Neural circuitry in the dorsal vagal complex

背侧迷走神经复合体的神经回路

• 批准号: 7643547
• 负责人: Bret N Smith
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643547
• 关键词: Amino Acids; Area; Binding; Biological; Brain; Cell model; Cells; Characteristics; Chromosome Pairing; Chronic; Communication; Complex; Condition; Data; Diabetes Mellitus; Digestion; Dorsal; Event; Functional disorder; Glutamates; Hyperglycemia; In Vitro; Insulin-Dependent Diabetes Mellitus; Label; Mediating; Membrane Potentials; Messenger RNA; Methods; Modeling; Molecular; Motor Neurons; Motor output; Mus; Neurons; Noise; Nucleus solitarius; Preparation; Proteins; Regulation; Rest; Signal Transduction; Slice; Stomach; Streptozocin; Synapses; Synaptic Transmission; Testing; Transgenic Mice; Translating; Vagus nerve structure; Viscera; Visceral Afferents; base; concept; dorsal motor nucleus; feeding; gamma-Aminobutyric Acid; gastrointestinal; interdisciplinary approach; male; neural circuit; neuronal cell body; patch clamp; photoactivation; photolysis; postsynaptic; receptor; research study; response; sensorimotor system

Neuronal communication in the dorsal vagal complex (DVC) is critical for integrating visceral afferent and other inputs, and translating that integrated signal into a coordinated motor output via the vagus nerve. In particular, GABAergic inhibition is a dominant regulator of neuronal function in the area. Despite the recognized importance of this circuitry to control of feeding and digestion, relatively little is known about local connections within the DVC. The general hypothesis of this proposal is that activity of neurons in the dorsal motor nucleus of the vagus (DMV) that control gastric function is prominently controlled by inhibitory GABAergic inputs arising from neurons in the nucleus tractus solitarius (NTS). The activity of NTS GABA neurons is tightly regulated by both glutamatergic excitatory and GABAergic inhibitory synaptic inputs. We propose that GABAergic control of motor output to the stomach is accomplished by both phasic and tonic postsynaptic GABAA receptor-mediated inhibition and that specific cellular interactions in the DVC are organized in a manner that consistent with the concept, well developed in other sensory-motor systems, that local inhibitory circuitry coordinates responses between functional areas of the solitary complex. Gastrointestinal dysfunction effects people with diabetes mellitus and is attributed to altered vagal control of the stomach. We propose that GABAA receptor-mediated currents in gastric-related DMV neurons are functionally altered in a model of type 1 diabetes mellitus. We will use a multidisciplinary approach to examine GABA-mediated synaptic transmission between neurons in the DVC, focusing particularly on inhibitory synaptic control of identified GABAergic neurons in the NTS, as well as on neurons in the DMV in the context of gastrointestinal control. Electrophysiological experiments will be done in vitro using brain slice preparations from mature male mice in which DMV and NTS neurons can be identified by their anatomical connection with the stomach, their GABA content, or both. With whole-cell patch-clamp recordings, we will use photoactivation of caged glutamate to stimulate selectively the soma-dendritic regions of local neurons in order to analyze GABA-mediated connections within the solitary complex. We aim to determine: 1) the contribution of tonic GABAergic currents to neuronal activity in the DMV; 2) how identified gastric-related GABAergic neurons in the NTS are regulated by GABA input; and 3) effects of hyperglycemia on GABA currents in a model of type 1 diabetes. We will correlate electrophysiological results with pharmacological and molecular biological analyses to construct a cellular model of local GABAergic control of DMV neuron activity.

背侧迷走神经复合体（DVC）中的神经元通讯对于整合内脏传入和其他神经元至关重要 输入，并通过迷走神经将整合的信号转化为协调的运动输出。特别是， GABA能抑制是该区域神经元功能的主要调节剂。尽管公认的 由于这一回路对控制摄食和消化的重要性，人们对局部连接的了解相对较少 在DVC。这一建议的一般假设是，运动背核中的神经元活动 控制胃功能的迷走神经（DMV）的活动主要受抑制性GABA能输入的控制， 孤束核（NTS）中的神经元。NTS GABA神经元的活动受到以下因素的严格调节： 既有谷氨酸能兴奋性突触输入又有GABA能抑制性突触输入。我们建议GABA能控制 运动输出到胃是由相位和紧张性突触后GABAA受体介导的 DVC中抑制和特异性细胞相互作用以与 在其他感觉-运动系统中得到很好发展的概念，即局部抑制回路协调反应 在孤独综合体的功能区域之间。胃肠道功能障碍影响糖尿病患者 这是由于胃的迷走神经控制改变。我们认为GABAA受体介导的 胃相关DMV神经元中的电流在1型糖尿病模型中发生功能性改变。我们将 使用多学科的方法来检查GABA介导的突触传递神经元之间的， DVC，特别关注NTS中识别的GABA能神经元的抑制性突触控制，以及 对DMV神经元的影响。将进行电生理学实验 使用来自成熟雄性小鼠的脑切片制备物进行体外研究，其中可以鉴定DMV和NTS神经元 通过它们与胃的解剖学连接，它们的GABA含量，或两者兼而有之。全细胞膜片钳 记录，我们将使用光活化笼谷氨酸选择性地刺激胞体树突状区域 的本地神经元，以分析GABA介导的连接内的孤立复杂。我们的目标是 确定：1）紧张性GABA能电流对DMV中神经元活动的贡献; 2）如何识别 孤束核中的胃相关GABA能神经元受GABA输入的调节; 3）高血糖的影响 1型糖尿病模型中的GABA电流。我们将把电生理结果与 药理学和分子生物学分析，以构建局部GABA能控制的细胞模型， 车管所神经元活动。