Pontine Control of REM Atonia

脑桥控制 REM Atonia

基本信息

批准号：
7994859
负责人：
Elda Arrigoni
金额：
$ 36.44万
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：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994859
关键词：
Abbreviations Acting Out Affect Animals Appearance Area Behavior Brain Stem Brain region Carbachol Cataplexy Cell Nucleus Cells Development Disease Disinhibition Dopamine Dreams Dynorphins Foundations Functional disorder Generations Genetic Glutamates Glycine Goals Health Injection of therapeutic agent Interneurons Knock-in Mouse Label Lateral Lateral Hypothalamic Area Lesion Maintenance Medial Mediating Motor Neurons Mus Muscarinic Acetylcholine Receptor Muscle Muscle Tonus Neurobiology Neurodegenerative Disorders Neurons Norepinephrine Paralysed Parkinson Disease Pathway interactions Physiology Play Pontine structure Preparation Presynaptic Terminals REM Sleep REM Sleep Behavior Disorder Regulation Reticular Formation Role Serotonin Signal Pathway Signal Transduction Slice Source Spinal Spinal Cord Staging Synapses System Tegmentum Mesencephali Testing Tracer Wakefulness Work adeno-associated viral vector cell type cholinergic cholinergic neuron dorsal raphe nucleus effective therapy gamma-Aminobutyric Acid hypocretin in vitro Model insight midbrain central gray substance monoamine noradrenergic patch clamp postsynaptic presynaptic prevent rapid eye movement receptor recombinase research study response spinal pathway

项目摘要

DESCRIPTION (provided by applicant): A defining feature of REM sleep is paralysis of nearly all muscles. In REM sleep behavior disorder (RBD), the absence of REM atonia permits the appearance of dream enactment. This disorder is strongly associated with neurodegenerative diseases such as Parkinson's disease, and it often appears in early stages when the disease involves the lower brainstem including the pons. Considerable evidence demonstrates that neurons of the sublaterodorsal (SLD) nucleus of the pons, also known as the subcoreuleus, generate muscle atonia during REM sleep. Lesions of this area produce REM without atonia while pharmacological activation triggers a REM-like state. We recently found that glutamatergic REM-active neurons in the SLD directly project to the glycinergic/GABAergic premotorneurons in the spinal cord. Our hypothesis is that these spinal projecting SLD (SLDsp) neurons play a critical role in the generation of muscle atonia during REM sleep. We will examine the electrophysiological actions of the cholinergic, monoaminergic and orexinergic afferents to the SLDsp neurons using patch- clamp recordings in a slice preparation. We will retrogradely prelabel the SLDsp neurons with fluorescent tracers microinjected in the spinal cord, and then use these animals for slice recordings. In Aim 1, and Aim 2, we will determine the electrophysiological responses to cholinergic and monoaminergic inputs. We will determine their pre- and postsynaptic effects, and we will identify their receptor subtypes and their electrophysiologically-mediated mechanisms. In Aim 3, we will focus on orexinergic inputs. We have found that SLDsp neurons are not directly affected by orexin, but instead orexin increases GABAergic synaptic input to these neurons. We will identify the source of this GABAergic input with a rescue experiment using inducible orexin receptor Ox1R and Ox2R knock-in mice. These mice are born lacking Ox1R or Ox2R or both. We will place injections of an adeno-associated viral vector containing Cre recombinase into specific brain regions of these mice to induce focal rescue of orexin receptors and to restore the orexinergic modulation of GABAergic synaptic input to the SLDsp neurons. Overall these experiments will help define the physiology underlying the regulation of REM-atonia neurons. In addition, these studies will provide essential insights into the mechanism for orexin effects on REM-atonia neurons, and how their absence results in cataplexy, as well as into the control of the REM-atonia neurons in RBD. PUBLIC HEALTH RELEVANCE During normal Rapid Eye Movement (REM) sleep, there is loss of muscle tone that prevents people from acting out their dreams. REM sleep behavior disorder (RBD) and cataplexy may be triggered by the dysfunction of the circuitry that controls REM-atonia The goal of our experiments is to define the physiology of REM sleep atonia, to better understand the neurobiology of RBD and cataplexy and to provide essential insights for the development of more effective treatments.

描述（由申请人提供）：快速眼动睡眠的一个决定性特征是几乎所有肌肉的麻痹。在快速眼动睡眠行为障碍 (RBD) 中，快速眼动乏力的缺失会导致梦境的出现。这种疾病与帕金森病等神经退行性疾病密切相关，并且通常出现在疾病涉及包括脑桥在内的下脑干的早期阶段。大量证据表明，脑桥侧背下核 (SLD) 的神经元（也称为核核下层）在快速眼动睡眠期间会产生肌肉无力。该区域的病变会产生无张力的快速眼动，而药物激活会触发类似快速眼动的状态。我们最近发现，SLD 中的谷氨酸能 REM 活性神经元直接投射到脊髓中的甘氨酸能/GABA 能前运动神经元。我们的假设是，这些脊髓投射 SLD (SLDsp) 神经元在快速眼动睡眠期间肌肉无力的产生中发挥着关键作用。我们将使用切片制备中的膜片钳记录来检查胆碱能、单胺能和食欲能传入神经元对 SLDsp 神经元的电生理作用。我们将用脊髓中显微注射的荧光示踪剂逆行预标记 SLDsp 神经元，然后使用这些动物进行切片记录。在目标 1 和目标 2 中，我们将确定对胆碱能和单胺能输入的电生理反应。我们将确定它们的突触前和突触后效应，并且我们将确定它们的受体亚型及其电生理介导的机制。在目标 3 中，我们将重点关注食欲素输入。我们发现 SLDsp 神经元并不直接受到食欲素的影响，而是食欲素增加了这些神经元的 GABA 突触输入。我们将通过使用诱导性食欲素受体 Ox1R 和 Ox2R 敲入小鼠的救援实验来确定这种 GABA 能输入的来源。这些小鼠生来就缺乏 Ox1R 或 Ox2R 或两者都缺乏。我们将向这些小鼠的特定大脑区域注射含有 Cre 重组酶的腺相关病毒载体，以诱导食欲素受体的局灶性救援，并恢复对 SLDsp 神经元的 GABA 突触输入的食欲素能调节。总的来说，这些实验将有助于定义快速眼动肌张力神经元调节的生理学。此外，这些研究将为了解食欲素对 REM-atonia 神经元的影响机制、其缺失如何导致猝倒以及 RBD 中 REM-atonia 神经元的控制提供重要的见解。公共卫生相关性在正常的快速眼动 (REM) 睡眠期间，肌肉张力会降低，从而阻碍人们实现梦想。 REM 睡眠行为障碍 (RBD) 和猝倒可能是由控制 REM 肌张力障碍的电路功能障碍引发的。我们实验的目标是定义 REM 睡眠肌张力障碍的生理学，更好地了解 RBD 和猝倒的神经生物学，并提供开发更有效治疗方法的重要见解。