Pontine circuitry regulating REM sleep and atonia

脑桥电路调节快速眼动睡眠和肌无力

• 批准号: 7728100
• 负责人: JUN LU
• 金额: $ 42.95万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728100
• 关键词: Alleles; Anatomy; Animals; Area; Axon; Behavior; Behavioral; Brain Stem; Cell Nucleus; Cells; Cholinergic Agonists; Cytomegalovirus; Data; Data Analyses; Dependovirus; Development; Diagnostic; Dorsal; Electroencephalography; Electronics; Elements; Embryonic Lethal Mutation; Excision; Exons; Feedback; Foundations; Functional disorder; Generations; Genes; Genetic; Genetic Recombination; Glutamates; Glycine; Goals; Hippocampus (Brain); Horns; Human; Immunohistochemistry; In Situ Hybridization; Inferior; Injection of therapeutic agent; Interneurons; Knock-out; Knockout Mice; Knowledge; Label; Laboratories; Lateral; Left; Lesion; Link; Location; Maps; Medial; Mediating; Messenger RNA; Methods; Modeling; Motor; Motor Activity; Motor Neurons; Mus; Muscarinic Antagonists; Muscle; Myoclonus; Neurons; Neurotoxins; Neurotransmitters; Olives - dietary; Outcome; Parasomnias; Phenotype; Physiological; Pilot Projects; Pontine structure; Population; Preparation; REM Sleep; REM Sleep Behavior Disorder; Rattus; Regulation; Research; Reticular Formation; Role; Satellite Viruses; Site; Sleep; Sleep Disorders; Specificity; Spinal; Spinal Cord; Structure of area postrema; Techniques; Tegmentum Mesencephali; Testing; Therapeutic; Time; Transfection; Wakefulness; Walking; Work; adeno-associated viral vector; basal forebrain; base; behavior change; cholinergic; cholinergic neuron; gamma-Aminobutyric Acid; hypocretin; insight; midbrain central gray substance; monoamine; motor control; neural circuit; neurochemistry; neurotransmission; noradrenergic; prevent; programs; promoter; public health relevance; rapid eye movement; rat Ran 2 protein; recombinase; sleep regulation; transmission process; vector; vesicular GABA transporter; vesicular glutamate transporter 2; virtual

Description (provided by applicant): Rapid eye movement (REM) sleep is a behavioral state characterized by activation of the cortical and hippocampal EEG, rapid eye movements and muscle atonia. While some progress has been made in recent years in the effort to delineate 1) the locus of the pontine switching circuitry for REM sleep, 2) the neurotransmitters regulating REM phenomenon, i.e., muscle atonia, activation of the cortical and hippocampal EEG, and 3) how dysfunction of this circuitry may form the neuropathologic basis of REM sleep behavior disorder, major gaps remain in our knowledge. Recent work by our laboratory has revealed the presence of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum that may form the neuroanatomical basis of the switching circuitry for REM sleep. These findings, which form the basis of the present research plan, posit a REM switching circuitry model that is analogous to an electronic 'flip-flop' switch. In this flip-flop switch arrangement, GABAergic REM-on neurons (located in the sublateraldorsal tegmental nucleus (SLD)) inhibit GABAergic REM-off neurons (located in the ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT)) and vice versa. Inside this pontine brainstem "switch" the REM-on area contains two populations of glutamatergic neurons, the first of which projects to the basal forebrain and regulates EEG components of REM sleep and the second which projects to the ventromedial medulla and spinal cord and regulates atonia during REM sleep. To demonstrate the critical role of glutamatergic SLD neurons in producing REM without atonia, we will selectively eliminate glutamatergic neurotransmission in the SLD by stereotaxically injecting an adeno-associated virus containing the gene for Cre recombinase (AAV-Cre) into the SLD of conditional knock-out mice with lox-P modified alleles of the vesicular glutamate transporter 2 (VGLUT2) genes. We will similarly eliminate GABAergic neurotransmission in the SLD and LPT by stereotaxically injecting AAV-Cre into mice with lox-P modified alleles of the vesicular GABA transporter (VGAT). Finally, we will examine the role of the ventromedial medulla in REM atonia by combining injections of orexin-saporin into rats and AAV-Cre injections into VGAT and VGLUT2 mice. Findings from the present proposal will provide a context for understanding the pathophysiologic mechanisms and etiological bases for a variety of sleep disorders, including REM sleep behavior disorder. PUBLIC HEALTH RELEVANCE: REM sleep behavior disorder (RBD) is a parasomnia characterized by the absence of motor atonia during REM sleep; however, the pathophysiologic basis of RBD remains unresolved. The objective of the present proposal is to delineate the role of the pontine sublaterodorsal nucleus in the pathophysiology of RBD. Results from our studies will provide the foundation for the development of diagnostic and therapeutic strategies for treating RBD.

描述（由申请人提供）：快速眼动（REM）睡眠是一种行为状态，其特征在于皮层和海马EEG的激活、快速眼动和肌肉弛缓。虽然近年来在努力描绘1）用于REM睡眠的脑桥切换电路的位点，2）调节REM现象的神经递质，即，肌张力减退、皮层和海马EEG的激活，以及3）该回路的功能障碍如何形成REM睡眠行为障碍的神经病理学基础，我们的知识中仍存在主要空白。我们实验室最近的工作揭示了在中桥脑被盖中存在相互抑制的REM关闭和REM开启区域，这可能形成REM睡眠转换回路的神经解剖学基础。这些发现，形成了本研究计划的基础，建立了一个REM开关电路模型，类似于电子“触发器”开关。在这种触发器开关排列中，GABA能REM-on神经元（位于背侧被盖下核（SLD））抑制GABA能REM-off神经元（位于中脑导水管周围灰质（vlPAG）和脑桥被盖外侧（LPT）），反之亦然。在这个脑桥脑干“开关”内，REM开启区域包含两个群体的多巴胺能神经元，第一个投射到基底前脑并调节REM睡眠的EEG成分，第二个投射到延髓腹内侧和脊髓并调节REM睡眠期间的肌张力减退。为了证明多巴胺能SLD神经元在产生REM而无张力中的关键作用，我们将通过立体定向注射含有Cre重组酶基因的腺相关病毒（AAV-Cre）到具有囊泡谷氨酸转运体2（VGLUT 2）基因的lox-P修饰等位基因的条件性敲除小鼠的SLD中，选择性地消除SLD中的多巴胺能神经传递。我们将通过立体定向注射AAV-Cre到具有囊泡GABA转运蛋白（VGAT）的lox-P修饰等位基因的小鼠中，类似地消除SLD和LPT中的GABA能神经传递。最后，我们将通过将食欲素-皂草素注射到大鼠中以及将AAV-Cre注射到VGAT和VGLUT 2小鼠中来检查延髓腹内侧在REM弛缓中的作用。本研究的发现将为理解包括REM睡眠行为障碍在内的各种睡眠障碍的病理生理机制和病因学基础提供背景。公共卫生相关性：REM睡眠行为障碍（RBD）是一种以REM睡眠期间缺乏运动性弛缓为特征的异眠症;然而，RBD的病理生理基础尚未得到解决。本建议的目的是描绘的作用，脑桥sublaterodorthorax核的病理生理学的RBD。我们的研究结果将为开发治疗RBD的诊断和治疗策略提供基础。