Unraveling a parabrachial circuit for the state-dependent control of rapid breathing

解开臂旁回路以实现快速呼吸的状态依赖控制

• 批准号: 10564191
• 负责人: Nathan Andrew Baertsch
• 金额: $ 74.61万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564191
• 关键词: Acceleration; Affective; Anatomy; Anesthesia procedures; Animals; Anxiety; Automobile Driving; Axon; Behavior; Behavioral; Biological Models; Brain; Brain region; Breathing; Bypass; Characteristics; Chemoreceptors; Complex; Data; Dependence; Dissociation; Dorsal; Emotional; Emotions; Ensure; Etiology; Feedback; Frequencies; Fright; Gene Expression; Generations; Genetic; Homeostasis; Hyperventilation; Lateral; Link; Maps; Mediating; Modernization; Mus; Neurons; Panic Disorder; Pathology; Pathway interactions; Pattern; Periodicity; Physiological; Pontine structure; Preparation; Prosencephalon; Regulation; Research; Respiration; Respiratory physiology; Rest; Role; Site; Sleep; Syndrome; Techniques; Testing; Transgenic Mice; Transgenic Organisms; Viral Vector; awake; cell type; emotion regulation; experimental study; flexibility; insight; mechanotransduction; motor behavior; neural; neural circuit; neuromechanism; novel; optogenetics; parabrachial nucleus; preBotzinger complex; preservation; respiratory; response; tool; vocalization

PROJECT SUMMARY Breathing, unlike most motor behaviors, is under automatic control to ensure homeostasis is maintained. This vital physiological regulation of respiratory activity has been the predominant focus of the control of breathing field. However, in awake animals, breathing is also conditionally modified by changes in behavior and emotion, making it highly dynamic. How these state-dependent control mechanisms allow breathing to conditionally dissociate from its underlying physiological regulation remains far less well understood. In mice, this distinction between automatic and state-dependent respiratory control is exemplified by the rapid breathing frequencies that are unique to the awake state. Thus, transgenic mouse lines that allow cell-type-specific manipulations are an excellent model system to unravel the neural circuits and mechanisms that integrate breathing with behavior and emotion. The parabrachial nucleus of the dorsal pons is an integrative hub for many affective states and behaviors, including breathing, and its constituent neurons are similarly diverse in their gene expression and axonal projections. This project characterizes a novel neural circuit in the lateral parabrachial nucleus (PBL) that exerts potent respiratory control specifically in the awake state and can drive rapid breathing frequencies not achievable by known mechanisms of respiratory rhythm generation. By combining modern intersectional transgenic, viral vector, and optogenetic tools, the proposed experiments explore how and when this PBL circuit controls rapid breathing (Aim 1); identify the brain regions downstream of these neurons that mediate their potent respiratory effects and state-dependence (Aim 2); and test whether the canonical medullary site for respiratory rhythm generation, the preBӧtzinger Complex, is also critical for generating the rapid and dynamic breathing patterns that characterize the awake state (Aim 3). These three interactive Aims will provide a comprehensive understanding of the network- and cellular-level mechanisms that mediate the unprecedented state-dependent respiratory control by this PBL circuit. More generally, this project will establish a framework for understanding the conditional control of breathing and significantly expand our basic scientific understanding of how breathing is integrated with behavior and emotion. Insights from these studies may also have significant implications for understanding pathologies associated with dysregulated rapid breathing such as hyperventilation syndrome and panic disorders.

项目摘要 与大多数运动行为不同，呼吸是自动控制的，以确保保持体内平衡。这 呼吸活动的重要物理调节一直是呼吸控制的主要重点 场地。但是，在清醒的动物中，呼吸也通过行为和情感的变化有条件地改变 使其高度动态。这些依赖状态的控制机制如何使呼吸有条件地 与基本的物理调节分离的理解远远不够。在小鼠中，这种区别 快速呼吸频率体现了自动和状态依赖性呼吸控制之间 这是清醒状态所独有的。那就是允许细胞类型特异性操作的转基因小鼠系 一个出色的模型系统，可以揭示将呼吸与呼吸整合的神经回路和机制 行为和情感。背核的副核核是许多情感的综合枢纽 包括呼吸在内的状态和行为，其成分神经元在其基因上同样是潜水员 表达和轴突项目。该项目描述了侧面瘫痪的新神经回路 核（PBL）在清醒状态下专门执行潜在的呼吸控制，可以快速推动 通过已知的呼吸节奏产生机制无法实现的呼吸频率。通过组合 现代交易转基因，病毒载体和光遗传学工具，拟议的实验探索了如何 当该PBL电路控制快速呼吸时（AIM 1）；确定这些下游的大脑区域 介导其潜在的呼吸作用和状态依赖性的神经元（AIM 2）；并测试是否 用于呼吸节律产生的典型髓质位点，PrebβTzinger络合物，对于 产生表征清醒状态的快速而动态的呼吸模式（AIM 3）。这三个 交互式目标将对网络和蜂窝级机制提供全面的理解 通过该PBL电路介导前所未有的状态依赖性呼吸控制。更普遍地，这 项目将建立一个框架，以了解呼吸的条件控制 扩展我们对呼吸如何与行为和情感融合在一起的基本科学理解。见解 从这些研究中也可能对了解与 快速呼吸失调，例如换气综合征和恐慌症。