Thomas Preat & Pierre-Yves Plaçais - Energy & Memory

Constraints on energy efficiency throughout evolution have resulted in highly conserved networks of metabolic pathways underlying the function of all eukaryotic cells. Brain cells, neurons and glia, are no exception to this, and pioneer works, including ours, outline that metabolic regulations are key players of brain cellular physiology, neuronal plasticity, and the resulting behaviors.
Our Energy & Memory team is globally interested in the still little-explored interaction between energy metabolism and memory formation. We use Drosophila melanogaster as a working species, leveraging both the unique panoply of genetic-based analytical tools, and the exquisite knowledge of neuronal circuits underlying olfactory associative memory from decades of research. We can therefore achieve precise in vivo manipulation and measurement of biochemical pathways in a cell-specific manner, in relation to behavior. Our strategy combines neurogenetics, behavior analysis and in vivo brain imaging using genetically encoded fluorescent probes.

Integrated analysis of the interplay between memory and energy metabolism
Through our integrated approach, we uncovered different patterns of learning-induced activation of metabolic pathways in the mushroom body, the brain center encoding olfactory memory in Drosophila. Addressing these questions in the ‘simple’ Drosophila brain is a powerful way to uncover novel and unexpected basic mechanisms to generate hypotheses testable in other species.
Our recent and ongoing research explore three main axes:
• Neuron-glia metabolic interactions underlying memory formation
• Plasticity of the neuronal mitochondrial network associated with memory formation
• State- and experience-dependent regulation and coordination of cellular metabolism by neuropeptides

The disruption of H2O2 signaling as a new framework for Alzheimer’s disease
Another major objective of our team is to contribute to deciphering the molecular and cellular disorders that are at the root of Alzheimer’s disease (AD). Our project is motivated by the facts that AD is linked to early defect in brain energy metabolism and the accumulation of toxic reactive oxygen species. AD is characterized by a very long asymptomatic phase. The key question is: how does the human brain transition from a physiological to a pathological state years before memory impairment becomes apparent? We have recently discovered in Drosophila a new synaptic plasticity pathway involves in long-term memory formation. This pathway involves interactions between neurons and astrocytes that trigger the transient oxidation of specific signaling proteins. This plasticity mechanism, termed ANHOS (Astrocyte-to-Neuron H₂O₂ Signaling), is supported by the copper-binding function of the Amyloid Precursor Protein. Strikingly, we demonstrated that ANHOS is inhibited by human amyloid-beta 42, a primary factor in AD. Based on these results, we propose a new framework for studying the origin of AD, which would be linked to a lack of beneficial reactive oxygen species. One of our goal is to suggest new avenues of treatment.