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Endocrinology Vol. 140, No. 4 1520-1524
Copyright © 1999 by The Endocrine Society

ARTICLES

Neither Functional Rod Photoreceptors nor Rod or Cone Outer Segments Are Required for the Photic Inhibition of Pineal Melatonin1

Robert J. Lucas and Russell G. Foster

Department of Biology, Imperial College of Science Technology and Medicine, London, United Kingdom SW7 2AZ

Address all correspondence and requests for reprints to: Dr. Robert Lucas, Department of Biology, Sir Alexander Fleming Building, Imperial College Road, Imperial College of Science Technology and Medicine, London, United Kingdom SW7 2AZ. E-mail: r.j.lucas{at}ic.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Pineal melatonin production is rapidly suppressed by light. In mammals, the photoreceptors mediating this response are ocular; however, definitive information regarding their nature and precise location is absent. In an attempt to define these photoreceptors, we examined the sensitivity of pineal melatonin production to inhibition by controlled irradiance monochromatic green light ({lambda}max 509 nm) in C3H mice bearing either of two mutations affecting the retina: retinal degeneration (rd), a disruption of rod phototransduction, and retinal degeneration slow (rds), an ablation of photoreceptor outer segments. Diurnal profiles of pineal melatonin content were similar in both mutant genotypes and in wild-type mice; melatonin peaked between 3–5 h before lights on. All three genotypes exhibited irradiance dependent inhibition of pineal melatonin content; 2.6 x 10-2 microwatts/cm2 509 nm light induced complete suppression in all three genotypes, whereas lower irradiances were ineffective in all cases. Bilateral enucleation abolished responses even to 6 microwatts/cm2 509 nm light. These results demonstrate that the process of irradiance detection for pineal melatonin inhibition is buffered against considerable loss of photoreceptive capacity and that neither rod photoreceptors nor rod or cone outer segments are required for mediating this response in mice.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MELATONIN, the principal endocrine product of the mammalian pineal gland, regulates circadian and seasonal variations in physiology by acting as an internal representative of night. To perform this function it is essential that its production be strictly confined to the hours of darkness. This pattern of production is ensured by two complementary factors: a strong circadian rhythmicity in stimulation of the pineal gland, originating in the hypothalamic suprachiasmatic nuclei (SCN; site of a circadian clock in mammals), and a rapid inhibition of pineal melatonin production upon exposure to light (1). A multisynaptic neural pathway has been described by which photic information is transmitted from the retina via the retinohypothalamic tract to the SCN (2) and thence to the pineal (3). However, the nature of the photoreceptors providing input to this pathway remains unknown.

Previous descriptions of the spectral sensitivity of melatonin suppression in rats (4, 5) and Syrian hamsters (6) have suggested the involvement of rod photoreceptors in mediating these responses. However, definitive evidence associating any specific retinal photoreceptor with the task of regulating the mammalian pineal is absent. Here, we set out to examine the involvement of rod and cone photoreceptors in this process. To this end, we assessed the effect of two retinal degeneration mouse models, the retinal degeneration (rd) and retinal degeneration slow (rds) mutations, on the ability of light to acutely suppress pineal melatonin. rd is a mutation of the ß-subunit of the rod-specific phosphodiesterase (7, 8). The absence of a functional phosphodiesterase in homozygous rd/rd mice leads to a constitutive elevation of intracellular cGMP in rod photoreceptors, thus destroying their ability to respond to photic stimulation with appropriate changes in membrane potential. This primary ablation of rod phototransduction is accompanied by an attrition initially of rod and subsequently of cone photoreceptors. By 85–90 days (the age at which the current experiments were carried out), rod cell bodies are absent, and cone cell bodies are reduced by at least 50% (9). rds is an insertion mutation of the peripherin gene that encodes a key structural component of photoreceptor outer segments (10, 11, 12). Homozygous rds/rds mice never develop photoreceptor outer segments and show a gradual degeneration of both rod and cone cell bodies. By 85–90 days of age, the outer nuclear layer of the rds/rds retina is reduced by more than 50% (13).

