Neural Circuitry in the Dorsal Vagal Complex

背侧迷走神经复合体的神经回路

• 批准号: 9406120
• 负责人: Bret N Smith
• 金额: $ 37.39万
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9406120
• 关键词: Abdomen; Address; Affect; Animal Model; Area; Autonomic Dysfunction; Blindness; Blood Glucose; Brain; Brain Stem; Cell Nucleus; Chronic; Complex; Data; Dependence; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dorsal; Electrophysiology (science); Functional disorder; Future; GABA Receptor; Gastrointestinal tract structure; Genetic Transcription; Glucose; Goals; Health; Heart Diseases; Hepatic; Homeostasis; Human; Hyperglycemia; Hyperinsulinism; Hypertension; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Liver; Maintenance; Mediating; Metabolic Control; Modeling; Modification; Molecular; Motor Neurons; Motor output; Mus; Nervous System Trauma; Neurons; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; Organ; Output; Pancreas; Pathology; Patients; Peripheral; Physiological; Play; Regulation; Role; Slice; Stomach; Streptozocin; Stroke; Symptoms; Synapses; System; Testing; United States; Viscera; Visceral; Whole Blood; base; blood glucose regulation; cell motility; diabetes mellitus therapy; diabetic; dorsal motor nucleus; experimental study; gamma-Aminobutyric Acid; gastrointestinal; glucose metabolism; glucose production; mouse model; nerve supply; neural circuit; public health relevance; receptor; response; symptom treatment; trafficking; type I diabetic

 DESCRIPTION (provided by applicant): Diabetes mellitus is a major health concern, affecting nearly 26 million people in the United States. Serious complications resulting from diabetes including include heart disease, stroke, hypertension, blindness, nervous system damage, and autonomic dysfunction. A major impediment to developing successful diabetes treatments (versus treating symptoms) is the relative knowledge gap regarding the multifaceted and redundant systems that contribute to control of metabolic homeostasis. This proposal investigates disease-related plasticity of central neural circuitry involved in autonomic control, including control of blood glucose homeostasis. Experiments utilize murine models of type 1 and type 2 diabetes. Preautonomic neurons of the dorsal vagal complex, which contains second-order viscerosensory neurons in the nucleus tractus solitarius (NTS) and preganglionic parasympathetic motor neurons in the dorsal motor nucleus of the vagus (DMV), are glucosensors and also contribute significantly to autonomic regulation of glucose homeostasis. Vagal motor output is suppressed in diabetes, leading to autonomic dysregulation, including excess hepatic glucose production and gastric motility dysfunction. Preliminary results show that GABA neurons in the NTS in particular are responsive to elevated glucose. Paradoxically, GABAA receptor-mediated responses in the DMV are persistently enhanced in a model of type 1 diabetes, in a manner consistent with maintenance of prolonged hyperglycemia. Some, but not all of these responses are preserved in a type 2 diabetes model, suggesting a form of GABA receptor plasticity that mediates the decreased vagal output seen in diabetes. In addition, modulation of GABA receptors in the dorsal vagal complex has a significant effect on blood glucose levels, and this effect is hypothesized to be enhanced in diabetic mice versus controls. This proposal aims to determine the causes and underlying features of the recently-discovered, diabetes-induced plasticity of the GABAergic system in the vagal complex. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to altered GABAergic inhibition changes associated with diabetes development in the streptozotocin-treated mouse, a model of type 1 diabetes, and the TallyHo mouse, a model of type 2 diabetes. Aim 1 will determine insulin- and glucose- dependence of enhanced tonic GABA currents in diabetic mice, aim 2 will identify cellular mechanisms contributing to diabetes-associated GABA receptor plasticity in the DMV, and aim 3 will determine the effects of GABA receptor modulation in the dorsal vagal complex on systemic glucose homeostasis. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint, based on modulating specific inhibitory neural functions in the brainstem to address diabetes-related autonomic dysregulation in patients.

 描述（由申请人提供）：糖尿病是一个主要的健康问题，影响着美国近 2600 万人。糖尿病引起的严重并发症包括心脏病、中风、高血压、失明、神经系统损伤和自主神经功能障碍。开发成功的糖尿病治疗方法（相对于治疗症状）的一个主要障碍是关于有助于控制代谢稳态的多方面和冗余系统的相对知识差距。该提案研究了参与自主控制（包括血糖稳态控制）的中枢神经回路与疾病相关的可塑性。实验利用 1 型和 2 型糖尿病小鼠模型。背侧迷走神经复合体的自主神经前神经元包含孤束核 (NTS) 中的二阶内脏感觉神经元和迷走神经背运动核 (DMV) 中的节前副交感运动神经元，它们是葡萄糖传感器，对葡萄糖稳态的自主调节也有显着贡献。糖尿病患者迷走神经运动输出受到抑制，导致自主神经失调，包括肝葡萄糖产生过多和胃动力功能障碍。初步结果表明，NTS 中的 GABA 神经元对升高的葡萄糖尤其敏感。矛盾的是，DMV 中 GABAA 受体介导的反应在 1 型糖尿病模型中持续增强，其方式与长期高血糖的维持一致。这些反应中的一些（但不是全部）在 2 型糖尿病模型中得以保留，表明 GABA 受体可塑性的一种形式可以介导糖尿病中迷走神经输出的减少。此外，调节背侧迷走神经复合体中的 GABA 受体对血糖水平有显着影响，并且假设与对照组相比，糖尿病小鼠的这种影响会增强。该提案旨在确定最近发现的糖尿病引起的迷走神经复合体中 GABA 能系统可塑性的原因和根本特征。对照小鼠和糖尿病小鼠切片中迷走神经复合体神经元的电生理记录将用于获得与链脲佐菌素治疗的小鼠（1型糖尿病模型）和TallyHo小鼠（2型糖尿病模型）中与糖尿病发展相关的GABA能抑制变化改变相关的功能细胞数据。目标 1 将确定糖尿病小鼠中增强的强直 GABA 电流的胰岛素和葡萄糖依赖性，目标 2 将确定 DMV 中糖尿病相关 GABA 受体可塑性的细胞机制，目标 3 将确定背侧迷走神经复合体中 GABA 受体调节对全身葡萄糖稳态的影响。结果将指导未来从系统角度进行疾病缓解疗法的研究，其基础是调节脑干中的特定抑制性神经功能，以解决患者与糖尿病相关的自主神经失调问题。