Pituitary Adenylate Cyclase-Activating Peptide (PACAP) in the Retinohypothalamic Tract: A Potential Daytime Regulator of the Biological Clock

Apr 1, 1997The Journal of neuroscience : the official journal of the Society for Neuroscience

Daytime role of PACAP in the light pathway controlling the biological clock

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Abstract

Activation of the retinohypothalamic tract (RHT) can advance circadian rhythm by 3.5 hours during the subjective day through a PACAP-dependent mechanism.

Intense PACAP-immunoreactivity was observed in retinal connections to the rat suprachiasmatic nucleus (SCN) and intergeniculate leaflet (IGL).
Bilateral eye enucleation nearly eliminated PACAP-immunoreactivity in the SCN and IGL.
PACAP afferents originate from small ganglion cells throughout the retina.
Application of PACAP-38 significantly advanced SCN neuronal activity during the subjective day but not at night.
The phase advance effect is mediated by PACAP-R1 receptors, identified in the ventral SCN.
The signaling mechanism involves a cAMP-dependent pathway that can be inhibited by a specific cAMP antagonist.

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The retinohypothalamic tract (RHT) relays photic information from the eyes to the suprachiasmatic nucleus (SCN). Activation of this pathway by light plays a role in adjusting circadian timing via a glutamatergic pathway at night. Here we report a new signaling pathway by which the RHT may regulate circadian timing in the daytime as well. We used dual immunocytochemistry for pituitary adenylate cyclase-activating peptide (PACAP) and the in vivo tracer cholera toxin subunit B and observed intense PACAP-immunoreactivity (PACAP-IR) in retinal afferents in the rat SCN as well as in the intergeniculate leaflet (IGL) of the thalamus. This PACAP-IR in the SCN as well as in the IGL was nearly lost after bilateral eye enucleation. PACAP afferents originated from small ganglion cells distributed throughout the retina. The phase of circadian rhythm measured as SCN neuronal activity in vitro was significantly advanced (3.5 +/- 0.4 hr) by application of 1 x 10(-6) M PACAP-38 during the subjective day [circadian time (CT)-6] but not at night (CT14 and CT19). The phase-shifting effect is channeled to the clock via a PACAP-R1 receptor, because mRNA from this receptor was demonstrated in the ventral SCN by in situ hybridization. Furthermore, vasoactive intestinal peptide was nearly 1000-fold less potent in stimulating a phase advance at CT6. The signaling mechanism was through a cAMP-dependent pathway, which could be blocked by a specific cAMP antagonist, Rp-cAMPS. Thus, in addition to its role in nocturnal regulation by glutamatergic neurotransmission, the RHT may adjust the biological clock by a PACAP/cAMP-dependent mechanism during the daytime.

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Pituitary Adenylate Cyclase-Activating Peptide (PACAP) in the Retinohypothalamic Tract: A Potential Daytime Regulator of the Biological Clock

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