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The Eye as Metronome of the Body
SURVEY OF OPHTHALMOLOGY VOLUME 47 • NUMBER 1 • JANUARY–FEBRUARY 2002
MAJOR REVIEW
The Eye as Metronome of the Body Virginia Lubkin, MD,1 Pouneh Beizai, MD,2 and Alfredo A. Sadun, MD, PhD3 1
New York Eye and Ear Infirmary, New York, New York; 2Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California; and 3Doheny Eye Institute, USC School of Medicine, Los Angeles, California, USA Abstract. Vision is much more than just resolving small objects. In fact, the eye sends visual information to the brain that is not consciously perceived. One such pathway entails visual information to the hypothalamus. The retinohypothalamic tract (RHT) mediates light entrainment of circadian rhythms. Retinofugal fibers project to several nuclei of the hypothalamus. These and further projections to the pineal via the sympathetic system provide the anatomical substrate for the neuro-endocrine control of diurnal and longer rhythms. Without the influence of light and dark, many rhythms desynchronize and exhibit free-running periods of approximately 24.2–24.9 hours in humans. This review will demonstrate the mechanism by which the RHT synchronizes circadian rhythms and the importance of preserving light perception in those persons with impending visual loss. (Surv Ophthalmol 47:17–26, 2002. © 2002 by Elsevier Science Inc. All rights reserved.) Key words. circadian rhythms • diurnal rhythms • light entrainment • retinohyopothamic tract • vision
Ophthalmologists, sometimes myopic in their view of the ultra-elegant organ of the body, may have to contend with the realization that the ramifications of vision extend very far. Consequently, the maintenance of vision is an overreaching obligation. The eye controls a panorama of life’s major functions, such as fertility, seasonal gestation, sleep/wake rhythms, adrenal behavior, animal feeding patterns, hibernation, and mood itself. Investigations dating back about 25 years have made it apparent that there is a retino-hypothalamic tract that courses via the optic nerve and chiasm to several hypothalamus nuclei, including the suprachiasmatic nucleus of the hypothalamus. With a few synapses and a circuitous route, this visual information ultimately afferents to that antique remnant of the third eye, the pineal gland. This mysterious organ, belittled for centuries as the “appendix of the nervous system” is the source of the melatonin that may
be involved in or a marker of the sleep/wake rhythms. Disruptions lead to jetlag, problems with shift-work, and sleep impairments. Notwithstanding the thousands of animal experiments of diurnal behavior in dozens of animal species, there remains a dearth of publications in the ophthalmologic or optometric literature concerning these clinical ramifications of blindness. The publications in little-read journals and unpublicized meetings of associations—particularly those of psychologists and physiologists—have failed to gain the attention of the medical world; hence, the lack of dialogue on alterations of circadian rhythm in blindness. However, there is evidence of myriad bodily involvements consequent to blindness. This requires that ophthalmologists investigate the possible multitude of phenomena affecting a million blind patients, many of whom have degrees of retinal destruction. The complete panorama of those impairments, which 17
© 2002 by Elsevier Science Inc. All rights reserved.
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affect a variety of bodily functions in our blind patients, must be first understood, then considered and then dealt with.
synchronized endogenous circadian rhythms, whereas bilateral transsection of the optic tract did not.33,93 Therefore, it was proposed that a retinofugal pathway exists which entrains the endogenous circadian rhythms. Later, through neuroanatomical methods employing autoradiography,53 horseradish peroxidase,68 and electrophysiology23 in animals, and paraphenylene-diamine in humans,80,81 the pathways mediating light/ dark entrainment of endogenous circadian rhythms were found and collectively named the retinohypothalamic tract. With input from the environment, such as the light/dark cycle, the endogenous period is entrained to 24 hours. If the external stimulus is removed by creating a “constant” environment, the organism would continue to show circadian rhythms, but it would have a free-running period consistent with its own internal clock; in humans this is approximately 24.2 to 24.9 hours, which is probably the intrinsic period of the endogenous pacemaker (which, intriguingly, is about the length of the earth’s rotation 100– 200 million years ago).11,45,51,77 For example, Ebling and his colleagues found that when normal rams were subjected to constant darkness or constant light, their melatonin rhythms were eliminated.13 It should be noted, however, that in most animals vision is not the important sense; yet in humans, it is the predominant sense. For example, in humans, blindness alone can alter the diurnal rhythm of serum melatonin, whereas studies in rats suggest that it takes the combination of blindness and anosmia to produce this complete effect.9,75,88 Hence, blindness has a more devastating effect on the circadian rhythm in humans. The circadian rhythms in blind persons with no light perception have been studied extensively.26,45,108 These individuals exhibit changes in their circadian rhythms with respect to cortisol,27,35,37,51,64,65 melatonin,88 growth hormone,32 and gonadotropins.4 Hence, behavioral abnormalities in sexual maturation, fertility, menopause, and sleep/wake cycle are seen.108 This may even impact longevity.42 Therefore, it appears very important that clinicians remain aware of the critical role that visual pathways play in subserving circadian rhythms and the neuroendocrine implications that exist for blind persons. Ophthalmologists should be cognizant of the problems that may arise with loss of light perception and try to salvage this sense even though otherwise useful visual perception may be lost.
