Energy, chaperones, and memory: synapse-specific mechanisms of consolidation in the fly brain

In this project, we aim to elucidate the mechanistic basis of long-term memory (LTM) formation at the synapse, focusing on key factors that have been identified as crucial to this process: neuromodulation as a primer for consolidation, as well as mitochondria and heat shock proteins as local mediators. In Drosophila melanogaster, dopamine and serotonin regulate memory gating by integrating external and internal states, thereby promoting synapse-specific consolidation. Beyond their essential role in energy provision, mitochondria are actively recruited to LTM-associated synapses, but not to those involved in short-term memory. Moreover, alterations in mitochondrial calcium signaling can enhance memory performance beyond wild-type levels. Heat shock proteins, in turn, directly influence memory performance at the behavioral level, suggesting a role that extends past mere chaperoning. To disentangle the mechanistic interplay among these factors, we employ a multidisciplinary approach that integrates behavioral and molecular analyses in Drosophila, connectomics dataset analysis, and mathematical modeling to generate and test predictions.