NMDA modulation of diabetes-induced glutamate synaptic plasticity

项目摘要 糖尿病是一个主要的健康问题，影响着美国近2600万人。严重 糖尿病并发症包括心脏病、中风、高血压、失明、神经系统 损伤和自主神经功能紊乱开发成功的糖尿病治疗方法的主要障碍 （相对于治疗症状）是关于多方面和冗余系统的相对知识差距 有助于控制代谢平衡。这项提案研究了与疾病相关的可塑性 参与自主控制的中枢神经回路，包括血糖稳态的控制。 实验利用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。 2型糖尿病是一种常见的糖尿病类型。前自主神经元 背侧迷走神经复合体，其中包含二级内脏感觉神经元在束核 孤束核（NTS）和迷走神经背侧运动核的副交感神经节前运动神经元 (DMV)是葡萄糖传感器，并且还显著地有助于葡萄糖稳态的自主调节。 糖尿病患者迷走神经运动输出受到抑制，导致自主神经功能失调，包括过度的肝 葡萄糖产生和胃运动功能障碍。初步结果表明，谷氨酸释放在 DMV在1型糖尿病模型中持续增强，其方式与1型糖尿病的发展一致。 可能是对长期高血糖的代偿性反应，这表明稳态可塑性， 减轻糖尿病中出现的迷走神经输出减少。此外，NMDA受体调节具有 与对照相比，糖尿病小鼠对谷氨酸释放的影响相对较大。这个探索性的提议 旨在确定最近发现的糖尿病引起的 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 来自对照和糖尿病小鼠的切片中的神经元将用于获得与NMDA相关的功能细胞数据 受体敏感性的变化与糖尿病的发展在链脲佐菌素治疗的小鼠， 1型糖尿病的发病机制目的1将确定最近鉴定的NMDA受体是否位于突触前 接触DMV细胞的末端在糖尿病中上调。目标2将确定是否突触后 NMDA受体在已鉴定的投射到脊髓背角的NMDA能NTS神经元的体细胞核部分上， DMV在糖尿病中上调。这些变化对葡萄糖和胰岛素的敏感性也将是 鉴定结果将指导未来的研究，旨在从系统的角度改善疾病治疗， 基于调节脑干中特定的神经功能， 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.