The starting point of our project was the discovery that dopamine input on the mushroom body, the brain area that integrates olfactory signals with salient stimuli of positive or negative valence, triggers an increase in pyruvate consumption by mitochondria in these neurons, which is necessary and sufficient to initiate the formation of long-term memory. Since then, an important part of our work consisted in identifying how this dopamine input circuit was controlled. First, we have identified a new pair of neurons that uses the serotonin neuromodulator to activate the energy-modulating dopamine input. We additionally showed that the phosphodiesterase-encoding gene dunce must is inhibited in these serotonergic neurons to allow for long-term memory encoding, thus establishing this gene as a so-called ‘memory checkpoint’ gene (Scheunemann et al., Neuron 2018). Strikingly, we further found that this neuron is subjected to a post-mating regulation that enables dunce inhibition, which explained why virgin females could not properly form long-term memory (Scheunemann et al., Science Advances 2019). Second, we also identified another GABA-ergic feedback circuit that allows the proper shaping over time of the activity of the energy-regulating dopamine neurons (Pavlowsky et al., Current Biology, 2018).
In parallel, we initiated a systematic study of neuron-glia interaction during long-term memory formation. We showed that a particular type of glial cells, that enwraps the neuronal cell bodies, is activated during memory formation, and we delineated the full molecular mechanism of the neuron-to-glia and glia-to-neuron metabolic dialogue (de Tredern et al., Cell Reports 2021).
Developing a pioneer expertise in the fluorescent imaging of energy metabolism fostered collaboration with the group of Irene Miguel-Aliaga, on a project focused on inter-organ communication in Drosophila. Using fluorescent sensors that we provided, this group showed that carbohydrate metabolism in the intestine is sexually dimorphic and that gut-derived citrate promotes food intake and sperm production (Hudry et al., Cell 2019).
Finally, we have discovered a new source of energy required for memory formation under starvation (Silva et al, Nature Metabolism 2022). Thus, we have shown that glial cells (non neuronal cells of the brain), use fat to produce small energetic molecules called ketone bodies, which are transferred to neurons and sustain their activity. Before our work, it was thought that ketone bodies used by the brain in mammals originated only from the liver.
