PITUITARY ADENYLATE CYCLASE-ACTIVATING PEPTIDE (PACAP) IN THE RETINOHYPOTHALAMIC TRACT - A POTENTIAL DAYTIME REGULATOR OF THE BIOLOGICAL CLOCK

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 glutamatergi c pathway at night. Here we report a new signaling pathway by which th e RHT may regulate circadian timing in the daytime as well. We used du al immunocytochemistry for pituitary adenylate cyclase-activating pept ide (PACAP) and the in vivo tracer cholera toxin subunit B and observe d intense PACAP-immunoreactivity (PACAP-IR) in retinal afferents in th e rat SCN as well as in the intergeniculate leaflet (IGL) of the thala mus. This PACAP-IR in the SCN as well as in the IGL was nearly lost af ter bilateral eye enucleation. PACAP afferents originated from small g anglion cells distributed throughout the retina. The phase of circadia n 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 duri ng the subjective day [circadian time (CT)-6] but not at night (CT14 a nd CT19). The phase-shifting effect is channeled to the clock via a PA CAP-R1 receptor, because mRNA from this receptor was demonstrated in t he ventral SCN by in situ hybridization. Furthermore, vasoactive intes tinal peptide was nearly 1000-fold less potent in stimulating a phase advance at CT6. The signaling mechanism was through a cAMP-dependent p athway, which could be blocked by a specific cAMP antagonist, RpcAMPS. Thus, in addition to its role in nocturnal regulation by glutamatergi c neurotransmission, the RHT may adjust the biological clock by a PACA P/cAMP-dependent mechanism during the daytime.