title: PACAP-deficient mice exhibit light parameter-dependent abnormalities on nonvisual photoreception and early activity onset.
abstract: BACKGROUND
  The photopigment melanopsin has been suggested to act as a dominant photoreceptor in nonvisual photoreception including resetting of the circadian clock (entrainment), direct tuning or masking of vital status (activity, sleep/wake cycles, etc.), and the pupillary light reflex (PLR). Pituitary adenylate cyclase-activating polypeptide (PACAP) is exclusively coexpressed with melanopsin in a small subset of retinal ganglion cells and is predicted to be involved extensively in these responses; however, there were inconsistencies in the previous reports, and its functional role has not been well understood.
  
  
  RESULTS
  Here we show that PACAP-deficient mice exhibited severe dysfunctions of entrainment in a time-dependent manner. The abnormalities in the mutant mice were intensity-dependent in phase delay and duration-dependent in phase advance. The knockout mice also displayed blunted masking, which was dependent on lighting conditions, but not completely lost. The dysfunctions of masking in the mutant mice were recovered by infusion of PACAP-38. By contrast, these mutant mice show a normal PLR. We examined the retinal morphology and innervations in the mutant mice, and no apparent changes were observed in melanopsin-immunoreactive cells. These data suggest that the dysfunctions of entrainment and masking were caused by the loss of PACAP, not by the loss of light input itself. Moreover, PACAP-deficient mice express an unusually early onset of activities, from approximately four hours before the dark period, without influencing the phase of the endogenous circadian clock.
  
  
  CONCLUSIONS
  Although some groups including us reported the abnormalities in photic entrainments in PACAP- and PAC(1)-knockout mice, there were inconsistencies in their results. The time-dependent dysfunctions of photic entrainment in the PACAP-knockout mice described in this paper can integrate the incompatible data in previous reports. The recovery of impaired masking by infusion of PACAP-38 in the mutant mice is the first direct evidence of the relationship between PACAP and masking. These results indicate that PACAP regulates particular nonvisual light responses by conveying parametric light information--that is, intensity and duration. The "early-bird" phenotype in the mutant mice originally reported in this paper supposed that PACAP also has a critical role in daily behavioral patterns, especially during the light-to-dark transition period.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kawaguchi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Isojima
authors.forename: Norihito
authors.initials: N
authors.lastname: Shintani
authors.forename: Michiyoshi
authors.initials: M
authors.lastname: Hatanaka
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Guo
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Okumura
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D017403:In Situ Hybridization; D008027:Light; D055537:Light Signal Transduction / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology / Q000528:radiation effects*; D056950:Period Circadian Proteins / Q000235:genetics; D017440:Photoperiod; D010786:Photoreceptor Cells / Q000378:metabolism / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency* / Q000235:genetics; D011680:Pupil / Q000502:physiology / Q000528:radiation effects; D012160:Retina / Q000502:physiology / Q000528:radiation effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017299:Rod Opsins / Q000235:genetics; D013997:Time Factors; D000099210:Melanopsin
chemical_list: D056950:Period Circadian Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D017299:Rod Opsins; D000099210:Melanopsin; C539023:Per1 protein, mouse