International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Department of Integrative Neurophysiology, Faculty of Medicine, Kanazawa University, Kanazawa 920-8640, Japan.
J Neurosci. 2018 Jul 11;38(28):6366-6378. doi: 10.1523/JNEUROSCI.2835-17.2018. Epub 2018 Jun 18.
The hypothalamus plays an important role in the regulation of sleep/wakefulness states. While the ventrolateral preoptic nucleus (VLPO) plays a critical role in the initiation and maintenance of sleep, the lateral posterior part of the hypothalamus contains neuronal populations implicated in maintenance of arousal, including orexin-producing neurons (orexin neurons) in the lateral hypothalamic area (LHA) and histaminergic neurons in the tuberomammillary nucleus (TMN). During a search for neurons that make direct synaptic contact with histidine decarboxylase-positive (HDC+), histaminergic neurons (HDC neurons) in the TMN and orexin neurons in the LHA of male mice, we found that these arousal-related neurons are heavily innervated by GABAergic neurons in the preoptic area including the VLPO. We further characterized GABAergic neurons electrophysiologically in the VLPO (GABA neurons) that make direct synaptic contact with these hypothalamic arousal-related neurons. These neurons (GABA or GABA neurons) were both potently inhibited by noradrenaline and serotonin, showing typical electrophysiological characteristics of sleep-promoting neurons in the VLPO. This work provides direct evidence of monosynaptic connectivity between GABA neurons and hypothalamic arousal neurons and identifies the effects of monoamines on these neuronal pathways. Rabies-virus-mediated tracing of input neurons of two hypothalamic arousal-related neuron populations, histaminergic and orexinergic neurons, showed that they receive similar distributions of input neurons in a variety of brain areas, with rich innervation by GABAergic neurons in the preoptic area, including the ventrolateral preoptic area (VLPO), a region known to play an important role in the initiation and maintenance of sleep. Electrophysiological experiments found that GABAergic neurons in the VLPO (GABA neurons) that make direct input to orexin or histaminergic neurons are potently inhibited by noradrenaline and serotonin, suggesting that these monoamines disinhibit histamine and orexin neurons. This work demonstrated functional and structural interactions between GABA neurons and hypothalamic arousal-related neurons.
下丘脑在调节睡眠/觉醒状态方面起着重要作用。虽然腹外侧视前核（VLPO）在睡眠的启动和维持中起着关键作用，但下丘脑的外侧后部包含参与觉醒维持的神经元群体，包括外侧下丘脑区域（LHA）中的产食欲素神经元（orexin 神经元）和结节乳头核（TMN）中的组胺能神经元。在寻找与 TMN 中的组氨酸脱羧酶阳性（HDC+）、组胺能神经元（HDC 神经元）和 LHA 中的食欲素神经元直接形成突触联系的神经元时，我们发现这些与觉醒相关的神经元被视前区中的 GABA 能神经元（包括 VLPO）大量支配。我们进一步在 VLPO 中对这些与下丘脑觉醒相关的神经元进行电生理特性的 GABA 能神经元进行了特征描述（GABA 神经元），这些神经元（GABA 神经元）都被去甲肾上腺素和血清素强烈抑制，表现出 VLPO 中促进睡眠的神经元的典型电生理特征。这项工作提供了 GABA 能神经元和下丘脑觉醒神经元之间单突触连接的直接证据，并确定了单胺类物质对这些神经元通路的影响。通过狂犬病病毒介导的两种与下丘脑觉醒相关的神经元群体（组胺能和食欲素能神经元）的输入神经元追踪，显示它们在各种脑区接受相似的输入神经元分布，在视前区包括腹外侧视前区（VLPO）有丰富的 GABA 能神经元支配，已知该区域在睡眠的启动和维持中起着重要作用。电生理实验发现，直接向食欲素或组胺神经元输入的 VLPO（GABA 神经元）中的 GABA 能神经元被去甲肾上腺素和血清素强烈抑制，表明这些单胺类物质抑制组胺和食欲素神经元。这项工作证明了 GABA 能神经元和下丘脑与觉醒相关的神经元之间的功能和结构相互作用。
