MetaTuNe

Local control of cerebral blood flow (CBF) and metabolism by neuronal activity is essential for brain function. This neurovascular and neurometabolic coupling (NVC/NMC) ensures cerebral glucose homeostasis and leads to a transient surge in extracellular lactate. Under physiological conditions, the neuronal uptake of lactate, which can be produced by astrocytes or supplied by the blood after a physical exercise, supports NVC/NMC, learning and memory. The excess of lactate, however, is also deleterious since its use is responsible for epileptiform activities and the associated CBF decrease. We have recently shown that lactate consumed by cortical neurons increases their activity through a closure of ATP-sensitive potassium channels. Our preliminary data also revealed that pyramidal cells, pivotal players in NVC/NMC, cause vasodilation or vasoconstriction, when discharging at moderate or high frequencies, respectively. These observations suggest that moderate neuronal activity would increase CBF and lactate supply, while lactate high-levels and/or elevated neuron activity would exert a negative feedback control of CBF so as to restrict energy metabolites supply and mitigate network hyperactivity. Thus, based on our preliminary work and current knowledge, we hypothesize that lactate can differentially tune NVC depending on neuronal activity and metabolic context: at moderate activity levels, lactate may promote vasodilation, learning and memory, but at high levels may favor vasoconstriction to exert a feedback control on brain energy supply and network activity. To explore this hypothesis, our project aims at: 1) Investigating the molecular mechanisms underlying lactate regulation of NVC 2) Determining the effect of systemic lactate on the feedback control in NVC 3) Evaluating the contribution of local astrocytic lactate to NVC regulation 4) Probing the impact of increased systemic and/or cerebral lactate on learning and memory By addressing the relative contribution of neurons, astrocytes and blood vessels to energy supply and by combining ex vivo and in vivo approaches MetaTuNe will provide a comprehensive overview of the metabolic regulation of activity-dependent CBF and will thus contribute to precisely decipher the functional impact of NVC and NMC on learning and memory. Using complementary ex vivo and in vivo approaches combining multimodal imaging with polychromatic optogenetic and pharmacological manipulations as well as behavioral testing, we believe that this project will provide a better understanding of NVC/NMC coordination and its importance in learning and memory. Furthermore, since the NVC/NMC is the physiological basis for functional imaging, MetaTuNe will also contribute to a better interpretation of brain imaging signals. This project could also lead to the identification of diagnostic biomarkers and contribute to define personalized therapeutic protocols. In the long-term, MetaTuNe could thus promote the adjustment of a lifestyle (e.g. physical activity) adapted to neurological disorders such as epilepsy, Alzheimer's disease or migraine, in which neuro-glio-vascular and metabolic alterations overlap, and thus contribute to a personalized medicine.