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（由申请人提供）：描绘复杂行为背后的神经元具有根本意义，我们将利用一种强大的方法，即光遗传学，来诱导基因靶向神经元的兴奋性发生极快的变化，从而影响小鼠的稳健和持续的调节行为。即呼吸是一种介导气体交换以支持新陈代谢和调节 pH 的显着行为，呼吸肌活动的可靠和稳健的节律模式对于维持哺乳动物的呼吸至关重要。患有睡眠呼吸暂停、早产儿呼吸暂停、先天性中枢通气不足综合征、通气过度综合征、雷特综合征，甚至婴儿猝死综合征的人类的正常呼吸模式会导致严重的不良健康后果，甚至导致死亡等各种神经退行性疾病。帕金森病如果呼吸为了在正常和病理条件下理解呼吸中枢模式的产生机制，我们必须重点关注对于正常呼吸模式的产生至关重要的两个大脑部位，即前波辛格复合体和后梯形核/面旁呼吸组。在病毒传递系统中，我们将在这些区域的几个关键神经元亚群中表达基因编码的视蛋白，呼吸中枢模式发生器组织的一个完全未被探索的方面是这些关键群体在其轴突目标位点的活动。通过植入小鼠这些部位的光纤传递的光脉冲，这些神经元的兴奋性会发生快速变化，从而产生明显的、甚至是深刻的呼吸扰动。对这种扰动的分析将为理解呼吸节律和模式的机制提供一个非凡的窗口。一代。