In a previous examination of melatonin suppression in rd/rd mice, Goto and Ebihara (14) reported that although rd/rd mice were capable of exhibiting photic melatonin suppression, their sensitivity to light was significantly reduced when compared to wild-type animals. The ability of rd/rd mice to show melatonin suppression indicates that photoreceptors other than rods are capable of mediating this response. However, the reduction in sensitivity was interpreted as strong evidence that, when present, rod photoreceptors contribute to this pathway. On this basis, Goto and Ebihara (14) concluded that regulation of the mammalian pineal is mediated by both rod and non-rod photoreceptors. However, this interpretation is complicated by strain differences between the rd/rd (C3H/He strain) and wild-type (CBA/Ms) mice. Thus, it is possible that the differences reported were related to strain background rather than retinal phenotype. The present study set out to resolve this issue and to independently examine the requirement for rod and cone outer segments by comparing photic sensitivity in C3H mice homozygous for either the rd or rds mutation with that in mice wild-type at both loci. Our results indicate that despite the large reductions in photoreceptive capacity induced by rd and rds mutations, there is no concomitant reduction in the sensitivity of pineal melatonin production to monochromatic (509-nm) light exposure in either genotype. These findings demonstrate that neither rod photoreceptors nor rod/cone outer segments are required for the acute inhibition of pineal melatonin in mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
All experiments described were performed in accordance with the Animals (Scientific Procedures) Act of 1986. Breeding colonies of C3H mice homozygous for either the rd or rds mutations or wild type at both loci were maintained at 22 C and 50% humidity at Imperial College. Commercially available C3H/He mice are homozygous for the rd mutation. C3H mice wild-type at this loci and bearing the rds mutation (from O20/A strain) were generated by S. Sanyal (Erasmus University, Rotterdam, The Netherlands) and donated to form the basis of these breeding colonies. The genotype of the breeding and experimental colonies was periodically verified using techniques based on PCR amplification of genomic DNA. 1) The rd mutation has introduced a novel (DdeI) restriction site to the rd locus; PCR primers specific to this portion of the gene were used to amplify a 298-bp portion of the gene covering this novel restriction site. The amplified DNA was subsequently digested with DdeI to test for the presence of the novel restriction site. 2) Testing for the rds mutation employed PCR primers specific for this allele. All three colonies were also tested for contamination with elements specific to the C57 strain genome by PCR amplification of microsatellite markers previously shown to be polymorphic between C57 and C3H strains (Harlan UK Ltd., Bicester, UK).

All experimental animals were stably entrained to a 12-h light, 12-h dark cycle for at least 2 weeks before sampling. At around 85–90 days of age (mean ± SEM; rd/rd, 82 ± 0.5; rds/rds, 89 ± 2.1; wild-type, 91 ± 1.6) animals were sampled according to one of the following protocols.

Diurnal profile
To describe diurnal profiles of pineal melatonin content for each of the genotypes, pineals were collected from between six and eight animals of each genotype at 2-h intervals through the dark phase of the light-dark cycle and at one time point during the light phase, zeitgeber time (ZT) 8, 13, 15, 17, 19, 21, or 23 (where ZT12 is the time of lights off). Animals were killed by cervical dislocation and bilaterally enucleated under infrared illumination. Subsequently, the pineal was quickly removed under white fluorescent light and snap-frozen on dry ice. Pineals were stored at -80 C until assayed for melatonin content.

Exposure to monochromatic 509-nm light
Mice of all three genotypes were individually exposed to 15 min of defined irradiance monochromatic 509 nm light timed to start between ZT20 and ZT21 of the light-dark cycle. A remote source light-pulsing apparatus was employed, as previously described (15). Importantly, this apparatus employs a fiber optic cable to ensure that the mice are not exposed to any heat output of the light source during pulsing. The spectral transmission of this light source was controlled using a monochromatic filter (Oriel Corp., Stratford, CT; {lambda}max, 509 nm; half-band width, 10 nm). Irradiance was controlled by the use of a series of neutral density impedance filters (Oriel Corp.) and was measured using an optical power meter (Graseby Optronics, Orlando, FL). Between six and eight animals from each genotype were exposed to monochromatic green light at irradiances of 1.2 x 10-4, 1.2 x 10-3, and 2.6 x 10-2 microwatts (µW)/cm2. In addition, six to eight animals from each genotype were placed in the pulsing apparatus for 15 min without exposure to light to act as experimental controls. At the end of the 15-min pulses, mice were removed from the pulsing apparatus under infrared illumination, their eyes were removed, and pineals were collected as described above.

Enucleated mice
Young adult mice from each of the three genotypes (five wild-type, three rd/rd, and two rds/rds) were bilaterally enucleated under halothane anesthesia. After recovering from the surgery, these animals were exposed to 12-h light, 12-h dark cycles. To assess circadian phase in these animals they were singly housed with free access to a running wheel from which circadian rhythms of wheel-running activity were monitored using a DataQuest system (Minimitter Co. Inc., Sunriver, OR). Enucleated mice did not entrain to the light-dark cycle, but after some transient arrhythmicity exhibited free running rhythms. When at least 14 days of stable circadian activity rhythm had been observed, mice were exposed to a 15-min 509-nm light pulse of 6 µW/cm2 using the apparatus described above. These pulses were timed with respect to the free running activity rhythm to start around circadian time (CT) 20, where CT12 is the time of activity onset. At the end of the pulse they were killed by cervical dislocation under infrared light, and pineals were collected.

