Are there rods and cones in the pineal gland

Fibres from the suprachiasmatic nucleus of the hypothalamus follow the sympathetic pathway to supply the pineal gland. With the onset of darkness, these sympathetic fibres release noradrenalin to initiate the intracellular release of stored serotonin and NAT.

Melatonin has high lipid 35 and aqueous 36 solubility allowing it to cross the blood—brain barrier into the circulation and into cell organelles. The day—night cycle modifies this rhythm. Subjects kept in total darkness or constant illumination and some blind people revert to an intrinsic cycle of melatonin secretion of between As they lose up to an hour a day, they are completely out of synchrony after 2—3 weeks.

They both had severe sleep difficulties, which were corrected by melatonin supplementation. Light has two effects on melatonin: day—night light cycles modify the rhythm of its secretion and brief pulses of light of sufficient intensity and duration abruptly suppress its production. However, the rhythm of melatonin synthesis in the retina and ciliary body is synchronized with, but independent from, the rhythm of melatonin synthesis in the pineal gland.

Patients who are blind from ocular causes and who have abnormal sleep—wake cycles may benefit from exogenous melatonin, as may patients with cortical visual impairment and neurodevelopmental delay. Sleep plays a major role in brain maturation and chronic sleep disorders can adversely affect a child's development. Exogenous melatonin has proved useful in visually impaired children with sleep—wake rhythm disorders. Physicians should use the clinical response to determine the appropriate dose.

Therefore, the type of sleep disorder should influence the type of formulation chosen. When the treatment is successful it should be temporarily discontinued after 6—12 months, to see whether it is still necessary. Some individuals with severe neuropsychiatric developmental disorders may require melatonin supplementation for their lifetime. Melatonin has also proved useful in alleviating jet lag.

Like all other tissues, the eye is subject to the effect of melatonin. In addition, a number of structures within the eye synthesize it. The retina has a light-mediated feedback system; melatonin mediates darkness-related adaptive changes, and dopamine mediates light-related changes.

Melatonin is synthesized in the retina by a subpopulation of photoreceptors in a diurnal rhythm. Dopamine has the opposite effect to melatonin and can mimic light in entraining and phase shifting the circadian oscillator which controls melatonin rhythmicity. Intraocular pressure IOP has a diurnal variation, the trough occurring when melatonin concentration levels are highest, so it is not surprising that melatonin has been studied as a possible antiglaucoma agent. Melatonin receptors have been found in the iris—ciliary processes in rabbits 62 and localized to the nonpigmented ciliary epithelium in the frog.

Studies regarding the effect of melatonin on IOP have had conflicting results. The hypotensive effect was enhanced with repeated doses, reducing IOP by 7. In their third randomized experiment, they administered one dose of melatonin or placebo at hours and measured the IOP hourly up to midnight. Those given melatonin had a statistically significant but not a clinically significant reduction in IOP.

Melatonin is produced within the lens in a circadian rhythm, 9 where it acts as an antioxidant; melatonin administered to rats immediately following ultraviolet-B light was found to reduce cataract formation.

Melatonin has been shown to be an important antioxidant both at physiological and pharmacological concentrations. Melatonin receptors have been demonstrated in the corneal epithelium, stroma, and endothelium as well as the sclera of Xenopus frog eyes. Normal corneal growth and development is dependent on a regular diurnal rhythm of light and dark; young chicks exposed to continuous illumination develop severe corneal flattening and thickening.

Several papers have shown that women blind to light have a reduced risk of developing breast cancer. People living in low levels of ambient lighting such as the Arctic also have a lower prevalence of breast cancer. Conversely, women exposed to light at night eg night and shift workers have a higher incidence of breast cancer. A simultaneous decline in serum melatonin levels with increasing tumour growth has been demonstrated in preoperative breast cancer patients.

The chief urinary metabolite of melatonin closely parallels serum melatonin concentrations. In the UK, melatonin is available only on prescription. However, numerous synthetic melatonin preparations are available in health-food stores in the USA and Canada. Anecdotal reports of headache, restlessness, confusion, nausea, tachycardia, and pruritus have been attributed to the use of melatonin.

