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

ABSTRACT 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.