Identifying deficits in brainstem respiratory circuits during viral encephalitis

识别病毒性脑炎期间脑干呼吸回路的缺陷

• 批准号: 8970067
• 负责人: John D Morrey
• 金额: $ 17.7万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970067
• 关键词: Adult; Affect; Arbovirus Encephalitis; Arboviruses; Area; Brain Stem; Breathing; Calcium; Cell Nucleus; Cells; Cervical; Cessation of life; Chemoreceptors; Complex; Control Groups; Data; Disease; Electrodes; Electromyography; Encephalitis; Frequencies; Gases; Generations; Goals; Health; Histologic; Hypercapnia; Hypoglossal nerve structure; Image; Inflammation; Institutional Review Boards; Investigation; Lead; Lung diseases; Measurement; Measures; Motor; Motor Neurons; Motor output; Mus; Neonatal; Nerve; Neurologic; Neurons; Outcome; Pathogenesis; Pathology; Phase; Physiological; Plant Roots; Plethysmography; Preparation; Procedures; Publishing; Research Project Grants; Respiration; Respiratory Diaphragm; Respiratory Failure; Respiratory Insufficiency; Respiratory distress; Respiratory physiology; Rodent Model; Site; Slice; Somatostatin; Specificity; Spinal Cord; Staging; Structure of phrenic nerve; Suction; Surface; Synapses; Testing; Viral Encephalitis; Virus; Virus Diseases; West Nile virus; base; design; human subject; immunoreactivity; in vivo; infected vector rodent; inhibitor/antagonist; motor neuron function; next generation; novel; outcome forecast; pup; respiratory; response; virus envelope

 DESCRIPTION (provided by applicant): The overall goal is to identify respiratory neuro-circuits within the brainstem damaged by arbovirus encephalitis that eventually lead to respiratory distress and failure. Respiratory insufficiency is a serious outcome of arbovirus encephalitis and can result in a poor prognosis. Rodent models have been used to establish that neurological deficits cause the respiratory distress, which is the primary patho- physiological mechanism of death for West Nile virus (WNV) and other viral encephalitis. However, the respiratory neuro-circuits damaged by the virus are unknown, which is subject of this application. The hypothesis to be tested is that WNV damages the retrotrapazoid nucleus/parafacial respiratory group (RTN/pFRG) controlling response to hypercapnia and the pre-Bötzinger complex (preBötC) controlling generation of breathing rhythm. The specific aims are: Aim 1. Identify deficits in spontaneous rhythmic activity in the medullary core rhythm generator (preBötC) from WNV-infected neonatal mice. Suction electrode measurements will be obtained from cranial nerve XII rootlets in the preBötC slice from pups with respiratory deficits. Aim 2. Identify deficits in respiratory circuitry using brainstem-spinal cord preparations (en bloc preparations) in neonatal WNV-infected mice. Nerve root discharges of the XII and phrenic nerves will be simultaneously measured using suction electrodes. The ventral surface of the medulla will be imaged for calcium to pin point chemoreceptor deficits to the RTN/pFRG. Aim 3. Deficits identified in Aims 1 and 2 will be corroborated in adult WNV-infected mice. Chemosensory, rhythmogenesis, and phrenic motor neurons functions will be ascertained by measuring nerve discharges in XII and phrenic nerves. Procedures will be performed within a single mouse so that we can better understand the contributions of each type of deficit to the total WNV-induced respiratory failure. Upon completion of these in vivo measurements, the brainstem and spinal cord containing regions of respiratory function will be analyzed histologically to determine if functional deficits correlate with anatomical pathology. If WNV infection adversely affects central breathing function, it would represent a paradigm shift for the neurological mechanism of pathogenesis for viral encephalitis. Importantly, results of this project will provide supporting data for an IRB application to measure respiratory function in WNV-infected human subjects in a forthcoming project

 描述（由适用提供）：总体目标是识别脑干脑干内因arbovirus脑炎造成的呼吸神经电路，有时会导致呼吸窘迫和失败。呼吸功能不全是肌动病毒脑炎的严重结果，可能导致预后不佳。啮齿动物模型已被用来确定神经缺乏会导致呼吸窘迫，这是西尼罗河病毒（WNV）和其他病毒性脑炎的主要病理生理机制。但是，该病毒受损的呼吸神经电路尚不清楚，这是该应用的主题。要检验的假设是WNV损害了控制对高碳酸盐的反应和控制呼吸节奏产生的对高碳酸盐症的反应和pre-Bötzinger络合物（PreBötc）的反应。具体目的是：目标1。确定来自WNV感染的新生儿小鼠的髓质核心节奏发电机（PREBötc）中的发音节奏活性的定义。吸气电极测量将从颅神经XII根中获得，从幼崽的幼崽中，呼吸不足。 AIM 2。使用脑干脊髓制剂确定呼吸电路的定义（En Bloc 制剂）在新生儿WNV感染的小鼠中。 XII的神经根放电将同时使用吸力电极同时测量。髓质的腹表面将成像以使钙定义为RTN/PFRG。 AIM 3。在成年WNV感染的小鼠中将证实目标1和2中发现的缺陷。通过测量XII和phrenic神经中的神经放电，可以确定化学感应，节律生成和Phrenic运动神经元功能。过程将在单个小鼠中进行，以便我们可以更好地了解每种类型的缺陷对全WNV诱导的呼吸衰竭的贡献。这些体内测量完成后，将在组织学上分析脑干和包含呼吸功能区域的脊髓和脊髓，以确定功能缺陷是否与解剖病理学相关。如果WNV感染对中央呼吸功能产生不利影响，则代表 病毒脑炎发病机理的神经系统机制。重要的是，这个项目的结果 将为IRB应用提供支持数据，以在即将到来的项目中测量WNV感染的人类受试者的呼吸功能