GABAergic Interneurons Regulate Brainstem Neural Circuitry

GABA能中间神经元调节脑干神经回路

• 批准号: 9594647
• 负责人: Stefano Vicini
• 金额: $ 34.99万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9594647
• 关键词: Achalasia; Affect; Agonist; Anatomy; Area; Attention; Brain; Brain Stem; Breeding; Cell Nucleus; Characteristics; Complex; Data; Disease; Dorsal; Electrophysiology (science); Event; Foundations; Functional disorder; Goals; Homeostasis; Hyperglycemia; Hyperinsulinism; In Vitro; Injections; Interneurons; Knowledge; Label; Medial; Mediating; Melanocortin 4 Receptor; Methods; Modeling; Monitor; Morphology; Mus; Neurons; Obesity; Optics; Organ; Output; Parkinson Disease; Peripheral; Phenotype; Play; Population; Positioning Attribute; Property; Publishing; Pyloric antrum; Reflex action; Reflux; Regulation; Research; Role; Signal Transduction; Somatostatin; Source; Stomach; Synapses; System; Techniques; Technology; Testing; Transgenic Mice; Transgenic Organisms; Viral; Virus; autonomic reflex; base; brain circuitry; cell motility; cell type; diabetic gastroparesis; dorsal motor nucleus; gamma-Aminobutyric Acid; gut-brain axis; hindbrain; in vivo; in vivo Model; insight; melanocortin receptor; mouse model; neural circuit; neurochemistry; neuropeptide Y; neuroregulation; optogenetics; presynaptic; relating to nervous system; response; tool

The goal of this proposal is to determine the role of two specific GABAergic interneurons, somatostatin (Sst) and neuropeptide Y (Npy) expressing neurons, in the regulation of Brainstem neural circuitry controlling gastric function. Our studies, focusing on the major brain nuclei of this circuit that form the dorsal vagal complex (DVC) in the hindbrain, namely the medial nucleus tractus solitarius (mNTS) and dorsal motor nucleus of the vagus (DMV), indicate that local GABA signaling in these nuclei is critical for modulation of vagal output to the stomach. However, the identity of the GABA neurons to which this inhibitory signaling can be attributed is lacking. Recent advances in transgenic mouse models, virus injection and optogenetic techniques have made it possible to isolate and selectively stimulate specific cell types. Using these technologies, we have begun to acquire nascent data on the identity and role of the neurons involved in GABA signaling in the DVC. Furthermore, these techniques have been instrumental in obtaining information on the likely mechanisms by which a regulator of energy homeostasis, namely an endogenous agonist of the melanocortin receptor system (McR), produces its differential effects on gastric function (e.g., tone and motility) in the NTS (inhibitory) and in the DMV (excitatory). The focus of the present proposal is on the genetically and virally defined Sst and Npy neurons in the DVC. We will investigate the functional role of these neurons in DVC circuitry by determining their electrophysiological and morphological characteristics in relation to other neurons that comprise the neural circuitry controlling gastric function via trans-synaptic labeling. Our previously published data and preliminary findings show that optogenetic stimulation of Sst/Npy neurons in the NTS or DMV strongly influence the activity of neurons along the Brain-Gut axis. Based on these results, we will pursue our overall hypothesis that Sst and Npy neurons in the DVC serve as key complementary components that regulate the vago-vagal gastric circuitry. Finally, we will assess the role of Sst and Npy neurons in an in vivo model of gastric function. In this model, we will test the hypothesis that stimulation of Sst and Npy GABA neurons in the mNTS and DMV will selectively affect gastric tone and motility. The knowledge gained from our proposed studies will contribute greatly to understanding vago-vagal circuitry controlling gastric function, with the potential of providing an important template for studying homeostasis in other autonomic reflex systems.

这项计划的目的是确定两个特定的GABA能中间神经元，生长抑素， (Sst)和神经肽Y（Npy）表达神经元，在调节脑干神经回路 控制胃功能。我们的研究，集中在形成背侧神经回路的主要脑核， 迷走神经复合体（DVC），即内侧孤束核（mNTS）和背侧运动核 迷走神经核（DMV）的研究表明，这些核中的局部GABA信号传导对于迷走神经的调节是至关重要的。 输出到胃。然而，这种抑制性信号传导的GABA神经元的身份可能是不确定的。 缺少属性。转基因小鼠模型、病毒注射及光遗传学技术的研究进展 使分离和选择性刺激特定细胞类型成为可能。利用这些技术，我们 已经开始获得新生的数据的身份和作用的神经元参与GABA信号在脑 DVC。此外，这些技术有助于获得有关可能机制的信息， 能量稳态的调节剂，即黑皮质素受体的内源性激动剂， 系统（McR），对胃功能产生不同的影响（例如，张力和运动性）（抑制性） 在车管所也是兴奋性的本提案的重点是基因和病毒定义的Sst， DVC中的Npy神经元。我们将研究这些神经元在DVC电路中的功能作用， 确定它们与其他神经元相关的电生理和形态学特征， 包括通过跨突触标记控制胃功能的神经回路。我们先前发布的 数据和初步发现表明，NTS或DMV中的Sst/Npy神经元的光遗传学刺激强烈地 影响沿着脑肠轴的神经元的活动。根据这些结果，我们将继续努力， 假设DVC中的Sst和Npy神经元作为调节的关键互补成分 迷走-迷走胃回路最后，我们将评估Sst和Npy神经元在体内模型中的作用 胃的功能。在这个模型中，我们将测试刺激Sst和Npy GABA神经元的假设， mNTS和DMV将选择性地影响胃张力和运动。从我们的建议中获得的知识 研究将大大有助于了解迷走神经-迷走神经回路控制胃功能， 为研究其他自主反射系统的稳态提供了一个重要的模板。