An Inhibitory Lateral Hypothalamic-Preoptic Circuit Mediates Rapid Arousals from Sleep.

Among the neuronal populations implicated in sleep-wake control, the ventrolateral preoptic (VLPO) nucleus has emerged as a key sleep-promoting center. However, the synaptic drives that regulate the VLPO to control arousal levels in vivo have not to date been identified. Here, we show that sleep-promoting galaninergic neurons within the VLPO nucleus, defined pharmacologically and by single-cell transcript analysis, are postsynaptic targets of lateral hypothalamic GABAergic (LH) neurons and that activation of this pathway in vivo rapidly drives wakefulness. Ca imaging from LH neurons indicate that they are both wake and rapid eye movement (REM)-sleep active. Consistent with the potent arousal-promoting property of the LH → VLPO pathway, presynaptic inputs to LH neurons originate from several canonical stress- and arousal-related network nodes. This work represents the first demonstration that direct synaptic inhibition of the VLPO area can suppress sleep-promoting neurons to rapidly promote arousal.