CRCNS: Discovering the Neural Mechanisms of Breathing Rhythms - Eupnea and Sigh

CRCNS：发现呼吸节律的神经机制 - 平静和叹息

基本信息

批准号：
10220857
负责人：
Gregory Douglas Conradi Smith
金额：
$ 16.37万
依托单位：
COLLEGE OF WILLIAM AND MARY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-09 至 2023-01-31
项目状态：
已结题

项目摘要

This project aims to explain the neural mechanisms of breathing. Breathing in mammals consists of eupnea, periodic inspiratory pumping movements that draw air into the lungs for gas exchange, and sighs, larger less frequent breaths that periodically reinflate gas-exchange air sacs or express emotion, Eupnea and sigh rhythms are well coordinated and originate from the same set of brainstem neurons, but their underlying neural mechanisms remain incompletely understood. Using computational simulation and experimental tests of model predictions, this project will elucidate the mechanisms for eupnea and sigh rhythms in three SPECIFIC AIMS. In Aim 1, the project will ascertain the excitatory microcircuit dynamics for eupnea rhythm. An existing model of eupnea rhythm will be made mathematically tractable for geometric and bifurcation analyses, and its exclusive focus on synaptic dynamics will be augmented with biophysically realistic somatic membrane properties, In Aim 2, the project will explore the biochemical oscillatory mechanisms that give rise to sigh rhythm by developing and contrasting models of metabotropic signaling and intracellular Ca2+ oscillations that generate sigh-like network rhythm, In Aim 3, the project will examine the synaptic mechanisms that couple and coordinate the eupnea and sigh rhythms. Experiments will determine the synaptic transmission that coordinates eupnea and sigh, which will then constrain the models from Aims 1 and 2. This project will yield two deliverables of high intellectual merit: 1) an explanation of the cellular and synaptic mechanisms of eupnea- and sigh-related breathing rhythms, and ii) a biophysically realistic model for the core microcircuit that drives inspiratory breathing movements, both eupnea and sigh, suitable for inclusion within comprehensive models of the full behavior (e.g., with more motor phases and sensory feedback). Because rhythms are a ubiquitous aspect of brain function, the rhythmogenic mechanisms of breathing are of broad interest. This project will provide new knowledge regarding the cellular and synaptic neural origins of breathing that will inform the treatment and prevention of respiratory neuropathologies that afflict persons of all ages. The project will support STEM training of Ph.D. students and undergraduates, a thriving biomathematics consortium at William & Mary, and a summer internship program for public high schools, RELEVANCE (See instructions): Breathing consists of eupnea, regular breaths that pump oxygen into the lungs for gas exchange, and sighs, larger but less frequent breaths that reinflate gas-exchange air sacs or express emotion. This project applies mathematical models and experiments to explain how the mammalian brainstem generates breathing rhythms: eupnea and sigh. This knowledge will inform the treatment and prevention of respiratory neuropathologies that afflict persons of all ages from 'premies' to the elderly.

该项目旨在解释呼吸的神经机制。哺乳动物的呼吸包括 Eupnea，定期的吸气动作运动，将空气吸入肺部以进行天然气交换，并叹了口气，更大的频率频繁呼吸，会定期重新充实气体囊或表达情绪，Eupnea 叹息的节奏是很好的协调，起源于同一组脑干神经元，但它们的潜在的神经机制仍未完全理解。使用计算模拟和模型预测的实验测试，该项目将阐明Eupnea和叹息的机制三个特定目标的节奏。在AIM 1中，该项目将确定EUPNEA节奏的兴奋性微电路动力学。现有 EUPNEA节奏的模型将在数学上用于几何和分叉分析，并且可以使它的独家关注对突触动态的专注将通过生物物理上逼真的体膜增强在AIM 2中，该项目将探索引起叹息的生化振荡机制通过开发和对比的代谢信号传导和细胞内CA2+振荡模型来节奏在AIM 3中产生类似叹息的网络节奏，该项目将检查突触机制夫妇并协调Eupnea和叹息节奏。实验将确定突触传播这会协调Eupnea和叹息，然后将限制AIM 1和2的模型。该项目将产生两个高知名度的可交付成果：1）蜂窝和突触的解释 EUPNEA和叹息相关的呼吸节奏的机制，以及II）一种生物物理上现实的模型驱动鼓舞性呼吸运动的核心微电路，均适合纳入在全面行为的综合模型中（例如，具有更多的运动阶段和感觉反馈）。因为节奏是脑功能无处不在的方面，所以呼吸的节奏机制是广泛关注。该项目将提供有关细胞和突触神经起源的新知识呼吸将为呼吸神经病理学的治疗和预防呼吸而痛苦各个年龄段。该项目将支持博士学位的STEM培训。学生和本科生，一个繁荣的 William＆Mary的生物制作联盟，以及公立高中的暑期实习计划，相关性（请参阅说明）：呼吸由eupnea组成，定期呼吸将氧气泵入肺部以进行气体交换，以及叹息，更大但频繁的呼吸不足，可以重新充实气囊或表达情绪。这个项目应用数学模型和实验来解释哺乳动物脑干如何产生呼吸节奏：Eupnea和叹息。这些知识将为呼吸道治疗和预防提供信息神经病理学，使各个年龄段的人从“首映”到老年人。