Neuropeptides phase shift the mammalian circadian pacemaker

Abstract

We studied the influence on circadian rhythms of peptides that have been reported to be colocalized in suprachiasmatic nucleus (SCN) neurons. Gastrin-releasing peptide (GRP1–27), peptide histidine isoleucine (PHI), and vasoactive intestinal polypeptide (VIP) were microinjected into the suprachiasmatic nucleus (SCN) region of Syrian hamsters free running under three different constant lighting conditions. All peptide injections caused phase-dependent phase shifts of hamster locomotor activity rhythms which were unaffected by constant lighting conditions. GRP1–27 (150 pmol) caused large phase delays when injected at circadian times (CT) 12–16, modest phase advances when administered at CT20–24, and few shifts during the subjective day. Injections of saline vehicle at any of these phases caused only very small phase shifts. Phase delays induced by GRP1–27 at CT12–14 were dose dependent, unrelated to injection volume (at a constant dose), and attenuated by pretreatment with the BN/GRP-preferring receptor antagonist BIM 26226. VIP (150 pmol) caused moderate phase delays at CT12–14 and moderate phase advances at CT20–24. PHI (150 pmol) caused moderate phase delays at CT12–14 only. Coadministration of 150 pmol of GRP1–27, PHI, and VIP in an equimolar neuropeptide cocktail (50 pmol of each peptide) caused phase delays at CT12–14 and phase advances at CT20- 24 which did not differ from those induced by 150 pmol of GRP1–27 alone at these phases. The shifts induced by 150 pmol of the peptide cocktail were smaller than the sum of the shifts induced by 50 pmol doses of each peptide administered separately at those phases. Since the phase- delaying effects of the cocktail were weaker than the summed effects of the component 50 pmol doses of the peptides, these data demonstrate a lack of synergism among the effects of these peptides. Since GRP1–27 (150 pmol) evoked shifts similar in magnitude to those of the cocktail, there is no evidence that these apparently colocalized neuropeptides must interact to exert maximal effects on the circadian pacemaker.

Phenotype Matters: Identification of Light-Responsive Cells in the Mouse Suprachiasmatic Nucleus

“…night (Piggins and Rusak, 1993;Piggins et al, 1994Piggins et al, , 1995Albers et al, 1995;McArthur et al, 2000). It has also been shown that the phase-shifting effects of a gastrin-releasing peptide injection can be blocked by the application of the gastrin-releasing peptide antagonist [D-F5Phe6,D-Ala11]BN(6 -13)OMe (Piggins et al, 1995).…”

“…It has also been shown that the phase-shifting effects of a gastrin-releasing peptide injection can be blocked by the application of the gastrin-releasing peptide antagonist [D-F5Phe6,D-Ala11]BN(6 -13)OMe (Piggins et al, 1995). In mice, gastrin-releasing peptide injections induce mPer1 gene expression in dorsal SCN neurons, and gastrin-releasing peptide receptor-deficient mice show both blunted mPer1 and behavioral phase-shifting responses (Aida et al, 2002).…”

Synchrony and entrainment properties of robust circadian oscillators

“…Preliminary results demonstrate that controlled VIP pulses cause phase shifts similar to those resulting from light pulses, suggesting that the VIP signal and target are similar to those of light and may be modelled correspondingly. The target of VIP signalling is therefore assumed to be per transcription (Piggins et al 1995). Experimental data demonstrate that isolated (uncoupled) neurons exhibit both a broad distribution of periods and temporal (cycle-to-cycle) variability (Herzog et al 2004).…”

Circadian clock resetting in the mouse changes with age

“…The peptide and activation of the associated receptor also resets the circadian clock in vitro and in vivo in a pattern resembling that of photic stimulation (McArthur et al 2000;Piggins et al 1995). In hamsters this mechanism involves the NMDA receptor (Kallingal and Mintz 2006).…”