Medullary Control of REM Sleep

About This Grant

SUMMARY Rapid eye movement sleep (REMS) is regulated by dynamic interactions between REMS-promoting (REM-on) and REMS-suppressing (REM-off) neurons. Once REMS is entered, the activity in distinct brainstem nuclei gives rise to its distinct phasic features such as rapid eye movements and pontine (P-) waves, defining hallmarks of phasic REMS. Research within the last decade has identified multiple cell populations that control REMS and mapped their connectivity. However, the population-level dynamics underlying REMS initiation and its phasic features remain poorly understood. In the initial grant phase, we showed that inhibitory neurons in the dorsomedial medulla (dmM) strongly promote REMS via their projections to the dorsal and median raphe. In addition, we identified an excitatory subpopulation expressing corticotropin-releasing hormone (CRH) that reliably induces P-waves. These neurons project to the dorsolateral pons, a critical site for P-wave generation in rodents. In preliminary experiments, we performed high- density electrophysiological recordings in dorsal (DR) and median raphe (MR) and in the dorsolateral pons. Performing dynamical systems analysis, we uncovered two key features: First, the population activity in DR/MR exhibits consistent trajectories passing from an NREM attractor to a REM attractor through a specific entry point, and second, the dorsolateral pons shows bistable dynamics that switch between tonic and phasic REMS states. The central objective of this proposal is to understand how distinct populations in the dmM shape downstream midbrain and pontine population dynamics to facilitate transitions to REMS and regulate phasic REMS. This will be accomplished in two aims. First, we will perform high-density recordings combined with opto- and chemogenetic manipulation and viral tracing to reveal how inhibitory dmM inputs and subpopulations within DR and MR shape the population dynamics to initiate REMS. Second, we will investigate how projections from the dmM to the dorsolateral pons regulate P-waves and phasic REM by combining electrophysiological recordings in pons and medulla with optogenetic perturbation. By integrating state-of-the-art systems neuroscience techniques with dynamical systems analysis, our study will uncover how distinct medullary populations regulate the population dynamics in midbrain and pontine areas to regulate REMS induction and its substage architecture. Since disturbances in REMS, particularly in its timing and phasic features, are key symptoms of mood disorders such as major depressive disorder (MDD), our findings will provide critical mechanistic insights and may identify novel therapeutic targets for restoring healthy sleep in depression.