GABAergic Interneurons Regulate Brainstem Neural Circuitry

这项提议的目标是确定两个特定的GABA能中间神经元生长抑素的作用 脑干神经回路调控中的SST和NPY表达神经元 控制胃功能。我们的研究集中在构成背侧神经回路的主要脑核 后脑迷走神经复合体(DVC)，即孤束内侧核(MNTS)和背运动 迷走神经核(DMV)，表明这些核团中的局部GABA信号对迷走神经的调节至关重要 排出到胃里。然而，这种抑制信号可以到达的GABA神经元的身份 缺乏归因性。转基因小鼠模型、病毒注射和光遗传技术的研究进展 使分离和选择性刺激特定类型的细胞成为可能。使用这些技术，我们 已经开始获得有关参与GABA信号转导的神经元的身份和作用的新数据 DVC。此外，这些技术在获得有关可能机制的信息方面起到了重要作用 它是能量平衡的调节器，即黑素皮质素受体的内源性激动剂 系统(MCR)，在NTS(抑制性)对胃功能(如张力和运动)产生不同的影响。 在车管所里(兴奋)。本提案的重点是遗传和病毒定义的SST和 DVC内的NPY神经元。我们将通过以下方式研究这些神经元在DVC电路中的功能作用 确定它们的电生理和形态特征与其他神经元的关系 包括通过跨突触标记控制胃功能的神经回路。我们以前出版的 数据和初步结果表明，对NTS或DMV中SST/NPY神经元的光遗传刺激作用强烈 影响脑肠轴上神经元的活动。基于这些结果，我们将全面追求我们的 假设DVC中的SST和NPY神经元作为关键的互补成分来调节 迷走神经胃环。最后，我们将评估SST和NPY神经元在活体模型中的作用 对胃功能的影响。在这个模型中，我们将检验刺激SST和NPY GABA神经元在脑内的假设 MNTS和DMV会选择性地影响胃的张力和运动。从我们的建议中获得的知识 研究将大大有助于理解迷走神经回路控制胃功能， 为研究其他自主神经反射系统的动态平衡提供了一个重要的模板。

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.