Inhibitory Modulation and Circuitry in the Rostral Solitary Nucleus

头端孤立核的抑制调节和电路

• 批准号: 9889099
• 负责人: Susan P Travers
• 金额: $ 33.15万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889099
• 关键词: Affect; Amygdaloid structure; Behavior; Brain; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cells; Clinical; Code; Computer Models; Data; Dental; Dental caries; Diabetes Mellitus; Diet; Electrodes; Elements; Exhibits; Feeding behaviors; Food Selections; Glutamates; Health; Heterogeneity; Human; In Vitro; Injections; Interneurons; Ion Channel; Light; Link; Location; LoxP-flanked allele; Mouse Strains; Mus; Neuraxis; Neurons; Neurotransmitters; Nucleus solitarius; Obesity; Output; Pathway interactions; Perception; Pharmacology; Phenotype; Potassium; Process; Property; Prosencephalon; Proteins; Reflex action; Role; Signal Transduction; Source; Study models; Taste Perception; Techniques; Testing; Transgenic Mice; Viral; Visceral; base; cell type; excitatory neuron; experimental study; functional plasticity; gamma-Aminobutyric Acid; gastrointestinal; hedonic; in vitro testing; in vivo; inhibitory neuron; insight; neurophysiology; novel; optogenetics; promoter; relating to nervous system; response; sugar; synthetic enzyme; voltage

PROJECT SUMMARY The sense of taste profoundly affects food selection and is thus inextricably linked to health concerns including caries exacerbated by sugar overconsumption and the sequela of obesity such as cardiovascular disease and diabetes. Understanding how taste is represented and processed in the brain thus has important clinical implications. The central processing of gustatory signals first occurs in the rostral nucleus of the solitary tract (rNST). A major difficulty in discerning how taste is represented in this nucleus is phenotypic heterogeneity. Output neurons are primarily glutamatergic and are responsible for representing the chemosensory properties of tastants and relaying this information to circuits that affect perception, behavior, and reflexes, whereas GABA/glycinergic neurons modulate the output cells. Due to technical challenges, it is thus far been impossible to correlate taste response properties with neurotransmitter phenotype. Moreover, little is known about the impact that GABAergic circuits exert on gustatory processing. Recent advances utilizing transgenic mice in combination with optogenetics can overcome these barriers by introducing the light-sensitive protein channelrhodopsin in specific cell types. This makes it possible to use neurophysiological recording techniques to identify GABAergic neurons in vivo, based on responses to light, and to simultaneously describe chemosensitive properties from the same cell. These techniques also allow temporally precise and repeatable activation or deactivation of GABAergic circuitry. The present proposal will use strains of mice that express either channelrhodopsin or archaerhodopsin in GABAergic neurons. Aim 1 will investigate the impact of optogenetically induced GABAergic modulation on non-GABAergic neurons in vivo, and contrast GABAergic modulation of rNST taste responses that arise from local neurons in the rNST, with those from the caudal NST, a local medullary source of visceral signals, or from the central nucleus of the amygdala. Aim 2 will investigate cellular mechanisms of GABAergic modulation in vitro combined with computational modeling to investigate interactions between hyperpolarization-sensitive ion channels and inhibition. A second study will test the hypothesis that inhibition differentially affects afferent signaling in neurons that contribute to an ascending pathway compared to local reflexive pathways. Aim 3 will define properties of GABAergic neurons and characterize subtypes. The first study will record in vivo from GAD65-ChR2 mice to identify GABAergic neurons by responsiveness to light and test the hypothesis that the chemosensitive responses of GABAergic rNST neurons differ from non-GABAergic neurons. A second aim will record in vitro from mice expressing tdTomato in GAD65+ neurons to identify subtypes based on location, inhibitory modulation, and the presence of the hyperpolarization-sensitive Ih current. A causal role for these currents in modulating afferent responses will be tested. These studies will provide novel insights into taste coding and ultimately contribute toward understanding how taste signaling interacts with circuits that control feeding behavior.

项目概要 味觉深刻影响食物选择，因此与健康问题密不可分，包括 糖分过量消耗以及心血管疾病和肥胖等后遗症会加剧龋齿 糖尿病。因此，了解味觉如何在大脑中表达和处理具有重要的临床意义 影响。味觉信号的中央处理首先发生在孤束的喙核中 （rNST）。辨别味觉在这个核中如何表达的一个主要困难是表型异质性。 输出神经元主要是谷氨酸能神经元，负责代表化学感应特性 促味剂并将这些信息传递给影响感知、行为和反射的电路，而 GABA/甘氨酸能神经元调节输出细胞。由于技术上的挑战，目前还不可能 将味觉反应特性与神经递质表型相关联。此外，人们对这方面知之甚少 GABA 能回路对味觉处理的影响。利用转基因小鼠的最新进展 与光遗传学相结合可以通过引入光敏蛋白来克服这些障碍 特定细胞类型中的视紫红质通道。这使得使用神经生理学记录技术成为可能 根据对光的反应识别体内 GABA 能神经元，并同时描述 来自同一细胞的化学敏感性。这些技术还允许时间精确且可重复 GABA能电路的激活或失活。目前的提案将使用表达 GABA能神经元中的通道视紫红质或古视紫红质。目标 1 将调查以下影响 光遗传学诱导体内非 GABA 能神经元的 GABA 能调节，以及对比 GABA 能神经元 调节 rNST 味觉反应，这些反应由 rNST 中的局部神经元和尾部 NST 的神经元产生， 内脏信号的局部髓质来源，或来自杏仁核的中央核。目标 2 将进行调查 体外 GABA 能调节的细胞机制结合计算模型进行研究 超极化敏感离子通道和抑制之间的相互作用。第二项研究将测试 假设抑制对神经元中的传入信号有不同的影响，这些信号有助于上行 途径与局部反射途径相比。目标 3 将定义 GABA 能神经元的特性和 表征亚型。第一项研究将记录 GAD65-ChR2 小鼠的体内情况，以鉴定 GABAergic 通过对光的反应来检测神经元并测试 GABA 能的化学敏感性反应的假设 rNST 神经元不同于非 GABA 能神经元。第二个目标是在体外记录小鼠的表达 GAD65+ 神经元中的 tdTomato 根据位置、抑制调节和存在来识别亚型 超极化敏感 Ih 电流。这些电流在调节传入反应中的因果作用 将受到测试。这些研究将为味觉编码提供新颖的见解，并最终有助于 了解味觉信号如何与控制进食行为的电路相互作用。