I. Circadian Rhythms Every day at approximately 6:00 a.m. our serum cortisol level peaks.35 How does our body control the spurt of cortisol release so that it occurs at the same time and amount every day? It is thought that our body has an internal clock with a free-running period of about 25 hours51,98 and that this endogenous rhythm is entrained to the 24-hour (solar) period.24 In addition to cortisol,24,35,37,51,108 other hormones such as growth hormone,36 melatonin,33,45 folliclestimulating hormone, and testosterone12,15 have daily rhythmical levels. Blood pressure and core body temperature also vary predictably day by day, with both values rising during the day and falling during sleep. In fact, in vitro studies have shown that certain tissues, such as the adrenal gland,1,87 heart,97 gut, and liver,23 can independently maintain rhythmical activity with different periods and phases. The periods and phases of these physiological parameters must be synchronized with respect to each other and the environment in order for them to have the most benefit and effective advantage on organs and systems in the body. The current theory is that multiple independent oscillators exist in the body and that their periods are locked together with different phases by a pacemaker system, thus generating coherent circadian rhythms. Any physiological or psychological process with a period in the range of 20–28 hours may be described as having a circadian rhythm (circa, about; dies, a day). This circadian pacemaker system has three major components: 1) the suprachiasmatic nucleus of the hypothalamus (SCN), generator of circadian rhythms; 2) neuronal inputs or entrainers into the SCN from other parts of the brain, the most important one being the retinohypothalamic tract (RHT); and 3) output fibers from the SCN to target tissues which couples their internal rhythmicity to that of the SCN. The result of all this is a stable, predictable, and coherent system of circadian rhythms. Circadian rhythms are entrained by factors termed zeitgebers (zeit, time; geber, to give). Zeitgebers synchronize our internal clocks with the environment. In humans, zeitgebers are thought to be rhythmic changes in the environment, such as social factors, lighting, feeding, and activity. The light/dark cycle, however, seems to be the most important factor in synchronization of the endogenous circadian rhythms in animals and humans.2,64 What is the mechanism by which the light/dark cycle entrains endogenous circadian rhythms? Bilateral transsection of the optic nerve in the rat resulted in de-
II. Retinohypothalamic Tract The retinohypothalamic tract (RHT) is a direct afferent pathway from the retina to several hypothalamic nuclei. This tract sends visual signals, including those from the light/dark cycle, to the hypothalamus,
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which in turn uses this information to pace its clock and synchronize the endogenous circadian rhythm. The RHT has been described in humans80–82,84 as well as several experimental animal models, such as the rat,69,90,94 guinea pig,69 golden hamster,10,70,75,95 and other rodents.76 It has yet to be established which class of photoreceptors in the retina subserve the RHT. However, there is some evidence that this information is not mediated by the dominant threecone system.6 It is known that there is great buffering against the loss of irradiance detection; that is, even if there is sufficient loss of photoreceptors to induce visual loss, detection of light and dark still remains intact.48 It remains to be determined if the photoreceptors that mediate the RHT are different from those used for other aspects of vision, whether they have a very low threshold or if there is simply upregulation of input to the surviving photoreceptors for light/dark detection in blind persons.112 In animals and probably humans, light transduction of photoreceptors leads to activation of a subset of ganglion cells, mainly W type cells. These cells have axons that run with fibers of other types of retinal ganglion cells to compose the optic nerve. Therefore, fibers of the RHT begin in the retina, course through the optic nerve and branch off at the level of the optic chiasm to project to various nuclei in the hypothalamus. Based on anatomical studies in rats, the RHT has been divided into a medial and lateral component. The medial component contains ganglion fibers from cells distributed across the entire retina and projects bilaterally to the hypothalamic SCN,57,58,67 anterior hypothalamus, and retrochiasmatic areas.31,55 The lateral component, on the other hand, receives input mostly from ganglion cells located in the superior temporal quadrant of the retina38 and projects contralaterally to the lateral hypothalamus and supraoptic nucleus (SON).31,43,44,49 There is also a bidirectional internuclear pathway between the (two hypothalamic centers) SCN and the paraventricular nucleus (PVN).109 Animal experiments, for example, enucleation,86 optic nerve transsection,33,93 or destruction of suprachiasmatic nuclei,71,92 have shown that lesions anywhere in the RHT result in altered circadian rhythms, such as abnormally timed locomotor activity, melatonin secretion, and estrous period. Lesions in the optic tracts will not result in circadian rhythm abnormalities because the RHT has already branched off from the optic chiasm. This indicates also that fibers controlling conscious vision (via the lateral geniculate nucleus) and those mediating circadian rhythm entrainment are two of perhaps as many as six separate systems. How does the RHT system, with inputs to the SCN, SON, and perhaps other hypothalamic nuclei, synchro-
nize endogenous circadian rhythms? It is important to consider the functions of the RHT target tissues in order to understand how entrainment of circadian rhythms occur. Many of the effector functions of the RHT target tissues are still being investigated.
