Neural pathway of REM sleep atonia

快速眼动睡眠乏力的神经通路

• 批准号: 8811479
• 负责人: JUN LU
• 金额: $ 38.06万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811479
• 关键词: Acting Out; Acute; Affect; Alzheimer' s Disease; Animals; Area; Behavior; Breathing; Cell Nucleus; Cells; Cerebrum; Chloride Channels; Cholinergic Receptors; Clozapine; Complex; Coupled; Data; Designer Drugs; Dorsal; Dreams; Electroencephalography; Eye Movements; Facial nerve nucleus; Felis catus; Functional disorder; Glutamates; Glycine; Grant; Health; Horns; Hour; Human; In Situ Hybridization; Inferior; Interneurons; Ivermectin; Lesion; Measures; Methods; Motor; Motor Activity; Motor Cortex; Motor Manifestations; Motor Neurons; Movement; Mus; Muscle; Names; Neural Pathways; Neurodegenerative Disorders; Neurons; Olives - dietary; Operating System; Oxides; Paralysed; Parkinson Disease; Parvalbumins; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Pontine structure; Population; REM Sleep; REM Sleep Behavior Disorder; Rattus; Regulation; Research Personnel; Reticular Formation; Role; Running; Series; Site; Skeletal Muscle; Sleep; Sleep Disorders; Spinal; Spinal Cord; Spinal Cord Lesions; Staining method; Stains; Synaptic Vesicles; Techniques; Testing; Work; design; driving behavior; gamma-Aminobutyric Acid; genetic manipulation; ideation; killings; locus ceruleus structure; mouse model; neural circuit; neuropathology; novel; prevent; rapid eye movement; receptor; research study; transmission process; vesicular GABA transporter

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.

描述(由申请者提供)：紧张症的丧失是REM睡眠行为障碍(RBD)的主要症状，该疾病先于许多神经退行性疾病，如帕金森氏病和阿尔茨海默病。了解紧张症的神经回路不仅提供了运动系统在睡眠中如何运作，而且还提供了RBD的神经病理部位。我们已经发现，被盖背外侧下核(SLD)中的谷氨酸能神经元投射到脊髓抑制性中间神经元，从而抑制了REM睡眠中的运动活动。我们后来证实，SLD谷氨酸功能的丧失导致了RBD样表型。争论的焦点是延髓是否参与了张力的调节。我们发现SLD有三叉神经投射到旋转内侧(RVM)的GABA/甘氨酸网状脊髓瘤、延髓腹内侧(VMM)的谷氨酸能网状脊髓神经元和脊髓GABA/甘氨酸中间神经元。虽然RVM和VMM的病变在REM睡眠中表现出相运动活动的抑制，但远低于SLD的病变。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，延髓中继器在张力中起次要作用。在这项授权中，我们将使用一种新的技术DREADD，在该技术中，将修饰的G偶联胆碱能受体插入只有激活氯氮平-N-氧化物(CNO)才能激活的神经元中。我们设计了一系列实验，使用DREADD方法结合病变激活或抑制选择性神经元，以确定调节张力的运动前部位。在目标1中，我们探讨了DREADD激活SLD是否诱导了延髓腹侧和脊髓中间神经元的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，我们询问运动皮质是否驱动RBD的复杂行为。我们的数据支持SLD向脊髓抑制性中间神经元的直接投射在REM睡眠中运动皮质驱动的运动行为抑制中起主导作用。