Neuronal feedback loop of the suprachiasmatic nucleus generates robust circadian rhythms

Jan 4, 2026Nature communications

Feedback within the brain’s main clock supports strong daily rhythms

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Abstract

Arginine vasopressin (AVP) neurons oscillate intrinsically with a short period and reduced amplitude in mice lacking vasoactive intestinal polypeptide (VIP).

VIP amplifies and phase-delays the AVP neuronal rhythm, lengthening its period to approximately 24 hours in constant darkness.
AVP neuron-specific VIP receptor dysfunction shortens the behavioral circadian period.
Blockade of neurotransmitter release specifically in AVP neurons lengthens the circadian period.
Weak, unstable, long-period calcium rhythms in VIP neurons and other SCN cell types occur when AVP neuronal oscillation is reduced.
AVP neurons are identified as the primary pacesetter cells for the overall rhythm of the SCN.

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The central circadian clock of the suprachiasmatic nucleus (SCN) comprises a network of diverse neuronal and glial cell types, yet its operating mechanism remains elusive. Here, by monitoring cellular calcium rhythms in vivo using dual-color fiber photometry in mice lacking vasoactive intestinal polypeptide (VIP), we demonstrate that arginine vasopressin (AVP) neurons oscillate intrinsically with a short period and reduced amplitude. This indicates that VIP normally amplifies and phase-delays the AVP neuronal rhythm each day, thereby lengthening its period to approximately 24 h in constant darkness. Consistently, the behavioral circadian period is shortened by AVP neuron-specific VIP receptor dysfunction and lengthened by AVP neuron-specific blockade of neurotransmitter release. VIP neurons and other SCN cell types occasionally exhibit weak, unstable, long-period calcium rhythms only when the AVP neuronal oscillation is attenuated due to VIP deficiency or AVP neuron-specific Bmal1 deletion. Given that AVP neurons serve as the primary pacesetter cells of the SCN ensemble rhythm, these results indicate that an SCN neuronal feedback loop (SNFL), composed of the AVP cellular oscillator and VIPergic signaling, is essential for generating robust circadian rhythms.

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Neuronal feedback loop of the suprachiasmatic nucleus generates robust circadian rhythms

Abstract

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