运动上调海马蛋白酶体活性对神经发生的影响及其机制

神经干细胞（NSCs）分化产生神经元，参与神经功能活动的过程称为神经发生。然而，随年龄增加NSCs增殖和分化能力降低，出现神经发生障碍，这是神经退行性疾病发生的关键事件。有证据显示蛋白酶体活性与干细胞“干性”相关。我们已证实上调蛋白酶体活性有助于维持NSCs活力，近期结果提示运动可增强海马蛋白酶体活性，提高小鼠认知功能，推测蛋白酶体活性是神经发生的重要环节。为此，本课题应用VitalView跑轮监测系统，在体研究运动上调成年和中老年鼠蛋白酶体活性对神经发生的影响。同时，采用形态学、电生理学和行为学手段，检测长期运动改善蛋白酶体活性对预防和治疗老年认知功能障碍的意义。最后，利用高通量测序和siRNA文库筛选平台，经高内涵成像系统挖掘运动激活蛋白酶体活性的关键靶点，分析靶基因对NSCs潜能的影响。旨在发现调控NSCs活力的新途径，全面解析运动促进神经发生的机制，为倡导健康生活方式提供理论依据。

Neurogenesis is the process in which the neurons newly derived from neural stem cells (NSCs) functionally integrate into the existing circuits. During ageing, NSCs progressively lose their proliferating and differentiating potentials, subsequently resulting in neurogenesis suppression that has been regarded as the critical factor contributive to neurodegenerative diseases. Evidence is accumulating to suggest an association between the proteasome activity and the stemness of NSCs. We have previously demonstrated that enhancement of proteasome activity could help maintain the normal viability of NSCs. Additionally, the recent data provided by us showed that proteasomes might be activated by physical exercise, concurrent with improved learning and memory functions. In the present study, we shall further unmask the role of proteasomes in modulating adult neurogenesis, including proliferation, differentiation, migration and integration of NSCs. Particularly, we shall in depth explore whether and how up-regulation of proteasome activity by persistent physical exercise could exert preventive and curative effects on mitigating cognitive deficits related to ageing, by use of the VitalView on-line wheel running system in combination with morphological, electrophysiological and behavioral methods. Furthermore, the high-throughput sequencing, siRNA library screening and high-content imaging will be applied to identify the key target genes that control the proteasome activity and thus affect the biological properties of NSCs. The overall goal of our study is to elucidate the mechanism mediating the physical exercise-elicited promotion of proteasome activity and neurogenesis; this will not only assist in devising new strategies to counteract ageing-exerted adverse effects on NSCs, but also set a theoretical basis for better advocating the active healthy lifestyle.