Melatonin assay
A direct RIA was employed for the detection of melatonin concentrations in pineal homogenates (after Ref. 16). Briefly, single pineal glands were rapidly homogenized in assay buffer using ultrasound. These samples were then incubated in duplicate with a specific antiserum for melatonin raised in sheep (Stockgrand Ltd., Guildford, UK), and [3H]melatonin (Amersham, Aylesbury, UK) was added. Free and antibody-bound fractions of melatonin were separated using dextran (Sigma Chemical Co., Poole, UK)-coated activated charcoal (Sigma Chemical Co.), and the amount of bound [3H]melatonin was estimated using a scintillation counter (Fluoransafe, Fisher Life Science, Loughborough, UK; RackBeta, Wallac AC, Turku, Finland). The concentration of melatonin in the sample was estimated by comparison with standards of known melatonin (Sigma Chemical Co.) concentration. Quality control samples were included at 73 and 159 pg/ml; the intraassay coefficients of variation were 4.6% and 4.2%, and the interassay coefficients of variation were 10.5% and 7.6% for the lower and higher quality controls, respectively. The minimum detectable dose was 10 pg/ml. The assay was validated for use with mouse pineal homogenates by demonstrating parallelism over the range 10–200 pg/ml.

Statistical analysis
The effect of increasing irradiances of 509 nm light on pineal melatonin content was tested in each genotype using a one-way ANOVA; post-hoc t tests were made against the unpulsed control group employing Bonferroni’s correction. The t test comparisons were made between pineal melatonin content in enucleated mice exposed to 6 µW/cm2 of light and intact animals with either peak (not light pulsed) or completely suppressed (exposed to 2.6 x 10-2 µW/cm2 light) melatonin. Because of the differences in estimating circadian phase from the external light cycle compared with the running wheel activity rhythm, pineal samples from intact animals at ZT19, -20, and -21 were compared with the enucleated animals exposed to 6 µW/cm2 at CT20. To check for differences between genotypes in peak melatonin production or the response to enucleation, one-way ANOVA tests were employed on the pineal melatonin contents of the nonlight-pulsed and enucleated mice. Statistical significance was defined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mice from all three genotypes showed a robust diurnal rhythmicity in pineal melatonin content under exposure to a 12-h light, 12-h dark cycle (Fig. 1Go). In each case melatonin content was basal during the light phase and reached a peak during the second half of the dark phase before falling again preceding lights on. Pineal melatonin content was stable between ZT19 and ZT21 in all three genotypes.



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  		Figure 1. Diurnal rhythms of pineal melatonin content in rd/rd, rds/rds, and wild-type C3H mice. The mean ± SEM melatonin content, normalized against the mean value for each genotype at ZT21, is plotted by ZT (where ZT12 is the time of lights off). A portion of the corresponding light-dark cycle is depicted below; the shaded portion represents darkness.

 
There was no significant effect of genotype on the ability of the pineal to produce melatonin (by one-way ANOVA, P > 0.05) in the absence of a light pulse; mean ± SEM at ZT20, 138 ± 19.2 for wild-type, 109.5 ± 7.6 for rd/rd, and 160.8 ± 16.8 for rds/rds; Fig. 2AGo).



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  		Figure 2. A, Melatonin content (mean ± SEM) of pineal glands collected between ZT20 and ZT 21 from rd/rd, rds/rds, and wild-type C3H mice without exposure to a light pulse. Pineal melatonin content was not significantly different in the three genotypes (by one-way ANOVA, P > 0.05). B, Melatonin content (mean ± SEM) of pineal glands collected between ZT20 and ZT21 from rd/rd, rds/rds, and wild-type C3H mice following 15 min exposure to controlled irradiance monochromatic 509 nm light. All three genotypes showed an irradiance-dependent suppression of pineal melatonin content (by one-way ANOVA, P < 0.001), with 2.6 x 10-2 µW/cm2 sufficient to induce significant suppression with respect to that in the unpulsed controls (by post-hoc t tests with Bonferroni’s correction: **, P < 0.01).

