Roles of Neuropeptides, VIP and AVP, in the Mammalian Central Circadian Clock

Abstract

In mammals, the central circadian clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Individual SCN cells exhibit intrinsic oscillations, and their circadian period and robustness are different cell by cell in the absence of cellular coupling, indicating that cellular coupling is important for coherent circadian rhythms in the SCN. Several neuropeptides such as arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) are expressed in the SCN, where these neuropeptides function as synchronizers and are important for entrainment to environmental light and for determining the circadian period. These neuropeptides are also related to developmental changes of the circadian system of the SCN. Transcription factors are required for the formation of neuropeptide-related neuronal networks. Although VIP is critical for synchrony of circadian rhythms in the neonatal SCN, it is not required for synchrony in the embryonic SCN. During postnatal development, the clock genes cryptochrome (Cry)1 and Cry2 are involved in the maturation of cellular networks, and AVP is involved in SCN networks. This mini-review focuses on the functional roles of neuropeptides in the SCN based on recent findings in the literature.

Keywords: AVP; VIP; circadian rhythm; entrainment; neuronal coupling; suprachiasmatic nucleus; synchronization.

FIGURE 1

Neuropeptides expressed in the suprachiasmatic nucleus (SCN) and intracellular signaling. (A) A variety of neuropeptides expressed in the SCN (top). Cells with an autonomous circadian oscillator are schematically shown in the SCN in coronal plane. Circles of different sizes indicate the percentage of neurons expressed in the SCN. Arginine vasopressin (AVP), enkephalin (ENK), and angiotensin II (AII) are expressed mainly in the dorsal area of the SCN, whereas vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), neurotensin (NT), and calretinin (CALR) are mainly expressed in the ventral SCN. Neuromedin-S (NMS) is broadly expressed in the SCN, and gamma aminobutyric acid (GABA) in almost all SCN neurons. Schematic view of the intracellular pathways mediating neuropeptide signals in the SCN (bottom). Neuropeptides bind G-protein-coupled receptors (Gq, Gs) and modulate second messenger signaling such as cAMP or Ca²⁺. These signals facilitate the phosphorylation of CREB proteins and change the transcription of Per genes. Some signaling from transcription–translation feedback loop (TTFL) could modulate cAMP or Ca²⁺ rhythms. (B) Schematic drawing demonstrating the distribution of eight types of peptidergic neurons within the unilateral coronal SCN slice. Directions are shown in the lower right SCN.

FIGURE 2

Developmental changes in cellular coupling mechanisms in the suprachiasmatic nucleus (SCN). (A) Tissue-level PER2:LUC bioluminescence from the cultured SCN in neonate or adult mice (left). Wild-type (WT) SCNs show circadian rhythms in both neonatal and adult SCNs. Cryptochrome (Cry)1^{– /–}/Cry2^{– /–} SCNs show robust circadian rhythms in the neonate SCN, but not in the adult SCN. Whereas Cry1^{– /–}/Cry2^{– /–}/vasoactive intestinal polypeptide (Vip)2r^{– /–} SCN is arrhythmic both in the neonate and adult, which is due to desynchronization of cellular circadian rhythms. Arginine vasopressin (Avp)-ELuc bioluminescence from the cultured SCN in neonate or adult mice (right). Circadian Avp expression rhythms are observed in the WT SCN, but they are arrhythmic and expression is attenuated in Cry1^{– /–}/Cry2^{– /–} SCN both at neonatal and adult periods. (B) Schematic view of a model of cellular coupling in the SCN during postnatal development. CRY1 and CRY2 are involved in the developmental shift from CRY-independent (via VIP) to CRY-dependent (via AVP) networks in the SCN. Green and pink circles indicate VIP and AVP neurons, respectively. Green and pink arrows indicate signaling via VIP and AVP, respectively. This shift is observed around postnatal days 14–21. Modified from Ono et al., 2016.