A Noradrenergic Mechanism Functions to Couple Motor Behavior with Arousal State
A Noradrenergic Mechanism Functions to Couple Motor Behavior with Arousal State
复制标题
DOI：
10.1016/j.cub.2013.07.014
复制
发表时间：
2013-09-23
期刊：
影响因子：
9.2
通讯作者：
Peever, John H.
中科院分区：
文献类型：
--
作者：
Burgess, Christian R.;Peever, John H.
背景：支持日常运动行为需要适当水平的骨骼肌张力。但是，将肌肉紧张度与清醒行为相结合的大脑机制尚不清楚。我们通过研究患有猝倒的小鼠来解决这个问题--一种由运动和唤醒行为分离引起的情况。猝倒的特征是在清醒时不自觉地失去肌肉张力，这会导致在其他正常意识状态下的姿势崩溃。猝倒是由下丘脑肌素(食欲素)细胞的丢失引起的，但尚不清楚这种丢失是如何在猝倒期间触发运动不活动的。在这里，我们使用下丘脑泌素基因敲除小鼠来确定猝倒的神经化学原因，并确定正常情况下连接唤醒和运动系统的生化机制。结果：利用遗传学、行为学、电生理学和药理学方法，我们证明去甲肾上腺素系统起到同步运动和唤醒系统的作用。具体地说，我们证明了兴奋性去甲肾上腺素能驱动力通过激活骨骼黑质神经元上的α(1)受体来维持清醒时的姿势肌肉张力。失去这种正常的兴奋性驱动，会通过减少运动神经元的兴奋，在痉挛期间触发运动停顿。然而，失去这种驱动力并不影响觉醒，因为小鼠在猝倒期间保持清醒，这表明去甲肾上腺素系统不是维持清醒所必需的。人工恢复运动神经元去甲肾上腺素能驱动，可防止运动不活跃，抢救猝倒。结论：我们认为降钙素缺乏症是通过短路去甲肾上腺素驱动骨骼运动神经元而导致猝倒的。我们认为去甲肾上腺素系统的功能是耦合控制姿势肌肉张力和行为唤醒状态的大脑系统。
Background: Appropriate levels of skeletal muscle tone are needed to support routine motor behaviors. But, the brain mechanisms that function to couple muscle tone with waking behaviors are unknown. We addressed this question by studying mice with cataplexy-a condition caused by a decoupling of motor and arousal behaviors. Cataplexy is characterized by involuntary loss of muscle tone during wakefulness, which results in postural collapse during otherwise normal consciousness. Cataplexy is caused by loss of hypocretin (orexin) cells, but it is unknown how this loss triggers motor inactivity during cataplexy. Here, we used hypocretin knockout mice to identify the neurochemical cause of cataplexy and to determine the biochemical mechanisms that normally function to couple arousal and motor systems.Results: Using genetic, behavioral, electrophysiological, and pharmacological approaches, we show that the noradrenergic system acts to synchronize motor and arousal systems. Specifically, we show that an excitatory noradrenergic drive maintains postural muscle tone during wakefulness by activating alpha(1) receptors on skeletal nnotoneurons. Loss of this normal excitatory drive triggers motor inactivity during cataplexy by reducing motoneuron excitation. However, loss of this drive does not affect arousal since mice remain awake during cataplexy, suggesting the noradrenergic system is not required for maintaining wakefulness. Artificial restoration of noradrenergic drive to motoneurons prevents motor inactivity and rescues cataplexy.Conclusions: We conclude that hypocretin deficiency causes cataplexy by short-circuiting the noradrenergic drive to skeletal nnotoneurons. We suggest that the noradrenergic system functions to couple the brain systems that control postural muscle tone and behavioral arousal state.