 
All three genotypes showed an irradiance-dependent suppression of pineal melatonin content in response to 15 min of exposure to monochromatic 509 nm light (Fig. 2BGo; by one-way ANOVA, P < 0.01). There was no indication that either rd/rd or rds/rds mice showed a decrease in sensitivity compared with wild-type animals, with all three genotypes showing suppression (P < 0.01, by post-hoc t tests with Bonferroni’s correction against unpulsed animals) in response to 2.6 x 10-2 µW/cm2.

Enucleation effectively abolished pineal melatonin suppression in response to light exposure. Animals of all three genotypes showed a similar response (by one-way ANOVA, P > 0.05) to 6 µW/cm2 light after enucleation (Fig. 3Go). Pineal melatonin content was significantly (by t test, P < 0.0001) elevated compared with that in intact animals exposed to 2.6 x 10-2 µW/cm2 light. There was a modest reduction compared with intact animals not exposed to a light pulse, but this was not statistically significant (by t test, P > 0.05).



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  		Figure 3. Melatonin content (mean ± SEM) of pineal glands from intact C3H mice (all genotypes) collected from ZT19 to ZT21 without exposure to light or from ZT20 to ZT21 after exposure to 15 min of 2.6 x 10-2 µW/cm2 509 nm light and from enucleated C3H mice (all genotypes) collected between CT20 and CT21 after exposure to 15 min of 6 µW/cm2 509 nm light. The t test comparisons indicated that the pineal melatonin content of the enucleated mice was significantly (P < 0.001) higher than that of the intact light-pulsed animals, but was not significantly different from that of the intact unpulsed animals (P > 0.05). See text for discussion.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Despite the massive decrease in photoreceptive capacity in both rd/rd and rds/rds mice, neither of these genotypes showed evidence of a reduction in the sensitivity of pineal melatonin production to photic inhibition. These findings indicate that the photic pathway mediating pineal melatonin suppression is buffered against considerable loss of photoreceptive capacity. Moreover, the defined retinal phenotypes of these two mutants allow us to make two more specific conclusions: 1) as rd/rd mice lack functional rod photoreception, our results confirm that rod photoreceptors are not required for mediating this response; and 2) as rds/rds mice never develop rod or cone outer segments, it is clear that these structures are not required for photic suppression of pineal melatonin.

The results of bilateral enucleation reported here confirm previous reports in mammals that the photoreceptors regulating the mammalian pineal are located in the eyes (1, 17). There has been a recent report suggesting that humans are capable of showing circadian phase shifts through an as yet undefined extraocular photoreceptor (18; for review, see Ref. 19). However, that study did not extend to an examination of pineal melatonin suppression, and here we report that after bilateral enucleation, melatonin was not significantly suppressed even by an irradiance more than 2 orders of magnitude higher than that capable of complete suppression in intact animals. Although not statistically significant, pineal melatonin content did appear moderately lower in enucleated animals exposed to bright light compared with that in intact, unpulsed mice. However, we do not consider that this supports the hypothesis of extraocular photoreception in mammals. It is most likely that this effect is accounted for by three difficulties associated with ensuring that pineals were collected at the same phase of the melatonin rhythm in free running (enucleated) and entrained (intact) animals. Firstly, different phase reference points (ZT12, lights off, and CT12, activity onset) were employed for intact and enucleated animals which may not be wholly comparable in terms of the circadian phase they represent or the accuracy with which they do this. Secondly, free running (enucleated) mice typically exhibited a period significantly different from 24 h. Finally, the phasing of melatonin production in mammals varies according to night length (for review, see Ref. 20) and may well have been altered during the several weeks following blinding.

Although it seems clear that the photoreceptors regulating the mammalian pineal are exclusively ocular, their precise nature remains unknown. The murine retina contains three known photoreceptor cell types: rods with a maximal absorbance ({lambda}max) around 498 nm (21) and two populations of cone photoreceptors absorbing green ({lambda}max = 508 nm) (22) and UV ({lambda}max = 359 nm) (23) light. The rd mutation blocks functional phototransduction in rods (7, 8), and by 80 days of age, rd/rd mice lack rod photoreceptors (9). Consequently, the demonstration of melatonin suppression in rd/rd mice indicates that functional rod photoreceptors are not required for mediating this response. This finding implicates the green cones in regulation of the pineal, as these are the sole remaining photoreceptors in the rd/rd retina sensitive to 509 nm light. This hypothesis is currently under examination in our laboratory using mice lacking green cone photoreceptors. In addition, the involvement of some as yet unidentified nonrod-, non-cone-based photopigment cannot be excluded.

