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Volume 17, Number 7,
Issue of April 1, 1997
pp. 2637-2644
Copyright ©1997 Society for Neuroscience
Pituitary Adenylate Cyclase-Activating Peptide (PACAP) in the
Retinohypothalamic Tract: A Potential Daytime Regulator of the
Biological Clock
Received Aug. 22, 1996; revised Jan. 17, 1997; accepted Jan. 23, 1997.
Jens Hannibal1,
Jian M. Ding3,
Dong Chen4,
Jan Fahrenkrug1,
Philip J. Larsen2,
Martha U. Gillette3, 4, and
Jens D. Mikkelsen2, 5
1 Department of Clinical Biochemistry, Bispebjerg
Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark,
2 Institute of Medical Anatomy, University of Copenhagen,
DK-2400 Copenhagen NV, Denmark, Departments of 3 Cell and
Structural Biology and 4 Molecular and Integrative
Physiology, University of Illinois, Urbana, Illinois, and
5 Department of Neurobiology, Research and Development, H. Lundbeck A/S, DK-2500 Valby Copenhagen, Denmark
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 × 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.
Key words:
suprachiasmatic nucleus;
circadian;
phase shifting;
brain
slice;
PACAP receptor;
cAMP;
rat;
intergeniculate leaflet;
ganglion
cells
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