Neural pathway of REM sleep atonia

快速眼动睡眠乏力的神经通路

基本信息

批准号：
9029358
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
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029358
关键词：
Acting Out Acute Affect Alzheimer&apos s Disease Animals Area Behavior Breathing Cell Nucleus Cells Cerebrum Chloride Channels Cholinergic Receptors Clozapine Complex Coupled Data 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 Muscular Atrophy 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 designer receptors exclusively activated by designer drugs 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

项目摘要

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（由申请人提供）：缺乏张力是快速眼动睡眠行为障碍（RBD）的一个主要症状，这种疾病比帕金森病和阿尔茨海默病等许多神经退行性疾病早了十年。了解失张力症的神经回路不仅可以了解运动系统在睡眠期间的运作方式，还可以了解 RBD 的神经病理学轨迹。我们之前已经发现，背侧被盖核下（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。此后我们证实，SLD 谷氨酸功能的丧失会导致 RBD 样表型。争议在于延髓参与肌张力不全的调节。我们发现，SLD 对头内侧延髓 (RVM) 中的 GABA/甘氨酸网状脊髓神经元、腹内侧延髓 (VMM) 中的谷氨酸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 睡眠期间显示出相性运动活动的去抑制，但其程度远低于 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不全，而髓质中继在肌张力不全中发挥的作用不太重要。在这笔资助中，我们将使用一种新技术 DREADD，其中将修饰的 G 偶联胆碱能受体插入仅由激活的氯氮平-N-氧化物 (CNO) 激活的神经元中。我们设计了一系列实验，使用 DREADD 方法激活或抑制损伤组合中的选择性神经元，以识别调节肌张力障碍的运动前位点。在目标 1 中，我们询问 DREADD 激活 SLD 是否会在腹侧延髓和脊髓中间神经元中诱导 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 对肌无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损伤或甘氨酸-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。我们的数据表明，SLD 向脊髓抑制性中间神经元的直接投射在抑制快速眼动睡眠期间运动皮层驱动的运动行为中发挥着主导作用。