A medullary hub for controlling REM sleep and pontine waves.

Rapid-eye-movement (REM) sleep is a distinct behavioral state associated with vivid dreaming and memory processing. Phasic bursts of electrical activity, measurable as spike-like pontine (P)-waves, are a hallmark of REM sleep implicated in memory consolidation. However, the brainstem circuits regulating P-waves, and their interactions with circuits generating REM sleep, remain largely unknown. Here, we show that an excitatory population of dorsomedial medulla (dmM) neurons expressing corticotropin-releasing-hormone (CRH) regulates both REM sleep and P-waves in mice. Calcium imaging showed that dmM CRH neurons are selectively activated during REM sleep and recruited during P-waves, and opto- and chemogenetic experiments revealed that this population promotes REM sleep. Chemogenetic manipulation also induced prolonged changes in P-wave frequency, while brief optogenetic activation reliably triggered P-waves along with transiently accelerated theta oscillations in the electroencephalogram (EEG). Together, these findings anatomically and functionally delineate a common medullary hub for the regulation of both REM sleep and P-waves.

Regulation of REM sleep by inhibitory neurons in the dorsomedial medulla.

The two major stages of mammalian sleep-rapid eye movement sleep (REMs) and non-REM sleep (NREMs)-are characterized by distinct brain rhythms ranging from millisecond to minute-long (infraslow) oscillations. The mechanisms controlling transitions between sleep stages and how they are synchronized with infraslow rhythms remain poorly understood. Using opto- and chemogenetic manipulation in mice, 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. Fiber photometry revealed that their activity is strongly increased during REMs and fluctuates during NREMs in close synchrony with infraslow oscillations in the sleep spindle band of the electroencephalogram. The phase of this rhythm influenced the latency and probability with which dmM activation induced REMs. Thus, dmM inhibitory neurons strongly promote REMs, and their slow activity fluctuations may coordinate the timing of REMs episodes with infraslow brain rhythms.

Cerebellar modulation of the reward circuitry and social behavior.

The cerebellum has been implicated in a number of nonmotor mental disorders such as autism spectrum disorder, schizophrenia, and addiction. However, its contribution to these disorders is not well understood. In mice, we found that the cerebellum sends direct excitatory projections to the ventral tegmental area (VTA), one of the brain regions that processes and encodes reward. Optogenetic activation of the cerebello-VTA projections was rewarding and, in a three-chamber social task, these projections were more active when the animal explored the social chamber. Intriguingly, activity in the cerebello-VTA pathway was required for the mice to show social preference in this task. Our data delineate a major, previously unappreciated role for the cerebellum in controlling the reward circuitry and social behavior.