Pontine Control of REM Atonia

脑桥控制 REM Atonia

• 批准号: 7848685
• 负责人: Elda Arrigoni
• 金额: $ 1.1万
• 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: 2009-07-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848685
• 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; 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; public health relevance; rapid eye movement; receptor; recombinase; research study; response; spinal pathway

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）：REM睡眠的一个定义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，缺乏快速眼动肌张力允许梦的出现。这种疾病与神经退行性疾病如帕金森病密切相关，并且当疾病涉及包括脑桥的下脑干时，它通常出现在早期阶段。大量的证据表明，脑桥的亚侧背核（SLD）神经元，也称为核下肌，在REM睡眠期间产生肌肉张力减退。该区域的病变产生无张力的REM，而药理学激活触发REM样状态。我们最近发现，SLD中的多巴胺能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REM睡眠期间肌肉张力减退的产生中起着关键作用。我们将在切片制备中使用膜片钳记录来检查胆碱能、单胺能和食欲素能传入SLDsp神经元的电生理作用。我们将在脊髓中显微注射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，我们将确定它们的受体亚型和它们的电生理介导的机制。在目标3中，我们将关注食欲素能输入。我们已经发现SLDsp神经元不直接受食欲素影响，而是食欲素增加对这些神经元的GABA能突触输入。我们将使用诱导型食欲素受体Ox 1 R和Ox 2 R基因敲入小鼠进行拯救实验，以确定这种GABA能输入的来源。这些小鼠出生时缺乏Ox 1 R或Ox 2 R或两者兼而有之。我们将把含有Cre重组酶的腺相关病毒载体注射到这些小鼠的特定脑区，以诱导食欲素受体的局灶性拯救，并恢复对SLDsp神经元的GABA能突触输入的食欲素能调节。总的来说，这些实验将有助于确定REM-弛缓神经元调节的生理学基础。此外，这些研究将提供重要的见解食欲素对REM-弛缓神经元的作用机制，以及它们的缺乏如何导致紧张症，以及RBD中REM-弛缓神经元的控制。 在正常的快速眼动（REM）睡眠期间，肌肉张力的丧失会阻止人们实现他们的梦想。REM睡眠行为障碍（RBD）和紧张症可能是由控制REM-张力缺乏的电路功能障碍触发的。我们实验的目标是定义REM睡眠张力缺乏的生理学，以更好地理解RBD和紧张症的神经生物学，并为开发更有效的治疗方法提供必要的见解。