Neuroglial interactions underlying the generation of the sigh

叹息产生背后的神经胶质细胞相互作用

• 批准号: 10630173
• 负责人: Jan M. Ramirez
• 金额: $ 80.43万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630173
• 关键词: Alveolar; Apnea; Arousal; Astrocytes; Atelectasis; Behavior; Brain Stem; Breathing; Calcium; Calcium Oscillations; Characteristics; Complement; Data; Failure; Frequencies; Generations; Glutamates; Grant; Image; In Vitro; Link; Membrane; Metabotropic Glutamate Receptors; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; Neuroglia; Neurons; Periodicity; Physiological; Preparation; Property; Q-Type Calcium Channels; Receptor Activation; Recurrence; Refractory; Role; Slice; Sodium; Spatial Distribution; Sudden infant death syndrome; Synapses; Synaptic Transmission; Testing; Viral Vector; beta-adrenergic receptor; excitatory neuron; extracellular; in vivo; inhibitory neuron; insight; neuroregulation; optogenetics; pharmacologic; postsynaptic; preBotzinger complex; presynaptic; prevent; pulmonary function; receptor; respiratory; tool; uptake

PROJECT SUMMARY Sighs are critical for survival. They maintain normal lung functions by preventing atelectasis. Moreover, sighs have also been implicated in arousal, and failure to sigh has been associated with Sudden Infant Death Syndrome. The Ramirez lab has demonstrated that sighs are generated within the preBötzinger complex in the ventrolateral medulla. Indeed, the same neurons that generate eupneic inspiratory rhythmic activity seem to generate also sighs. This leads to an important, yet unresolved puzzle: How can the same neuronal network generate two types of breathing rhythm with strikingly different timing characteristics? The eupneic inspiratory rhythm occurs at a frequency of 1-2 Hz, while sighs are generated in the range of several minutes. Here we test the hypothesis that sighs are generated by neuroglial interactions that involve purinergic and glutamatergic interactions between glia and neurons with specific intrinsic and synaptic properties. This hypothesis is tested in three specific aims: Aim 1 will characterize the glial properties critical for the generation of sighs. We will evaluate the pharmacological, and neuromodulatory properties of isolated glia, and glia embedded within the respiratory network, using calcium imaging and optogenetic tools. Aim 2 will characterize the specific neuronal properties that are critical for the generation of sighs. We will test the hypothesis that these neuronal properties involve P/Q-type calcium channel dependent synaptic transmission that is modulated by metabotropic glutamate receptors (mGluR8), as well as intrinsic membrane properties that involve the persistent sodium current that is modulated by muscarinic receptors and beta-adrenergic receptors. Aims 1 and 2 will be performed in in vitro slice preparations that are amenable to a rigorous cellular level analysis. These two aims are complemented by aim 3 in which we will implement our insights gained in vitro in an in vivo preparation that is also amenable to optogenetic manipulations. This grant will provide critical insights into the generation of the sigh. In addition, this project will provide fundamental insights into neuroglial interactions. These insights will not only be relevant in the context of sigh rhythmogenesis, but these studies will also be important for understanding the generation of rhythmic behaviors in general.

项目摘要 叹息对于生存至关重要。他们通过预防质量来维持正常的肺功能。而且，叹息 还暗示着唤醒，并且未能叹息与猝死有关 综合征。拉米雷斯实验室已经证明，叹气是在prebötzinger综合体中产生的 腹外侧髓质。确实，产生欣喜的励志节奏活动的神经元似乎 也会叹息。这导致了一个重要但尚未解决的难题：相同的神经元网络如何 产生两种类型的呼吸节奏，具有明显不同的定时特征？欣快的灵感 节奏以1-2 Hz的频率发生，而叹气的范围为几分钟。我们在这里 测试假设，即神经相互作用产生的叹息，涉及嘌呤能和谷氨酸能 神经胶质与神经元之间的相互作用与特定的内在和突触特性。该假设已检验 在三个特定目标中：AIM 1将表征对产生叹息至关重要的神经胶质特性。我们将 评估分离的神经胶质的药物和神经调节特性，以及嵌入在 呼吸网络，使用钙成像和光遗传学工具。 AIM 2将表征特定的神经元 对产生叹息至关重要的特性。我们将测试这些神经元特性的假设 涉及由代谢性调节的P/Q-Type钙通道依赖性突触传播 谷氨酸受体（MGLUR8）以及涉及持续钠的内在膜特性 目标1和2将是 进行了进行严格的细胞水平分析的体外切片制剂。这两个目标 由AIM 3完成，我们将在体内准备中实施体外获得的见解， 也适合光学遗传操作。这项赠款将为产生的关键见解 叹。此外，该项目将提供对神经相互作用的基本见解。这些见解会 不仅在叹息节奏发生的背景下是相关的，而且这些研究对于 了解一般的节奏行为的产生。