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PACAP-deficient mice exhibit light parameter-dependent abnormalities on nonvisual photoreception and early activity onset.

Kawaguchi C, Isojima Y, Shintani N, Hatanaka M, Guo X, Okumura N, Nagai K, Hashimoto H, Baba A - PLoS ONE (2010)

Bottom Line: 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).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.These results indicate that PACAP regulates particular nonvisual light responses by conveying parametric light information--that is, intensity and duration.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

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.

Methodology/principal findings: 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/significance: 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.

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PLR in Adcyap1−/− mice.(A) Photographs of pupillary constriction 1 min post-irradiation. Darkness: scotopic conditions; carlbachol: 1 min after topical instillation of carlbachol under dark conditions. White broken lines indicate pupillary diameters. (B–D) Time courses of pupillary miosis during 1 min post-irradiation [(B) 20lx; (C) 100lx; (D) 600lx]. The graphs indicate normalized pupil area relative to time 0. Values denote means ± SEM (n = 4–7). No statistical differences were seen in all light intensities (two–way repeated-measures ANOVA).
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pone-0009286-g003: PLR in Adcyap1−/− mice.(A) Photographs of pupillary constriction 1 min post-irradiation. Darkness: scotopic conditions; carlbachol: 1 min after topical instillation of carlbachol under dark conditions. White broken lines indicate pupillary diameters. (B–D) Time courses of pupillary miosis during 1 min post-irradiation [(B) 20lx; (C) 100lx; (D) 600lx]. The graphs indicate normalized pupil area relative to time 0. Values denote means ± SEM (n = 4–7). No statistical differences were seen in all light intensities (two–way repeated-measures ANOVA).

Mentions: There were no differences in pupil sizes under scotopic conditions between genotypes (Adcyap1−/−, 1.06±0.18 mm2; Adcyap1+/+, 0.98±0.10 mm2). A PLR was detected in Adcyap1−/−mice in response to 460–490 nm blue light, and this was similar in magnitude and time course to that detected in Adcyap1+/+ mice at all light intensities (two–way repeated-measures ANOVA, Fig. 3B–D). Additionally, the minimal pupil areas attained by Adcyap1−/− mice in 1 min of steady light were comparable to those of Adcyap1+/+ mice (Fig. 3A).


PACAP-deficient mice exhibit light parameter-dependent abnormalities on nonvisual photoreception and early activity onset.

Kawaguchi C, Isojima Y, Shintani N, Hatanaka M, Guo X, Okumura N, Nagai K, Hashimoto H, Baba A - PLoS ONE (2010)

PLR in Adcyap1−/− mice.(A) Photographs of pupillary constriction 1 min post-irradiation. Darkness: scotopic conditions; carlbachol: 1 min after topical instillation of carlbachol under dark conditions. White broken lines indicate pupillary diameters. (B–D) Time courses of pupillary miosis during 1 min post-irradiation [(B) 20lx; (C) 100lx; (D) 600lx]. The graphs indicate normalized pupil area relative to time 0. Values denote means ± SEM (n = 4–7). No statistical differences were seen in all light intensities (two–way repeated-measures ANOVA).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2823792&req=5

pone-0009286-g003: PLR in Adcyap1−/− mice.(A) Photographs of pupillary constriction 1 min post-irradiation. Darkness: scotopic conditions; carlbachol: 1 min after topical instillation of carlbachol under dark conditions. White broken lines indicate pupillary diameters. (B–D) Time courses of pupillary miosis during 1 min post-irradiation [(B) 20lx; (C) 100lx; (D) 600lx]. The graphs indicate normalized pupil area relative to time 0. Values denote means ± SEM (n = 4–7). No statistical differences were seen in all light intensities (two–way repeated-measures ANOVA).
Mentions: There were no differences in pupil sizes under scotopic conditions between genotypes (Adcyap1−/−, 1.06±0.18 mm2; Adcyap1+/+, 0.98±0.10 mm2). A PLR was detected in Adcyap1−/−mice in response to 460–490 nm blue light, and this was similar in magnitude and time course to that detected in Adcyap1+/+ mice at all light intensities (two–way repeated-measures ANOVA, Fig. 3B–D). Additionally, the minimal pupil areas attained by Adcyap1−/− mice in 1 min of steady light were comparable to those of Adcyap1+/+ mice (Fig. 3A).

Bottom Line: 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).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.These results indicate that PACAP regulates particular nonvisual light responses by conveying parametric light information--that is, intensity and duration.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

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.

Methodology/principal findings: 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/significance: 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.

Show MeSH
Related in: MedlinePlus