NMDA modulation of diabetes-induced glutamate synaptic plasticity

NMDA 调节糖尿病诱导的谷氨酸突触可塑性

• 批准号: 8833310
• 负责人: Bret N Smith
• 金额: $ 18.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833310
• 关键词: Abdomen; Accounting; Address; Affect; Animal Model; Area; Autonomic Dysfunction; Blindness; Blood Glucose; Brain; Brain Diseases; Brain Stem; Cell Nucleus; Cells; Chronic; Complex; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease; Dorsal; Equilibrium; Functional disorder; Future; Gastrointestinal tract structure; Glucose; Glutamates; Goals; Health; Heart Diseases; Hepatic; Homeostasis; Human; Hyperglycemia; Hypertension; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Liver; Mediating; Metabolic Control; Modeling; Modification; Motor Neurons; Motor output; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nervous System Trauma; Neurons; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Organ; Output; Pancreas; Pathology; Patients; Peripheral; Play; Presynaptic Terminals; Receptor Activation; Regulation; Relative (related person); Risk; Role; Slice; Staging; Stomach; Streptozocin; Stroke; Symptoms; Synapses; Synaptic plasticity; System; Testing; Tissues; United States; Vagus nerve structure; Viscera; Whole Blood; base; blood glucose regulation; cell motility; diabetes mellitus therapy; diabetic; dorsal motor nucleus; gastrointestinal; glucose metabolism; glucose production; neural circuit; neuronal cell body; postsynaptic; presynaptic; receptor; receptor function; receptor sensitivity; research study; response

DESCRIPTION (provided by applicant): Diabetes mellitus is a major health concern, affecting nearly 26 million people in the United States. Serious complications result 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.

描述（由申请人提供）：糖尿病是一个主要的健康问题，影响了美国近2600万人。严重的并发症是由糖尿病引起的，包括心脏病，中风，高血压，失明，神经系统损害和自主神经功能障碍。开发成功的糖尿病治疗（与治疗症状相对于治疗症状）的主要障碍是有关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。该提案调查了与自主神经控制有关的中央神经回路的可塑性，包括控制血糖稳态。实验利用了1型糖尿病模型，但发现将更广泛地适用于其他形式的糖尿病，因为自主功能障碍会增加患2型糖尿病的风险。背部迷走神经复合物的术前神经元，其中含有二阶内脏神经元（tractus tractus solitarius（NTS）和gangionic副交感神经元神经元中的背部运动核（DMV）（DMV）中，也有明显的自动调节量。迷走性运动输出在糖尿病中受到抑制，导致自主神经功能障碍，包括过量的肝葡萄糖产生和胃运动功能障碍。初步结果表明，在1型糖尿病模型中，DMV中的谷氨酸释放持续增强，这种方式与对长期高血糖的可能补偿性反应的发展相一致，这表明稳态可塑性表明抑制糖尿病中降低的模糊产量会减轻。此外，NMDA受体调制对糖尿病小鼠与对照组的谷氨酸释放的影响相对较大。该探索性提案旨在确定最近发现的，糖尿病引起的刺激驱动器增强DMV神经元的原因和基本特征。来自对照和糖尿病小鼠切片中迷走神经复合物神经元的电生理记录将用于获得与NMDA受体敏感性有关的功能性细胞数据，该数据与链霉菌治疗小鼠的糖尿病发育相关，这是一种1型1型糖尿病的模型。 AIM 1将确定在糖尿病中接触DMV细胞的最近识别的NMDA受体是否在接触DMV细胞上。 AIM 2将确定在糖尿病中投射到DMV的已鉴定谷氨酸能NTS神经元的突触后NMDA受体是否在鉴定出的谷氨酸能NTS神经元中是否上调。这些变化对葡萄糖和胰岛素的敏感性也将被鉴定。结果将基于调节脑干中的特定神经功能以最终解决患者中与糖尿病相关的自主神经失调的研究，从而指导旨在从系统性角度进行疾病改良疗法的未来研究。