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睡眠浅，越睡越累？哈佛医学院首次定位大脑深度睡眠关键蛋白，提供失眠新疗法

2022-05-04 乐一 MedSci原创

Nature子刊深度睡眠
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Nature Communications：通过对丘脑网状神经元上的GABAA alpha3亚基进行敲除，可有效增强小鼠的深度睡眠。

睡眠，这个锚定在人类基因中的生理活动，占据了人类生命总长的三分之一。
据世界卫生组织调查，全球约有27%人口存在睡眠障碍，而在中国，成年人失眠的发病率高达38%！2022年中国睡眠研究会发布的《2022中国健康睡眠调查白皮书》显示，近3/4的人曾有睡眠困扰，入睡困难成为头号难题。其中，未成年人平均睡眠时长仅7小时；25-60岁之间的人群，随着年龄的增长睡眠时长逐渐减少，睡眠时长超过6小时的占比也逐渐降低——对于青壮年，“睡不好”可主要归因于“压力山大”；而对于老者，身体欠佳可能是影响睡眠的主因。
图片
（图源：中国睡眠研究会）
除了睡眠时长外，睡眠质量也会影响我们的睡觉体验。我们经常会有这样的“迷惑经历”：睡了长长一觉后醒来却精疲力竭。这是因为没有足够的深度睡眠。作为睡眠的重要组成部分，深度睡眠被称作是“黄金睡眠”，占整个睡眠时间的25%，可以缓解人们一天的劳累，促进人体的新陈代谢，对身体大有裨益。
那么大脑是如何调节人体进入深度睡眠的呢？多年来，科学家们一直致力于解决这一问题，以试图借此寻找缓解睡眠问题的有效方法。
近期，哈佛医学院的研究人员在Nature Communications发表的一项研究为这个长期谜团提供了关键线索：他们发现，通过对丘脑网状神经元上的GABAA alpha3亚基进行敲除，可有效增强小鼠的深度睡眠。
图片

（图片来源：Nature Communications）

众所周知，睡眠主要可以分为两种，一种是快速眼动睡眠（REM睡眠），另一种是非快速眼动睡眠（NREM睡眠）。REM睡眠阶段是梦境最主要发生的时期；除REM睡眠之外的阶段，都被统称为NREM睡眠。按照睡眠的深度，NREM睡眠可被分为阶段1、阶段2和阶段3。阶段1和阶段2被统称为“浅睡眠”，阶段3则是“深度睡眠”。当进入深度睡眠时，脑部就会开始出现称为“Delta波”的深、慢脑电波，此阶段噪音和活动可能无法对人们产生响应，也就是平常我们说的“沉睡”。
图片
一晚上睡眠阶段的变化（图源：网络）
研究小组将注意力集中在丘脑神经元上，丘脑是大脑中负责调节睡眠和清醒等功能的区域。利用基因编辑技术，研究人员破坏了一种编码结合抑制性神经递质的蛋白GABAA——该家族蛋白是安眠药的靶标，常用的安眠药（如非苯二氮卓类药物和苯二氮卓类等）都可以通过激活GABAA受体从而改善睡眠。
不过，激活的GABAA活性却减少了Delta振荡，这表明 GABAA受体会阻止人体进入深度睡眠，也就是说，安眠药入睡的睡眠质量并不高。
在这项研究中，研究者们敲除了小鼠丘脑中GABAA α3基因（因为丘脑网状中主要为α3亚型），以研究丘脑网状神经元上的GABA A受体对NREM中Delta振荡的影响，以反映深度睡眠的好坏。有趣的是，与基线(BL)记录相比，α3敲除 小鼠具有更高的NREM Delta振荡功率。
图片
NREM Delta振荡功率（图源：Nature Communications）
在人类中，Delta振荡在NREM 睡眠的最深阶段N3最为突出，觉醒阈值也会随着NREM睡眠的深度而增加。鉴于人类更有可能从较轻的 N1 或 N2 阶段中醒来，因此研究人员分析了NREM → REM 和 NREM → 清醒转变之前的Delta振荡。出乎意料的是，研究人员发现α3敲除后只有NREM → REM期间可以明显增加Delta振荡；而NREM→清醒前则没有明显差异。
图片
Delta功率（图源：Nature Communications）
除此之外，在过渡到REM之前，整个NREM周期内 Delta振荡频率均持续保持较高水平，且GABAA α3被抑制，Delta振荡水平更高。这一过程还存在着显著的线性关系：随着NREM → REM转换时的NREM持续时间越长，Delta振荡频率增加的越大。
这使得研究人员兴奋不已。为了再次确认这种深度睡眠的改善是由于抑制了GABAA α3亚基，他们对丘脑网状核进行了组织学检验，并确定丘脑大部分区域的GABAA α3的确均被敲除。由此，研究人员得出了一个重要的结论——丘脑网状核中对GABAA α3基因的抑制决定了NREM 期间Delta振荡功率的升高，诱导了机体的深度睡眠。
图片
Cas9-sgRNA分布检测（图源：Nature Communications）
目前常用的安眠药虽然在治疗失眠方面具有良好的疗效，但也有众所周知的弊端：许多药物让人们快速入睡的同时却会抑制大脑恢复性Delta波活动，服用安眠药入睡不一定是恢复性的，睡眠质量会大打折扣。
“我们的发现代表着在精确定位睡眠调节的分子基础上迈出了重要的一步，并指出了一种促进自然、恢复性睡眠的替代药物策略，”高级研究员Radhika Basheer说，“我们相信我们的研究结果为开发一种新的睡眠药物奠定了基础——这种药物可以通过促进Delta波振荡来实现对深度睡眠至关重要的维持。”
生命在于深度睡眠。希望这种助眠的新型安眠药早日研发，使睡眠障碍者也可以拥有睡觉又快又香甜的“春天”~
 
参考资料
[1] Uygun DS, Yang C, Tilli ER, Katsuki F, Hodges EL, McKenna JT, McNally JM, Brown RE, Basheer R. Knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep in mice. Nat Commun. 2022 Apr 26;13(1):2246. doi: 10.1038/s41467-022-29852-x.

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    2023-03-02 zhangyxzsh

    #关键蛋白#

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    2023-01-28 朱睿睿

    #医学院#

    0

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    2022-05-05 ms6323715314570549

    #哈佛医学院#

    0

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    2022-05-05 kcb074

    #新疗法#

    0

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    2022-05-05 amyloid

    #哈佛#

    0

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    2022-05-04 ms600000165

    mark学习

    0

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