Dorsal Raphe Serotonergic Neurons-Ventral Tegmental Area Neural Pathway Promotes Wake From Sleep

Background: Dorsal raphe nucleus (DRN) serotonergic neurons projecting to the ventral tegmental area (VTA) neural circuit participate in regulating wake-related behaviors; however, the effect and mechanism of which in regulating sleep-wake are poorly understood.

Methods: Fiber photometry was used to study DRN serotonergic afferent activity changes in the VTA during sleep-wake processes. Optogenetics and chemogenetics were took advantage to study the effects of DRN serotonergic afferents modulating VTA during sleep-wake. In vivo electrophysiology was employed to investigate how VTA neuronal firings were influenced by upregulation of DRN serotonergic afferents during sleep-wake.

Results: We found that DRN serotonergic afferent activity in the VTA was higher during wake than during NREM and REM sleep. Chemogenetic activation of VTA-projecting DRN serotonergic neurons increased wake, and optogenetic activation of DRN serotonergic terminals in the VTA induced wake during NREM and REM sleep. Furthermore, we found that optogenetic activation of DRN serotonergic terminals in the VTA increased glutamatergic neuronal firing, decreased dopaminergic neuronal firing, but not influenced GABAergic neuronal firing during NREM sleep.

Conclusion: Our findings provide evidence in understanding the role of DRN serotonergic neurons-VTA neural pathway in regulating sleep-wake, in which dynamic VTA dopaminergic, glutamatergic, and GABAergic neuronal firing changes responded to the wake promoting effect of DRN serotonergic afferents.