Neural Circuitry Regulating Circadian Sleep-Wake Rhythm

Corresponding author e-mail: ilu@bidmc.harvard.edu Sleep-wake behavior is under control of the circadian pacemaker, the suprachiasmatic nucleus (SCN). Over the last decade, we have identified that for circadian control of sleep-wake behavior, the SCN projects to the ventral subparaventricular zone (SPZ), which then project to the dorsomedial hypothalamic nucleus (DMH). Lesions of the ventral SPZ and DMH abolish circadian rhythm of sleep-wake behavior. The key question is via which circuits the DMH control circadian rhythm of sleep-wake behavior. If we assume that the DMH has to target either sleep or arousal system or both, then we should examine circadian rhythm of sleep-wake behavior following lesions in sleep and arousal structures. At this point, only one sleep promoting area is found in the ventrolateral preoptic nucleus (VLPO). Interestingly, lesions of the VLPO do not significantly affect circadian rhythmicity of sleep-wake behavior, even though sleep is reduced by a half. Lesions of most arousal groups including the basal forebrain cholinergic neurons, locus coeruleus, raphe nucleus, tuberomamillary nucleus, orexin neurons, pontine cholinergic neurons and mesopontine dopaminergic neurons appear not to alter circadian sleep-wake rhythm. We recently have identified a novel arousal neuronal group in the parabrachical nucleus (PB) in the brainstem. All the PB neurons contain vesicular glutamate transporter 2 (VLGUT2) and thus are glutamatergic. To eliminate VGLUT2 gene, we inject an adeno-associated viral (AAV) vector containing Cre into the PB in flox-VGLUT2 mice. We found that loss of the glutamate signaling in the PB significantly reduces the amplitude of circadian sleep-wake rhythm and wakefulness by about 30%, and unmasks ultradain sleep-wake rhythm. We hypothesize that the DMH controls circadian sleep-wake rhythm via arousal systems including the PB. Support: NIH NS051609 and NS 062727 Publication History Article published online: 16 June 2026 © 2009. Brazilian Sleep Academy. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) Thieme Revinter Publicações Ltda. Rua Rego Freitas, 175, loja 1, República, São Paulo, SP, CEP 01220-010, Brazil