III. Target Areas of the RHT A. HYPOTHALAMUS
When the SCN is destroyed in rats, circadian rhythms of hormonal release55 and the sleep-wake cycle disappear.28 Transplantation of fetal SCN into the same host restores rhythmical behavior according to the donor’s activity.39,83 The SCN is proposed to be one and perhaps the only pacemaker of the multioscillator system.59 After ablating the SCN in rats, Stephan and Zucker93 demonstrated a loss of circadian rhythm in the rats’ drinking behavior and locomotor activity. In a similar study, Moore and Eichler55 found a loss of circadian corticosterone rhythm. These lesion experiments, coupled with electrophysiological studies showing the diurnal multiunit activity in the SCN after surgical isolation, demonstrate that the SCN acts as the primary circadian oscillator.29 In primates, it is thought that at least two circadian pacemakers exist, the SCN being one of them.19,59 The SCN has higher neuronal activity in the light period and lower activity in the dark period,29 which probably reflects the effect of light/visual inputs via the RHT afferents directly into this nucleus. Thus, the SCN generates its own rhythmical activity, and input from the RHT entrains its activity to the lightdark cycle. Therefore, SCN projections to other nuclei serve to synchronize their functions with the light/dark cycle as well. The neuroanatomy of the SCN has been studied extensively in the rat.22,56 The SCN is located superior to the optic chiasm and lateral to the third ventricle. Three subdivisions of the SCN exist: 1) the rostral area and the caudal area, the latter consisting of 2) a dorsomedial division, and 3) a ventrolateral division. Most of the retinal afferents are confined to the ventrolateral region, whereas the rostral area receives none. The SCN contains three types of peptide hormones: vasopressin (VP), vasoactive intestinal peptide (VIP), and somatostatin (SOM). These peptides and their mRNA show diurnal rhythmicity;63 neuronal inputs from retinal ganglion cells during the daytime reduce VIP mRNA and VIP levels,13 whereas levels of VP99 and SOM62 mRNA and peptides are increased. Vasopressin-containing neurons are located in the rostral and dorsomedial regions,102 and VIP in the ventrolateral area and SOM is present throughout the nucleus.54,96 Hence, based on these observations, the SCN is the primary circadian pacemaker. It receives and in-
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tegrates afferent visual information regarding the light/dark cycle to entrain endogenous rhythms via the RHT. Although numerous independent oscillators exist, it is the SCN of the hypothalamus that maintains phase control over those rhythms. The efferent connections of the SCN may play a role in its ability to control rhythmic hormonal release and autonomic function.8 Lesions of the SCN produce an increase in basal and stress-induced corticosterone levels in rats.32 When VP is infused into the hypothalamic paraventricular (PVN) region of these same animals, the serum corticosterone levels decrease.96 Therefore, it was concluded that VP-sensitive cells in the SCN contributed fibers to the paraventricular cells. These PVN cells contain corticotropin-releasing hormone (CRH), and control the circadian rhythm of corticosterone release through the hypothalamic– pituitary–adrenal axis. It is hypothesized that the SCN modulates the release of other pituitary hormones, as most pituitary-controlling neuroendrcrine neurons are located in the medial hypothalamus, where the SCN sends numerous projections. In addition, because the SCN projects to the PVN of the hypothalamus and the latter has fiber connections to brain stem and spinal cord preganglionic sympathetic neurons, the SCN could, potentially, affect autonomic functions such as blood pressure, body temperature, and serum glucose levels.61 Anatomical studies have also shown direct connections from the SCN to the preoptic area.13,101 Further experiments are needed to examine the role of the SCN in controlling rhythmical motor activity, appetite, and sexual activity through its connections to the hypothalamic paraventricular nucleus, hypothalamic dorsomedial nuclei,105,106 and gonadotropin-releasing hormone neurons in the preoptic area,101 respectively.
