Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
Department of Neural Regulation, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Proc Natl Acad Sci U S A. 2023 Oct 10;120(41):e2301951120. doi: 10.1073/pnas.2301951120. Epub 2023 Oct 5.
Narcolepsy is a sleep disorder caused by deficiency of orexin signaling. However, the neural mechanisms by which deficient orexin signaling causes the abnormal rapid eye movement (REM) sleep characteristics of narcolepsy, such as cataplexy and frequent transitions to REM states, are not fully understood. Here, we determined the activity dynamics of orexin neurons during sleep that suppress the abnormal REM sleep architecture of narcolepsy. Orexin neurons were highly active during wakefulness, showed intermittent synchronous activity during non-REM (NREM) sleep, were quiescent prior to the transition from NREM to REM sleep, and a small subpopulation of these cells was active during REM sleep. Orexin neurons that lacked orexin peptides were less active during REM sleep and were mostly silent during cataplexy. Optogenetic inhibition of orexin neurons established that the activity dynamics of these cells during NREM sleep regulate NREM-REM sleep transitions. Inhibition of orexin neurons during REM sleep increased subsequent REM sleep in "orexin intact" mice and subsequent cataplexy in mice lacking orexin peptides, indicating that the activity of a subpopulation of orexin neurons during the preceding REM sleep suppresses subsequent REM sleep and cataplexy. Thus, these results identify how deficient orexin signaling during sleep results in the abnormal REM sleep architecture characteristic of narcolepsy.
发作性睡病是一种由食欲素信号缺失引起的睡眠障碍。然而，食欲素信号不足导致发作性睡病异常快速眼动（REM）睡眠特征（如猝倒和频繁转为 REM 状态）的神经机制尚不完全清楚。在这里，我们确定了在睡眠期间抑制发作性睡病异常 REM 睡眠结构的食欲素神经元的活动动态。食欲素神经元在觉醒时高度活跃，在非快速眼动（NREM）睡眠期间表现出间歇性同步活动，在从 NREM 到 REM 睡眠的转变之前处于静止状态，并且这些细胞的一小部分在 REM 睡眠期间活跃。缺乏食欲素肽的食欲素神经元在 REM 睡眠期间活动减少，并且在猝倒期间大部分处于沉默状态。对食欲素神经元的光遗传抑制表明，这些细胞在 NREM 睡眠期间的活动动态调节 NREM-REM 睡眠转变。在 REM 睡眠期间抑制食欲素神经元会增加“完整食欲素”小鼠随后的 REM 睡眠和缺乏食欲素肽的小鼠随后的猝倒，表明在前一个 REM 睡眠期间，食欲素神经元的一个亚群的活动抑制了随后的 REM 睡眠和猝倒。因此，这些结果确定了睡眠期间缺乏食欲素信号如何导致发作性睡病特征性的异常 REM 睡眠结构。
