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: 10418629
• 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/10418629
• 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; Pharmacology; 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; base; beta-adrenergic receptor; excitatory neuron; extracellular; in vivo; inhibitory neuron; insight; neuroregulation; optogenetics; 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 精子对生存至关重要。它们通过防止肺不张来维持正常的肺功能。而且， 也与觉醒有关，而不叹气与婴儿猝死有关 综合征Ramirez实验室已经证明，叹息是在前Bötzinger复合物中产生的， 延髓腹外侧事实上，产生正常吸气节律活动的神经元似乎 生亦叹。这就引出了一个重要但尚未解决的难题：同样的神经元网络 产生两种具有明显不同的时间特征的呼吸节律？正常呼吸的吸气 节律以1-2 Hz的频率发生，而叹息在几分钟的范围内产生。这里我们 检验sigh是由涉及嘌呤能和多巴胺能的神经胶质细胞相互作用产生的假设 神经胶质和神经元之间的相互作用具有特定的内在和突触特性。这一假设得到验证 在三个具体的目标：目标1将表征的神经胶质细胞的特性的产生的叹息。我们将 评价分离的神经胶质细胞和包埋在神经胶质细胞中的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学工具。目的2将表征特定的神经元 这些性质对于产生叹气是至关重要的。我们将检验这些神经元特性 涉及P/Q型钙通道依赖性突触传递 谷氨酸受体（mGluR 8），以及涉及持续钠离子通道的内在膜特性。 由毒蕈碱受体和β-肾上腺素能受体调节的电流。目标1和2将是 在适合于严格的细胞水平分析的体外切片制备中进行。这两个目标 由目标3补充，在目标3中，我们将在体内制剂中实施我们在体外获得的见解， 也可以进行光遗传学操作。这笔赠款将提供关键的见解，一代的 哎。此外，该项目将提供神经胶质细胞相互作用的基本见解。这些见解将 不仅与叹息节律发生有关，而且这些研究也对以下方面很重要： 理解一般节奏行为的产生。