Corticotropin-Releasing Factor Neurons in the Hypothalamus Likely Have Role in Sleep/Wake Regulation

With sleep and wakefulness being regulated by several neuronal populations, the study authors sought determine which neuronal pathways are crucial for the circadian regulation of sleep/wakefulness.

A possible link between the suprachiasmatic nucleus (SCN) of the hypothalamus with sleep/wake regulation among mammals was found during a study of sleep regulation in mice by researchers from Nagoya University in Japan, which was published in Scientific Advances.

Five mouse lines were used for this study. Mice underwent surgical implantation of optogenetics, corticotropin-releasing factor (CRF) neuronal stimulation and inhibition, electrophysiological recording, and locomotor activity and sleep/wake assessment.

The investigators first identified that the axons of the SCN neurons were densely present in the paraventricular nucleus (PVN) of the hypothalamus. CRF neurons, involved with stress response, were also found in the PVN. When these CRF neurons were activated, the mice were more likely to wake (P <.05) and less likely to be in rapid eye movement (REM; P <.05) or non-REM sleep (P <.05).

To determine the downstream components of this wakefulness response, an anterograde tracing experiment identified axons localized in the lateral hypothalamus, which also contained orexin neurons. During wakefulness, the investigators observed optogenetic activation of nerve terminals in the lateral hypothalamus by CRF neurons, activating orexin neurons in the lateral hypothalamus (LH).

During a stress test, calcium signals in CRF neurons increased, during wakefulness a similar response was observed (P <.05), although this signal gradually decreased. Calcium signaling during REM and non-REM sleep was not observed in the CRF neurons (P =.069).

With the suppression of CRF neurons in the PVN, time in wakefulness was decreased (P <.05) and time in non-REM sleep was increased (P <.05). After partial ablation (50%-60%) of the CRF in the PVN, locomotor activity was reduced during wakefulness, however free-running behavior did not differ.

With fluorescent expression by the CRF neurons in both the SCN and PVN, a clear circadian calcium rhythm was observed by time-lapse photography. SCN and PVN rhythms appeared to be in antiphase, in which calcium peaked in the SCN during the day (P <.01) and in the PVN at night (P <.05).

This study was limited by not incorporating data on corticosterone release, which is known to effect physiological functions and nocturnal and diurnal behavior.

These findings suggested sleep and wake regulation involved calcium signaling by an SCN-PVN-LH pathway facilitated by CRF neurons.


Ono D, Mukai Y, Hung CJ, Chowdhury S, Sugiyama T, Yamanaka A. The mammalian circadian pacemaker regulates wakefulness via CRF neurons in the paraventricular nucleus of the hypothalamus. Sci Adv. 2020;6(45):eabd0384. doi:10.1126/sciadv.abd0384