Abstract

The “core” region of the suprachiasmatic nucleus (SCN), a central clock responsible for coordinating circadian rhythms, shows a daily rhythm in phosphorylation of extracellular regulated kinase (pERK). This cellular rhythm persists under constant darkness and, despite the absence of light, is dependent upon inputs from the eye. The neural signals driving this rhythmicity remain unknown and here the roles of glutamate and PACAP are examined. First, rhythmic phosphorylation of the NR1 NMDA receptor subunit (pNR1, a marker for receptor activation) was shown to coincide with SCN core pERK, with a peak at circadian time (CT) 16. Enucleation and intraocular TTX administration attenuated the peak in the pERK and pNR1 rhythms, demonstrating that activation of the NMDA receptor and ERK in the SCN core at CT16 are dependent on retinal inputs. In contrast, ERK and NR1 phosphorylation in the SCN shell region were unaffected by these treatments. Intraventricular administration of the NMDA receptor antagonist MK-801 also attenuated the peak in SCN core pERK, indicating that ERK phosphorylation in this region requires NMDA receptor activation. As PACAP is implicated in photic entrainment and is known to modulate glutamate signaling, the effects of a PAC1 receptor antagonist (PACAP 6-38) on SCN core pERK and pNR1 also were examined. PACAP 6-38 administration attenuated SCN core pERK and pNR1, suggesting that PACAP induces pERK directly, and indirectly via a modulation of NMDA receptor signaling. Together, these data indicate that, in the absence of light, retinal-mediated NMDA and PAC1 receptor activation interact to induce cellular rhythms in the SCN core. These results highlight a novel function for glutamate and PACAP release in the hamster SCN apart from their well-known roles in the induction of photic circadian clock resetting.

Highlights

  • The hypothalamic suprachiasmatic nucleus (SCN) is a central clock essential for circadian (i.e.,24 hr) rhythms in a wide variety of behavioral and physiological endpoints, as well as for the ability of light to entrain rhythms to the twenty-four hour world [1,2,3]

  • Analysis of double-labelled cells revealed that the vast majority of core phosphorylated extracellular-regulated kinase (pERK) neurons observed at CT16 colocalized with phosphorylation of the NR1 NMDA receptor subunit (pNR1) (93.5 +/2 4.6% per animal, Fig. 3M-O), whereas fewer pNR1 cells (12.7 +/2 2.7%) at this time point colocalized with pERK

  • PACAP6–38 significantly attenuated the number of pNR1 cells in the SCN core compared to vehicle (p = 0.0105; Fig. 8D-F), indicating that PAC1 receptor activation contributes to NR1 phosphorylation. These results demonstrate that NMDA and PAC1 receptor signaling interact to induce retinal-mediated SCN core ERK phosphorylation that occurs in the absence of light

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Summary

Introduction

The hypothalamic suprachiasmatic nucleus (SCN) is a central clock essential for circadian (i.e., ,24 hr) rhythms in a wide variety of behavioral and physiological endpoints, as well as for the ability of light to entrain rhythms to the twenty-four hour world [1,2,3]. In rodents, phosphorylated extracellular-regulated kinase (pERK; known as MAP kinase) defines two subpopulations of endogenously rhythmic SCN cells whose peak expression is in anti-phase to each other. While most cellular rhythms are intrinsic to the SCN [10,11,12], the endogenous rhythm in SCN core pERK is dependent upon the eye as it is selectively abolished by enucleation [9]. Retinal input induces cellular rhythmicity in a sub-compartment of the master circadian clock, even in the absence of light

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