Fig. 1 demonstrates the retinal hypothalamic fiber projection that terminates in the paraventricular nucleus. Fibers destined for the supraoptic and suprachiasmatic nuclei split off earlier from the optic tract near the optic chiasm. B. PINEAL GLAND
The pineal gland secretes melatonin in a rhythmical fashion. Melatonin levels are low during the day and high at night.88 The circadian rhythm of melatonin production and release has been shown to be dependent on the light portion of the light/dark cycle. Exposure to bright light during the night when melatonin levels are highest quickly causes suppression of further melatonin production.46 In addition, phase shifts in the light/dark cycle in humans produce phase shifts in melatonin rhythm.85 Therefore, the RHT and its connections in the hypothalamus also play a critical role in entrainment of melatonin circadian rhythm.3,30 The synchronization of circadian rhythms is accomplished via a long and circuitous multi-synaptic pathway by which light input from the RHT leads to entrainment of melatonin circadian rhythm (Fig. 2). Retinofugal visual projections via the RHT arrive at the SCN, which, in turn, generates a circadian signal. This signal is transmitted to the parvocellular autonomic component of the PVN of the hypothalamus. PVN efferent axons project to the upper thoracic intermediolateral cell column of the autonomic nervous system. Preganglionic sympathetic fibers (neuron II) project to the superior cervical ganglion behind the mandible of the jaw, which synapses on postganglionic sympathetic fibers that, in turn, go to the pineal gland.52 Ophthalmologists are quite familiar with the latter three segments of this pathway which, if interrupted,
Fig. 1. Coronal section through optic chiasm and hypothalamus demonstrating retinofugal projections to the paraventricular nucleus. PVN: paraventricular nucleus. POT: paraventricular optic tract. SON: supraoptic nucleus. OT/OX: optic tract/optic chiasm junction. 3V: IIIrd ventricle.
THE EYE AS METRONOME OF THE BODY
21 Fig. 2. Pathway from retina to pineal through hypothalamus and spinal cord sympathetic neurons for the light/dark entrainment of diurnal and longer rhythms.
leads to Horner’s syndrome.16 Would a child with bilateral Horner’s syndrome also have a deafferented and hence desynchronized pineal? Would this alter the timing of developmental milestones such as puberty? Studies in enucleated hamsters demonstrated that superior cervical ganglionectomy and pinealectomy are equivalent; in that the normal gonadal evolution seen with the absence of light perception was prevented.72,73 Even if the pineal tissue was grafted in a ganglionectemized hamster, the inhibitory substance (thought to be melatonin) was not released because of the absence of sympathetic innervation. In a different study performed in ganglionectemized nonblinded rats, neither the pineal weight nor the enzymes used to make melatonin showed any reduction after exposure to light.111 Therefore, these researchers concluded that an intact sympathetic nervous system is needed for light/dark entrainment of the pineal gland. Thus, bilateral denervation of the pineal gland has the potential to result in clinical abnormalities. Due to the abundance of melatonin-binding sites in the median eminence and anterior pituitary gland, the pineal gland is thought to be the coupler of circadian rhythms and endocrine functions. Melatonin-binding sites have been identified in the pars tuberalis of the anterior pituitary gland, the median eminence as well as the SCN of rats21 and hamsters.91
For over 30 years,98,113 scientists have thought that both the human neuroendrocrine axis and that of other polyestrous mammals is influenced by environmental lighting. Now, we have two mechanisms that may explain this phenomenon: 1) the output of the SCN to the PVN of the hypothalamus and medial hypothalamus, whose cells contain many of the hormone-releasing factors of the neuroendocrine axis; and 2) the indirect output of the SCN to the pineal gland whose product, melatonin, has massive amounts of binding sites in the median eminence and anterior pituitary. These anatomical data support the findings of the earlier scientists. Melatonin circadian rhythms modulate the hypothalamic–pituitary–gonadal system. Male hamsters, when deprived of light—either by removing their eyes or keeping them in constant darkness—undergo atrophy of the gonads.25 In both cases this is prevented by pinealectomy. In another study, seminal vesicle weight, and serum leuteinizing hormone(LH) and follicle-stimulating hormone (FSH) were reduced in the golden hamster on shorter days.12 This response was blocked when the hamsters were exposed to a periodic light stimulus during the night. These experiments along with similar studies in rats7,74 illustrate the importance of light input, the pineal gland, and circadian rhythms in the reproductive functioning and sexual maturation of animals.34
