Sleep Neurobiology and Circuitry

7000万美国人患有某种睡眠障碍。行为、情绪和记忆力会随着 睡眠不足，随着持续睡眠不足，情况会变得更糟。睡眠不足与阿尔茨海默氏症有关 疾病。有大量关于让我们保持清醒的神经元(唤醒神经元)的数据，而 人们对让我们入睡的神经元知之甚少。事实上，当前的睡眠-唤醒网络模型 规则列出了许多觉醒神经元群体，而只有一个睡眠群体位于视前区。 通过识别直接将特定神经元表型与睡眠联系起来的电路，将出现更好的催眠药。至 提供了这一证据，我们将使用深部脑成像方法来可视化表型特异性的活动 下丘脑中的神经元，这是大脑中调节睡眠和唤醒的神经元所在的部分。目标 1将根据我们发表在 上一个资金时期，对这些神经元的光遗传刺激显著增加了非REM和REM 睡在老鼠和大鼠身上。AIM 2将使用新的逆行轴突轨迹跟踪工具将ChR2插入投影 特定的MCH神经元，从机械上证明驱动特定的电路诱导睡眠。清晰度 方法将用于可视化电路。在目标3中，光遗传学将驱动这些电路诱导睡眠 高度兴奋的状态。提供了所有目标的可靠初步数据，表明这些方法是 在实验室中投入使用，该项目将成功完成。 从翻译的角度来看，这些研究对睡眠障碍，如失眠， 在这种情况下，睡眠需要根据强烈的唤醒动力来触发。这些目标将为 将睡眠活跃神经元整合到睡眠-觉醒调节的整体模型中。

70 million Americans suffer from some sort of sleep disorder. Behavior, mood and memory deteriorate with sleep loss and it gets worse with continuing sleep deprivation. Lack of sleep has been linked to Alzheimer’s disease. There is considerable amount of data on the neurons that keep us awake (arousal neurons) whereas very little is known about the neurons that make us fall asleep. Indeed, current network models of sleep-wake regulation list many arousal neuronal populations compared to only one sleep group located in the preoptic area. Better hypnotics will emerge by identifying circuits that directly link specific phenotypes of neurons to sleep. To provide this evidence, we will use the deep-brain imaging method to visualize activity of phenotype specific neurons in the hypothalamus, a part of the brain where neurons regulating sleep and arousal are located. Aim 1 will image neurons containing melanin concentrating hormone (MCH) based on our evidence published in the last funding period that optogenetic stimulation of these neurons robustly increases both non-REM and REM sleep in mice and rats. Aim 2 will use new retrograde axon-track tracing tools to insert ChR2 into projection specific MCH neurons to mechanistically demonstrate that driving specific circuits induces sleep. The CLARITY method will be used to visualize the circuit. In Aim 3, optogenetics will drive these circuits to induce sleep in conditions of high arousal. Solid preliminary data are presented for all aims indicating that these methods are operational in the lab, and that the project will be completed successfully. From a translational perspective these studies are potentially useful in sleep disorders, such as insomnia, where sleep needs to be triggered against a strong arousal drive. These aims will provide a framework for integrating the sleep-active neurons within an overall model of sleep-wake regulation.