Functional Dissection of Medullary Respiratory Microcircuits

髓质呼吸微电路的功能解剖

基本信息

批准号：
9241447
负责人：
JACK L FELDMAN
金额：
$ 48.23万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241447
关键词：
Address Affect Amyotrophic Lateral Sclerosis Apnea Applications Grants Area Automobile Driving Behavior Birth Blood gas Bombesin Bombesin Receptor Brain Brain Stem Breathing Cell Nucleus Cessation of life Collaborations Complex Consequentialism Disease Dissection Elements Emotions Exercise Failure Gases Gastrin releasing peptide Generations Glutamates Grant Health Hour Human Hyperventilation Implant In Vitro Laboratories Life Ligands Light Mammals Mediating Metabolic Metabolism Methodology Methods Movement Multiple System Atrophy Mus Muscle Names Nature Nervous System Physiology Nervous system structure Neurodegenerative Disorders Neurons Nucleus solitarius Opsin Optical Methods Pacemakers Parkinson Disease Pathologic Pattern Peptides Periodicity Physiologic pulse Population Population Group Problem Solving Progress Reports Public Health Respiration Respiration Disorders Respiratory Muscles Respiratory physiology Rett Syndrome Rodent Role Site Sleep Sleep Apnea Syndromes Structure Sudden infant death syndrome Syndrome System Testing Trapezoid bone structure Viral Volition central pattern generator congenital central hypoventilation syndrome designer receptors exclusively activated by designer drugs experimental study in vivo insight interest neural circuit neuromechanism neuromedin B neuron loss novel optical fiber optogenetics photolysis preBotzinger complex premature public health relevance receptor respiratory

项目摘要

DESCRIPTION (provided by applicant): Delineating neurons that underlie complex behaviors is of fundamental interest. We will exploit a powerful method, optogenetics, for inducing extremely rapid changes in excitability of genetically targeted neurons to affect a robust and vita ongoing regulatory behavior in mice, i.e., breathing. Breathing is a remarkable behavior that mediates gas exchange to support metabolism and regulate pH. A reliable and robust rhythmic pattern of respiratory muscle activity is essential for breathing in mammals. Failure to maintain a normal breathing pattern in humans suffering from sleep apnea, apnea of prematurity, congenital central hypoventilation syndrome, hyperventilation syndrome, Rett syndrome, and perhaps Sudden Infant Death Syndrome, leads to serious adverse health consequences, even death. Various neurodegenerative diseases, such as Parkinson's disease, multiple systems atrophy and amyotrophic lateral sclerosis, are associated with sleep disordered breathing that we hypothesize results from the loss of neurons in brain areas controlling respiration. If breathing is to be understood in normal and in pathological conditions, the mechanisms for respiratory central pattern generation must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preBötzinger Complex and the retro trapezoid nucleus/parafacial respiratory group. Using a viral delivery system, we will express genetically encoded opsins in several key subpopulations of neurons in these regions. A totally unexplored aspect of the organization of the respiratory central pattern generator is the actions of these critical populations at their axonal target sites. Rapid changes in excitability of these neurons by administration of light pulses delivered via an optical fiber implanted in these sites i mice should produce noticeable, even profound perturbations in breathing. Analysis of such perturbations will provide an extraordinary window into understanding mechanisms of respiratory rhythm and pattern generation.

描述（由适用提供）：划定基于复杂行为的神经元具有基本利益。我们将探索一种强大的方法，即光遗传学，以引起遗传靶向神经元的激动人心的极快变化，以影响小鼠（即呼吸）的强大而持续的调节行为。呼吸是一种非凡的行为，可介导气体交换以支持新陈代谢并调节pH。呼吸肌活动的可靠和强大的节奏模式对于哺乳动物的呼吸至关重要。无法保持患有睡眠呼吸暂停，早产呼吸暂停，先天性中央中性疾病综合征，高换气综合征，RETT综合征以及可能猝死综合症的人类呼吸模式正常，甚至导致严重的不良健康后果，甚至导致死亡。各种神经退行性疾病，例如帕金森氏病，多个系统萎缩和肌萎缩性侧索硬化症，与睡眠无序的呼吸有关，我们假设由控制呼吸的大脑区域中神经元的丧失导致。如果在正常和病理条件下要了解呼吸，则必须揭示呼吸中心模式产生的机制。我们专注于对正常呼吸模式的产生至关重要的两个大脑部位，即prebötzinger络合物和梯形核核/偏瘫呼吸组。使用病毒输送系统，我们将在这些区域的几个关键神经元亚群中表达一般编码的Opsins。呼吸中心模式发生器组织的一个完全出乎意料的方面是这些关键人群在其轴突目标部位的作用。通过在这些部位植入的光纤维传递的光脉冲通过给予我小鼠的光纤维传递的光脉冲来快速变化。对这种扰动的分析将为理解呼吸节奏和模式产生的机制提供一个非凡的窗口。