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Darkness, or the absence of light perception, stimulates the pineal gland to synthesize and secrete melatonin, which, in turn, inhibits the reproductive system. Rats housed in constant darkness or made blind suffer a delay in sexual maturation, whereas rats kept under constant light undergo premature ovulation.17 After some time, the experimental rats maintained the same reproductive activity as the control rats.100 During the experiments on the reproductive activity of rats, researchers noted that rats subjected to constant darkness or prepubertal blinding also exhibited a lag in bodily growth.6 Consequently, the regulation of growth hormone by the pineal gland was studied.89 It was concluded that rats blinded before puberty had lower amounts of growth hormone and a smaller pituitary size when compared to normal rats. When these blinded rats were pinealectemized, the growth hormone levels were normal. Therefore, it was concluded that the pineal gland plays an inhibitory role in the production and release of growth hormone by the pituitary. More recently, it has been hypothesized that melatonin circadian rhythms may play a role in thyroid gland physiology. Melatonin inhibits the synthesis and release of hypothalamic thyrotropin-releasing hormone through its actions in the median eminence. In a study performed on female hamsters, the levels of thyroxin (T4), triiodothyronine (T3), and thryotropin (TSH) were all decreased after highdose administration of melatonin in the light period.104 In addition, shortening the photoperiod resulted in reduced levels of these hormones in rats and hamsters.78 Interestingly, pinealectomy restored thyroid hormones to normal. Thus, free-running melatonin rhythms may impact many different systems and cycles, such as sleep, reproductive systems, and even growth.
neal gland. As indicated previously, both these areas are important regulators of the neuroendocrine system, activity, sleep/wake cycle, and more. It should be kept in mind, however, that even though a blind person has no light perception, he or she may indeed have a functioning RHT pathway because the level of light needed to stimulate the system and synchronize the SCN may be very low. Minimal vision, even light perception and perhaps the intact eye in clinically no-light perception, and, hence, the RHT system should be preserved in individuals with eye disease in order to avoid disturbances in circadian rhythms and clinical symptoms related to gonadal dysfunction, sexual maturation, infertility, mood disorders, sleep/wake cycles, and so on. Sack and colleagues measured serum cortisol and melatonin levels in 20 blind patients and found that half of them had free-running rhythms with a period of about 25 hours.78 Although Migeon and colleagues found no difference in the diurnal variation of cortisol between normal and blind persons,50 Krieger and Rizzo,37 along with many other researchers, found desynchronization of the cortisol circadian rhythm in blind persons.64 However, it was debated whether abnormal sleep/wake cyles and activity or absence of the light/dark cycle was the culprit.37 Orth and colleagues66 concluded that some stimulus other than the sleep/wake cycle entrains the cortisol rhythm in humans, as deprivation or prolongation of sleep in a normal individual did not change the cortisol circadian rhythm. In another experiment, they showed that increasing the time a normal individual spent in the dark shifted the peak plasma cortisol level from the time of awakening to the time of illumination.62 These studies show the importance of the light/dark cycle in synchronization of cortisol circadian rhythms in humans. There is also strong evidence in rats that the eyes and the light-dark cycle are important for entrainment of the hypothalamic– pituitary–adrenal function.110 When the rats were blinded by optic enucleation, their cortisol secretion demonstrated a free-running rhythm. Furthermore, the melatonin circadian rhythms are more often abnormal in blind persons without light perception than those who are blind with light perception.47 In addition, the melatonin circadian secretory rhythms vary from one blind person to another.45 The melatonin circadian rhythm free-runs with a periodicity of 24.1 to 24.9 hours. Therefore, endogenous rhythms drift later and later every 24 hours; and in 2 to 3 weeks’ time, will be 180 degrees out of phase with the light/dark cycle. This may result in abnormal sleep/wake cycles, as the individual’s sleep propensity is highest in the daytime. Therefore, the blind may experience daytime sleepiness as well as nightime insomnia. Appropriately
