Dissecting neural circuits for breathing patterns

剖析呼吸模式的神经回路

基本信息

批准号：
10319313
负责人：
Peng Li
金额：
$ 42.07万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319313
关键词：
Ablation Acute Afferent Pathways Blood gas Brain Brain Death Brain region Breathing COVID-19 Calcium Carotid Body Characteristics Clinical Research Coughing Development Drug abuse Emotional Esthesia Foreign Bodies Foundations Functional disorder Future Ganglia Gastrin releasing peptide Gene Expression Genetic Heterogeneity Homeostasis Hypoxia In Situ Hybridization Interoception Irritants Knowledge Label Lung Mediating Medical Molecular Mus Neural Pathways Neuraxis Neurons Nucleus solitarius Organ Outcome Panic Disorder Pathologic Pathway interactions Pattern Peripheral Pharmacotherapy Phase Phobias Physiological Play Population Post-Traumatic Stress Disorders Process RNA Research Respiratory physiology Role Seizures Signal Transduction Sleep Apnea Syndromes Specificity Stimulus Sudden infant death syndrome Synapses Tachykinin Techniques Testing Viral Visceral Work base cognitive process effective therapy experimental study expiration in vivo nervous system disorder neural circuit neuromechanism novel novel therapeutics optogenetics particle relating to nervous system response sensory stimulus single molecule single-cell RNA sequencing transcriptome

项目摘要

Proposal Summary Breathing is a vital function constantly regulated by the interoceptive signals from the body, and breathing patterns are known to impact emotional and cognitive processes. Breathing patterns with essential pulmonary interoception functions, such as sighing and coughing, are relevant to many pathological conditions, including sleep apnea, sudden infant death syndrome, excessive coughing, COVID-19, and various nervous system disorders, such as panic disorder, phobias, post-traumatic stress disorder, drug abuse, and even brain death. Therefore, there is a critical need to identify the neural mechanisms underlying the interoceptive control of breathing and how they fail under pathological conditions, to develop more effective treatments to breathing abnormalities. Sighing is an augmented breath with a deep, double-size inspiration that is dramatically induced in hypoxia. In contrast, coughing is a protective breathing pattern with a characteristic enlarged expiration phase triggered by tussive agents exposed in the airways. However, the neural circuits underlying these essential and discrete breathing patterns and how the brain interprets and integrates these different interoceptive sensory stimuli are largely unknown. In our preliminary studies, we identified two neuronal populations with distinct gene expression, connectivity, neural activity, and function, in the nucleus of the solitary tract (NTS), the first relay center in the brain that receives interoceptive afferent signals from the visceral organs. These neurons respectively mediate hypoxia induced sighing and tussive challenge induced coughing, two discrete breathing patterns associated with different interoceptive signals. Based on these findings, we propose to test our hypothesis that these two distinct NTS neurons are the key nodes in two segregated interoceptive neural circuits for controlling discrete breathing patterns and for representing these internal states, by receiving distinct afferent inputs and differently activating downstream brain circuits. We will integrate state-of-the-art techniques, including genetic targeting, viral-based neural circuit tracing, activity dependent neuron targeting, optogenetics and chemogenetics, genetic ablation, respiratory physiology, single molecule fluorescent RNA in situ hybridization, and in vivo calcium recording, to identify the neural circuits and pathways underlying these two interoceptive processes in vivo in freely moving mice. By focusing on these two distinct NTS neuron populations and neural circuits, we will delineate the distinct interoceptive afferent pathways from the periphery to the brain, identify the brain regions that mediate sighing and coughing, and define the higher brain regions for interpreting and integrating these distinct interoceptive signals. This work will provide novel molecular and cellular specificity for the interoceptive neural circuits for sighing and coughing respectively, and reveal the organizing principles of the NTS and the brain to ascertain differential interoceptive signals and inputs through the vagal afferent pathways. Furthermore, the proposed studies will also build the foundation for future clinical studies on the role of interoception in neuropathological conditions.

提案摘要呼吸是一种重要的功能，一直受到身体的互感信号的调节，呼吸模式已知会影响情绪和认知过程。具有必要肺间断功能（例如叹气和咳嗽）的呼吸模式与许多病理状况有关，包括睡眠呼吸暂停，猝死综合症，过度咳嗽，Covid-19以及各种神经系统疾病，例如恐慌症，恐慌症，恐慌症，恐慌症，恐惧症，恐慌症，创伤后应激障碍，药物滥用甚至脑死亡。因此，迫切需要确定对呼吸的互感控制及其在病理条件下如何失败的神经机制，以开发更有效的治疗方法来呼吸异常。叹气是一种增强的呼吸，具有深厚的双重灵感，在缺氧中急剧引起。相比之下，咳嗽是一种保护性呼吸模式，其特征性扩大的到期阶段是由暴露在气道中暴露的打击剂触发的。但是，这些基本和离散的呼吸模式以及大脑如何解释和整合这些不同的感受性的感觉刺激是未知的。在我们的初步研究中，我们确定了两个神经元种群，具有不同基因表达，连通性，神经活动和功能，在孤立区（NTS）的细胞核中，这是大脑中第一个接收感受性传入信号的大脑中心中心，从。这些神经元分别介导缺氧引起的叹息和打击挑战引起的咳嗽，这两种与不同感受性信号相关的离散呼吸模式。基于这些发现，我们建议测试我们的假设，即这两个不同的NTS神经元是两个隔离的互感神经回路中的关键节点，用于控制离散的呼吸模式，并通过接收不同的传入输入来代表这些内部状态，并通过不同。我们将整合最先进的技术，包括遗传靶向，基于病毒的神经回路追踪，依赖性神经元靶向，光遗传学和化学遗传学，遗传学消融，呼吸生理学，单分子荧光RNA原位杂交以及体内钙化记录，以确定在自由移动的小鼠中体内这两个间断过程的神经回路和途径。通过专注于这两个不同的NTS神经元种群和神经回路，我们将描述从周围到大脑的独特感受性的传入途径，确定介导叹息和咳嗽的大脑区域，并定义较高的大脑区域以解释和整合这些较高的大脑区域互感信号。这项工作将为分别为叹息和咳嗽的间断神经回路提供新的分子和细胞特异性，并揭示NTS和大脑的组织原理，以确定通过迷走神经传入途径的差异性互感信号和输入。此外，拟议的研究还将为未来的临床研究奠定基础，以了解神经病理条件中的互动作用。