NMDA modulation of diabetes-induced glutamate synaptic plasticity

项目总结 糖尿病是一个主要的健康问题，在美国有近2600万人受到影响。严重的 糖尿病引起的并发症包括心脏病、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的主要障碍 (相对于治标)是关于多方面和冗余系统的相对知识差距 有助于控制新陈代谢动态平衡。这项建议调查了疾病相关的可塑性。 参与自主神经控制的中枢神经回路，包括控制血糖动态平衡。 实验利用了1型糖尿病的模型，但研究结果将更广泛地适用于其他形式的糖尿病 糖尿病，因为自主神经功能障碍会增加患2型糖尿病的风险。自主神经前神经元 迷走神经背侧复合体，其中含有二级内脏感觉神经元的束核 迷走神经背侧运动核内孤立性和节前副交感运动神经元 (DMV)是葡萄糖感受器，对葡萄糖稳态的自主调节也有重要作用。 糖尿病患者迷走运动输出受到抑制，导致自主神经失调，包括肝功能亢进。 葡萄糖产生和胃动力障碍。初步结果显示，谷氨酸在体内的释放 在1型糖尿病模型中，DMV持续增强，其方式与 对长期高血糖可能的代偿性反应，提示体内平衡可塑性 缓解糖尿病患者迷走神经输出减少的症状。此外，NMDA受体的调节有一种 与对照组相比，糖尿病小鼠对谷氨酸释放的影响相对更大。这项探索性的建议 旨在确定新近发现的糖尿病诱发的病因和潜在特征 增强对DMV神经元的紧张性兴奋驱动。迷走神经复合体的电生理记录 来自对照组和糖尿病小鼠的切片中的神经元将被用来获得与NMDA相关的功能细胞数据 在链脲佐菌素治疗的小鼠中，与糖尿病发生相关的受体敏感性变化 1型糖尿病模型。AIM 1将确定最近发现的NMDA受体是否位于突触前 糖尿病患者接触DMV细胞的终末表达上调。目标2将确定突触后 已识别的谷氨酸能NTS神经元的体树突部的NMDA受体投射到 糖尿病患者的DMV表达上调。这些变化对葡萄糖和胰岛素的敏感性也将是 已确认身份。结果将从系统的角度指导未来旨在改变疾病的疗法的研究， 基于调节脑干中的特定神经功能，最终解决糖尿病相关问题 患者的自主神经失调。

Project summary Diabetes mellitus is a major health concern, affecting nearly 26 million people in the United States. Serious complications resulting from diabetes including 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 a model of type 1 diabetes, but findings will more broadly apply to other forms of diabetes, since autonomic dysfunction increases the risk of developing 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 glutamate release in the DMV is persistently enhanced in a model of type 1 diabetes, in a manner consistent with development of a possible compensatory response to prolonged hyperglycemia that suggests homeostatic plasticity that mitigates against the decreased vagal output seen in diabetes. In addition, NMDA receptor modulation has a relatively larger effect on glutamate release in diabetic mice versus controls. This exploratory proposal aims to determine the causes and underlying features of the recently-discovered, diabetes-induced enhancement of tonic excitatory drive to DMV neurons. Electrophysiological recordings from vagal complex neurons in slices from control and diabetic mice will be used to obtain functional cellular data related to NMDA receptor sensitivity changes associated with diabetes development in the streptozotocin- treated mouse, a model of type 1 diabetes. Aim 1 will determine if recently-identified NMDA receptors located on presynaptic terminals contacting DMV cells are upregulated in diabetes. Aim 2 will determine if postsynaptic NMDA receptors on the somadendritic portion of identified glutamatergic NTS neurons that project to the DMV are upregulated in diabetes. The sensitivity of these changes to glucose and insulin will also be identified. Results will guide future studies aimed at disease-modifying therapies from a systemic standpoint, based on modulating specific neural functions in the brainstem to eventually address diabetes- related autonomic dysregulation in patients.