REM睡眠肌张力弛缓神经环路及REM睡眠行为障碍机制研究

睡眠障碍已成为日益严重的社会及医学问题，其中快动眼睡眠行为障碍（RBD）与帕金森病（PD）等神经退行性疾病密切相关。RBD以REM睡眠期肌张力失弛缓为主要特征，最终80%以上都将发展成神经退行性疾病。调控REM睡眠肌张力弛缓神经环路及RBD发病机制亟待阐明。背外侧被盖核下区（SLD）是调控REM睡眠的关键脑区，损毁SLD谷氨酸能神经元引发RBD样行为；临床尸检发现RBD患者SLD脑区有路易斯小体病变，提示调控REM睡眠肌张力弛缓神经环路发生突触核蛋白病变导致RBD。本项目借助腺相关病毒载体，拟采用化学遗传学、光遗传学技术，结合脑电记录、电生理及逆向跨单级突触神经环路示踪技术，揭示SLD调控REM睡眠肌张力弛缓的神经环路，初探RBD可能的发病机制。研究结果将丰富和发展睡眠-觉醒调节理论，为PD等神经退行性疾病的发病机制增添新内容，并为探索预防、延缓或阻止神经退行性病变进程提供新方向。

REM sleep behavior disorder (RBD) is a major health problem characterized by dysfunction of atonia during REM sleep, and will eventually develop into a synucleinopathy, such as Parkinson’s diease (PD). Understanding the neural circuit of atonia provides not only how the motor system operates during sleep but also the neuropathology of RBD. The sublaterodorsal tegmental nucleus (SLD) confirmed as a key brainstem area in regulating REM sleep, loss of glutamate function of the SLD results in RBD-like phenotype. Postmortem evidence shows RBD patients have Lewy bodies in SLD, indicates that RBD arises from degeneration of the circuits that control REM sleep. In this project, we will apply chemogenetic/optogenetic/lesion approaches to selectively modulate the activity of SLD-spinal pathway, and adopt electrophysiological and electron microscopy techniques, to clarify the role and how the circuit controlling REM sleep atonia. We also aim to specific the role of SLD GABAergic neuron in regulating muscle activity during REM sleep. Furthermore, we degenerating the SLD by overexpression of human mutant A53T-a-synuclein in SLD, to elucidate the pathogenesis of RBD and its relationship with REM sleep atonia circuits. The results will lay the foundation for understanding the pathophysiology of RBD, bring contributions to the enrichment and development of sleep-wake regulation theory, and play an important role in exploring methods of prevention and treatment neurodegenerative disorders such as PD.