Neural Circuitry in the Dorsal Vagal Complex

 描述（由申请人提供）：糖尿病是一个主要的健康问题，影响美国近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（与治疗症状相比）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。这项建议调查疾病相关的可塑性中枢神经回路参与自主控制，包括控制血糖稳态。实验利用1型和2型糖尿病的鼠模型。迷走神经背侧复合体的前自主神经元（Preautonomic neurons）是葡萄糖感受器，也对葡萄糖稳态的自主调节有重要作用，其中包括孤束核（NTS）中的二级内脏感觉神经元和迷走神经背侧运动核（DMV）中的节前副交感运动神经元。迷走神经运动输出在糖尿病中被抑制，导致自主神经失调，包括过量的肝葡萄糖产生和胃动力障碍。初步结果显示，特别是NTS中的GABA神经元对升高的葡萄糖有反应。巧合的是，DMV中GABAA受体介导的反应在1型糖尿病模型中持续增强，其方式与维持长期高血糖一致。在2型糖尿病模型中保留了一些但不是所有这些反应，表明GABA受体可塑性的一种形式介导了糖尿病中观察到的迷走神经输出减少。此外，背侧迷走神经复合体中GABA受体的调节对血糖水平具有显著影响，并且假设这种影响在糖尿病小鼠中相对于对照增强。这项建议旨在确定最近发现的糖尿病诱导的迷走神经复合体中GABA能系统可塑性的原因和潜在特征。来自对照和糖尿病小鼠切片中迷走复合神经元的电生理记录将用于获得与链脲佐菌素处理的小鼠（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能抑制改变相关的功能细胞数据。目的1将确定糖尿病小鼠中增强的紧张性GABA电流的胰岛素和葡萄糖依赖性，目的2将确定有助于DMV中糖尿病相关GABA受体可塑性的细胞机制，目的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。结果将指导未来的研究，旨在从系统的角度来看，疾病修饰疗法的基础上，调节特定的抑制性神经功能的脑干，以解决糖尿病相关的自主神经失调的患者。

 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.