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.

项目总结 叹息是生存的关键。它们通过预防肺不张来维持正常的肺功能。此外，叹息 也与唤醒有关，而不叹息与婴儿猝死有关 综合症。Ramirez实验室已经证明，叹息是在Prebötzinger复合体中产生的 延髓腹外侧。事实上，产生有氧吸气节律活动的神经元似乎 也会产生叹息。这导致了一个重要但仍未解开的谜团：相同的神经元网络如何 产生两种截然不同的呼吸节律？常青树吸气 节奏发生在1-2赫兹的频率，而叹息产生在几分钟的范围内。在这里我们 检验叹息是由涉及嘌呤能和谷氨酸能的神经胶质细胞相互作用产生的假设 具有特定固有和突触特性的神经胶质细胞和神经元之间的相互作用。这一假设得到了检验。 在三个具体的目标中：目标1将描述对叹息产生至关重要的神经胶质属性。我们会 评价神经胶质细胞的药理学和神经调节特性 呼吸网络，使用钙成像和光遗传工具。目标2将描述特定神经元的特征 对于叹息的产生至关重要的属性。我们将检验这样一种假设，即这些神经元特性 涉及P/Q型钙通道依赖的突触传递，受代谢性调节 谷氨酸受体(MGluR8)，以及涉及持久性钠的固有膜特性 受M受体和β-肾上腺素能受体调节的电流。目标1和目标2将是 在能够进行严格的细胞水平分析的体外切片准备中进行。这两个目标 与之相辅相成的是目标3，在目标3中，我们将在体内准备中实施我们在体外获得的见解 也容易受到光基因操作的影响。这笔赠款将为新一代 叹息。此外，该项目将提供对神经胶质细胞相互作用的基本见解。这些洞察力将 这些研究不仅与叹息节律发生有关，而且对 从总体上理解节奏性行为的产生。