Metabolic cost of neuronal activity

大脑和神经活动是人体能量的主要消耗来源。然而，很少有人知道神经元活动如何与代谢过程详细相关，以及它们如何相互影响。为了解决这方面的问题，我们通过研究外侧上橄榄核(LSO)的细胞代谢建立了一个新的模型系统，LSO是参与处理听觉信号的主要脑干核团之一。我们已经发表了关于这个核团的神经能量学的第一批数据，并将其与同类众所周知的代谢模型区域(海马体和大脑皮层)进行了比较。听觉核团，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之间明确的关联。这些核团中的神经元具有局部同质性。在LSO和其他听觉核团中，神经元表现出极高的最大动作电位(AP)放电率，达到数百赫兹，因此神经元活动的动态范围很广。一些神经元还具有突出的生物物理特性，例如输入电阻仅为5欧姆的漏膜。我们将监测蒙古沙鼠急性脑干切片中不同听觉核团的代谢活动，长爪沙鼠是一种公认的听觉模型动物。具体来说，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来测量耗氧量和胞外代谢物浓度。电活动也将被监测，以获得与刺激期间代谢变化的可靠关联。数学和计算模型应补充实验方法，并描述能量(ATP)的产生以及各种神经元过程对其的消耗。通过这种互补的方法，我将回答以下问题：(1)神经元的新陈代谢如何与其电活动，特别是AP的放电率有关？(2)生物物理的特殊性(例如，低膜电阻，巨大的突触)是否会导致代谢过程中的特殊能量需求或开关/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械知识。最后，我们将研究参与代谢状态调节神经元活动的介质。通过选择一个专门的、但众所周知的具有特殊特性的系统，我期待着对神经能量学的新的一般性见解，并对代谢专门化和大脑区域之间的可转移性的知识做出重大贡献。这些信息将与不同的领域相关，如以神经元代谢为基础的脑功能成像，以及被认为涉及神经能量学的各种神经病理学。

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.