The evidence suggests that rod photoreceptors are not required for the acute suppression of pineal melatonin. However, it remains possible that, where present in the wild-type mouse retina, they do contribute to this response. Although several investigators have reported significant suppression in rats or Syrian hamsters by light outside the normal sensitivity of rodopsin (24, 25, 26), the overall spectral sensitivity of pineal melatonin inhibition in these species is consistent with the involvement of a rod-like opsin photopigment (4, 5, 6). Similarly, action spectra for light-induced changes in electrical activity within the mammalian pineal suggest input from both rod and cone photoreceptors (27). These findings suggest that multiple photoreceptor types mediate pineal responses to light. Previously, Goto and Ebihara (14) have presented data from rd/rd mice that seem to support this hypothesis. They reported that although rd/rd mice are capable of showing pineal responses to white light, their sensitivity was greatly reduced compared with that of wild-type animals. However, that study compared C3H/He rd/rd mice with CBA/Ms wild types. Here we have demonstrated that when wild-type and rd/rd mice from the same (C3H) strain are compared, no decrease in sensitivity is evident. This finding indicates that a complete loss of rod phototransduction has no demonstrable effect on the sensitivity of pineal suppression. Consequently, our data suggest either that rod photoreceptors are not involved in regulating this response or that in their absence some other photoreceptor can completely compensate for their loss.

Pineal melatonin production is under photic control via two independent mechanisms. In this report we have examined the acute effects of light on melatonin production. However, light also effects melatonin production by entraining the circadian clock in the SCN that drives the activity of the pineal. To date, both anatomical and experimental evidence supports the hypothesis that the same photoreceptors mediate these parallel irradiance-dependent processes. Both processes are intimately associated with the SCN (2, 28), which receive a direct retinal projection via the retinohypothalamic tract (29, 30) and, through variations in stimulatory input, regulate the activity of the pineal gland according both to circadian phase and environmental illumination (3). In Syrian hamsters, the spectral sensitivity of both pineal melatonin suppression (6, 24) and circadian phase shifting (31) has been examined. In each case, maximal responses were observed to light of around 500 nm, suggesting that these two processes are mediated by photoreceptors with a similar absorbance spectrum. However, although the spectral sensitivity of phase shifting and melatonin suppression responses in this species are similar, the absolute sensitivities of these two tasks are significantly different, with melatonin suppression sensitive to irradiances 1.4 log units lower than those required for phase shifts (32). Whether these differences in sensitivity are caused by differential processing of output from the same photoreceptors or the use of different photoreceptors is unknown. Here, we have shown that both rd/rd and rds/rds mice show unattenuated photic inhibition of pineal melatonin. Previous reports confirm that these genotypes also exhibit unattenuated phase shifts in response to appropriate light pulses (15, 33). Together these data suggest that whatever the ocular elements mediating these two irradiance-dependent responses, both are spared by the massive photoreceptor degenerations caused by the rd and rds mutations.

Although it seems likely that different irradiance detection tasks employ the same ocular photoreceptors, the hypothesis that these are the same photoreceptors known to mediate vision (i.e. rods and cones) is currently unproven. The presence of a dedicated retinohypothalamic tract in mammals indicates that at some structural level, visual and irradiance detection functions are separated. Whether this separation extends to the use of different photoreceptor cells and pigments remains unknown. A previous study using a shuttle-box classical conditioning paradigm has suggested that aged rd/rd mice are visually blind (34). Consequently, the demonstration shown here and reported previously (15, 34) that irradiance detection is not significantly impaired in rd/rd mice suggests that visual blindness is not necessarily associated with impaired irradiance detection. This conclusion is supported by reports of visually blind humans showing responses consistent with the presence of functioning irradiance detection (35). It seems clear from these various reports that irradiance detection functions are buffered against a loss of photoreceptive capacity that is sufficient to induce visual blindness. Whether the basis of this buffering is the use of a dedicated irradiance detection photoreceptor or an up-regulation of input from the remaining conventional photoreceptors remains to be determined.

In summary, neither rd nor rds mutations induced a significant decrease in the sensitivity of pineal melatonin production to photic inhibition. By contrast, enucleation abolished this response. Thus, our results confirm that the photoreceptors mediating the acute suppression of pineal melatonin are located in the eye. In addition, they demonstrate that at least in mice, neither rod photoreception nor rod or cone outer segments are required for photic regulation of the pineal.


   Footnotes
 
1 This work was supported by a Biotechnology and Biological Sciences Research Council research grant (to R.G.F.). Back

Received August 20, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals