Neuronal Circuit Controlling Sleep-Promoting Ventrolateral Preoptic Neurons

控制促进睡眠的腹外侧视前神经元的神经元回路

基本信息

批准号：
10570184
负责人：
Elda Arrigoni
金额：
$ 37.43万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570184
关键词：
Affect Afferent Pathways Aging Anatomy Arousal Behavior Behavioral Behavioral Model Brain Brain Stem Cells Data Development Disease Disinhibition Enterobacteria phage P1 Cre recombinase Exhibits FLP recombinase Fiber Galanin Hypersomnias Hypothalamic structure In Vitro Influentials Interneurons Intervention Knowledge Lateral Lesion Maps Mediating Methodology Modeling Neurons Optics Pathway interactions Patients Photometry Population Process Prosencephalon Publishing Regulation Research Role Signal Transduction Sleep Sleep Disorders Sleep disturbances Sleeplessness Slice Source Specificity Synapses Synaptic Potentials Testing Time Wakefulness Work base brain circuitry cholinergic cholinergic neuron combinatorial drug development in vivo insight monoamine nervous system disorder neurochemistry neuronal circuitry novel novel therapeutics optogenetics postsynaptic neurons preoptic nucleus presynaptic response sleep regulation transmission process

项目摘要

Project Summary/Abstract Sleep is an active process requiring the participation of delimited nodes of sleep-promoting cell populations. Work over the last twenty years has demonstrated that galanin expressing neurons in the ventrolateral preoptic (VLPOGal) neurons are necessary for normal sleep and cortical slow wave activity. There remain however several fundamental gaps in our understanding of the cellular and synaptic basis by which VLPOGal neurons are regulated. One highly influential circuit model for behavioral sleep-wake control is the `flip-flop' model of sleep-state switching, which proposes that sleep-wake transitions are regulated by a reciprocal inhibition between sleep-promoting VLPOGal neurons and monoaminergic and cholinergic wake-promoting nodes of the forebrain and brainstem. The findings that reciprocal anatomical connections exist between the VLPO and monoamine and cholinergic neurons and that these cell groups exhibit, respectively, sleep- and wake-active firing profiles have provided general support for the model. However, the VLPO receives afferent inputs from many other sources including non-cholinergic and non-monoaminergic neurons directly involved in sleep and wake regulation. We have recently found that activation of GABAergic neurons of the lateral hypothalamus potently promotes arousal by directly inhibiting VLPOGal neurons. Here we seek to extend this finding by identifying other potential synaptic drives that control arousal levels, including both long-range and local synaptic drives. To this end, while it has been appreciated for some time that VLPOGal neurons are under local synaptic control, the details of this intra-VLPO circuit remains largely uncharacterized. We have found that VLPOGal neurons are directly inhibited by a group of local GABAergic neurons. We propose that this local GABAergic circuit serves as common entry node through which afferent wake- and sleep-promoting pathways control VLPOGal neurons, with the specific hypotheses that this occurs by 1) direct and feedforward inhibition to produce arousal and 2) disinhibition of VLPOGal neurons to produce sleep. The current proposal thus seeks to identify, first in vitro and then in vivo, the long-range afferent inputs that directly or indirectly regulate VLPOGal neurons to drive behavioral and cortical arousal via the local GABAergic network. To do so, we will first employ in Specific Aims 1 in vitro circuit mapping and focal deletion of GABAergic transmission in VLPO neurons to determine the necessity of the local GABAergic circuit for the control of VLPOGal neurons. In Specific Aim 2 we will identify with in vitro recordings the postsynaptic neurons in VLPO that are targeted by wake- and sleep-promoting inputs. Finally, in Specific Aim 3 we will use in vivo optogenetics to test whether the afferent inputs to the VLPO first identified in vitro slices are necessary to produce sleep and wake behavioral changes and fiber photometry to examine the state-dependent activity of these afferents to VLPO. Given the large knowledge gap this proposal seeks to fill, we expect results from this collaborative work to provide important and novel insights into the brain circuitry supporting sleep and wake regulation.

项目概要/摘要睡眠是一个活跃的过程，需要促进睡眠的细胞群的有限节点的参与。过去二十年的工作表明，腹外侧视前区表达甘丙肽的神经元 (VLPOGal) 神经元对于正常睡眠和皮质慢波活动是必需的。然而仍然存在我们对 VLPOGal 神经元的细胞和突触基础的理解存在几个基本差距受到监管。行为睡眠-觉醒控制的一种极具影响力的电路模型是“触发器”模型睡眠状态切换，提出睡眠-觉醒转换是通过相互抑制来调节的促进睡眠的 VLPOGal 神经元与单胺能和胆碱能促进唤醒的节点之间前脑和脑干。研究结果表明 VLPO 和 VLPO 之间存在相互的解剖学联系单胺和胆碱能神经元，并且这些细胞群分别表现出睡眠活跃和觉醒活跃射击曲线为该模型提供了总体支持。然而，VLPO 接收来自许多其他来源，包括直接参与睡眠的非胆碱能和非单胺能神经元唤醒调节。我们最近发现下丘脑外侧 GABA 能神经元的激活通过直接抑制 VLPOGal 神经元有效促进觉醒。在这里，我们试图通过以下方式扩展这一发现识别控制唤醒水平的其他潜在突触驱动，包括远程和局部突触驱动。为此，虽然人们已经认识到 VLPOGal 神经元在局部突触控制，该 VLPO 内电路的细节在很大程度上仍然未知。我们发现 VLPOGal 神经元直接受到一组局部 GABA 能神经元的抑制。我们建议这个地方 GABAergic 电路作为公共入口节点，传入唤醒和睡眠促进途径通过该节点控制 VLPOGal 神经元，具体假设是通过 1）直接和前馈抑制来发生产生唤醒和 2) 解除 VLPOGal 神经元的抑制以产生睡眠。因此，当前的提案旨在首先在体外，然后在体内，识别直接或间接调节 VLPOGal 的远程传入输入神经元通过局部 GABA 网络驱动行为和皮质唤醒。为此，我们首先要用于特定目标 1 VLPO 中 GABA 能传输的体外电路图绘制和局部删除神经元来确定局部 GABA 能电路控制 VLPOGal 神经元的必要性。在具体目标 2 我们将通过体外记录来识别 VLPO 中的突触后神经元，这些神经元是促进唤醒和睡眠的输入。最后，在特定目标 3 中，我们将使用体内光遗传学来测试是否首先在体外切片中识别出的 VLPO 的传入输入对于产生睡眠和唤醒行为是必要的变化和纤维光度测定来检查这些传入 VLPO 的状态依赖性活动。鉴于该提案旨在填补巨大的知识空白，我们期望这项协作工作的结果能够提供对支持睡眠和觉醒调节的大脑回路的重要而新颖的见解。