Sleep Neurobiology and Circuitry

7000万美国人患有某种睡眠障碍。行为，情绪和记忆力恶化， 睡眠不足，持续睡眠不足会使情况变得更糟。睡眠不足与老年痴呆症有关 疾病有相当数量的数据关于保持我们清醒的神经元（唤醒神经元），而 我们对使我们入睡的神经元知之甚少。事实上，目前的睡眠-觉醒网络模型 调节列出了许多唤醒神经元群体相比，只有一个睡眠组位于视前区。 更好的催眠药将通过识别直接将特定神经元表型与睡眠联系起来的回路而出现。到 为了提供这一证据，我们将使用脑深部成像方法来可视化表型特异性 下丘脑是大脑的一部分，调节睡眠和觉醒的神经元就位于这里。目的 1将成像神经元含有黑色素浓缩激素（MCH）的基础上，我们的证据发表在 上一个资助期，这些神经元的光遗传学刺激强烈增加了非REM和REM 在小鼠和大鼠中睡觉。目标2将使用新的逆行轴突追踪工具将ChR 2插入投射 特定的MCH神经元，以机械地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回路， 高度兴奋的状态坚实的初步数据提出的所有目标表明，这些方法是 在实验室中运行，该项目将顺利完成。 从转化的角度来看，这些研究对睡眠障碍，如失眠， 睡眠需要在强烈的唤醒驱动下触发。这些目标将提供一个框架， 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.