Metabolic cost of neuronal activity

大脑和神经活动是人体能量的主要消耗者。然而，很少有人知道神经元活动如何与代谢过程的细节，以及它们如何相互影响。为了解决这方面的问题，我们建立了一个新的模型系统，通过研究细胞代谢的外侧上级橄榄（LSO），一个主要的脑干核团参与处理听觉信号。我们已经发表了第一个数据的神经能量学的这个核，并将其与著名的代谢模型区域（海马和大脑皮层）的同一物种。听觉核，如LSO，具有独特的，明确定义的结构-功能关系，允许神经元及其生理功能的明确相关性。这些核中的神经元具有局部均匀的性质。在LSO和其他听觉核中，神经元表现出几百Hz的极高的最大动作电位（AP）放电率，从而表现出广泛的神经元活动动态范围。一些神经元还具有出色的生物物理特性，例如输入电阻仅为5 MOhm的漏膜。我们将监测蒙古沙鼠（长爪沙鼠），一个良好的听觉模型动物的急性脑干切片中不同的听觉核团的代谢活动。详细地说，我们将通过荧光成像测量代谢中间产物（ATP，NADH和FAD），以及通过电化学记录测量耗氧量和细胞外代谢物浓度。还将监测电活动，以获得与刺激期间代谢变化的可靠相关性。数学和计算建模应补充实验方法，并描述能量（ATP）的生产以及各种神经元过程的消耗。通过这种互补的方法，我将回答以下问题：（1）神经元的代谢如何与其电活动，特别是AP放电率成比例？(2)生物物理特化（例如低膜电阻、巨大突触）是否会导致代谢过程中的异常能量需求或转换/适应？该项目还将通过研究不同细胞代谢过程的相关性以及星形胶质细胞对神经元代谢的贡献来贡献机制知识。最后，我们将研究介体参与调节神经元活动的代谢状态。通过选择一个专门的，但众所周知的系统具有特殊的性能，我期待新的一般性的见解神经能量学和代谢专业化的知识和从一个大脑区域到另一个的可转移性的重大贡献。这些信息将与不同的领域有关，如功能性脑成像，其中神经元代谢是基础，以及各种神经病理学，其中建议涉及神经能量学。

The brain and neuronal activity are among the major consumers of the body’s energy. However, little is known how neuronal activity correlates with metabolic processes in detail and how they mutually influence each other. To address questions in this context, we have established a novel model system by studying cellular metabolism in the lateral superior olive (LSO), one of the major brainstem nuclei involved in processing auditory signals. We have published first data on neuroenergetics of this nucleus and compared it with well-known metabolic model regions (hippocampus and cerebral cortex) of the same species. Auditory nuclei, such as the LSO, have a unique, well-defined structure-function relationship that allows for unequivocal correlation of neurons and their physiological function. Neurons in these nuclei are organised with locally homogeneous properties. In the LSO and other auditory nuclei, neurons exhibit extremely high maximal action potential (AP) firing rates of several hundred Hz and thereby a broad dynamic range of neuronal activity. Some of the neurons are also characterised by outstanding biophysical properties such as leaky membranes with an input resistance of only five MOhm. We will monitor metabolic activity in different auditory nuclei in acute brainstem slices of the Mongolian gerbil (Meriones unguiculatus), a well established auditory model animal. In detail, we will measure metabolic intermediates (ATP, NADH, and FAD) by fluorescence imaging as well as oxygen consumption and extracellular metabolite concentrations by electrochemical recordings. Electrical activity will also be monitored to obtain a reliable correlation with metabolic changes during stimulation. Mathematical and computational modelling shall complement the experimental approach and describe both energy (ATP) production as well as its consumption by various neuronal processes. By means of this complementary approach, I will answer the following questions: (1) How does metabolism of a neurone scale with its electrical activity, especially with AP firing rate? (2) Do biophysical specialisations (e.g. low membrane resistance, giant synapses) cause exceptional energy demands or switches/adaptations in metabolic processes? The project will also contribute mechanistic knowledge by studying the relevance of different cellular metabolic processes and the contribution of astrocytes to neuronal metabolism. Finally, we will study mediators involved in the regulation of neuronal activity by the metabolic state. By choosing a specialised, but well-known system with exceptional properties, I expect new general insights into neuroenergetics and a major contribution to the knowledge of metabolic specialisations and of transferability from one brain region to another. This information will be relevant for as different fields as functional brain imaging, where neuronal metabolism is the basis, and various neuropathologies, in which neuroenergetics was suggested to be involved.