These may have been caused by impurities in some melatonin products. The relationship between melatonin and sex hormones in humans is still being elucidated. Melatonin has been elegantly demonstrated to be progonadal in short-day breeders such as sheep, and antigonadal in long-day breeders such as the Syrian hamster.

Extremely high circulating levels of melatonin may delay puberty and cause hypogonadism, as noted in a case report of a boy. Across the animal spectrum, there is evidence of circadian time-keeping activity, dating back hundreds of millions of years, attesting to the fundamental importance of synchrony with the environment to the survival of each organism. A key molecule responsible for this, melatonin, was discovered less than 50 years ago and is now produced biosynthetically.

Although just as valid as other biosynthetically produced hormones such as growth hormone or oestrogen, its relatively recent discovery means that many of its actions remain obscure. Although associated with the pineal gland and produced primarily in relation with the day—night cycle, melatonin turns out to have a huge spectrum of potential applications. Outside ophthalmology, melatonin is being evaluated in areas as diverse as cancer, haematology, toxicology, sleep, cardiology, ageing, immunity, and osteoporosis.

Its fundamental role in morphological signaling during embryogenesis might suggest a possible application of this hormone in extreme prematurity where infants, in the absence of maternal melatonin, have consecutively no, little, and disturbed melatonin production over the course of their development.

In this context, melatonin's role in the pathogenesis of retinopathy of prematurity and myopia of prematurity should be assessed.

In the adult, melatonin could have a role in cataract prevention, IOP reduction, and neuroprotection. The areas outlined above are a glimpse of the exciting possibilities that exist. Only through continuing careful scientific evaluation will this fundamental molecule find its true place within the practice of modern medicine.

Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc ; 80 : CAS Google Scholar. Melatonin immunoreactivity in the photosynthetic prokaryote Rhodospirillum rubrum : implications for an ancient antioxidant system.

Cell Mol Biol Res ; 41 : — Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron ; 19 : 91— The timed infusion paradigm for melatonin delivery: what has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses?

J Pineal Res ; 15 : — Hughes RJ, Badia P. Sleep-promoting and hypothermic effects of daytime melatonin administration in humans. Sleep ; 20 : — Methoxyindoles and photoreceptor metabolism: activation of rod shedding. Science ; : — Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates.

Biochem Mol Biol Int ; 35 : — Increase in the level of retinal melatonin and persistence of its diurnal rhythm in rats after pinealectomy.

J Endocrinol ; 91 : — Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin.

J Pineal Res ; 34 : 75— Existence and role of endogenous ocular melatonin. J Ocul Pharmacol ; 1 : — Melatonin in the lacrimal gland: first demonstration and experimental manipulation.

Biochem Biophys Res Commun ; : — Serotoninergic and melatoninergic systems are fully expressed in human skin. It also influences the suprachiasmatic nucleus, the primary pacemaker of the brain.

As neither rods nor cones seem to represent the nonvisual retinal photoreceptors, the presence of additional photoreceptors has been supposed. Cryptochrome 1, a photosensitive molecule identified in retinal nerve cells and in a subpopulation of retinal photoreceptors, is a good candidate for the nonvisual photoreceptor molecule as well as for a member of pacemaker molecules in the retina.

When comparing various visual and nonvisual photoreceptors, transitory, "semi visual" directional light-perceptive cells can be detected among them, such as those in the parietal eye of reptiles. Measuring diffuse light intensity of the environment, semivisual photoreceptors also possess some directional light perceptive capacity aided by complementary lens-like structures, and screening pigment cells.

Semivisual photoreception in aquatic animals may serve for identifying environmental areas of suitable illumination, or in poikilotermic terrestrial species for measuring direct solar irradiation for thermoregulation.

