Energy and Neural Circuit Excitability

项目摘要 葡萄糖是大脑使用的主要燃料。虽然替代能源衬底可以暂时维持 大脑的需要在低血糖发作期间，大脑内的葡萄糖感觉神经元仍然对 通过改变它们的电气行为来减少能源供应。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。最新研究 这表明，大脑皮质下结构丘脑的神经回路特别容易受到低水平的影响。 血液中的葡萄糖含量。在这个项目中，我们的目标是确定导致这种增强的机制 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。 我们的多方面方法利用生物传感器成像和电生理技术，在两个完整的动物中 以及体外准备，以检验葡萄糖代谢直接调节神经的一般假设 丘脑中的回路来加剧癫痫发作。以我们的初步数据为起点，我们将从 在测量癫痫发作的同时进行旨在扰乱葡萄糖代谢的实验。总而言之，这些 实验将确定丘脑是大脑中产生癫痫的关键节点，是一种葡萄糖敏感剂。 结构。 结合我们的血糖和癫痫测量，我们将使用电生理和成像 急性脑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层面上进行。前者是实现的 通过传统的膜片钳记录，而后者是在已建立的丘脑切片模型中实现的 癫痫发作；我们的实验室在这两种技术方面都有丰富的经验。通过进行这些实验，我们的目标是 精确定位丘脑回路中特别容易受到低血糖条件影响的机制。 我们的具体目标包括： Aim 1低血糖激活的AMPK通过放大GAAB受体刺激棘波惊厥 活动。 目标2二甲双胍诱导的乳酸酸中毒触发癫痫发作。 完成后，我们预计项目的结果将为以下方面提供新的重要见解 推动全身性癫痫发作的基本细胞和电路水平的机制，因此为新的 全面性癫痫治疗的途径。

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.