Metabolic underpinnings of age-dependent cognitive and neural circuit decline in Drosophila – MetabolicBrainAging

Decline in brain function, and the accompanying loss in cognitive abilities, is one of the most incapacitating consequences of aging. Although it is becoming clear that not all neural circuits nor brain functions are equally affected by aging, we still do not know the physiological characteristics that render certain cells or circuits more prone to dysfunction. Metabolic deficits, oxidative damage, and altered neuronal signaling are three functional manifestations of aging in brain tissues in many species. The objective of this project is to determine the causal relationships between declines of these modalities and their implication in aging-induced memory deficits. The Drosophila nervous system meets the major requirements to address this question, as being, first, well characterized at the cellular and circuit level, second, subject to natural aging on a time scale compatible with scientific research, and finally, amenable to in vivo imaging of these modalities. This project brings together two teams that combine long-standing expertise in innate and learned olfactory behavior in Drosophila, as well as a recent complementary focus on oxidative stress, energy metabolism and neuron-glia interaction as witnessed by recent high-profile publications and unpublished data. The thematic and technical complementarities between the two partners are essential to implement a cross-modality approach that is key to reach the objective of this project. Through the three aims defined in this proposal, we will establish (i) a multimodal map of functional decline in neuronal circuits and glial cells involved in olfaction and olfactory memory, (ii) challenge the sensitivity of memory circuits –neurons and glia– to oxidative stress, and finally (iii) investigate the causal link between impairments in energy metabolism and cognitive deficits. The ambition of this project is to characterize in Drosophila, the fundamental mechanisms responsible for age-induced functional decline of brain function, and answer the question why some neural circuits and neural processes are more sensitive to aging, with the expectation that our findings shall pave the way to identify and ultimately protect age-sensitive brain cells and circuits in humans.