Phase Shifting of Circadian Rhythms and Depression of Neuronal Activity in the Rat Suprachiasmatic Nucleus by Neuropeptide Y: Mediation by Different Receptor Subtypes

Abstract

Neuropeptide Y (NPY) has been implicated in the phase shifting of circadian rhythms in the hypothalamic suprachiasmatic nucleus (SCN). Using long-term, multiple-neuron recordings, we examined the direct effects and phase-shifting properties of NPY application in rat SCN slices in vitro (n = 453). Application of NPY and peptide YY to SCN slices at circadian time (CT) 7.5-8.5 produced concentration-dependent, reversible inhibition of cell firing and a subsequent significant phase advance. Several lines of evidence indicated that these two effects of NPY were mediated by different receptors. NPY-induced inhibition and phase shifting had different concentration-response relationships and very different phase-response relationships. NPY-induced phase advances, but not inhibition, were blocked by the GABAA antagonist bicuculline, suggesting that NPY-mediated modulation of GABA may be an underlying mechanism whereby NPY phase shifts the circadian clock. Application of the Y2 receptor agonists NPY 13-36 and (Cys2,8-aminooctanoic acid5,24,D-Cys27)-NPY advanced the peak of the circadian rhythm but did not inhibit cell firing. The Y1 and Y5 agonist [Leu31,Pro34]-NPY evoked a substantial inhibition of discharge but did not generate a phase shift. NPY-induced inhibition was not blocked by the specific Y1 antagonist BIBP-3226; the antagonist also had no effect on the timing of the peak of the circadian rhythm. Application of the Y5 agonist [D-Trp32]-NPY produced only direct neuronal inhibition. These are the first data to indicate that at least two functional populations of NPY receptors exist in the SCN, distinguishable on the basis of pharmacology, each mediating a different physiological response to NPY application.

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

“…Consistent with previous studies (Bouskila and Dudek, 1993;Gribkoff et al, 1998;Mrugala et al, 2000), all WT slices showed clear circadian rhythms in SCN MUA (Fig. 4a) (supplemental Figs.…”

Disrupted Neuronal Activity Rhythms in the Suprachiasmatic Nuclei of Vasoactive Intestinal Polypeptide-Deficient Mice

“…Consistent with previous findings (Bouskila and Dudek 1993;Brown et al 2005Brown et al , 2006Gribkoff et al 1998;Mrugala et al 2000), all wild-type (VIP/PHI ϩ/ϩ ) slices (n ϭ 7) exhibited clear rhythms in SCN MUA ( (F) mice also show firing rate rhythms that peak during the projected day, whereas cells from VIP/PHI Ϫ/Ϫ mice (G and H) express rhythms with variable phasing (top) or are arrhythmic (bottom). All graphs show average firing rate (Hz) each minute from 1 representative slice, moderately smoothed using a 1-h moving average.…”

Circadian clock resetting in the mouse changes with age

“…This supports earlier unpublished findings from administration of NPY in vivo (Duncan unpublished, cited in Duncan and Franklin 2007). Further, while phase shifts to NPY in the rat and hamster may require actions at GABAa receptors Gribkoff et al 1998 but see Biello et al 1997a, b) our work here would suggest that resetting to NPY in the mouse may not, as phase shifts to the GABAa agonist muscimol was decreased with age, while phase shifts to NPY remain unaltered. Phase shifts to NPY are thought to be mediated by the Y2 receptor (Golombek et al 1996;Huhman et al 1996), while attenuation of photic stimuli by NPY are mediated by the Y5 receptor (Gamble et al 2005;Yannielli et al 2004).…”