IV. Circadian Rhythm Abnormalities in Blind Persons Environmental cues, such as social interactions, clocks, regular activity, and feeding, might provide the cues necessary to establish normal circadian rhythms in blind individuals. However, fixed-interval feeding in blind rats did not entrain the circadian pacemaker.20 Likewise, many blind persons without light perception exhibit free-running temperature,18 cortisol, and melatonin levels,45,47 despite having a daily routine.35,51 Circadian rhythm abnormalities occur and there is a difference between blind persons with and without light perception. Most blind persons without light perception are not able to activate their RHT pathway, which leads to desynchronization of the SCN and its target tissues, such as the PVN of the hypothalamus and pi-
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timed exogenous administration of melatonin in the blind has been widely investigated and found to curb their sleeping difficulties.18,79 Melatonin plays a role in many physiological and behavioral processes, such as aging, calcium homeostasis, neuroendocrine, and immune and reproductive regulation; any changes in its circadian rhythms could potentially cause clinical symptoms in any of these areas.107 Even though the experimental data prove that light input to the SCN and the pineal gland modulates gonadal structure and function in rats6,60 and hamsters,25 there are conflicting data with respect to humans. Neonatal ablation of the SCN nucleus, prior to the development of the RHT system, produces constant vaginal estrous in female rats.12 This demonstrates the importance of circadian rhythms in reproductive functioning. Bellastella and colleagues noted a decreased plasma level of LH, FSH, testosterone, and subnormal plasma LH, FSH, PRL response to GnRH-TRH in prepubertal blind boys.4 This may result in delayed maturation of the hypothalamic-pituitary gonadal axis and delayed pubertal development. In contrast, Bodenheimer5 conducted a study measuring the same hormones in blind men (total quantities) and found no differences in hormone levels between sighted men and blind men with no light perception. However, in the Bodenhemier study, the blind men lost their sight after puberty. There is also much controversy regarding the influence of light perception on the female reproductive system. Rats who have been kept in constant darkness or those that have undergone optic enucleation show a delay in sexual maturation.17 Zacharias and Wurtman113 also concluded that sexual maturation in humans is dependent on environmental light perception. With use of a questionnaire, they compared the age of menarche between blind and nonblind girls; they found that blind girls without light perception underwent menarche 7 months earlier than their nonblind counterparts. Thomas and Pizzarello,98 on the other hand, found no significant difference in the age of menarche between blind and nonblind girls living in an institution. They conluded that any stimulus, not just light stimulus, with a 24-hour periodicity can entrain the circadian rhythms. Institutions that have fixed daily schedules may help set the periodicity in blind persons. Lehrer also postulated that blindness has no impact on fertility,40,41 even though many years earilier, Elden14 had thought otherwise because fewer blind women were becoming pregnant than the national birth rate predicted. Furthermore, Lehrer found a negative linear correlation between age at loss of light perception and age at menopause,41 which could imply that pineal stimulation and production of melatonin can lengthen life span.
Bodily growth may be stunted in blind persons without light perception. Krieger and Glick measured growth hormone levels in five blind persons.34 The normal peak plasma growth hormone level seen following the onset of sleep was absent. Growth hormone levels were also lower in blinded rats; however, the blinded pinealectemized rats displayed normal levels of growth hormone.86 Hence, the abnormal pineal circadian rhythms in blind persons could lead to deficient growth.
V. Conclusion The importance of light entrainment of circadian rhythms is becoming more and more apparent as further information is unraveled regarding the role of SCN in other neuroendocrine functions, such as thyroid hormone, growth hormone, and GnRH. Controversies regarding the critical nature of light/dark cycle input to neuroendocrine systems such as fertility remain unresolved. Future studies comparing large clinical populations with different degrees of vision will be important. Circadian rhythms are vital to physiological and behavioral processes in animals and especially in humans. Light entrainment of the circadian rhythms to the 24-hour solar period is important as studies in blinded rats and humans have proven to us. Freerunning circadian rhythms can cause problems with sleep/wake cycles, mood,103 growth, reproductive functioning and other endocrine systems, and aging. Circadian rhythms may also impact maturation, developmental milestones, and longevity. Therefore, it is incumbent upon the clinician to recognize the importance of preserving even minimum vision, such as light perception, especially in the setting of profound bilateral visual loss.