Abstract The role of the nonvisual photoreception is to synchronise periodic functions of living organisms to the environmental light periods in order to help survival of various species in different biotopes. Bioinformatic Analysis of gRrh and gRgr. Sequence analysis indicates that mRNA encoding each chick opsin protein is very similar to mammalian opsins of the same class. Each of the opsins contains seven transmembrane regions indicative of the GPCR superfamily and also contains a lysine in the seventh transmembrane domain, corresponding to K of peropsin and K of RGR opsin Fig.

This amino acid residue has been shown to be responsible for chromophore binding, 13 leading to the assumption that both of these genes probably encode photosensitive proteins. However, they represent different subgroups from either the visual opsins or the many putative extraocular opsins such as pinopsin, parapinopsin, encephalopsin, tmt-opsin, and melanopsin.

The sequence of gRrh belongs in a separate peropsin class of opsins with human peropsin, whereas gRgr belongs to the RGR opsin class, closer to members of retinochrome 30 and retinochrome-like opsins than to members of other classes of vertebrate opsins Fig. Multiple tissue Northern blot analysis at high stringency revealed that gRrh and gRgr mRNA are not widely expressed in the chicken, with high levels of expression visualized only in the brain and retina. The gRrh probes hybridized to one transcript at approximately 2.

Likewise, gRgr probes revealed two transcripts in the retina and brain, a major one occurring at approximately 2 kb, and minor transcript at approximately 4 kb.

No expression was visualized in heart, liver, skeletal muscle, intestine, and kidney Fig. ISH of chick brain, with radioactive-labeled probes, indicated very strong expression of both gRgr and gRrh in the pineal gland, confirming our initial observation from pineal cDNA libraries, 21 but also lower levels of expression throughout the brain Fig.

This expression was specific, because corresponding sense controls were completely blank data not shown. These cells appeared to be astrocytes, although this is very difficult to determine by ISH. Nonetheless, the distribution of gRgr mRNA was different from the distribution of either arylalkylamine- N -acetyl transferase AANAT or pinopsin in the chick pineal gland, both of which are localized in follicular PINs, 5 16 and so it is unlikely that they are expressed by follicular PINs.

Sense controls were blank Fig. Sense controls were blank for gRrh as well Fig. In the retina, the relative distributions of gRgr and gRrh differ from their distribution in pineal in that retinal gRgr appears more widespread than gRrh , although the Northern analyses did not indicate differences in level of expression. Little, if any expression was seen in the sense control for each gene Figs. We could not exclude expression in the RPE, because digoxigenin precipitate would be obscured by the pigment, and background hybridization with radioactive probes was very high.

ISH of both gRrh Fig. In addition, Northern blot analysis of retina also showed a rhythm of gRrh and gRgr mRNA, which oscillated on a hour basis in LD and DD, similar to the pattern visualized in the pineal gland. Each gene exhibited high levels during the light phase of the day and reduced mRNA levels at late night Fig.

Nearly all organisms ranging from bacteria to humans possess an endogenous circadian clock that permits the organism to regulate its internal physiology to the surrounding environment temporally.

In mammals, the biological clock that controls behavioral, physiological, and biochemical rhythms resides in the suprachiasmatic nucleus SCN. The localization of a master pacemaker to a single structure, as seen in mammals, varies, depending on the species in question. For example, in birds it comprises a complex system of multiple oscillators coupled together. These oscillators are located in the ocular retinas, the pineal gland, and the avian homologue of the mammalian SCN.

The avian pineal gland is a photosensitive structure but lacks both traditional rod- and cone-type photoreceptor cells and a pigmented epithelium. The phase-shifting effects of light by the chick pineal gland, but not the acute effects, are remarkably resistant to vitamin A deprivation, 47 suggesting that the two effects of light are mediated by at least two different photopigments.

The understanding of the molecular elements that regulate the generation of circadian rhythm have advanced significantly in recent years.

The molecular components that these clocks comprise have been identified in diverse animal species ranging from D. In mammals, this autoregulatory loop is believed to be very similar and to be entrained to LD cycles through the action of both opsin-based photopigments, including melanopsin and, perhaps, the flavin-based blue-light photopigment cryptochrome cry.

