Resolution of the Mechanisms Responsible for Atonia during REM Sleep

 描述(申请人提供)：直到20世纪90年代的S，人们一直认为快速眼动睡眠中的肌肉张力障碍是由于运动神经元的甘氨酸能突触后抑制所致。来自不同实验室的这一共识是建立在实验的基础上的，在这些实验中，神经递质激动剂和拮抗剂在自然发生的睡眠和清醒状态下，对细胞内记录的运动神经元进行并列注射。随后，细胞外记录研究开始出现，这对先前的共识提出了质疑；提出的数据表明，快速眼动睡眠的失弛是由于各种其他机制，如障碍，以及其他神经递质，如5-羟色胺和去甲肾上腺素。因此，尽管进行了50年的研究，但目前对于导致快速眼动睡眠中张力的神经化学机制还没有达成一致意见。提出了一种创新的研究方法，旨在解决目前涉及REM睡眠期间运动活动的状态依赖控制的不可调和数据。在拟议的实验中，我们将同等重视探索障碍和突触后抑制在REM睡眠中对运动神经元控制的贡献。为了实现我们的目标，我们将在自然发生的REM睡眠中检查舌下活动运动神经元，并将其与阻塞性睡眠呼吸暂停动物模型中在缺氧性REM睡眠中获得的数据进行比较。首次发现舌下运动神经元的细胞内活动和舌下运动神经元的细胞外活动 肌肉将同时被记录下来。定量数据也将在REM睡眠期间与神经递质的细胞旁和反向透析给药一起获得 激动剂和拮抗剂。因此，突触后和障碍过程对抑制舌下运动神经元活动的作用将被记录在案。我们推测，促进REM睡眠诱导的舌下运动神经元抑制的机制与控制其他脑干和脊髓运动神经元活动的机制相同，但在病理条件下除外。具体地说，在常氧REM睡眠中，我们认为突触后抑制是松弛的原因，而在低氧条件下，如阻塞性睡眠呼吸暂停时，除突触后抑制外，易化还会导致舌下运动神经元活动的抑制。验证我们的假设和所获得的数据将为理解在正常和病理性(低氧)REM睡眠中控制张力的神经机制提供必要的基础。我们还相信，这些数据将直接用于开发合理的运动障碍治疗方法。 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猝倒等。

 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.