Method of Literature Search A Medline/Ovid search was conducted for all database years (1968–present). Search words were: circadian and vision, diurnal and vision, retino-hypothalamic, circadian rhythms, retinohypothalamic tract, diurnal rhythms, visual entrainment, hypothalamus. These searches were limited to English journals and abstracts. From this bibliography we proceeded with a classical search of primary sources. On two occasions we obtained help in translating from the German.
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4. Bellastella A, Criscuolo T, Sinisi AA, et al: Influence of blindness on plasma luteinizing hormone, follicle- stimulating hormone, prolactin, and testosterone levels in prepubertal boys. J Clin Endocrinol Metab 64:862–4, 1987 5. Bodenheimer S, Winter JS, Faiman C: Diurnal rhythms of serum gonadotropins, testosterone, estradiol and cortisol in blind men. J Clin Endocrinol Metab 37:472–5, 1973 6. Brainard GC, Hanifin JP, Rollag MD, et al: Human melatonin regulation is not mediated by the three cone photopic visual system. J Clin Endocrinol Metab 86:433–6, 2001 7. Browman LG: The effect of optic enucleation on the male albino rat. Anat Record 78:59–73, 1940 8. Buijs RM, Kalsbeek A, van der Woude TP, et al: Suprachiasmatic nucleus lesion increases corticosterone secretion. Am J Physiol 264:R1186–92, 1993 9. Chen HJ, Reiter RJ: Influence of subcutaneous deposits of melatonin on the antigonadotrophic effects of blinding and anosmia in male rats. A dose-response study. Neuroendocrinology 30:169–73, 1980 10. Costa MS, Santee UR, Cavalcante JS, et al: Retinohypothalamic projections in the common marmoset (Callithrix jacchus): a study using cholera toxin subunit B. J Comp Neurol 415:393– 403, 1999 11. Dieckhues B: [The influence of ocular perception on the human endocrine system (authors transl)]. Klin Monatsbl Augenheilkd 165:291–6, 1974 12. Earnest DJ, Turek FW: Periodic exposure to a brief light signal stimulates neuroendocrine-gonadal activity in golden hamsters. J Androl 5:64–9, 1984 13. Ebling FJ, Lincoln GA, Wollnik F, Anderson N: Effects of constant darkness and constant light on circadian organization and reproductive responses in the ram. J Biol Rhythms 3:365–84, 1988 14. Elden CA: Sterility of blind women. Jpn J Fertil Steril 36:396, 1981 15. Faiman C, Winter JS: Diurnal cycles in plasma FSH, testosterone and cortisol in men. J Clin Endocrinol Metab 33:186–92, 1971 16. Fields CR, Barker FM 2nd: Review of Horners syndrome and a case report. Optom Vis Sci 69:481–5, 1992 17. Fiske VM: Effect of light on sexual maturation, estrous cycles, and anterior pituitary of the rat. Endocrinology 29:187, 1941 18. Folkard S, Arendt J, Aldhous M, Kennett H: Melatonin stabilises sleep onset time in a blind man without entrainment of cortisol or temperature rhythms. Neurosci Lett 113:193–8, 1990 19. Fuller CA, Lydic R, Sulzman FM, et al: Circadian rhythm of body temperature persists after suprachiasmatic lesions in the squirrel monkey. Am J Physiol 241:R385–91, 1981 20. Gibbs FP: Fixed interval feeding does not entrain the circadian pacemaker in blind rats. Am J Physiol 236:R249–53, 1979 21. Gitler MS, Zeeberg BR, John C, Reba RC: Specific in vivo binding of [125I]-iodomelatonin to melatonin receptors in rat brain. Neuropharmacology 29:603–8, 1990 22. Guldner FH: Synaptology of the rat suprachiasmatic nucleus. Cell Tissue Res 165:509–44, 1976 23. Hardeland R: Circadian rhythmicity in cultured liver cells. I. Rhythms in tyrosine aminotransferase activity and inducibility and in (3H) leucine incorporation. Int J Biochem 4:581–90, 1973 24. Hellman L, Nakada F, Curti J, et al: Cortisol is secreted episodically by normal man. J Clin Endocrinol Metab 30:411–22, 1970 25. Hoffman RA, Reiter RJ: Pineal gland: influence on gonads of male hamsters. Science 148:1609–10, 1965 26. Hollwich F: The influence of light via the eyes on animals and man. Ann NY Acad Sci 117:105–31, 1964 27. Hollwich F, Dieckhues B: [Endocrine system and blindness]. Dtsch Med Wochenschr 96:363–8, 1971 28. Ibuka N, Kawamura H: Loss of circadian rhythm in sleepwakefulness cycle in the rat by suprachiasmatic nucleus lesions. Brain Res 96:76–81, 1975 29. Inouye ST, Kawamura H: Persistence of circadian rhythmicity in a mammalian hypothalamic island containing the suprachiasmatic nucleus. Proc Natl Acad Sci USA 76:5962–6, 1979 30. Jagota A, Olcese J, Harinarayana Rao S, Gupta PD: Pineal
