Neural pathway of REM sleep atonia

描述（由申请人提供）：失弛缓是REM睡眠行为障碍（RBD）的主要体征，其先于许多神经退行性疾病，如帕金森病和阿尔茨海默病十年。了解弛缓的神经回路不仅提供了运动系统在睡眠期间如何运作，而且还提供了RBD的神经病理学位点。我们以前已经发现，在sublaterodoral被盖核（SLD）的多巴胺能神经元的项目，脊髓抑制性中间神经元，这提出了抑制运动活动在REM睡眠。我们已经证实，SLD的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了肌张力缺乏的调节。结果表明，SLD向延髓头内侧（RVM）的GABA/甘氨酸网状脊髓神经元、延髓腹内侧（VMM）的GABA能网状脊髓神经元和脊髓GABA/甘氨酸中间神经元有三叉投射。尽管RVM和VMM的病变在REM睡眠期间显示出不受抑制的阶段性运动活动，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肌张力，而延髓中继在肌张力中的作用较小。在本研究中，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仅被激活的氯氮平-N-氧化物（CNO）激活的神经元中。我们设计了一系列的实验，使用DREADD方法激活或抑制选择性神经元的组合损伤，以确定运动前区的网站，调节张力不足。在目标1中，我们问是否SLD激活DREADD诱导Fos在腹侧延髓和脊髓中间神经元。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对肌张力缺乏的控制是否依赖于脊髓甘氨酸/GABA中间神经元（SLD激活和脊髓中间神经元的损伤或甘氨酸-GABA的缺失）。最后，在目标4中，我们问运动皮层是否驱动RBD的复杂行为。我们的数据支持的直接投射的SLD脊髓抑制性中间神经元在REM睡眠期间由运动皮层驱动的运动行为的抑制中发挥主导作用。

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.