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Energy and Neural Circuit Excitability

能量和神经回路兴奋性

基本信息

批准号：
10416150
负责人：
Mark Beenhakker
金额：
$ 41.91万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10416150
关键词：
5&apos -AMP-activated protein kinase Absence Epilepsy Acute Agonist Animals Baclofen Behavior Biochemical Biosensor Blood Brain Cells Cellular Stress Cessation of life Chemosensitization Childhood Data Diabetes Mellitus Diet Dose Drug Delivery Systems Electroencephalography Electrophysiology (science)Energy Supply Epilepsy Generalized Epilepsy Generalized seizures Glucose Goals Human Hypoglycemia Image Imaging Techniques In Vitro Ketone Bodies Knowledge Lactic Acidosis Measurement Measures Mediating Metabolic Metabolic stress Metabolism Metformin Modeling Motor Seizures Neurons Neurosciences Optical Methods Pattern Pharmaceutical Preparations Phosphorylation Play Preparation Protein Kinase Rattus Regulation Rodent Role Seizures Slice Stress Structure Techniques Testing Thalamic structure Work childhood epilepsy design experience experimental study glucose metabolism insight neural circuit neural network novel novel therapeutics patch clamp receptor receptor function relating to nervous system response

项目摘要

Project Summary Glucose is the primary fuel used by the brain. While alternative energy substrates can transiently sustain the brain’s needs during hypoglycemic episodes, glucose-sensing neurons within the brain nonetheless respond to diminishing energy supplies by altering their electrical behavior. This cellular response often has significant ramifications for the electrical activity patterns produced by glucose sensitive neural networks. Recent studies indicate that neural circuits in the thalamus, a subcortical brain structure, are particularly vulnerable to low levels of glucose in the blood. In this project, we aim to identify the mechanisms responsible for this heightened glucosensitivity, and to determine how these mechanisms promote hypoglycemia-associated epileptic seizures. Our multifaceted approach utilizes biosensor imaging and electrophysiological techniques, in both whole animals and in vitro preparations, to test the general hypothesis that glucose metabolism directly modulates neural circuits in the thalamus to exacerbate seizures. Using our preliminary data as a launching point, we will begin by carrying out experiments designed to disrupt glucose metabolism while measuring seizures. Collectively, these experiments will establish the thalamus, a critical seizure-generating node in the brain, as a glucosensitive structure. In conjunction with our glucose and seizure measurements, we will utilize electrophysiological and imaging techniques in acute brain slice preparations to directly measure the sensitivity of thalamic neurons to glucose metabolism. These experiments will be performed both at the cellular and circuit level. The former is achieved by conventional patch clamp recordings, while the latter is achieved in well-established slice models of thalamic seizures; our lab has extensive experience with both techniques. By performing these experiments, we aim to pinpoint mechanisms within the thalamic circuit that are particularly vulnerable to hypoglycemic conditions. Our Specific Aims include:  Aim 1 Hypoglycemia-activated AMPK incites spike-wave seizures by amplifying GABAB receptor activity.  Aim 2 Metformin-induced lactic acidosis triggers seizures. When complete, we expect that the results of our project will provide new and significant insights into fundamental cellular- and circuit-level mechanisms that drive generalized seizures, and therefore pave new avenues for generalized epilepsy treatments.

项目摘要葡萄糖是大脑使用的主要燃料。虽然替代能源基板可以暂时维持虽然大脑在低血糖发作期间的需求，但大脑内的葡萄糖感应神经元仍然会对低血糖发作做出反应。通过改变它们的电行为来减少能量供应。这种细胞反应通常具有显著的葡萄糖敏感神经网络产生的电活动模式的分支。最近的研究这表明丘脑（一种皮层下的大脑结构）中的神经回路特别容易受到低水平的影响，血液中的葡萄糖在这个项目中，我们的目标是确定负责这种提高的机制，葡萄糖敏感性，并确定这些机制如何促进低血糖相关的癫痫发作。我们多方面的方法利用生物传感器成像和电生理技术，在整个动物和体外制剂，以测试葡萄糖代谢直接调节神经细胞的一般假设。丘脑中的神经回路来加剧癫痫使用我们的初步数据作为出发点，我们将开始，进行旨在破坏葡萄糖代谢的实验，同时测量癫痫发作。总的来说，这些实验将建立丘脑，一个关键的神经生成节点在大脑中，作为葡萄糖敏感结构结合我们的葡萄糖和癫痫测量，我们将利用电生理和成像急性脑切片制备中直接测量丘脑神经元对葡萄糖敏感性的技术新陈代谢.这些实验将在细胞和电路水平上进行。前者实现了通过传统的膜片钳记录，而后者是在成熟的丘脑切片模型中实现的。癫痫发作;我们的实验室对这两种技术都有丰富的经验。通过这些实验，我们的目标是精确定位丘脑回路中特别容易受到低血糖状况影响的机制。我们的具体目标包括：目的1低血糖激活的AMPK通过增强GABAB受体诱发棘波癫痫发作活动二甲双胍诱导的乳酸酸中毒引发癫痫发作。完成后，我们希望我们的项目结果将提供新的和重要的见解，基本的细胞和电路水平的机制，驱动全身性癫痫发作，因此铺平了新的癫痫病的治疗方法