Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness.
Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness.
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DOI：
10.5665/sleep.2972
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发表时间：
2013-09
期刊：
影响因子：
5.6
通讯作者：
Sawako Tabuchi;Tomomi Tsunematsu;T. Kilduff;Shouta Sugio;Ming Xu;Kenji F. Tanaka;Satoru Takahashi;M. Tominaga;A. Yamanaka
中科院分区：
文献类型：
--
作者：
Sawako Tabuchi;Tomomi Tsunematsu;T. Kilduff;Shouta Sugio;Ming Xu;Kenji F. Tanaka;Satoru Takahashi;M. Tominaga;A. Yamanaka
研究目的 中缝背核的血清素能 (5HT) 神经元接收来自下丘脑食欲素（下丘脑分泌素）神经元的兴奋性输入，并通过 5HT1A 受体相互抑制食欲素神经元。然而，人们对这种负反馈电路对于睡眠/觉醒调节的生理意义知之甚少。设计 使用 Tet-off 系统特异性地、可逆地控制食欲素神经元中的 5HT1A 受体表达水平。比较 5HT1A 过表达小鼠和对照小鼠的体外食欲素神经元对 5HT 的反应性以及睡眠/觉醒模式。测量和结果 当 5HT1A 受体在 Orexin-EGFP 的食欲素神经元中过度表达时；食欲素-tTA； TetO Htr1a 小鼠中，5HT 诱导的食欲素神经元抑制时间延长。在没有多西环素的情况下，Orexin-tTA； TetO Htr1a 小鼠在黑暗期的前半段（夜间啮齿动物的最大活动时间）表现出严重的睡眠/觉醒碎片化，但在睡眠时间最长的明亮期不影响睡眠/觉醒。然而，当食欲素神经元中的 5HT1A 受体在多西环素存在下降低至基础表达水平时，食欲素-tTA 中的睡眠/觉醒模式；早期活跃期的 TetO Htr1a 小鼠与同窝的 TetO Htr1a 小鼠没有区别。这些结果强烈表明，食欲素神经元的抑制性血清素输入的增强导致了觉醒的碎片化。相比之下，光照期的睡眠/觉醒结构不受食欲素神经元中 5HT1A 受体过度表达的影响。结论 抑制性血清素输入可能在黑暗早期对食欲素神经元起负反馈作用，有助于稳定觉醒发作，从而有助于睡眠和觉醒的昼夜节律。
STUDY OBJECTIVE Serotonergic (5HT) neurons of the dorsal raphe nuclei receive excitatory input from hypothalamic orexin (hypocretin) neurons and reciprocally inhibit orexin neurons through the 5HT1A receptor. However, the physiological significance of this negative feedback circuit for sleep/wakefulness regulation is little understood. DESIGN 5HT1A receptor expression level was specifically and reversibly controlled in the orexin neurons using the Tet-off system. The responsiveness of orexin neurons to 5HT in vitro and the sleep/wakefulness patterns were compared between 5HT1A-overexpressing and control mice. MEASUREMENTS AND RESULTS When the 5HT1A receptor was overexpressed in orexin neurons of Orexin-EGFP; orexin-tTA; TetO Htr1a mice, 5HT-induced inhibition of orexin neurons was prolonged. In the absence of doxycycline, Orexin-tTA; TetO Htr1a mice exhibited severe fragmentation of sleep/wakefulness during the first half of the dark period-the time of maximal activity in nocturnal rodents-without affecting sleep/wakefulness during the light period when sleep time is maximal. However, when the 5HT1A receptor in orexin neurons was reduced to basal expression levels in the presence of doxycycline, sleep/wakefulness patterns in Orexin-tTA; TetO Htr1a mice during the early active period were indistinguishable from those of littermate TetO Htr1a mice. These results strongly suggest that enhancement of inhibitory serotonergic input to orexin neurons caused fragmentation of wakefulness. In contrast, sleep/wakefulness architecture in the light period was unaffected by 5HT1A receptor overexpression in the orexin neurons. CONCLUSION Inhibitory serotonergic input likely functions as negative feedback to orexin neurons in the early dark period and helps stabilize wakefulness bouts, thereby contributing to the diurnal rhythm of sleep and wakefulness.