Exploration of neuronal ensembles responsible for sleep and body temperature regulation

Abstract

Sleep is a behaviour we experience every day but the fundamental function(s) and the neuronal circuitry underlying it remain mystery. Previous study from our laboratory suggests the lateral preoptic (LPO) area of the hypothalamus plays an important role in recovery sleep (RS) after sleep deprivation (SD) as well as 2-adrenergic agonist (dexmedetomidine)-induced sedation and hypothermia. Preliminary data of whole-brain mapping of the neuronal activity of 5-hr SD mice and 2- hr RS (followed 5-hr SD) mice by cFos expression confirmed that the LPO shows higher neuronal activity in RS mice compared to SD mice. Cell-type specific ablation of galaninergic neurons in the LPO abolished sleep homeostasis in mice, in terms of the amount of RS as well as the increased slow wave activity (SWA) of RS after SD which is a hallmark of sleep homeostasis. In addition, mice with ablation of LPOGal neurons have a permanent elevation in their body temperature compared to control mice. LPOGal neurons are also involved in mediating dexmedetomidine (DEX)-induced sedation and hypothermia. Mice without LPOGal neurons have reduced effects: administration of DEX cannot induce high-power  oscillations or sustained hypothermia. Together, LPOGal neurons unite sleep homeostasis and 2-adrenergic sedation. Preliminary whole-brain cFos mapping also revealed a few other potential brain regions that might be involved in sleep/wake regulation, including the ventral tegmental area (VTA). Chemogenetic activation and inactivation increase the neuronal activity of VTAVglut2 and VTAVgat neurons, respectively, and both increase wakefulness. VTAVglut2/Nos1 neurons promote wakefulness by sending excitatory projections to both the lateral hypothalamus (LH) and nucleus accumbens (NAc), whereas the wake-inhibiting effect of VTAVgat neurons is achieved by sending inhibitory projections to local VTAVglut2 and VTADA neurons as well as to the orexin neurons in the LH, implying the significance of the VTA in sleep/wake regulation.