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

项目摘要 与大多数运动行为不同，呼吸是在自动控制下，以确保维持体内平衡。这 呼吸活动的重要生理调节一直是呼吸控制的主要焦点 领域然而，在清醒的动物中，呼吸也会因行为和情绪的变化而有条件地改变， 使其高度动态化。这些依赖于状态的控制机制如何允许呼吸有条件地 与其潜在的生理调节分离仍然远未被很好地理解。在小鼠中， 自动呼吸控制和依赖状态的呼吸控制之间的区别， 这是清醒状态所独有的。因此，允许细胞类型特异性操作的转基因小鼠系是 这是一个很好的模型系统，可以解开将呼吸与 行为和情绪脑桥背侧臂旁核是许多情感神经元的整合中枢， 状态和行为，包括呼吸，以及其组成神经元在基因上也是相似的。 表达和轴突投射。该项目的特点是一种新的神经回路在外侧臂旁 一个核团（PBL），在清醒状态下发挥有效的呼吸控制作用，并能快速驱动 呼吸频率不能通过已知的呼吸节律产生机制实现。通过组合 现代交叉转基因，病毒载体和光遗传学工具，拟议的实验探索如何 当这个PBL回路控制快速呼吸时（目标1）;识别这些回路下游的大脑区域 神经元介导其有效的呼吸作用和状态依赖性（目标2）;并测试是否 呼吸节律产生的典型延髓部位，前B细胞tzinger复合体，也是呼吸节律产生的关键。 产生表征所述清醒状态的所述快速且动态的呼吸模式（目标3）。这三 交互式目标将提供对网络级和蜂窝级机制的全面理解 介导了PBL回路前所未有的状态依赖性呼吸控制。一般来说，这 该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绪相结合的基本科学理解。见解 从这些研究中也可能有重要的意义，了解病理相关的 呼吸急促失调，如过度换气综合征和恐慌症。

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.