Spinal circuitry for ventilatory control and compensation

用于通气控制和补偿的脊髓回路

• 批准号: 9922391
• 负责人: STEVEN ALLEN CRONE
• 金额: $ 34.78万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922391
• 关键词: ALS patients; Amyotrophic Lateral Sclerosis; Asses; Atelectasis; Behavior; Brain Stem; Breathing; Cause of Death; Cervical; Chest; Chronic; Communication impairment; Data; Disease; Disease Progression; Electromyography; Exercise; Failure; Financial compensation; Foundations; Functional disorder; Glutamates; Goals; Health; Impairment; Injury; Lateral; Lead; Life; Location; Lumbar spinal cord structure; Measurement; Mechanical ventilation; Medial; Molecular; Molecular Profiling; Motor; Motor Neurons; Mus; Muscle; Muscle function; Nerve Degeneration; Neuromuscular Diseases; Neurons; Patients; Pattern; Pharmacology; Play; Prevention; Rabies virus; Respiration Disorders; Respiratory Diaphragm; Respiratory Failure; Respiratory Muscles; Respiratory Tract Infections; Rest; Role; Signal Pathway; Sleep; Spinal; Spinal Cord; Spinal cord injury; Testing; Therapeutic; Transgenic Organisms; Viral; Work; cost; designer receptors exclusively activated by designer drugs; experimental study; hazard; improved; mad itch virus; molecular subtypes; motor neuron degeneration; mouse model; neural circuit; neuroregulation; novel strategies; premature; prevent; recruit; respiratory; therapy development; ventilation

Crone, S. A. Project Summary The proposed studies investigate the role of spinal V2a neurons in the control of auxiliary (non- diaphragmatic) respiratory muscles (ARMs) for inspiration. These muscles are normally used to increase ventilation during exercise, but they are also used to augment diaphragm function after injury or disease. Despite the importance of ARMs for enhancing ventilation or compensating for loss of diaphragm function, little is known about the neural circuits that drive their activity in either health or disease. ARM activity increases ventilation in ALS model mice at early disease stages, but there is a central deficit that prevents activation of ARMs for breathing at late disease stages, despite the fact that these muscles are active and functional for voluntary behaviors. Either increasing (through Gq signaling pathways) or decreasing (through Gi signaling pathways) the excitability of V2a neurons is able to increase ARM activity at rest in healthy and ALS model mice. Thus, these neurons are a potential target to increase ARM activity and ventilation in patients with ALS, other neuromuscular diseases, or spinal cord injury. However, the V2a class of neurons appears to be composed of subtypes that play distinct roles in the control of breathing. In order to develop therapies to improve breathing by altering the activity, preventing degeneration, or replacing degenerated V2a neurons, it is necessary to determine the location and molecular subtypes of V2a neurons that impact ventilation and to understand their specific roles. Aim 1 will use transgenic and viral strategies to increase excitability, decrease excitability, or ablate V2a neurons in cervical, thoracic, or lumbar spinal cord to identify how respiratory muscle activity is regulated by V2a neurons at different segmental levels. Aim 2 will investigate the molecular diversity of V2a neurons within the cervical cord by investigating differences in connectivity and function within respiratory circuits of a medial V2a subtype and a lateral V2a subtype. Aim 2 will also asses the effects on ventilation of altering excitability of only V2a neurons with direct excitatory connections to respiratory motor neurons. Aim 3 will assess the long- term impact that degeneration of V2a neurons has on breathing by prematurely ablating cervical V2a neurons in a mouse model of ALS. The potential benefit (and hazards) of chronically increasing the excitability of V2a neurons on ARM activity, motor neuron degeneration, and ventilatory health in ALS model mice will also be assessed. By accomplishing these aims, we will pinpoint the location, molecular identity, and connectivity of spinal V2a neurons that pattern respiratory muscle activity as well as assess the potential of pharmacologically altering the excitability of V2a neurons to improve breathing in a mouse model of ALS.

Crone，S。A. 项目摘要 拟议的研究研究了脊柱V2A神经元在辅助控制中的作用（非 - diaphragmatic）呼吸道肌肉（臂）以获得灵感。这些肌肉通常用于增加 运动过程中的通风，但它们也用于增强受伤或疾病后的隔膜功能。尽管 武器对增强通风或补偿diaphragm功能丧失的重要性，几乎没有 知道促进其在健康或疾病中活动的神经回路。手臂活动增加 在早期疾病阶段，ALS模型小鼠的通风，但中心赤字可防止激活 尽管这些肌肉活跃并且功能正常，但在晚期疾病阶段进行呼吸 自愿行为。增加（通过GQ信号通路）或减少（通过GI信号传导 途径）V2A神经元的兴奋性能够在健康和ALS模型小鼠中增加静止的手臂活动。 因此，这些神经元是增加ALS患者的手臂活性和通风的潜在靶标 神经肌肉疾病或脊髓损伤。但是，V2A类神经元似乎由 在呼吸控制中起着不同作用的亚型。为了开发疗法以改善呼吸 通过改变活动，预防变性或替换退化的V2A神经元，有必要 确定影响通气的V2A神经元的位置和分子亚型，并了解其 特定角色。 AIM 1将使用转基因和病毒策略来提高兴奋性，降低兴奋性或消融性 宫颈，胸腔或腰脊髓中的V2A神经元，以确定如何调节呼吸肌活动 通过V2A神经元在不同的节段水平上。 AIM 2将研究V2A神经元内的分子多样性 通过研究内侧呼吸回路内连通性和功能的差异，宫颈绳 V2A亚型和横向V2A亚型。 AIM 2还将评估对更改兴奋性通风的影响 只有与呼吸运动神经元直接兴奋性连接的V2A神经元。 AIM 3将评估长期 V2A神经元的变性对呼吸的术语影响通过过早消融宫颈V2A神经元中的呼吸 ALS的鼠标模型。长期增加V2A的兴奋性的潜在益处（和危害） ALS模型小鼠的手臂活动，运动神经元变性和通气健康的神经元也将是 评估。通过实现这些目标，我们将确定位置，分子身份和连通性 脊柱V2A神经元，其对呼吸肌肉活性进行模式以及评估药理的潜力 改变V2A神经元的兴奋性以改善ALS小鼠模型中的呼吸。