The mammalian circadian pacemaker regulates wakefulness via CRF neurons in the paraventricular nucleus of the hypothalamus

Abstract

In mammals, the daily rhythms of physiological functions are timed by the central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Although the importance of the SCN for the regulation of sleep/wakefulness has been suggested, little is known about the neuronal projections from the SCN, which regulate sleep/wakefulness. Here, we show that corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus mediate circadian rhythms in the SCN and regulate wakefulness. Optogenetic activation of CRF neurons promoted wakefulness through orexin/hypocretin neurons in the lateral hypothalamus. In vivo Ca2+ recording showed that CRF neurons were active at the initiation of wakefulness. Furthermore, chemogenetic suppression and ablation of CRF neurons decreased locomotor activity and time in wakefulness. Last, a combination of optical manipulation and Ca2+ imaging revealed that neuronal activity of CRF neurons was negatively regulated by GABAergic neurons in the SCN. Our findings provide notable insights into circadian regulation of sleep/wakefulness in mammals.

Circadian Rhythms of the Hypothalamus: From Function to Physiology

“…However, other studies centered on the examination of SCN grafts reveal that the PVN is still heavily dependent on the SCN for rhythmic activity [ 114 ]. A prime example of this includes a recent optogenetic study, which identifies a SCN–PVN–LH neurocircuit involved in the regulation of wakefulness [ 115 ]. These data suggest that the cortisol-releasing hormone (CRH) neurons in the PVN may act as a “pulse generator”, whose excitability is regulated by SCN innervations [ 115 ].…”

“…The DMH, which receives heavy innervation from the SPVZ, is thought to integrate circadian signals to regulate sleep and wakefulness [ 66 , 223 ]. Recently, SCN projection to CRH-PVN neurons have also been shown to contribute to wakefulness [ 115 ], highlighting how much still remains to be uncovered in the hypothalamic role of sleep regulation, circadian rhythms and metabolism.…”

“…These findings underscore a bidirectional relationship between the HPA axis and rhythmic ARC and PVN neurons, suggesting an important feedback loop whereby stress-induced chronodisruption influences metabolism and food intake. The recent identification of a neurocircuit whereby GABAergic SCN neurons project to CRH-PVN neurons which excite the OX-LH neurons stimulating wakefulness in mice [ 115 ] further highlights the diverse involvement of the CRH neurons and their CORT production in balancing homeostatic processes.…”

Neurobiological and Hormonal Mechanisms Regulating Women’s Sleep

“…Like other stress systems, the HPA has been correlated with wakefulness. Sleep deprivation increases HPA activity, and optogenetic activation of CRF neurons within the HPA promotes wakefulness while chemogenetic inhibition decreases wake time ( Minkel et al, 2014 ; Li et al, 2020 ; Ono et al, 2020 ). The HPA axis has also been correlated with circadian rhythmicity, suggesting the possibility that HPA activity could influence the circadian system to regulate sleep ( Kalsbeek et al, 1995 ; Tousson and Meissl, 2004 ).…”

Efficacy of melatonin in non-intensive care unit patients with COVID-19 pneumonia and sleep dysregulation

“…While the POA contains not only sleep-promoting neurons but also wake-promoting neurons (9), noradrenergic neurons in the locus coeruleus, serotonergic neurons in the dorsal raphe, and histaminergic neurons in the tuberomammillary nucleus are only implicated in regulation of wakefulness (10). Orexin/hypocretin neurons in the lateral hypothalamus play a crucial role to maintain wakefulness by orchestrating the activity of these monoaminergic neurons (11).…”