Sleep Neurobiology and Circuitry

描述（由申请人提供）： 7000万美国人患有某种睡眠障碍。大脑如何在意识状态之间切换尚不清楚，但研究人员现在已经确定，一个分布式神经元网络负责唤醒，非REM和REM睡眠。一阶电路模型已经出现，并已使用传统的病变和基因删除方法进行了测试。我们现在建议使用基因转移方法来修复网络。这种方法已被证明是一种有效的神经生物学工具，在许多神经退行性疾病，但令人惊讶的是，没有人用它来纠正睡眠障碍。在这个项目中，重组腺相关病毒载体（rAAV-血清型8）将被用来转移基因的唤醒肽hypocretin（也称为食欲素）到一个特定的神经元表型。四个目标的一个综合系列将在两个小鼠模型中测试特定的假设，该模型具有下丘脑泌素基因或下丘脑泌素神经元的靶向缺失。适当的控制实验提出加强的结论。这些目标得到了我们非常强有力的初步数据的支持，这些数据显示下丘脑泌素基因产物在特定神经元中的稳健表达，沿着两种小鼠模型中发作性睡眠行为的明确下降。这些研究将证明遗传药理学可以作为修复网络的有价值的神经生物学工具。

DESCRIPTION (provided by applicant): 70 million Americans suffer from some sort of sleep disorder. How the brain switches between states of consciousness is not known, but researchers have now determined that a distributed network of neurons are responsible for wake, non-REM and REM sleep. First-order circuit models have emerged, and these have been tested using traditional lesion and gene deletion methods. We now propose to repair the network using the gene transfer method. This approach has proven to be an effective neurobiological tool in a number of neurodegenerative diseases but surprisingly no one has used it to correct a sleep disorder. In this project recombinant adeno-associated viral vector (rAAV-serotype 8) will be used to transfer the gene for the arousal peptide hypocretin (also known as orexin) into a specific neuronal phenotype. An integrated series of four aims will test specific hypotheses in two murine models with targeted deletions of the hypocretin gene or of the hypocretin neurons. Experiments with appropriate controls are proposed to strengthen the conclusions. These aims are supported by our very strong preliminary data that shows robust expression of the hypocretin gene product in specific neurons along with unambiguous decline of narcoleptic behavior in the two murine models. These studies will demonstrate that genetic pharmacology can serve as a valuable neurobiological tool to repair the network.