluntary exercise, which will possibly provide rationale for effective treatment of learning and memory disorders.

自主运动增强学习记忆已成定论，内源性大麻素（eCB）在学习记忆中亦发挥重要作用，但具体机制均有待阐明。文献报道，运动可通过上调脑源性神经营养因子（BDNF），调节海马神经突触可塑性，而我们前期研究发现，胶质细胞表面的大麻素受体CB1R参与BDNF合成。我们还发现，自主运动能够上调海马eCB水平，并增强去极化对抑制性突触后电流的抑制作用（DSI）。据此我们提出，自主运动可能通过以下两种eCB依赖的海马突触可塑性机制促进学习记忆：1）在CA1区GABA能传入突触强化eCB介导的DSI，导致突触传递去抑制；2）促进eCB释放，作用于胶质细胞CB1R，合成BDNF，增强兴奋性突触传递。本研究以常规和细胞类型特异性CB1R基因敲除小鼠为模型，结合电生理、行为学和分子生物学方法，阐明eCB在自主运动增强学习记忆中的重要作用，揭示介导上述作用的突触可塑性机制，为学习记忆障碍的有效干预提供理论依据。

自主运动增强学习记忆已成定论，但其具体机制并不清楚。我们以常规和细胞类型特异性内源性大麻素I 型受体（CB1R）基因敲除小鼠为模型，结合电生理、行为学和分子生物学方法， 对内源性大麻素（eCB）在运动增强学习记忆中的作用及其机制进行了系统研究，发现：1）自主运动可同时上调脑源性神经营养因子（BDNF）及CB1R水平，且二者存在协同作用；2）自主运动能够上调海马eCB水平，并增强去极化对兴奋性突触后电流的抑制作用（DSE）； 3）自主运动通过谷氨酸能神经元表面的CB1R上调小鼠海马CA1区BDNF表达，增强学习记忆能力。本研究阐明了eCB介导的运动增强学习记忆的新机制，为学习记忆障碍的有效干预提供理论依据。