The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.
The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.
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喙内侧被盖核对于非快速动眼睡眠至关重要
DOI：
10.1371/journal.pbio.2002909
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发表时间：
2018-04
期刊：
影响因子：
9.8
通讯作者：
Huang ZL
中科院分区：
文献类型：
--
作者：
Yang SR;Hu ZZ;Luo YJ;Zhao YN;Sun HX;Yin D;Wang CY;Yan YD;Wang DR;Yuan XS;Ye CB;Guo W;Qu WM;Cherasse Y;Lazarus M;Ding YQ;Huang ZL
头内侧被盖核（RMTg），也称为腹侧被盖区的GABA能尾，投射到中脑多巴胺能系统、中缝背核、蓝斑和其他区域。RMTg是否参与睡眠-觉醒调节尚不清楚。在本研究中，大鼠RMTg神经元的药物遗传学激活促进了非快速眼动（NREM）睡眠，并增加了慢波活动（SWA）。相反，神经毒性损伤8或16天后的大鼠表现出NREM睡眠减少，开灯时SWA减少。SWA减少在损伤后至少持续25天。同样，大鼠RMTg神经元的药理学和药物遗传学失活减少了NREM睡眠。结合光遗传学的电生理实验表明，RMTg神经元和中脑多巴胺能神经元之间存在直接的抑制性联系。RMTg对睡眠-觉醒周期的双向作用通过使用药物遗传学方法调制腹侧被盖区（VTA）/黑质多巴胺能神经元活性来模拟。此外，在6小时睡眠剥夺后的2小时恢复期内，病变组和对照组大鼠的NREM睡眠量与基线水平相比均显著增加;然而，只有对照组大鼠的SWA与基线水平相比显著增加。总的来说，我们的研究结果揭示了RMTg在促进NREM睡眠和稳态调节中的重要作用。睡眠-觉醒行为由大脑中的神经元和神经递质网络控制。有多个群体的唤醒促进神经元，但很少有睡眠促进神经元已被确定。在这项研究中，我们发现，吻内侧被盖核，腹侧被盖区的GABA能尾，调节非快速眼动睡眠。我们发现，大鼠嘴内侧被盖核的神经元，当被药物遗传学激活时，增加和加深非快速眼动睡眠。对这些神经元的抑制表现出相反的效果。此外，大鼠的头内侧被盖核损伤后，睡眠剥夺的睡眠稳态反应降低。我们发现，在头内侧被盖核的神经元的终端刺激抑制中脑多巴胺能神经元。有趣的是，抑制这些多巴胺能神经元也具有促进睡眠的作用。目前的研究结果为延长非快速眼动睡眠、改善睡眠质量和治疗多巴胺相关精神疾病的睡眠障碍提供了潜在的靶点。
The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep–wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep–wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation. Sleep–wake behavior is controlled by networks of neurons and neurotransmitters in the brain. There are multiple populations of wake-promoting neurons, but few sleep-promoting neurons have been identified. In this study, we revealed that the rostromedial tegmental nucleus, the GABAergic tail of the ventral tegmental area, regulates non-rapid eye movement sleep. We show that neurons in the rat rostromedial tegmental nucleus, when activated by pharmacogenetics, increase and deepen non-rapid eye movement sleep. Inhibition of these neurons exhibits the opposite effects. Furthermore, rats with lesion in the rostromedial tegmental nucleus have a reduced response of sleep homeostasis following sleep deprivation. We show that stimulation of the terminals of the neurons in the rostromedial tegmental nucleus inhibits dopaminergic neurons in the midbrain. Interestingly, inhibition of these dopaminergic neurons also has sleep-promoting effects. The current results provide a potential target for prolonging non-rapid eye movement sleep, improving sleep quality, and treating sleep disorders in dopamine-implicated mental illness.
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