Neural pathway of REM sleep atonia

描述（由申请人提供）：张力丧失是快速眼动睡眠行为障碍（RBD）的主要症状，比许多神经退行性疾病如帕金森病和阿尔茨海默病早十年。了解张力失调的神经回路不仅提供了运动系统在睡眠中的运作方式，而且还提供了RBD的神经病理学位点。在此之前，我们已经发现嗅觉下被盖核（SLD）中的谷氨酸能神经元投射到脊髓抑制性中间神经元，从而抑制快速眼动睡眠期间的运动活动。我们已经证实，SLD谷氨酸功能的丧失导致rbd样表型。争论的焦点是延髓是否参与张力的调节。我们发现SLD在前内侧髓质（RVM）、腹内侧髓质（VMM）和脊髓GABA/甘氨酸中间神经元上有三叉状的投射。虽然RVM和VMM病变在REM睡眠期间表现出去抑制的相运动活动，但远低于SLD病变。因此，我们认为SLD主要通过激活脊髓抑制性中间神经元来控制张力，而髓质继电器在张力中起的作用较小。在这项资助中，我们将使用一种新的技术DREADD，将修饰的G偶联胆碱能受体插入到仅被激活氯氮平- n -氧化物（CNO）激活的神经元中。我们设计了一系列实验，使用DREADD方法激活或抑制病变组合中的选择性神经元，以确定调节张力的运动前部位。在目的1中，我们询问由DREADD激活的SLD是否会诱导腹侧髓质和脊髓中间神经元中的Fos。在目标2中，我们询问RVM或VMM的DREADD激活是否可以逆转rbd样表型。在目标3中，我们询问SLD对张力失调的控制是否取决于脊髓甘氨酸/GABA中间神经元（SLD激活和脊髓中间神经元病变或甘氨酸-GABA缺失）。最后，在目标4中，我们询问运动皮层是否驱动RBD的复杂行为。我们的数据支持SLD直接投射到脊髓抑制性中间神经元在REM睡眠期间运动皮层驱动的运动行为抑制中起主导作用。

DESCRIPTION (provided by applicant): Loss of atonia is a cardinal sign of REM sleep behavior disorder (RBD) that precedes many neural degenerative diseases such as Parkinson's disease and Alzheimer's disease by a decade. Understanding the neural circuit of atonia provides not only how the motor system operates during sleep but also the locus of neuropathology of RBD. We have previously identified that the glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD) project to the spinal cord inhibitory interneurons, which proposed to suppress the motor activity during REM sleep. We have since confirmed that loss of glutamate function of the SLD results in RBD-like-phenotype. The controversy has been the involvement of the medulla in regulation of atonia. We have revealed that the SLD has trifurcate projections to GABA/glycine reticulospinaneurons in the rostromedial medulla (RVM), glutamatergic reticulospinal neurons in the ventromedial medulla (VMM) and spinal cord GABA/glycine interneurons. Although lesions of the RVM and VMM show disinhibited phasic motor activity during REM sleep, it is far less than that of SLD lesions. We thus propose the SLD controls atonia mostly by activating spinal cord inhibitory interneurons, and the medullary relays play less critical role in atonia. In this grant, we will use a novel technique DREADD in which modified G coupled cholinergic receptors are inserted into the neurons that are only activated by activate clozapine-N-oxide (CNO). We design a series of experiments using DREADD method to activate or inhibit selective neurons in combination of lesions to identify the premotor sites that regulate atonia. In aim 1, we ask whether the SLD activation by DREADD induces Fos in the ventral medulla and spinal cord interneurons. In aim 2, we ask whether DREADD activation of the RVM or VMM can reverse RBD-like phenotype. In aim 3 we ask whether SLD control of atonia depends on the spinal glycine/GABA interneurons (SLD activation and lesions of spinal cord interneurons or deletion of glycine-GABA). Finally in aim 4, we ask whether the motor cortex drives complex behaviors of RBD. Our data support that the direct projections of the SLD to the spinal cord inhibitory interneurons play a dominant role in suppression of motor behaviors driven by the motor cortex during REM sleep.