We believe the presence of two putative photoisomerases within pineal tissues and in retinal layers associated with biological clock function provides two candidates for such a function. Both g Rgr and gRrh are expressed within the pineal parenchyma, where melatonin biosynthesis is known to occur, and in the INL and RGL of the ocular retina, where circadian photoreception is also present.

Both of these putative photoisomerases are also expressed throughout the brain. Because it is known that, like most nonmammalian vertebrates, birds possess intracranial photoreceptors that are sufficient for circadian entrainment and photoperiodic time measurement, it is tempting to suggest that these photoisomerases may mediate regeneration of extraocular opsin involved in these processes. Conversely, the presence of a DRY motif on the third intracellular loop of each projected protein Fig.

Whether these motifs function as part of an as yet unidentified second-messenger system involved in chromophore regeneration or a heretofore unknown signaling function for these opsins is at this point unknown. Clearly, further work is needed to delineate the functions of these two molecules in the visual cycles of the circadian clock.

Perhaps, the most interesting feature of the present study is the incomplete overlap of distribution of gRgr and gRrh with the several putative sensory photopigments that have been proposed for photoentrainment of rhythmic processes in the pineal gland, retina, and brain.

For example, although both gRgr and gRrh are present in the pineal gland, they do not directly colocalize with cells known either to produce melatonin or to contain either iodopsin or pinopsin, reputed pineal photosensory photopigments. Conversely, both gRgr and gRrh are localized in the RGCs, which have been shown to express melanopsin in mammals, teleost fish, and chicks, 10 17 57 suggesting that visual cycle processes may reside in the RGCs themselves.

Even so, it is important to point out that colocalization of photosensory photopigments and photoisomerases is not necessary for visual cycle function, because neither gRgr or gRrh is present in the photoreceptor layers of chicks Fig. We do not know which cell types express these mRNA species in vivo, but preliminary data in our laboratory strongly suggest that astrocytes express these and other opsin photopigments in vitro.

Submitted for publication October 10, ; revised November 19, ; accepted November 21, Disclosure: M. Bailey , None; V. Cassone , None. The publication costs of this article were defrayed in part by page charge payment.

Corresponding author: Vincent M. F igure 1. View Original Download Slide. This amino acid has been shown to be responsible for chromophore binding. Proteins used in analysis are as follows: AH B. F igure 2. Tissue specific expression. Lane B : brain without pineal tissue; lane L : liver; lane I : intestine; lane H : heart; lane M : skeletal muscle; lane K : kidney; and lane R : retina.

C 18S ribosomal RNA. The blots were repeated with similar results on independently obtained samples. F igure 3. Whether these differences in sensitivity are caused by differential processing of output from the same photoreceptors or the use of different photoreceptors is unknown. Previous reports confirm that these genotypes also exhibit unattenuated phase shifts in response to appropriate light pulses 15 , 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. 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. This conclusion is supported by reports of visually blind humans showing responses consistent with the presence of functioning irradiance detection 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.

Science : — Google Scholar. Klein DC , Moore RY Pineal N -acetyltransferase and hydroxyindole- o -methyl-transferase: control by the retino-hypothalamic tract and the suprachiasmatic nuclei.

Brain Res : — Nature : — Invest Ophthalmol Vis Sci 17 : — Nature : 70 — Neuron 6 : 61 — J Comp Neurol : — Neurosci Lett : — J Comp Physiol : 39 — Clin Chem 29 : — J Clin Endocrinol Metab 83 : — Campbell S , Murphy P Extraocular phototransduction in humans.

Foster RG Shedding light on the biological clock. Neuron 20 : — Chapman and Hall , London. Google Preview. Bridges CDB The visual pigments of some common laboratory animals. Endocrinology : — Neurosci Lett : 56 — J Neurobiol 28 : 1 — 8. Thiele G , Meissl H Action spectra of the lateral eyes recorded from mammalian pineal glands. Brain Res : 10 — Neuron 5 : — J Comp Neurol : 1 — Nelson DE , Takahashi JS Sensitivity and integration in a visual pathway for circadian entrainment in the hamster Mesocricetus auratus.

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