A top-down control of stress-induced REM sleep shortening.

Abstract

The cerebral structures orchestrating the daily cycles of wake, rapid eye movement (REM), and non-rapid eye movement (NREM) sleep have been identified in remarkable detail. However, the mechanisms by which they dynamically adapt to environmental challenges remain to be fully understood. Here, we show that the prefrontal cortex (PFC), a key hub in stress regulation, modulates sleep architecture through direct projections to the ventrolateral preoptic nucleus (VLPO), a major sleep center. We characterize the detailed sleep architecture in mice after social defeat stress (SDS) and discover, for the first time, a persistent shortening of REM sleep bouts during the light phase, which outlasts the normalization of overall NREM sleep, REM sleep, and wakefulness proportions. This shift, marked by an increase in short REM sleep episodes and a reduction in long ones, is reminiscent of the fragmentation of REM sleep bouts often described in stress-related conditions. Chemogenetic inhibition of PFC to VLPO projections has no effect under baseline conditions but prevents the SDS-induced shortening of REM sleep bouts. Interestingly, optogenetic activation of this pathway is sufficient to shorten REM sleep episodes, despite the absence of the stressor, and promotes rapid transitions into NREM sleep. Finally, using ex vivo optogenetics, we demonstrate that activation of PFC terminals induces monosynaptic currents in VLPO sleep-promoting neurons. Therefore, the PFC-VLPO pathway provides top-down regulation specifically recruited under stress to shorten REM sleep episodes and increase transitions into NREM sleep while preserving total NREM sleep duration.