The Development of Sleep/Wake Disruption and Cataplexy as Hypocretin/Orexin Neurons Degenerate in Male vs. Female Orexin/tTA; TetO-DTA Mice.
The Development of Sleep/Wake Disruption and Cataplexy as Hypocretin/Orexin Neurons Degenerate in Male vs. Female Orexin/tTA; TetO-DTA Mice.
复制标题
男性与女性 Orexin/tTA 中下丘脑分泌素/食欲素神经元退化导致睡眠/觉醒中断和猝倒的发展；
DOI：
10.1093/sleep/zsac039
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发表时间：
2022
期刊：
影响因子：
5.6
通讯作者：
*Kilduff TS.
中科院分区：
文献类型：
--
作者：
Sun Y;Tisdale R;Park S;Ma SC;Heu J;Haire M;Allocca G;Yamanaka A;Morairty SR;*Kilduff TS.
发作性睡病1型（NT 1）是一种睡眠障碍，在两性中的患病率相似，被认为是由于下丘脑分泌素/食欲素（Hcrt）神经元的丢失。已经创建了几种转基因品系来模拟这种疾病，并且越来越多地用于临床前药物开发和基础科学研究，但大多数研究仅使用雄性小鼠。我们比较了雄性与雌性eorexin-tTA; TetO-DTAmice中发作性睡眠病的发展，这是一种模型，其中Hcrt神经元变性可以通过从饮食中去除多西环素（DOX）来启动。EEG、EMG、皮下温度、粗大运动活动和视频记录在基线和DOX去除后1、2、4和6周进行24小时。在DOX（-）条件下，雌性DTA小鼠在第1周时表现出紧张症（NT 1的特征性症状），但在第2周之前雄性小鼠中并不始终存在紧张症。到第2周，两种性别动物在活动期内持续长时间清醒发作的能力受损，相当于NT 1中的小鼠日间过度嗜睡。随着Hcrt神经元的退化，皮下温度似乎在两种性别中以较低的水平进行调节。在变性过程中，两种性别都表现出“Delta状态”，其特征是活动突然停止，EEG中的高Delta活动，肌肉张力和姿势的维持，以及阶段性EMG活动的缺乏。由于两种性别的表型在第6周时无法区分，因此我们得出结论，在未来的研究中，两种性别可以安全地组合，以降低成本和动物使用。
Narcolepsy Type 1 (NT1), a sleep disorder with similar prevalence in both sexes, is thought to be due to loss of the hypocretin/orexin (Hcrt) neurons. Several transgenic strains have been created to model this disorder and are increasingly being used for preclinical drug development and basic science studies, yet most studies have solely used male mice. We compared the development of narcoleptic symptomatology in male vs. femaleorexin-tTA; TetO-DTAmice, a model in which Hcrt neuron degeneration can be initiated by removal of doxycycline (DOX) from the diet. EEG, EMG, subcutaneous temperature, gross motor activity, and video recordings were conducted for 24-h at baseline and 1, 2, 4, and 6 weeks after DOX removal. Female DTA mice exhibited cataplexy, the pathognomonic symptom of NT1, by Week 1 in the DOX(-) condition but cataplexy was not consistently present in males until Week 2. By Week 2, both sexes showed an impaired ability to sustain long wake bouts during the active period, the murine equivalent of excessive daytime sleepiness in NT1. Subcutaneous temperature appeared to be regulated at lower levels in both sexes as the Hcrt neurons degenerated. During degeneration, both sexes also exhibited the “Delta State”, characterized by sudden cessation of activity, high delta activity in the EEG, maintenance of muscle tone and posture, and the absence of phasic EMG activity. Since the phenotypes of the two sexes were indistinguishable by Week 6, we conclude that both sexes can be safely combined in future studies to reduce cost and animal use.