Medullary Control of REM Sleep

项目总结 快速眼动(REM)睡眠的特征是激活的脑电(EEG)和骨骼 肌肉麻痹，与生动的梦境有关。快速眼动睡眠障碍是情绪的症状 精神障碍，被认为是抑郁症的生物标记物。产生REM睡眠的核心电路位于 两个脑干区，脑桥和延髓。脑桥在快速眼动睡眠调节中的作用已经得到了很好的研究，而 直到最近，人们才意识到延髓的重要性。以前的研究，包括我们的初步研究 数据表明，延髓背内侧(DMM)神经元在REM睡眠控制中起着重要作用。然而， 关于DMM中促进快速眼动睡眠的神经元的分子特性及其活动，人们知之甚少 在睡眠期间和它们的下游目标。为了填补这一空白，我们将使用最先进的工具来实现电路 用于记录和干扰小鼠模型中的神经活动的映射和方法。 我们的长期目标是解开控制快速眼动睡眠的电路机制。我们的初步结果 显示DMM中表达促肾上腺皮质激素释放激素的基因定义的神经元群体 促肾上腺皮质激素释放激素(CRH)促进快速眼动睡眠。这项建议的中心目标是了解数字监测系统的活动如何 CRH神经元控制REM睡眠，并识别它们通过其诱导的脑桥下游靶点 快速眼动睡眠。在目标1中，我们将使用光发生和化学发生来操纵CRH神经元的活动 并研究激活和抑制如何影响快速眼动睡眠的启动和维持。 利用光学电极，我们将记录自由活动小鼠在多个时期的DMM CRH神经元的活动 觉醒、NREM和REM睡眠，测试他们的活动模式是否支持启动和 维持快速眼动睡眠。在目标2中，我们将研究DMM的轴突投射是否 脑桥下游区域对快速眼动睡眠的影响起着中介作用。我们将使用伪型狂犬病病毒来 并使用体内钙成像和光遗传学微扰来检查这一作用 路径。这项拟议的研究是创新的，因为它们将揭示未被探索的脑干环路在 REM睡眠控制，结果将扩展现有的延髓神经元如何与 脑桥突触后区域调节快速眼动睡眠。通过将REM睡眠定位为 基因定义的延髓神经元群体将提供一个强大的工具来理解 快速眼动睡眠和情绪障碍之间的联系。

PROJECT SUMMARY Rapid eye movement (REM) sleep is characterized by activated electroencephalogram (EEG) and skeletal muscle paralysis and is associated with vivid dreaming. Disturbances in REM sleep are symptomatic of mood disorders and are considered as a biomarker for depression. Core circuits generating REM sleep are located in two brainstem areas, the pons and medulla. The role of the pons in REM sleep regulation is well studied, while the importance of the medulla has only recently been appreciated. Previous studies, including our preliminary data, suggest an important role of neurons in the dosomedial medulla (dmM) in REM sleep control. However, little is known about the molecular identity of neurons in the dmM that promote REM sleep, about their activity during sleep and their downstream targets. To fill this gap, we will employ state-of-the-art tools for circuit mapping and methods for recording and perturbing neural activity in the mouse model. Our long-term objective is to unravel the circuit mechanisms controlling REM sleep. Our preliminary results show that a genetically defined population of neurons in the dmM that express corticotropin-releasing hormone (CRH) promotes REM sleep. The central objective of this proposal is to understand how the activity of dmM CRH neurons controls REM sleep and identify the downstream targets in the pons through which they induce REM sleep. In Aim 1, we will manipulate the activity of CRH neurons using opto- and chemogenetic approaches and examine how activation and inhibition affect the initiation and maintenance of REM sleep. Using optrodes, we will record the activity of dmM CRH neurons in freely moving mice across multiple periods of wakefulness, NREM, and REM sleep and test whether their activity pattern supports a role in initiating and maintaining REM sleep. In Aim 2, we will investigate whether the axonal projections from the dmM to downstream areas in the pons mediate the effects on REM sleep. We will use pseudo-typed rabies viruses for circuit mapping and employ in vivo calcium imaging and optogenetic perturbations to examine the role of this pathway. The proposed studies are innovative, as they will reveal the role of an unexplored brainstem circuit in REM sleep control, and the results will extend existing models of how neurons in the medulla interact with post-synaptic areas in the pons to regulate REM sleep. The capability to manipulate REM sleep by targeting a genetically defined population of medullary neurons will provide a powerful tool to understand the pervasive link between REM sleep and mood disorders.