Resolution of the Mechanisms Responsible for Atonia during REM Sleep

解决快速眼动睡眠期间缺乏张力的机制

• 批准号: 8991865
• 负责人: MICHAEL H CHASE
• 金额: $ 50.93万
• 依托单位: WEBSCIENCES INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991865
• 关键词: Agreement; Animal Model; Animals; Basic Science; Brain Stem; Cataplexy; Consensus; Data; Development; Dialysis procedure; Disease; Foundations; Hypoglossal nerve structure; Hypoxia; Joints; Journals; Laboratories; Literature; Mediating; Mental Depression; Methodology; Morale; Motor; Motor Activity; Motor Neurons; Muscle; Nerve; Neurons; Neurotransmitters; Norepinephrine; Obstructive Sleep Apnea; Paper; Participant; Process; Property; Publishing; REM Sleep; REM Sleep Behavior Disorder; Research; Research Personnel; Resolution; Role; Serotonin; Sleep; Sleep Wake Cycle; Spinal Cord; Synapses; Techniques; Testing; Time; Wakefulness; base; cholinergic; design; extracellular; hypoglossal nucleus; innovation; motor control; motor disorder; neurochemistry; neuromechanism; neurotransmitter agonist; neurotransmitter antagonist; postsynaptic; public health relevance; research study; response; therapeutic development; therapy development

 DESCRIPTION (provided by applicant): There was an established consensus, until the 1990's, that muscle atonia during REM sleep was due to the glycinergic postsynaptic inhibition of motoneurons. This consensus, from different laboratories, was based on experiments wherein neurotransmitter agonists and antagonists where administered juxtacellularly to intracellularly-recorded motoneurons during naturally-occurring states of sleep and wakefulness. Subsequently, extracellular recording studies began to appear which called into question the preceding consensus; data were presented indicating that the atonia of REM sleep was due a variety of other mechanisms, such as disfacilitation, and other neurotransmitters, such as serotonin and noradrenaline. Consequently, despite 50 years of research, currently there is no agreement regarding the neurochemical mechanisms that are responsible for atonia during REM sleep. An innovative research approach is proposed that is designed to resolve the present irreconcilable data involving the state-dependent control of motor activity during REM sleep. In the proposed experiments, we will place an equal emphasis on exploring the contributions of disfacilitation and postsynaptic inhibition with respect to the control of motoneurons during REM sleep. To accomplish our objectives, hypoglossal activity motoneuron will be examined during spontaneously-occurring REM sleep and compared with data obtained during hypoxic REM sleep in an Animal Model of Obstructive Sleep Apnea. For the first time, intracellular activity of hypoglossal motoneurons and the extracellular activity of the hypoglossal muscle will be simultaneously recorded. Quantitative data will also be obtained during REM sleep in conjunction with the juxtacellular and reverse dialysis administration of neurotransmitter agonists and antagonists. Consequently, the contributions of postsynaptic and disfacilitatory processes to the depression of hypoglossal motoneuron activity will be documented. We hypothesize that the mechanisms that promote the REM sleep-induced depression of hypoglossal motoneurons are the same as those that control the activity of other brainstem and spinal cord motoneurons, except during pathological conditions. Specifically, during normoxic REM sleep, we propose that postsynaptic inhibition is responsible for atonia, whereas disfacilitation results in the depression of hypoglossal motoneuron activity, in addition to postsynaptic inhibition, under hypoxic conditions such as those that occur during Obstructive Sleep Apnea. Verification of our hypotheses and the data that are obtained will provide the necessary foundational bases for understanding the neuronal mechanisms that control atonia during normal and pathological (hypoxic) REM sleep. We also believe that these data will be directly translatable to the development of rational therapies for the treatment of motor disorders of REM sleep, such as Obstructive Sleep Apnea, REM Sleep Behavior Disorder, and cataplexy, among others.

 描述（由申请人提供）：直到20世纪90年代，有一个公认的共识，即REM睡眠期间的肌肉弛缓是由于运动神经元的甘氨酸能突触后抑制。来自不同实验室的这一共识是基于实验，其中神经递质激动剂和拮抗剂在自然发生的睡眠和觉醒状态期间向细胞内记录的运动神经元跨细胞给药。随后，细胞外记录研究开始出现，对之前的共识提出了质疑;数据表明，REM睡眠的张力缺乏是由于各种其他机制，如障碍，以及其他神经递质，如血清素和去甲肾上腺素。因此，尽管有50年的研究，目前还没有达成一致意见的神经化学机制，负责在快速眼动睡眠张力不足。 提出了一种创新的研究方法，旨在解决目前不可调和的数据，涉及状态依赖性控制的运动活动在REM睡眠。在拟议的实验中，我们将同等重视探索的贡献，在快速眼动睡眠期间的运动神经元的控制，障碍和突触后抑制。为了实现我们的目标，舌下神经活动运动神经元将在自发发生的REM睡眠期间进行检查，并与阻塞性睡眠呼吸暂停动物模型中缺氧REM睡眠期间获得的数据进行比较。首次观察到舌下神经运动神经元的细胞内活动和舌下神经运动神经元的细胞外活动。 肌肉将同时记录。定量数据也将在REM睡眠期间与神经递质的非细胞和反向透析给药结合获得 激动剂和拮抗剂。因此，突触后和失易过程对舌下神经运动神经元活动抑制的贡献将被记录。 我们假设，除了在病理条件下，促进REM睡眠诱导的舌下神经运动神经元的抑郁症的机制是相同的，控制其他脑干和脊髓运动神经元的活动。具体来说，在含氧量正常的REM睡眠，我们建议，突触后抑制是负责张力不足，而障碍的结果，在抑郁症的舌下运动神经元的活动，除了突触后抑制，缺氧条件下，如阻塞性睡眠呼吸暂停发生。 验证我们的假设和所获得的数据将提供必要的基础，了解神经元的机制，控制在正常和病理性（缺氧）REM睡眠肌张力减退。我们还相信，这些数据将直接转化为治疗运动障碍的合理疗法的开发 快速眼动睡眠，如阻塞性睡眠呼吸暂停，快速眼动睡眠行为障碍，和cataemia，等等。