Unraveling respiratory rhythm generation in the medullary network

解开髓质网络中呼吸节律的产生

• 批准号: 10447726
• 负责人: Jan M. Ramirez
• 金额: $ 66.21万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447726
• 关键词: Animals; Brain; Brain Stem; Breathing; Calcium; Characteristics; Complex; Conflict (Psychology); Disease; Electrophysiology (science); Embryo; Epidemic; Equilibrium; Failure; Frequencies; Funding; Generations; Grant; Health; Image; In Vitro; Lead; Lesion; Maps; Metabolic; Modeling; Morbidity - disease rate; Motor Activity; Mus; Network-based; Neurons; Pathway Analysis; Pattern; Periodicity; Phase; Play; Pontine structure; Population; Regulation; Research; Respiration; Respiration Disorders; Role; Sensory; Sleep Apnea Syndromes; Slice; Spatial Distribution; Structure; Synapses; System; Testing; base; design; excitatory neuron; experimental study; expiration; in vitro activity; in vivo; inhibitory neuron; insight; mortality; network models; opioid epidemic; optogenetics; preBotzinger complex; respiratory; spatiotemporal; synaptic inhibition

PROJECT SUMMARY Breathing is vital for survival, and failure to breathe is fatal. This has become tragically evident in the context of the current opioid crisis. Breathing disturbances are also the cause of sleep apnea, which is another health issue of epidemic proportions. At the core of all these disturbances are neuronal networks located within the brainstem. Two of these networks, the preBötzinger complex (preBötC) and the parafacial respiratory group (pFRG) are thought to give rise to inspiration and active expiration, respectively. During the initial funding period of this grant, we identified a third excitatory microcircuit, the postinspiratory complex (PiCo), which gives rise to a third breathing phase: postinspiration – the expiratory phase that follows inspiration. Based on our discovery, we proposed the triple oscillator hypothesis: i.e. three excitatory microcircuits (preBötC, pFRG, PiCo) give rise to the three phases of breathing. However, the discovery of PiCo raised an important, unresolved issue: what is the role of the so-called Bötzinger complex (BötC), a fourth region that contains respiratory neurons, and that is located rostral of the preBötC? Here we test the overarching hypothesis that the preBötC is not a small microcircuit, as previously thought, but that this network forms a dynamically regulated column contiguous with the BötC. The extent of this column is dynamically regulated by synaptic inhibition, chemo- and mechanosensory afferents. The project tests this hypothesis in three specific aims: Aim 1 maps the extent of respiratory activity along the medullary column. We will use electrophysiological, calcium imaging and optogenetic approaches to characterize the neuronal discharge patterns within this column. Aim 2 investigates the cellular determinants that control the extent of this column using intracellular and optogenetic recordings. We specifically test the hypothesis that a balance between synaptic inhibition, and excitation regulates the regularity, frequency and spatial extent of the column. To conduct aims 1 and 2 we will employ horizontal brainstem slices that isolate the entire ventral medulla and that are amenable to a rigorous cellular and network analysis. Aim 3 explores the dynamic regulation of the column in alert and anesthetized in vivo animals. We test the hypothesis that vagal and chemosensory afferents play a critical role in regulating the spatial extent of this column by activating inhibitory neurons that are capable of shrinking and extending the inspiratory rhythmogenic network. The proposed research may lead to a better understanding of the fundamental question: how the brain generates rhythmic motor activity and how it integrates sensory information. Insights gained will also have important implications for understanding the cellular and systems level mechanisms underlying the mortality and morbidity associated with breathing disorders.

项目摘要 呼吸对生存至关重要，不能呼吸是致命的。这一点在以下背景下变得可悲地显而易见： 当前的鸦片危机呼吸障碍也是睡眠呼吸暂停的原因，这是另一种健康 流行病的比例问题。所有这些干扰的核心是位于大脑中的神经元网络。 脑干这些网络中的两个，preBötC复合体和旁面呼吸组 （pFRG）被认为分别引起吸气和主动呼气。在初始融资期间 在此期间，我们确定了第三个兴奋性微回路，吸气后复合体（皮科）， 上升到第三呼吸阶段：吸气后-吸气后的呼气阶段。基于我们 发现，我们提出了三重振荡器假说：即三个兴奋性微电路（preBötC，pFRG， 皮科）产生呼吸的三个阶段。然而，皮科的发现提出了一个重要的， 未解决的问题：所谓的Bötzinger复合体（BötC）的作用是什么？ 呼吸神经元，这是位于喙的preBötC？ 在这里，我们测试的首要假设，preBötC是不是一个小的微电路，如以前所认为的，但 这个网络形成了一个与BötC相邻的动态调节柱。此列的范围为 由突触抑制、化学和机械感觉传入动态调节。该项目测试了这一点 假设有三个具体目标：目标1绘制呼吸活动沿着髓柱的范围。我们 将使用电生理学，钙成像和光遗传学方法来表征神经元 在这一列的放电模式。目的2研究控制这种程度的细胞决定因素 柱使用细胞内和光遗传学记录。我们专门测试了一个假设， 在突触抑制和兴奋之间，调节列的规律性、频率和空间范围。 为了进行目标1和目标2，我们将采用水平脑干切片，分离整个腹侧延髓， 可以进行严格的细胞和网络分析目标3探讨了 在警觉和麻醉的体内动物中，我们验证了迷走神经和化学感受器 传入神经通过激活抑制性神经元， 能够收缩和伸展吸气节律网络。这项研究可能会导致 更好地理解基本问题：大脑如何产生有节奏的运动活动， 如何整合感官信息获得的见解也将对理解 与呼吸相关的死亡率和发病率的细胞和系统水平机制 紊乱