Gallopin, T. | Search bioRxiv

bioRxiv2022

Social defeat induces REM sleep fragmentation through the PFC-VLPO pathway

The brainstem and hypothalamic structures implementing the daily cycles of wake, REM and NREM sleep have now been identified in remarkable detail. However, sleep structure dynamically adapts to environmental stressors, likely requiring top-down cortical feedback that is as yet unidentified. Here, we investigate the role of projections from prefrontal cortex (PFC), a key hub in stress regulation, to the ventro-lateral preoptic areas (VLPO), a master regulator of sleep states. Using ex vivo optogenetics, we demonstrate that activation of PFC terminals induces monosynaptic excitatory glutamatergic currents in VLPO NREM-promoting neurons. In vivo, activation of PFC-VLPO projections interrupts ongoing REM in favour of NREM, leading to fragmented REM bouts. Remarkably, chemogenetic inhibition of PFC-VLPO projections has no effect in baseline conditions but it blocks the REM fragmentation induced by Social Defeat Stress. Therefore, the PFC-VLPO pathway provides a top-down regulation specifically recruited in stressful conditions to induce short, fragmented REM bouts and favor NREM sleep.

neuroscience↗

bioRxiv2021

LACTATE IS A MAJOR ENERGY SUBSTRATE FOR CORTICAL NEURONS AND ENHANCES THEIR FIRING ACTIVITY

Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with Kir6.2 and SUR1 subunits, which we show are functionally expressed in most neocortical neuronal types. We also demonstrate the ability of cortical neurons to take-up and metabolize lactate. We further reveal that ATP is produced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis. Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate, and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function. HighlightsO_LIMost cortical neurons subtypes express pancreatic beta-cell like KATP channels. C_LIO_LILactate enhances spiking activity via its uptake and closure of KATP channels. C_LIO_LICortical neurons take up and oxidize lactate. C_LIO_LICortical neurons produce ATP mainly by oxidative phosphorylation. C_LI

neuroscience↗