LACTATE ENHANCES PYRAMIDAL NEURON-DRIVEN VASOCONTRICTION

Brain function relies on an uninterrupted supply of oxygen and glucose provided by a dense vascular network tightly regulated by neuronal activity. Cortical pyramidal neurons play a central role in this regulation by controlling local cerebral blood flow through neurovascular coupling (NVC) and promoting astrocytic lactate release via neurometabolic coupling. Lactate is essential for learning and memory, but becomes detrimental in excess, and its role in NVC remains unclear. We previously showed that lactate uptake by pyramidal neurons enhances their excitability through the closure of ATP-sensitive potassium channels and that they exert a frequency-dependent bimodal control of NVC. These observations suggest that pyramidal neurons could constitute a hub integrating the beneficial and deleterious effects of lactate on the NVC. To test this hypothesis, we combined vascular imaging with calcium imaging or optogenetic control of pyramidal cells in slices of adult mice. Using CamK2a-GCaMP8 mice, we observed spontaneous calcium activity under basal conditions and that lactate induces vasoconstriction. To evaluate the influence of lactate on the NVC controlled by pyramidal cells we used CamK2a-ChR2 mice slices. In preconstricted arterioles, low-frequency (2 Hz) stimulation induced vasodilation, whereas high-frequency (≥ 10 Hz) photostimulation triggered vasoconstriction, similar to in vivo responses. Preliminary results further showed that lactate enhanced optogenetically-induced vasoconstriction. Together, these results highlight lactate as a key modulator of NVC. Determining how lactate shapes pyramidal neuron activity and the contribution of astrocytes in this fine tuning will be critical to decipher the multifaceted roles of lactate in neurovascular regulation.