Nicotinamide mononucleotide stimulates the activity of bursting slow-oscillation neurons in the supramammillary nucleus and enhances REM sleep.

Nicotinamide mononucleotide (NMN) plays an important role in enhancing NAD+ levels and maintaining tissue functions in both mice and humans. Here, we show that NMN stimulates GABAergic neurons expressing Slc12a8, an NMN transporter, in the supramammillary (SuM) nucleus and enhances rapid eye movement (REM) sleep. By juxtacellular recording in the SuM, we have identified bursting slow-oscillation (SO) neurons that discharge in rhythmic theta burst at maximal rates during REM. Their firing frequency significantly decreases in aged mice, and NMN restores it to the level of young mice. The Slc12a8-deficient mice show defects in NMN response, decreased percent theta power during REM sleep, and impaired novel object recognition. Optogenetic stimulation of the SuM GABAergic neurons projecting to the cortex triggers cortical SO and theta rhythm, whereas chemogenetic inhibition of those neurons predominantly decreases REM sleep. These findings suggest that NMN stimulates SuM bursting SO neurons and promotes REM sleep during aging.