陆军军医大学胡志安课题组在《Science》撰文揭示觉醒维持的关键机制

2018-10-29 佚名 细胞

早在上世纪20年代,人们发现流行性脑炎可引起患者精神不振、嗜睡。上世纪50年代,发现脑干网状结构参与觉醒的调控。这些研究加深了对觉醒维持机制的认识,但损毁已被发现的这些核团仅引起觉醒有限损害,觉醒维持的关键机制事实上并未取得根本性突破。

早在上世纪20年代,人们发现流行性脑炎可引起患者精神不振、嗜睡。上世纪50年代,发现脑干网状结构参与觉醒的调控。这些研究加深了对觉醒维持机制的认识,但损毁已被发现的这些核团仅引起觉醒有限损害,觉醒维持的关键机制事实上并未取得根本性突破。

2018年10月26日,陆军军医大学(原第三军医大学)基础医学院生理教研室胡志安课题组在《SCIENCE》杂志发表题为《The paraventricular thalamus is a critical thalamic area for wakefulness》(丘脑室旁核是丘脑中维持觉醒的关键核团)的研究论着,首次明确报道丘脑室旁核(PVT)是觉醒维持的关键脑区,并解析了PVT作用的神经环路机制。

丘脑很早就被推测与觉醒维持密切相关,临床报告也表明,卒中所致的丘脑受损可引起病人出现严重的嗜睡,甚至昏迷。但丘脑中包含三十余个核团,究竟是哪个核团对觉醒维持起关键作用?

胡志安课题组首先观察了睡眠/觉醒不同时期丘脑c-fos(反映神经元兴奋性的一种蛋白)的表达模式,发现位于丘脑中线核群的PTV的活动与觉醒关联紧密,研究人员进一步采用多通道放电和光纤钙成像记录技术,发现在睡眠向觉醒转换过程中,PVT的兴奋性显着增高,且在觉醒期间持续存在高兴奋性活动。

基于此,课题组提出丘脑室旁核是丘脑中维持觉醒的关键核团这一猜想。后续采用化学遗传学技术短时抑制PVT谷氨酸神经元,发现可明显降低觉醒量;采用白喉毒素特异性杀死PVT谷氨酸神经元或兴奋性毒素损毁PVT,可引起持续性的觉醒损害。

有趣的是,课题组发现在睡眠期特异地激活PVT谷氨酸能神经元,可快速诱发睡眠向觉醒转换,即使在麻醉状态下,激活PVT亦能够增加皮层的放电频率,并缩短麻醉向清醒转换所需要的时间,证实PVT对觉醒有触发作用。

丘脑室旁核又是如何发挥觉醒调控作用呢?课题组进而揭示PVT与皮层下伏隔核(NAc)之间可形成兴奋性的单突触功能联系。激活PVT→伏隔核通路能诱导睡眠向觉醒的转换。反之,抑制这一通路则可降低觉醒水平。下丘脑食欲素肽能神经元的输入使得PVT在觉醒期产生高兴奋性活动,进而促进觉醒维持。该结果表明PVT维持觉醒受到上游食欲素肽能神经元的调控。

觉醒维持关键机制的发现促进了我们对大脑工作原理的认识。在PVT维持觉醒的条件下,大脑才能产生意识和思维,完成感觉、运动、学习记忆等各项功能,生理性的抑制PVT活动则促使睡眠的发生。同时,该发现有望显着增进人们对疾病的认识,PVT损害可能是嗜睡、昏迷等意识障碍疾病发生的潜在因素。

据悉,该研究的全部实验在陆军军医大学完成。陆军军医大学2013级生理学硕博生任栓成为该论文第一作者,陆军军医大学基础医学院生理教研室何超博士、脑研究中心谌小维教授为该论文共同通讯作者。该研究是在国家自然科学基金、重庆市脑科学协同创新中心和陆军军医大学脑协同创新中心专项资助下完成。

原始出处:
Ren S1, Wang Y1, Yue F1,2, et al.The paraventricular thalamus is a critical thalamic area for wakefulness.Science. 2018 Oct 26;362(6413):429-434. doi: 10.1126/science.aat2512.

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    2019-09-20 guoyibin
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    2018-10-31 jichang

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