Neural control of expiratory duration in mammalian respiratory rhythm generation

哺乳动物呼吸节律产生中呼气持续时间的神经控制

• 批准号: 7683972
• 负责人: Kaiwen Kam
• 金额: $ 1.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683972
• 关键词: Accounting; Amyotrophic Lateral Sclerosis; Area; Behavior; Birth; Brain; Brain Stem; Breathing; Calcium; Cessation of life; Complex; Disease; Dyes; Elements; Exercise; Failure; Frequencies; Gases; Generations; Grant; Health; Hibernation; Homeostasis; Human; Length; Life; Light; Mediating; Metabolic; Metabolism; Modeling; Monitor; Multiple System Atrophy; Nervous system structure; Neurodegenerative Disorders; Neurons; Pacemakers; Parkinson Disease; Phase; Play; Respiration; Rett Syndrome; Role; Sleep; Sleep Apnea Syndromes; Sudden infant death syndrome; System; Testing; Time; Vertebrates; expiration; in vitro Model; neural circuit; neuromechanism; neuron loss; neuroregulation; optical imaging; preBotzinger complex; public health relevance; research study; respiratory; response

DESCRIPTION (provided by applicant): Breathing is a remarkable behavior in vertebrates that mediates gas exchange to support metabolism. Failure to maintain a normal breathing rhythm in humans suffering from disorders such as sleep apnea, 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 may result from the specific loss of neurons in brain areas controlling respiration. Control of breathing lies in the brain stem, where the preBotzinger Complex is both necessary and sufficient to generate respiratory rhythm. preBotzinger Complex bursting produces inspiration, while the interburst interval determines expiratory duration. Remarkably, changes in excitability can produce a fifty-fold range of frequencies by specifically tuning the length of the interburst interval. To determine the mechanisms underlying the dynamic modulation of interburst interval by excitability in the preBotzinger Complex, I propose 3 SPECIFIC AIMS-exploiting validated in vitro models of breathing-that will advance our understanding of the neural control of expiratory duration in respiratory rhythmogenesis. AIM 1: While neither pacemakers nor inhibition are essential for rhythm generation in the preBotzinger Complex, these elements may1 play a role in the effects of excitability on interburst interval. I will determine whether blockers of pacemaker currents or inhibition change the response curves. AIM 2: To determine whether the recruitment of active neurons defines the interburst interval and accounts for the cascade of excitation postulated by the group-pacemaker hypothesis, I will monitor the spontaneous activity of preBotzinger Complex neurons using optical imaging of calcium sensitive dyes. AIM 3: The preBotzinger Complex may employ different mechanisms for rhythm generation depending on excitability. I will investigate whether different mechanisms control expiratory duration at high and low frequencies by comparing temporally evolving intrinsic conductances at multiple time points during the interburst interval. These experiments will elucidate the organization and behavior of a fundamental rhythmic neural circuit, necessary for life. Public health relevance - In humans, continuous breathing from birth is essential to life and requires that the nervous system generate a reliable and robust rhythm. The proposed studies will significantly advance our understanding of the neural mechanisms underlying generation of respiratory rhythm and shed light on human disorders of breathing:

描述（由申请人提供）：呼吸是脊椎动物的一种重要行为，通过调节气体交换来支持新陈代谢。患有睡眠呼吸暂停、雷特综合症和婴儿猝死综合症等疾病的人无法维持正常的呼吸节奏，会导致严重的不良健康后果，甚至死亡。各种神经退行性疾病，如帕金森病、多系统萎缩和肌萎缩侧索硬化症都与睡眠呼吸障碍有关，这可能是由控制呼吸的大脑区域的神经元特异性丧失引起的。呼吸控制在脑干，在脑干，波青格前复合体是产生呼吸节奏的必要和充分条件。预波青格复合体的爆发产生吸气，而爆发间隔决定了呼气的持续时间。值得注意的是，兴奋性的变化可以通过特别调整爆发间隔的长度来产生50倍的频率范围。为了确定preBotzinger复合体的兴奋性对发作间隔的动态调节机制，我提出了3个特定的目标——利用经过验证的体外呼吸模型——这将促进我们对呼吸节律发生中呼气持续时间的神经控制的理解。目的1：虽然起搏器和抑制对波青格前复合体的节律产生都不是必需的，但这些因素可能在兴奋性对猝发间期的影响中起作用。我将确定起搏器电流阻滞剂或抑制剂是否会改变反应曲线。目的2：为了确定活跃神经元的募集是否定义了突发间期，并解释了群起搏器假说所假设的级联兴奋，我将使用钙敏感染料的光学成像来监测preBotzinger复合体神经元的自发活动。目的3：根据兴奋性，pre - botzinger复合体可能采用不同的节律产生机制。我将通过比较爆发间隔期间多个时间点的随时间变化的内在电导来研究是否不同的机制控制高频和低频下的呼气持续时间。这些实验将阐明生命所必需的基本节律性神经回路的组织和行为。公共卫生相关性-对人类来说，从出生开始持续呼吸对生命至关重要，并要求神经系统产生可靠而稳健的节奏。所提出的研究将大大促进我们对呼吸节律产生的神经机制的理解，并阐明人类呼吸障碍：