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

该项目旨在解释呼吸的神经机制。哺乳动物的呼吸包括 正常呼吸、将空气吸入肺部进行气体交换的周期性吸气泵送运动，以及叹气， 周期性地使气体交换气囊再膨胀或表达情感的较大的较不频繁的呼吸，正常呼吸 和叹息的节奏是很好的协调，并起源于同一组脑干神经元，但他们的 潜在的神经机制仍然不完全清楚。使用计算机模拟和 模型预测的实验测试，本项目将阐明eupnea和sigh的机制 三个具体目标的节奏。 在目标1中，该项目将确定正常呼吸节律的兴奋性微回路动力学。现有 将使正常呼吸节律的模型在数学上易于进行几何和分叉分析， 它对突触动力学的独特关注将通过生物病理学上真实的体细胞膜来增强 在目标2中，该项目将探索引起叹息的生化振荡机制。 通过开发和对比代谢型信号传导和细胞内Ca2+振荡模型， 在目标3中，该项目将研究产生类似叹息的网络节律的突触机制， 耦合并协调正常呼吸和叹息节律。实验将确定突触传递 它协调正常呼吸和叹气，然后将约束目标1和2的模型。 这个项目将产生两个高智力价值的交付成果：1）解释细胞和突触 正常呼吸和叹气相关的呼吸节律的机制，以及ii）用于呼吸节律的生物病理学现实模型。 驱动吸气呼吸运动（正常呼吸和叹气）的核心微电路，适合于包含 在完整行为的综合模型内（例如，具有更多的运动相位和感觉反馈）。 因为节奏是大脑功能的一个普遍存在的方面，所以呼吸的节奏发生机制是 广泛的兴趣。这个项目将提供关于细胞和突触神经起源的新知识 呼吸，将告知治疗和预防呼吸神经病变，折磨人 所有年龄段的人。该项目将支持博士的STEM培训。学生和本科生，一个蓬勃发展的 威廉和玛丽的生物数学联盟，以及公立高中的暑期实习计划， 相关性（参见说明）： 呼吸包括正常呼吸，有规律的呼吸将氧气泵入肺部进行气体交换， 叹息，更大但不太频繁的呼吸，使气体交换气囊重新膨胀或表达情感。这个项目 运用数学模型和实验来解释哺乳动物的脑干是如何产生 呼吸节律：正常呼吸和叹息。这些知识将为呼吸道疾病的治疗和预防提供信息。 神经病理学折磨着从“早产儿”到老年人的所有年龄段的人。

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.