Gastrin-Releasing Peptide Mediates Light-Like Resetting of the Suprachiasmatic Nucleus Circadian Pacemaker through cAMP Response Element-Binding Protein andPer1Activation

Nov 6, 2007The Journal of neuroscience : the official journal of the Society for Neuroscience

Gastrin-releasing peptide helps reset the body’s internal clock by activating key proteins in the brain’s timing center

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Abstract

Microinjections of gastrin-releasing peptide (GRP) into the suprachiasmatic nucleus (SCN) induced Per1 expression in various neurons.

GRP may serve as an intra-SCN light signal that communicates phase resetting information.
In vivo GRP injections increased Per1 expression throughout the SCN, affecting specific neuronal populations.
Blocking communication between neurons did not prevent overall Per1 induction but reduced it in arginine vasopressin-immunoreactive neurons.
In vitro application of GRP led to lasting increases in the firing rate of neurons expressing Per1.
Inhibition of Per1 with antisense technology reduced the spike frequency increase induced by GRP.
Disruption of CREB-mediated gene activation blocked GRP-induced phase shifts of PER2 rhythms in SCN slices.

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Circadian rhythmicity in the primary mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN) of the hypothalamus, is maintained by transcriptional and translational feedback loops among circadian clock genes. Photic resetting of the SCN pacemaker involves induction of the clock genes Period1 (Per1) and Period2 (Per2) and communication among distinct cell populations. Gastrin-releasing peptide (GRP) is localized to the SCN ventral retinorecipient zone, from where it may communicate photic resetting signals within the SCN network. Here, we tested the putative role of GRP as an intra-SCN light signal at the behavioral and cellular levels, and we also tested whether GRP actions are dependent on activation of the cAMP response element-binding protein (CREB) pathway and Per1. In vivo microinjections of GRP to the SCN regions of Per1::green fluorescent protein (GFP) mice during the late night induced Per1::GFP throughout the SCN, including a limited population of arginine vasopressin-immunoreactive (AVP-IR) neurons. Blocking spike-mediated communication with tetrodotoxin did not disrupt overall Per1::GFP induction but did reduce induction within AVP-IR neurons. In vitro GRP application resulted in persistent increases in the spike frequency of Per1::GFP-induced neurons. Blocking endogenous Per1 with antisense oligodeoxynucleotides inhibited GRP-induced increases in spike frequency. Furthermore, inhibition of CREB-mediated gene activation with decoy oligonucleotides blocked GRP-induced phase shifts of PER2::luciferase rhythms in SCN slices. Altogether, these results indicate that GRP communicates phase resetting signals within the SCN network via both spike-dependent and spike-independent mechanisms, and that activation of the CREB pathway and Per1 are key steps in mediating downstream events in GRP resetting of SCN neurons.

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Gastrin-Releasing Peptide Mediates Light-Like Resetting of the Suprachiasmatic Nucleus Circadian Pacemaker through cAMP Response Element-Binding Protein andPer1Activation

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