Brainstem mechanism underlying recurrent laryngospasm in Rett syndrome

Rett综合征复发性喉痉挛的脑干机制

• 批准号: 9175063
• 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
• 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/9175063
• 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; Reaction Time; 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; 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; vocalization

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.

清醒期间的重复呼吸暂停是一种基本的且潜在的威胁生命的RETT综合征症状 （RTT）。最近的一项临床试验表明，RTT患者中的许多呼吸暂停事件都是由行为上的 引起的非自愿呼吸（停止到期）而不是化学反射介导的中央呼吸暂停 （戒断灵感），并通过IGF-1药物治疗改善这种呼吸距离 恢复这些患者的BDNF信号传导。来自RTT突变小鼠模型的新兴证据表明 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 加法过度活跃）是由神经元在Köllliker-Fuse Nucus（KFN）的灵敏度引起的，pontin 在启发性期间控制喉部加法活性方面起着重要作用的细胞核（后 i）呼吸节奏的阶段以及在诸如发声和呼吸之类的行为任务中。一个 KFN中I后驱动神经元的标志是他们对NMDA受体活动的关键依赖 这将这些神经元与许多其他中枢神经元区分开来，这些神经元主要由AMPA接收器激发 - 介导的电流。在此提案中要检验的一个中心假设是kfn i驱动神经元是 来自上喉神经（SLN）的上升输入的位置 通过中脑周长灰色（PAG）介导的发光闭合行为控制的输入是 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接收器依赖性突触可塑性可能是行为诱发的喉部 在RTT处于细胞水平。作为基线（AIM 0），我们将检查IGF-1治疗是否可以改善 在RTT的突变小鼠模型中清醒期间的呼吸表型。 AIM 1将调查角色 kfn后I驱动神经元在调节通过升高的SLN输入引起的喉加加法反射 有或没有IGF-1治疗的突变体和野生型小鼠。在AIM 2中，我们将调查这些KFN的作用 神经元在调节这些动物中降低PAG输入引起的喉加工反应时。 这些多感官集成数据将经过一种新型的多尺度指纹测定，以验证 pag-kfn laryngeal i的神经元的功能连通性 通过匹配一组定时，响应和蜂窝特异性标记，这些途径由这些途径匹配 神经元。在AIM 3中，我们将采用并置标签/单个单元记录的多标签技术 结合顺行轴突跟踪，以从PAG和KFN映射收敛的输入到喉剂加法器 延髓的运动神经元。通过比较来自突变小鼠和野生型小鼠的这些结构功能数据，我们 目的是绘制参与反射协调和对发光闭合的自愿控制的中央电路 健康和RTT。该项目的结果将为正在进行和将来的临床试验提供评估的有效性 呼吸与中央呼吸暂停作为评估RTT患者药物治疗的可能结果指标。