Brainstem mechanism underlying recurrent laryngospasm in Rett syndrome

Rett综合征复发性喉痉挛的脑干机制

基本信息

批准号：
9264046
负责人：
CHI-SANG POON
金额：
$ 34.13万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264046
关键词：
AMPA Receptors Affect Anesthesia procedures Animal Model Animals Anxiety Apnea Arousal Autistic Disorder Behavior Control Behavioral Biological Assay Biological Markers Boston Brain Diseases Brain Stem Brain-Derived Neurotrophic Factor Breathing Cell Nucleus Central Sleep Apnea Childhood Neurological Disorder Clinical Clinical Research Clinical Trials Cognitive Data Dependence Development Disease Disease model Down Syndrome Dystonia Event Female Fingerprint Future Genes Genetic Goals Health Hyperactive behavior Impairment Individual Insulin-Like Growth Factor I Intellectual functioning disability Knowledge Label Laryngismus Larynx Lead Life Link Maps Measures Mediating Methyl-CpG-Binding Protein 2 Midbrain structure Moods Morbidity - disease rate Motor Neurons Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors Neurobehavioral Manifestations Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Organ Outcome Outcome Measure Parkinson Disease Pathologic Pathway interactions Patients Pediatric Hospitals Pharmacotherapy Phase Phenotype Play Pontine structure Population Prevalence Property Recurrence Reflex action Reporting Research Respiration Disorders Rett Syndrome Role Signal Transduction Site Speech Structure Structure of superior laryngeal nerve Symptoms Synaptic plasticity System Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Volition Wakefulness Wild Type Mouse awake base data integration expiration girls indexing midbrain central gray substance mortality motor control motor deficit multisensory mutant mutant mouse model nervous system disorder neuromechanism novel novel therapeutics respiratory response response biomarker transcription factor vocalization

项目摘要

Repetitive apnea during wakefulness is a cardinal and potentially life-threatening symptom of Rett syndrome (RTT). A recent clinical trial reveals that many of these apneic events in RTT patients result from behaviorally- induced involuntary breathholding (cessation of expiration) instead of chemoreflex-mediated central apnea (cessation of inspiration), and that such breathing disturbances are ameliorated by IGF-1 drug treatment to restore BDNF signaling in these patients. Emerging evidence from mutant mouse models of RTT suggests that such pathologic breathholding likely represents a form of recurrent laryngospasm (paroxysmal laryngeal adductor hyperactivity) caused by sensitization of neurons in the Kölliker-Fuse nucleus (KFN), a pontine nucleus which plays an important role in controlling laryngeal adductor activity during the post-inspiratory (post- I) phase of the respiratory rhythm and during behavioral tasks such as vocalization and breathholding. A hallmark of the post-I driver neurons in KFN is their critical dependence on NMDA receptor activity, a property which distinguishes these neurons from many other central neurons that are excited mainly by AMPA receptor- mediated currents. A central hypothesis to be tested in this proposal is that KFN post-I driver neurons are the site where ascending input from superior laryngeal nerve (SLN) mediating the laryngeal adductor reflex and descending input via midbrain periaqueductal gray (PAG) mediating behavioral control of glottic closure are integrated at the systems level, and that hyperactivity of these KFN neurons due to impairment of a form of NMDA and BDNF receptors-dependent synaptic plasticity may underlie the behaviorally-evoked laryngospasm in RTT at the cellular level. As a baseline (Aim 0), we will examine whether IGF-1 treatment ameliorates the breathholding phenotype during wakefulness in a mutant mouse model of RTT. Aim 1 will investigate the role of KFN post-I driver neurons in modulating the laryngeal adductor reflex induced by ascending SLN input in mutant and wild-type mice with or without IGF-1 treatment. In Aim 2, we will investigate the role of these KFN neurons in modulating the laryngeal adductor response induced by descending PAG input in these animals. These multisensory integration data will be subjected to a novel multiscale fingerprinting assay which verifies functional connectivity of the neurons that are upstream and downstream of the PAG-KFN-laryngeal post-I motoneuron pathway by matching a set of timing-, response- and cellular-specific markers shared by these neurons. In Aim 3, we will employ a multi-labeling technique with juxtacellular labeling/single unit recording combined with anterograde axonal tracing to map convergent inputs from PAG and KFN to laryngeal adductor motoneurons in medulla. By comparing these structure-function data from mutant mice and wild-type mice, our goal is to map the central circuits involved in coordination of reflex and volitional control of glottic closure in health and in RTT. Results of this project will inform ongoing and future clinical trials to evaluate the validity of breathholding vs. central apnea as possible outcome measures for assessing drug treatments of RTT patients.

唤醒期间的重复呼吸暂停是基本综合症的基本主教且潜在的威胁生命的症状（RTT）。诱发的非自愿呼吸（停止到期）而不是化学上的Feflex介导的中央呼吸暂停（戒断灵感），并且通过IGF-1药物治疗来改善这种呼吸障碍恢复这些患者的BDNF信号传导。这种病理性的呼吸可能代表了一种复发性喉部的形式（阵发性喉头加入器多动症）是由神经元在Kölliker-Fuse Nucleus（KFN）的敏化引起的，核在控制后呼吸术中起着重要作用的核（后 - i）呼吸节奏的阶段以及在诸如发声和轻便之类的行为任务中 KFN的I Post-i驱动神经元的标志是他们关于NMDA受体活动的关键部门将神经元与许多其他中部中部中部中部中部区分开来，主要由AMPA受体激发介导的电流。来自上喉神经（SLN）的上升输入的部位，介导喉部内收肌反射和通过脑介质灰色（PAG）介导的发光链球的行为控制的输入是吗？集成在系统级别，以及由于损害的形式而导致的这些KFN神经元的过度活动 NMDA和BDNF受体依赖性突触塑料可能是行为诱发的喉痉挛的基础在Celular水平的RTT中，我们将检查IGF-1处理是否占在RTT的突变小鼠模型中清醒期间的呼吸表型。通过组装SLN输入来调节喉部内收肌的反射，以调节喉部的驱动神经元。在AIM 2中进行有或没有IGF-1治疗的突变体和野生型小鼠调节喉部的神经元通过这些动物中降下的PAG输入引起的导管反应。这些多感官集成数据将受到新颖的多尺度指纹测定的验证 pag-kfn laryngeal后I的神经元的功能连通性通过匹配一组定时，响应和细胞特异性标记，这些途径共享神经元。与前图结合延髓中的运动神经元。目的是绘制反射和镜头的波动控制涉及的中央电路健康和RTT的结果。呼吸与中央呼吸暂停作为可能的结果指标，以评估RTT患者的药物trag tr症治疗。