Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function
Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function
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DOI：
10.1523/jneurosci.0073-14.2014
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发表时间：
2014-05-07
影响因子：
5.3
通讯作者：
Yamanaka, Akihiro
中科院分区：
文献类型：
--
作者：
Tabuchi, Sawako;Tsunematsu, Tomomi;Yamanaka, Akihiro
睡眠障碍发作性睡病是由于下丘脑食欲素/下丘脑泌素神经元的损失。虽然嗜睡症通常在青春期后发作，但目前的小鼠模型涉及出生时食欲素肽或食欲素神经元的丢失。为了建立更接近人类发作性睡病的食欲素/下丘脑泌素缺乏模型，在Tet-off系统的控制下在食欲素神经元中表达白喉毒素A（DTA）。在从青春期后的食欲素-tTA; TetO DTA小鼠的饮食中去除强力霉素后，食欲素神经退行性变迅速，在7天内有80%的细胞损失，并导致睡眠结构破坏。发作性睡病的病理学症状，catabelation，发生了14天时，类似的5%的食欲素神经元仍然存在。多西环素治疗后至少11周，catalysis频率增加。暂时去除强力霉素，几天后重新引入，使食欲素神经元的部分病变。DTA诱导的食欲素神经变性引起体重增加而不改变食物消耗，模拟人类嗜睡症的代谢方面。由于食欲素/下丘脑泌素系统已经涉及代谢和成瘾以及睡眠/觉醒调节的控制，食欲素-tTA; TetO DTA小鼠是一种新的模型，其中研究这些功能，用于药理学研究的cataerative，并研究网络重组的食欲素输入丢失。
The sleep disorder narcolepsy results from loss of hypothalamic orexin/hypocretin neurons. Although narcolepsy onset is usually postpubertal, current mouse models involve loss of either orexin peptides or orexin neurons from birth. To create a model of orexin/ hypocretin deficiency with closer fidelity to human narcolepsy, diphtheria toxin A (DTA) was expressed in orexin neurons under control of the Tet-off system. Upon doxycycline removal from the diet of postpubertal orexin-tTA; TetO DTA mice, orexin neurodegeneration was rapid, with 80% cell loss within 7 d, and resulted in disrupted sleep architecture. Cataplexy, the pathognomic symptom of narcolepsy, occurred by 14 d when similar to 5% of the orexin neurons remained. Cataplexy frequency increased for at least 11 weeks after doxycycline. Temporary doxycycline removal followed by reintroduction after several days enabled partial lesion of orexin neurons. DTA-induced orexin neurodegeneration caused a body weight increase without a change in food consumption, mimicking metabolic aspects of human narcolepsy. Because the orexin/hypocretin system has been implicated in the control of metabolism and addiction as well as sleep/wake regulation, orexin-tTA; TetO DTA mice are a novel model in which to study these functions, for pharmacological studies of cataplexy, and to study network reorganization as orexin input is lost.