Vasoactive intestinal peptide and the mammalian circadian system

Abstract

In mammals, the circadian oscillators that drive daily behavioral and endocrine rhythms are located in the hypothalamic suprachiasmatic nucleus (SCN). While the SCN is anatomically well-situated to receive and transmit temporal cues to the rest of the brain and periphery, there are many holes in our understanding of how this temporal regulation occurs. Unanswered questions include how cell autonomous circadian oscillations within the SCN remain synchronized to each other as well as communicate temporal information to downstream targets. In recent years, it has become clear that neuropeptides are critically involved in circadian timekeeping. One such neuropeptide, vasoactive intestinal peptide (VIP), defines a cell population within the SCN and is likely used as a signaling molecule by these neurons. Converging lines of evidence suggest that the loss of VIP or its receptor has a major influence on the ability of the SCN neurons to generate circadian oscillations as well as synchronize these cellular oscillations. VIP, acting through the VPAC(2) receptor, exerts these effects in the SCN by activating intracellular signaling pathways and, consequently, modulating synaptic transmission and intrinsic membrane currents. Anatomical evidence suggests that these VIP expressing neurons connect both directly and indirectly to endocrine and other output targets. Striking similarities exist between the role of VIP in mammals and the role of Pigment Dispersing Factor (PDF), a functionally related neuropeptide, in the Drosophila circadian system. Work in both mammals and insects suggests that further research into neuropeptide function is necessary to understand how circadian oscillators work as a coordinated system to impose a temporal structure on physiological processes within the organism.

Neuropeptides go the distance for circadian synchrony

“…The conclusion here that VIP-VPAC2R signaling dominates is consistent with the observation that loss of VIP or VPAC2R abolishes circadian rhythms in most behaviors and physiological processes in most mice (11,12). That GRP and AVP can, in the absence of VIP, suffice to sustain daily cycling is consistent with the observation that some or all VIP/VPAC2R-deficient mice can still show synchronized circadian rhythms under some conditions (16) and that GRP can induce rhythms in VPAC2R-null SCN (17).…”

“…They started by asking whether the SCN taken from a wild-type mouse is capable of rescuing daily rhythms in the SCN taken from an arrhythmic mouse. Previous studies had demonstrated that loss of vasoactive intestinal polypeptide (VIP) or its cognate receptor, VPAC2R (encoded by the Vipr2 gene) abolished synchronized circadian rhythms in the SCN and in locomotor behavior (11,12). The new study (2) shows that wild-type SCN can quickly restore rhythms to SCN lacking VIP.…”

Salivary VIP concentrations are elevated in humans after acute stress

“…There is also evidence which suggests that VIP may play a role in the regulation of the HPA-axis (Nussdorfer et al, 1998). VIP may also play a role centrally where it is a major peptide involved in the suprachiasmatic nucleus of the hypothalamus, which is the circadian pacemaker (Vosko et al, 2007). However, it is important to note that VIP's role in the CNS may have no correlation with its role in the parasympathetic nerves.…”

“…Other studies highlight the importance of VIP in relation to the regulation of circadian variations. Evidence suggests that VIP is important for the normal functioning of the suprachiasmatic nucleus in the hypothalamus (Loh et al, 2008;Vosko et al, 2007;Piggins et al, 2003). A study performed in VIP knockout mice demonstrates that the circadian rhythms of ACTH and corticosterone are lost and the authors suggest a role for VIP in regulating the mammalian master clock (Loh et al, 2008).…”

“…Vosko et al suggests that VIP plays a key role in circadian timekeeping. The review suggests that VIP is used as signaling molecule by the neurons of the SCN in order to generate circadian oscillations (Vosko et al, 2007).…”