Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom.
UK Dementia Research Institute, Imperial College London, London SW7 2AZ, United Kingdom.
J Neurosci. 2022 Jul 6;42(27):5389-5409. doi: 10.1523/JNEUROSCI.0350-21.2022. Epub 2022 Jun 1.
The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area (AHA) did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine; Dex). By contrast, fragmentation persisted under high sleep pressure produced by sleep deprivation (SD), mice had a high propensity to sleep but woke up. By analyzing changes in δ power, sleep homeostasis (also referred to as "sleep drive") remained intact after NMDA receptor ablation. We suggest NMDA glutamate receptor activation stabilizes firing of sleep-on neurons and that mechanisms of sleep maintenance differ from that of the sleep drive itself. Insomnia is a common affliction. Most insomniacs feel that they do not get enough sleep, but in fact, often have good amounts of sleep. Their sleep, however, is fragmented, and sufferers wake up feeling unrefreshed. It is unknown how sleep is maintained once initiated. We find that in mice, NMDA-type glutamate receptors in the hypothalamus are the main drivers of excitation and are required for a range of sleep properties: they are, in fact, needed for both sustained NREM sleep periods, and REM sleep generation. When NMDA receptors are selectively reduced from inhibitory preoptic (PO) neurons, mice have normal total amounts of sleep but high sleep-wake fragmentation, providing a model for studying intractable insomnia.
外侧视前区（LPO）下丘脑是 NREM 和 REM 睡眠诱导和 NREM 睡眠稳态的中心。尽管 LPO 是 NREM 睡眠所必需的，但我们发现令人惊讶的是，在 REM 睡眠期间钙信号最高。此外，同样令人惊讶的是，LPO 中的 NMDA 受体是兴奋的主要驱动因素。从 LPO 中删除 NMDA 受体 GluN1 亚基会消除所有细胞中的钙信号，并导致失眠。两性小鼠的 NREM 睡眠-觉醒模式高度碎片化，无法产生传统分类的 REM 睡眠。通过删除 NMDA 受体产生的睡眠表型取决于在下丘脑何处删除受体。从前下丘脑区域（AHA）删除受体不会影响睡眠-觉醒状态。睡眠碎片化源于 LPO 中的 GABA 神经元上的 NMDA 受体。睡眠碎片化可以通过睡眠药物（唑吡坦）或镇静剂（右美托咪定；Dex）暂时克服。相比之下，在睡眠剥夺（SD）产生的高睡眠压力下，碎片化仍然存在，小鼠有很高的睡眠倾向，但会醒来。通过分析 δ 功率的变化，NMDA 受体消融后睡眠稳态（也称为“睡眠驱动”）仍然完整。我们认为 NMDA 谷氨酸受体的激活稳定了睡眠神经元的发射，并且睡眠维持的机制与睡眠驱动本身不同。失眠是一种常见的疾病。大多数失眠者都觉得自己睡眠不足，但实际上，他们往往有足够的睡眠。然而，他们的睡眠是碎片化的，患者醒来时感觉没有恢复活力。目前尚不清楚睡眠一旦开始是如何维持的。我们发现，在小鼠中，下丘脑的 NMDA 型谷氨酸受体是兴奋的主要驱动因素，并且是一系列睡眠特性所必需的：它们实际上是维持 NREM 睡眠期和 REM 睡眠产生所必需的。当 NMDA 受体从抑制性视前（PO）神经元中选择性减少时，小鼠的总睡眠时间正常，但睡眠-觉醒碎片化程度高，为研究难治性失眠提供了模型。
