Metabolic cost of neuronal activity

• Applicant: Privatdozent Dr. Lars Kunz
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413134986

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.

• DFG Programme: Research Grants