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

• DOI: 10.1523/jneurosci.17-07-02637.1997
• Publication Date: 2018-04-02T21:55:42Z
• Authors: Jens Hannibal; Jian M. Ding; Dong Chen; Jan Fahrenkrug; Philip J. Larsen; Martha U. Gillette; Jens D. Mikkelsen
• Keywords: Male; Retinal Ganglion Cells; 0301 basic medicine; Cholera Toxin; Neurotransmitter Agents; Photoperiod; Neuropeptides; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Axonal Transport; Retina; Circadian Rhythm; Rats; 03 medical and health sciences; Biological Clocks; Animals; Pituitary Adenylate Cyclase-Activating Polypeptide; Suprachiasmatic Nucleus; RNA, Messenger; Receptors, Pituitary Hormone; Rats, Wistar; Photic Stimulation; Signal Transduction

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 thein vivotracer 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 activityin vitrowas significantly advanced (3.5 ± 0.4 hr) by application of 1 × 10−6mPACAP-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 byin situhybridization. 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.