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，其特征是皮质和海马脑电图激活、快速眼动和肌肉无力。近年来，在以下方面取得了一些进展：1) 快速眼动睡眠的脑桥开关电路的位置，2) 调节快速眼动现象的神经递质，即肌肉张力减弱、皮质和海马脑电图的激活，以及 3 ）这一回路的功能障碍如何构成快速眼动睡眠行为障碍的神经病理学基础，我们的知识仍然存在重大空白。我们实验室最近的工作揭示了中脑桥被盖中存在相互抑制的 REM-off 和 REM-on 区域，这可能构成 REM 睡眠切换电路的神经解剖学基础。这些发现构成了当前研究计划的基础，提出了一种类似于电子“触发器”开关的 REM 开关电路模型。在这种触发器开关排列中，GABA能REM-on神经元（位于背侧下被盖核（SLD））抑制GABA能REM-off神经元（位于腹外侧导水管周围灰质（vlPAG）和外侧脑桥被盖（LPT）），并且反之亦然。在脑桥脑干“开关”内，快速眼动启动区域包含两组谷氨酸能神经元，第一个神经元投射到基底前脑并调节快速眼动睡眠的脑电图成分，第二组投射到腹内侧延髓和脊髓并调节肌无力快速眼动睡眠期间。为了证明谷氨酸能 SLD 神经元在产生无张力的 REM 中的关键作用，我们将通过立体定位将含有 Cre 重组酶 (AAV-Cre) 基因的腺相关病毒注射到条件敲除的 SLD 中，选择性地消除 SLD 中的谷氨酸能神经传递。囊泡谷氨酸转运蛋白 2 (VGLUT2) 基因具有 lox-P 修饰等位基因的小鼠。我们将类似地通过将 AAV-Cre 立体定位注射到具有囊泡 GABA 转运蛋白 (VGAT) 的 lox-P 修饰等位基因的小鼠中来消除 SLD 和 LPT 中的 GABA 能神经传递。最后，我们将通过向大鼠注射食欲素-皂素和向 VGAT 和 VGLUT2 小鼠注射 AAV-Cre 相结合，研究腹内侧延髓在 REM 肌张力障碍中的作用。本提案的研究结果将为理解各种睡眠障碍（包括快速眼动睡眠行为障碍）的病理生理机制和病因学基础提供背景。公众健康相关性：快速眼动睡眠行为障碍 (RBD) 是一种异态睡眠，其特征是快速眼动睡眠期间缺乏运动肌无力；然而，RBD 的病理生理学基础仍未解决。本提案的目的是描述桥脑背下核在 RBD 病理生理学中的作用。我们的研究结果将为开发 RBD 的诊断和治疗策略奠定基础。