PROJECT SUMMARY Rapid eye movement (REM) sleep is a distinct brain state known for its association with vivid dreaming in humans, though it is also crucial for other cognitive functions such as memory consolidation and emotional processing. REM sleep is punctuated by short bursts of brain-wide electrical activity called ‘phasic events’, which can be measured as spike-like field potentials (P-waves) in the pons and as transient ‘theta bursts’ in the hippocampal EEG. A major knowledge gap in the field of REM sleep research lies in the identification of the neural circuits underlying i) REM sleep initiation, and ii) generation of phasic events within REM sleep. My early experiments in the Weber lab have suggested that a genetically distinct, heretofore unstudied population of neurons in the dorsomedial medulla (dmM) expressing corticotropin releasing hormone (CRH) could be important for both of these processes. I found that these novel dmM CRH+ neurons are selectively active during REM sleep, and that their activity is correlated with phasic hippocampal theta bursts. Importantly, optogenetic stimulation of the dmM CRH+ population promotes REM sleep in the mouse, suggesting that these neurons are functionally involved in controlling one or more features of REM sleep. Viral tracing experiments revealed CRH+ axons in the subcoeruleus area of the pons, which is the site of P-wave generation, as well as the nucleus incertus, a pontine region involved in the brainstem generation of the hippocampal theta rhythm. Given this preliminary data, I hypothesize that dmM CRH+ neurons are important for regulating i) REM sleep initiation, and ii) phasic events within REM sleep, via downstream projections to the pons. Aim 1 of my proposal will determine whether dmM CRH+ neurons promote REM sleep through interactions with the nucleus incertus, and whether these behavioral effects are mediated by the CRH neuropeptide itself. Aim 2 will test whether dmM CRH+ neurons are directly involved in generating pontine P- waves during REM sleep. Overall, these studies will rigorously interrogate the role of a novel pontomedullary circuit in REM sleep control, and elucidate the mechanisms by which the brainstem contributes to cognitive processing during this unique sleep stage.