Spinal circuitry for ventilatory control and compensation

用于通气控制和补偿的脊髓回路

基本信息

批准号：
10597015
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
项目类别：
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/10597015
关键词：
ALS patients Ablation Amyotrophic Lateral Sclerosis Atelectasis Behavior Brain Stem Breathing Cause of Death Cervical Chest Chronic Communication impairment Compensation Data Disease Disease Progression Electromyography Exercise Failure Foundations Functional disorder Glutamates Goals Health Impairment Injury Lateral 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 Play Prevention Rabies virus Respiration Disorders Respiratory Diaphragm Respiratory Failure Respiratory Muscles Respiratory Tract Infections Rest Role Signal Pathway Sleep Spinal Spinal Cord Spinal Manipulation Spinal cord injury Testing Therapeutic Transgenic Organisms Vertebral column 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 neuronal patterning neuronal survival neuroregulation novel strategies pharmacologic premature prevent recruit respiratory therapy development ventilation

项目摘要

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.

克罗恩，S.A. 项目概要拟议的研究调查了脊髓 V2a 神经元在控制辅助（非膈肌）呼吸肌（ARM）以获取灵感。这些肌肉通常用于增加运动期间的通气，但它们也可用于增强受伤或疾病后的膈肌功能。尽管 ARM 对于增强通气或补偿膈肌功能丧失的重要性，人们却知之甚少。了解在健康或疾病中驱动其活动的神经回路。 ARM 活动增加 ALS 模型小鼠在疾病早期阶段的通气，但存在中枢缺陷，无法激活尽管这些肌肉在疾病晚期阶段仍处于活跃状态并具有功能性，但用于呼吸的手臂自愿行为。增加（通过 Gq 信号通路）或减少（通过 Gi 信号通路）途径）V2a 神经元的兴奋性能够增加健康小鼠和 ALS 模型小鼠静息时的 ARM 活性。因此，这些神经元是增加 ALS 和其他患者 ARM 活动和通气的潜在目标。神经肌肉疾病，或脊髓损伤。然而，V2a 类神经元似乎由在呼吸控制中发挥不同作用的亚型。为了开发改善呼吸的疗法通过改变活性、防止变性或替换变性的 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具体角色。目标 1 将使用转基因和病毒策略来增加兴奋性、降低兴奋性或消融颈椎、胸椎或腰椎脊髓中的 V2a 神经元可识别呼吸肌活动的调节方式由不同节段水平的 V2a 神经元组成。目标 2 将研究 V2a 神经元的分子多样性通过研究内侧呼吸回路内连接性和功能的差异来研究颈髓 V2a 亚型和横向 V2a 亚型。目标 2 还将评估改变兴奋性对通气的影响仅与呼吸运动神经元有直接兴奋性连接的 V2a 神经元。目标 3 将评估长期 V2a 神经元变性通过过早消融颈部 V2a 神经元对呼吸产生长期影响 ALS 小鼠模型。长期增加 V2a 兴奋性的潜在好处（和危害）神经元对 ALS 模型小鼠 ARM 活动、运动神经元变性和通气健康的影响也将被研究评估。通过实现这些目标，我们将查明脊髓 V2a 神经元可模拟呼吸肌活动并评估药理潜力改变 V2a 神经元的兴奋性以改善 ALS 小鼠模型的呼吸。