Powering the Brain: the Cell Biology of Neuroenergetics

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Project Summary Synapses are conserved structures that govern information flow through neural circuits. My laboratory is interested in understanding how synapses are assembled and maintained in vivo to build the circuits that underlie behavior, and how they are modified to store memories. We recently made an unexpected discovery that is orthogonal to our research program and reframes our understanding of the principles governing synaptic function. We discovered that during energy stress, glycolytic proteins in C. elegans dynamically relocalize to synapses to meet local energy demands and power the synaptic vesicle cycle. Our findings underscore an important relationship between individual synapses and their local energy environments. Based on these findings we propose the bold hypothesis that local regulation of energy metabolism underlies the plastic properties of specific neurons and synapses, thereby governing circuit function and animal behavior. Our proposed hypothesis is unconventional. While functional magnetic resonance spectroscopy studies have demonstrated that brain metabolism is tightly linked to neuronal function at a circuit level, how energy metabolism is regulated at a subcellular level is not understood, or considered in the context of synaptic physiology and plasticity. Could energy metabolism be compartmentalized within cells to preferentially power specific cellular functions? Could local regulation of energy flow within neurons (neuroenergetics) restrict, or potentiate, information processing and circuit function? Understanding how neuroenergetics is locally regulated within neurons could be paradigm shifting, reframing our knowledge regarding the mechanisms that regulate synaptic function, both in physiology and in disease. In this Pioneer proposal, we rigorously examine our hypothesis with new cell biological probes to be used in vivo, in specific neurons and in behaving C. elegans to understand neuroenergetics in single synapses. We examine how membrane-less metabolic subcompartments form through liquid-phase transition, and the physiological implications of their localization to subcellular regions. Completion of the proposed work could have impact beyond the field of neuroscience, as it could broadly reframe the importance of local metabolism and its functional role in meeting local energy demands in cells.