Signaling within the Master Clock of the Brain: Localized Activation of Mitogen-Activated Protein Kinase by Gastrin-Releasing Peptide

Abstract

The circadian clock located in the mammalian suprachiasmatic nucleus (SCN) exhibits substantial heterogeneity in both its neurochemical and functional organization, with retinal input and oscillatory timekeeping functions segregated to different regions within the nucleus. Although it is clear that photic information must be relayed from directly retinorecipient cells to the population of oscillator cells within the nucleus, the intra-SCN signal (or signals) underlying such communication has yet to be identified. Gastrin-releasing peptide (GRP), which is found within calbindin-containing retinorecipient cells and causes photic-like phase shifts when applied directly to the SCN, is a candidate molecule. Here we examine the effect of GRP on both molecular and behavioral properties of the hamster circadian system. Within 30 min a third ventricle injection of GRP produces an increase in the number of cells expressing the phosphorylated form of extracellular signal-regulated kinases 1/2 (p-ERK1/2), localized in a discrete group of SCN cells that form a cap dorsal to calbindin cells and lateral to vasopressin cells. At 1 h after the peak of p-ERK expression these cap cells express c-fos, Period1, and Period2. Pharmacological blockade of ERK phosphorylation attenuates phase shifts to GRP. These data indicate that GRP is an output signal of retinorecipient SCN cells and activates a small cluster of SCN neurons. This novel cell group likely serves as a relay or integration point for communicating photic phase-resetting information to the rhythmic cells of the SCN. These findings represent a first step in deconstructing the SCN network constituting the brain clock.

Gastrin-Releasing Peptide Promotes Suprachiasmatic Nuclei Cellular Rhythmicity in the Absence of Vasoactive Intestinal Polypeptide-VPAC2Receptor Signaling

“…Previous studies implicated GRP in photic entrainment (Piggins et al, 1995;Romijn et al, 1996;Aida et al, 2002;Antle et al, 2005), but the present data raise the possibility that endogenous GRP-BB 2 signaling contributes to sustaining neuronal rhythms in the SCN. In this schema, GRP and other signaling factors and pathways (see below) are elements in a network of partially redundant systems regulating SCN rhythmicity and in which VIP-VPAC 2 signaling is a key component.…”

“…Activation of the BB 2 receptor produces primarily excitatory responses in cells throughout the rodent SCN (Piggins and Rusak, 1993;Piggins et al, 1994Piggins et al, , 2005Reynolds and Pinnock, 1997;Cutler et al, 2003; our study) and, like VIP, GRP is believed to be important for communicating phase information between neurons within the circadian clock (Antle et al, 2005). Interestingly, GRP, which promotes cellular rhythmicity in the Vipr2 Ϫ/Ϫ SCN, also increases the amplitude of such rhythms compared with those observed in untreated slices, supporting previous suggestions that a threshold of neuronal activity is required to sustain clock function (Van den Pol and Obrietan, 2002;Nitabach et al, 2002;Yamaguchi et al, 2003;Lundkvist et al, 2005).…”

Absence of Normal Photic Integration in the Circadian Visual System: Response to Millisecond Light Flashes

“…The ventral part of this region corresponds to a fairly circumscribed area containing neurons identifiable by calbindin, gastrin releasing peptide, and substance P content (Morin et al, 1992;Kalsbeek et al, 1993;Bryant et al, 2000;Muscat et al, 2003;Kriegsfeld et al, 2004). The dorsal part of the region corresponds to an area known to express phosphorylated extracellular signal-regulated kinase (Lee et al, 2003;Antle et al, 2005;Yan et al, 2005). The present analysis also demonstrates significant increases in lightinduced FOS in part of the SCN that appears relatively devoid of this protein.…”

c-Fos Expression in the Brains of Behaviorally “Split” Hamsters in Constant Light: Calling Attention to a Dorsolateral Region of the Suprachiasmatic Nucleus and the Medial Division of the Lateral Habenula

“…It is the site of a cluster of cells expressing the phosphorylated MAP kinases ERK1 and ERK2 during subjective night (Lee et al, 2003); like c-Fos, pERK1/2 expression in this region is resistant to treatment with the NMDA receptor blocker MK-801 administered before a light pulse (Coogan and Piggins, 2003). Antle et al (2005) have activated pERK cells in this region by intraventricular injections of gastrin-releasing peptide (GRP), naming them "cap" cells and suggesting that GRP may link them to light-responsive cells in the underlying calbindin-rich zone. We suspect that this photo-responsive, NMDA and non-NMDA antagonist-insensitive, GRP-sensitive, pERK-expressing central-dorsolateral region coincides with the c-Fos-and PER1-expressing region that we have observed on the subjective-night side of the split SCN.…”