Regulation of REM Sleep by Inhibitory Neurons in the Dorsomedial Medulla

Abstract

Mammalian sleep can be subdivided into two distinct brain states, rapid eye movement sleep (REMs) and non-REM sleep (NREMs). Each state is characterized by distinct brain rhythms ranging from millisecond to minute-long (infraslow) oscillations. The mechanisms controlling transitions between sleep states and how they are synchronized with infraslow brain rhythms remain poorly understood. Here, we show that GABAergic neurons in the dorsomedial medulla (dmM) promote the initiation and maintenance of REMs, in part through their projections to the dorsal and median raphe nuclei. Calcium imaging using fiber photometry demonstrated that dmM GABAergic neurons are strongly activated during REMs. During NREMs, their activity fluctuated in close synchrony with infraslow oscillations in the sigma power of the electroencephalogram (EEG). Together, these findings functionally and anatomically delineate a specific population of medullary neurons that powerfully control REMs. The slow oscillations in the activity of the dmM neurons may serve as a physiological link coordinating transitions from NREMs to REMs with infraslow brain rhythms.

Noradrenergic circuit control of non-REM sleep substates

“…Furthermore, the direct demonstration of LC’s role in HR variability could renew interest in the relation between HR variability and sleep disorders 56 . Finally, the neural systems underlying this coordination could reach beyond LC, as it is now clear that infraslow neuronal activities are present also in dorsomedial medulla during NREMS 57 .…”

“…The neural systems underlying this coordination could extend beyond LC, as infraslow neuronal activities were recently identified in dorsomedial medulla that projects to LC. 63 Furthermore, the direct demonstration of LC's role in HR variability will renew interest in the varied autonomic and central manifestations of arousal-like events during NREMS. 44 We find that mammalian sleep harnesses on wake promotion to enable sensory vigilance.…”

Noradrenergic circuit control of non-REM sleep substates

“…An interesting case is the coincidence of noradrenergic and cholinergic activity that occurs for tens of seconds prior to NREM-REMS transitions 6,12,13 and that gives rise to brief moments of high spindle activity, while hippocampus starts to generate REMS-related theta rhythmicity. 59 Infraslow activity variations during NREMS were recently also reported in REMS-regulating midbrain and medullar neurons 60,61 that target the serotonin-releasing raphe nuclei. 62 Therefore, not only NA but also levels of other neuromodulatory neurotransmitters, such as serotonin, are likely to fluctuate during NREMS.…”

“…71 Of particular interest are recent studies identifying infraslow fluctuations of neuronal activity in midbrain and dorsomedullar areas involved in the regulation of NREM-REMS cycle that innervate LC. 60,61 Alternatively, it is important to consider that the majority of LC neurons respond sensitively to CO 2 and pH changes. 73 Such chemosensation may activate LC during NREMS, for example, in response to pulsatile brain fluid exchange that, intriguingly, is anticorrelated to infraslow hemodynamic signals.…”

REM sleep, REM parasomnias, REM sleep behaviour disorder

“…During NREM sleep, their activity synchronizes with the infraslow oscillations of the EEG spindle band, modulating the latency of REM sleep episodes. Thus, dorsomedial and ventral medullary neurons promote REM sleep, and their slow activity-changes may coordinate NREM-REM sleep transitions 7 .…”