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吻内侧被盖核通过控制多巴胺系统调控睡眠觉醒的作用及机制

批准号81571296 学科分类睡眠与睡眠障碍 ( H0916 )
项目负责人杨素荣 负责人职称副教授 依托单位复旦大学
资助金额57.00
万元
项目类别面上项目 研究期限2016 年 01 月 01 日 至
2019 年 12 月 31 日
中文主题词γ-氨基丁酸;吻内侧被盖核;多巴胺;睡眠-觉醒;光遗传学
英文主题词gamma-aminobutyric acid (GABA);rostromedial tegmental nucleus (RMTg);dopamine;sleep-wake; optogenetics

摘要

中文摘要 睡眠问题是医学及社会难题,特别是多巴胺(DA)相关神经精神疾病伴有严重睡眠紊乱。吻内侧被盖核(RMTg)的γ-氨基丁酸 (GABA)能神经轴突与DA神经元形成密集突触,对DA神经元活性有很强抑制作用,因此,RMTg可能与睡眠觉醒密切相关,但作用机制不明。前期实验发现非特异毁损RMTg的大鼠睡眠量显著减少,而非特异激活RMTg的大鼠睡眠量显著增加。我们假说:RMTg的GABA能神经元主要通过控制DA系统活性调控睡眠觉醒。研究将应用囊泡GABA转运体(VGAT)-cre小鼠、光遗传学和DREADD等方法,选择性激活或抑制DA系统上游RMTg的GABA能神经元,结合神经示踪、电生理、免疫组化等方法,从分子到行为,揭示RMTg调控睡眠觉醒的作用、神经通路及机制。预期结果将丰富和发展睡眠觉醒调节理论,对理解DA调控睡眠觉醒作用及DA相关性睡眠障碍具有重要意义,为探索临床治疗新靶点奠定理论基础。
英文摘要 Sleep problems including insomnia are increasingly becoming serious medical and social puzzles. Severe sleep disorders were observed in nearly all patients with nervous and mental diseases involved in abnormal dopamine. The reason may be due to the unclear effects of DA in regulation of sleep and wakefulness because of the neglect of actions of GABAergic afferents on DA neurons. .Rostromedial Tegmental Nucleus (RMTg), a newly identified region in brainstem, is primarily comprised of gamma-aminobutyric acid (GABA) neurons. Its axons formed intensive synaptic contacts with midbrain DA cells. Compared with other GABAergic inputs, RMTg exerts a major inhibitory control on DA neurons. In our previous experiments, we found that nonselective lesions of RMTg neurons in rats produced a significant reduction in sleep, whereas, nonselective activation of RMTg neurons induced more sleep. Some references reported that inhibitory GABA neurons play important roles on brain functions elicited by DA. Taking into account the above considerations, we put forward the hypothesis: RMTg GABA neurons regulate sleep and wakefulness mainly through the control of DA system. .Here, we will take advantage of vesicular GABA transporter (VGAT)-cre mice and ontogenetic as well as DREADD manipulations to excite or inhibit activities of RMTg GABA neurons at upstream of midbrain DA system. Combined with neuroanatomical tracing, electrophysiology, immunohistochemistry and other approaches, we will investigate the roles, neural circuits, and neurobiological mechanisms of RMTg GABA neurons in sleep-wake regulation from molecular to behavioral levels. .The expected results will enrich and develop theories of sleep-wake regulation, have important significance for understanding the role of DA in sleep-wake regulation and DA-related sleep disorders, and lay the theoretical foundation for exploration of new targets for clinical therapy.
结题摘要

成果

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