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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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Impaired activity masking in Adcyap1−/− mice.(A) Wheel-running records for ZT12–18. Actograms are magnified to show direct responses to a two-hour light pulse at ZT13–15 on test days (red boxes) and no pulse during a comparable time on the three previous nights (yellow boxes). (B) Quantification of % activity suppression during the first hour (ZT13–14). The solid bar in each group denotes the median (n = 7–12). Open symbols: Adcyap1+/+, closed symbols: Adcyap1−/−. (C) The effect of PACAP supplementation (20 pmol) on masking responses 30 min before photic stimulation at ZT13 (100lx). The solid bar in each group denotes the median (n = 7–8). *p<0.05 versus Adcyap1+/+ in each intensity of light or vehicle-treated Adcyap1+/+, #P<0.05 versus vehicle-treated Adcyap1−/−; Mann-Whitney U test.
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pone-0009286-g002: Impaired activity masking in Adcyap1−/− mice.(A) Wheel-running records for ZT12–18. Actograms are magnified to show direct responses to a two-hour light pulse at ZT13–15 on test days (red boxes) and no pulse during a comparable time on the three previous nights (yellow boxes). (B) Quantification of % activity suppression during the first hour (ZT13–14). The solid bar in each group denotes the median (n = 7–12). Open symbols: Adcyap1+/+, closed symbols: Adcyap1−/−. (C) The effect of PACAP supplementation (20 pmol) on masking responses 30 min before photic stimulation at ZT13 (100lx). The solid bar in each group denotes the median (n = 7–8). *p<0.05 versus Adcyap1+/+ in each intensity of light or vehicle-treated Adcyap1+/+, #P<0.05 versus vehicle-treated Adcyap1−/−; Mann-Whitney U test.

Mentions: Masking modulates vital status with time by detecting ambient luminance [8], [9]; for example, nocturnal animals are active when the surroundings are dark (<∼0.2lx; positive masking) and passive in a brighter milieu (>∼10lx; negative masking) [21]. Such reactions occur without influencing the underlying circadian clock. We assessed masking by quantifying the amount of activity induced by a two-hour light pulse during early night, a stimulus that is specifically designed for the estimation of masking. Adcyap1+/+ mice exhibited clear light-induced locomotor suppression (negative masking) at each light intensity (Fig. 2A). Because this negative masking in Adcyap1+/+ mice was predominantly occurred in the first an hour during a two-hour-light exposure, we compared suppression rates during the first hour only between two genotypes. Adcyap1+/+ mice showed more than 50% suppression of activity rate at all of the light intensities investigated, but this negative masking was significantly impaired in Adcyap1−/− mice, at all intensities tested, and several mutants paradoxically became active (paradoxical positive masking), especially at the lowest light intensity (Fig. 2A, B). These abnormalities were ameliorated by intracerebroventricular administration of PACAP38 (20 pmol) 30 min before exposure to 100lx light, whereas this concentration of PACAP38 had no effect on the amount of activity in Adcyap1+/+ mice (Fig. 2C).


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)

Impaired activity masking in Adcyap1−/− mice.(A) Wheel-running records for ZT12–18. Actograms are magnified to show direct responses to a two-hour light pulse at ZT13–15 on test days (red boxes) and no pulse during a comparable time on the three previous nights (yellow boxes). (B) Quantification of % activity suppression during the first hour (ZT13–14). The solid bar in each group denotes the median (n = 7–12). Open symbols: Adcyap1+/+, closed symbols: Adcyap1−/−. (C) The effect of PACAP supplementation (20 pmol) on masking responses 30 min before photic stimulation at ZT13 (100lx). The solid bar in each group denotes the median (n = 7–8). *p<0.05 versus Adcyap1+/+ in each intensity of light or vehicle-treated Adcyap1+/+, #P<0.05 versus vehicle-treated Adcyap1−/−; Mann-Whitney U test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2823792&req=5

pone-0009286-g002: Impaired activity masking in Adcyap1−/− mice.(A) Wheel-running records for ZT12–18. Actograms are magnified to show direct responses to a two-hour light pulse at ZT13–15 on test days (red boxes) and no pulse during a comparable time on the three previous nights (yellow boxes). (B) Quantification of % activity suppression during the first hour (ZT13–14). The solid bar in each group denotes the median (n = 7–12). Open symbols: Adcyap1+/+, closed symbols: Adcyap1−/−. (C) The effect of PACAP supplementation (20 pmol) on masking responses 30 min before photic stimulation at ZT13 (100lx). The solid bar in each group denotes the median (n = 7–8). *p<0.05 versus Adcyap1+/+ in each intensity of light or vehicle-treated Adcyap1+/+, #P<0.05 versus vehicle-treated Adcyap1−/−; Mann-Whitney U test.
Mentions: Masking modulates vital status with time by detecting ambient luminance [8], [9]; for example, nocturnal animals are active when the surroundings are dark (<∼0.2lx; positive masking) and passive in a brighter milieu (>∼10lx; negative masking) [21]. Such reactions occur without influencing the underlying circadian clock. We assessed masking by quantifying the amount of activity induced by a two-hour light pulse during early night, a stimulus that is specifically designed for the estimation of masking. Adcyap1+/+ mice exhibited clear light-induced locomotor suppression (negative masking) at each light intensity (Fig. 2A). Because this negative masking in Adcyap1+/+ mice was predominantly occurred in the first an hour during a two-hour-light exposure, we compared suppression rates during the first hour only between two genotypes. Adcyap1+/+ mice showed more than 50% suppression of activity rate at all of the light intensities investigated, but this negative masking was significantly impaired in Adcyap1−/− mice, at all intensities tested, and several mutants paradoxically became active (paradoxical positive masking), especially at the lowest light intensity (Fig. 2A, B). These abnormalities were ameliorated by intracerebroventricular administration of PACAP38 (20 pmol) 30 min before exposure to 100lx light, whereas this concentration of PACAP38 had no effect on the amount of activity in Adcyap1+/+ mice (Fig. 2C).

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