Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States of America; Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States of America; Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States of America.
Exp Neurol. 2025 Jan;383:115035. doi: 10.1016/j.expneurol.2024.115035. Epub 2024 Oct 29.
The lateral hypothalamic region (LH) has been identified as a key region for arousal regulation, yet the specific cell types and underlying mechanisms are not fully understood. While neurons expressing orexins (OX) are considered the primary wake-promoting population in the LH, their loss does not reduce daily wake levels, suggesting the presence of additional wake-promoting populations. In this regard, we recently discovered that a non-OX cell group in the LH, marked by the expression of neurotensin (Nts), could powerfully drive wakefulness. Activation of these Nts neurons elicits rapid arousal from non-rapid eye movement (NREM) sleep and produces uninterrupted wakefulness for several hours in mice. However, it remains unknown if these neurons are necessary for spontaneous wakefulness and what their precise role is in the initiation and maintenance of this state. To address these questions, we first examined the activity dynamics of the Nts population across sleep-wake behavior using fiber photometry. We find that Nts neurons are more active during wakefulness, and their activity increases concurrently with, but does not precede, wake-onset. We then selectively destroyed the Nts neurons using a diphtheria-toxin-based conditional ablation method, which significantly reduced wake amounts and mean duration of wake bouts and increased the EEG delta power during wakefulness. These findings demonstrate a crucial role for Nts neurons in maintaining normal arousal levels, and their loss may be associated with chronic sleepiness in mice.
外侧下丘脑区域（LH）已被确定为调节觉醒的关键区域，但特定的细胞类型和潜在机制尚未完全了解。虽然表达食欲素（OX）的神经元被认为是 LH 中主要的促醒群体，但它们的缺失并不会降低每日觉醒水平，这表明存在其他促醒群体。在这方面，我们最近发现 LH 中的一个非-OX 细胞群，由神经降压素（Nts）表达标记，可以强有力地驱动觉醒。激活这些 Nts 神经元可以迅速从非快速眼动（NREM）睡眠中唤醒，并在小鼠中产生数小时不间断的觉醒。然而，目前尚不清楚这些神经元是否对自发性觉醒是必需的，以及它们在该状态的启动和维持中的确切作用是什么。为了解决这些问题，我们首先使用光纤光度法研究了 Nts 群体在睡眠-觉醒行为中的活动动态。我们发现 Nts 神经元在觉醒时更活跃，其活动与觉醒开始同时增加，但不先于觉醒开始增加。然后，我们使用基于白喉毒素的条件性消融方法选择性地破坏 Nts 神经元，这显著减少了觉醒量和觉醒期的平均持续时间，并增加了觉醒时的 EEG 德尔塔功率。这些发现表明 Nts 神经元在维持正常觉醒水平方面起着至关重要的作用，它们的缺失可能与小鼠的慢性嗜睡有关。
