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: 7481644
• 负责人: Kaiwen Kam
• 金额: $ 4.68万
• 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/7481644
• 关键词: Accounting; Amyotrophic Lateral Sclerosis; Area; Behavior; Birth; Brain; Brain Stem; Breathing; Calcium; Cessation of life; Complex; Condition; 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; Numbers; Pacemakers; Parkinson Disease; Phase; Play; Public Health; Range; 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; 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）：呼吸是脊椎动物介导气体交换以支持新陈代谢的显著行为。在患有诸如睡眠呼吸暂停、雷特综合征以及可能的婴儿猝死综合征的疾病的人中，不能维持正常的呼吸节律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，如帕金森氏病、多系统萎缩和肌萎缩性侧索硬化症与睡眠呼吸障碍有关，这可能是由于控制呼吸的大脑区域中的神经元的特定损失。控制呼吸的是脑干，这里的前博青格复合体是产生呼吸节律的必要和充分条件。preBotzinger复合爆发产生吸气，而爆发间期决定呼气持续时间。值得注意的是，兴奋性的变化可以通过专门调整爆发间隔的长度来产生50倍的频率范围。为了确定在preBotzinger复杂的兴奋性的爆发间期的动态调制的机制，我提出了3个具体的目的，利用有效的体外模型的呼吸，这将促进我们的理解呼吸节律的神经控制呼气持续时间。目标1：虽然起搏器和抑制都不是前Botzinger复合体中节律产生的必要因素，但这些因素可能在兴奋性对爆发间期的影响中发挥作用。我将确定起搏电流的阻断剂或抑制剂是否会改变反应曲线。目标2：要确定是否招聘的活跃神经元定义的爆发间期和帐户的级联兴奋假设的群起搏器假说，我将监测自发活动的preBotzinger复杂的神经元使用钙敏感染料的光学成像。目的3：前波青格复合体可能根据兴奋性采用不同的节律产生机制。我将调查是否不同的机制控制呼气持续时间在高和低频率通过比较时间演变的内在电导在多个时间点在爆发间期。这些实验将阐明生命所必需的基本节律神经回路的组织和行为。公共卫生相关性-在人类中，从出生开始的连续呼吸对生命至关重要，需要神经系统产生可靠和强大的节奏。拟议的研究将大大推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：