rhythms are synchronized to light-dark cycles in congenitally anophthalmic mutant rats. Brain Res 825:95–103, 1999 Johnson RF, Morin LP, Moore RY: Retinohypothalamic projections in the hamster and rat demonstrated using cholera toxin. Brain Res 462:301–12, 1988 Kalsbeek A, Buijs RM, van Heerikhuize JJ, et al: Vasopressincontaining neurons of the suprachiasmatic nuclei inhibit corticosterone release. Brain Res 580:62–7, 1992 Klein DC, Weller JL: Indole metabolism in the pineal gland: a circadian rhythm in N- acetyltransferase. Science 169: 1093–5, 1970 Krieger DT: Effect of ocular enucleation and altered lighting regimens at various ages on the circadian periodicity of plasma corticosteroid levels in the rat. Endocrinology 93: 1077–91, 1973 Krieger DT, Allen W, Rizzo F, Krieger HP: Characterization of the normal temporal pattern of plasma corticosteroid levels. J Clin Endocrinol Metab 33:14, 1971 Krieger DT, Glick S: Absent sleep peak of growth hormone release in blind subjects: ccorrelation with sleep EEG stages. J Clin Endocrinol Metab 33:847–50, 1971 Krieger DT, Rizzo F: Circadian periodicity of plasma 11hydroxycorticosteroid levels in subjects with partial and absent light perception. Neuroendocrinology 8:165–9, 1971 Leak RK, Moore RY: Identification of retinal ganglion cells projecting to the lateral hypothalamic area of the rat. Brain Res 770:105–14, 1997 Lehman MN, Silver R, Gladstone WR, et al: Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain. J Neurosci 7:1626–38, 1987 Lehrer S: Fertility of blind women. Fertil Steril 38:751–2, 1982 Lehrer S: Fertility and menopause in blind women. Fertil Steril 36:396–8, 1981 Lehrer S: Pineal effect on longevity. J Chronic Dis 32:411–2, 1979 Levine JD, Weiss ML, Rosenwasser AM, Miselis RR: Retinohypothalamic tract in the female albino rat: a study using horseradish peroxidase conjugated to cholera toxin. J Comp Neurol 306:344–60, 1991 Levine JD, Zhao XS, Miselis RR: Direct and indirect retinohypothalamic projections to the supraoptic nucleus in the female albino rat. J Comp Neurol 341:214–24, 1994 Lewy AJ, Newsome DA: Different types of melatonin circadian secretory rhythms in some blind subjects. J Clin Endocrinol Metab 56:1103–7, 1983 Lewy AJ, Wehr TA, Goodwin FK, et al: Light suppresses melatonin secretion in humans. Science 210:1267–9, 1980 Lockley SW, Skene DJ, Arendt J, et al: Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 82:3763–70, 1997 Lucas RJ, Foster RG: Neither functional rod photoreceptors nor rod or cone outer segments are required for the photic inhibition of pineal melatonin. Endocrinology 140:1520–4, 1999 Mai JK: Distribution of retinal axons within the lateral hypothalamic area. Exp Brain Res 34:373–7, 1979 Migeon CJ, Tyler FH, Makoney JP, et al: The diurnal variation of plasma levels and urinary excretion of 17-hydroxycorticosteroids in normal subjects, night wokers and blind subjects. J Clin Endocrinol Metab 16:622–33, 1956 Miles LE, Raynal DM, Wilson MA: Blind man living in normal society has circadian rhythms of 24.9 hours. Science 198: 421–3, 1977 Moore RY: Neural control of the pineal gland. Behav Brain Res 73:125–30, 1996 Moore RY: Retinohypothalamic projections in mammals: a comparative study. Brain Res 49:403–9, 1979 Moore RY, Brecha N, Card JP, Yamada T: Distribution of somatostatin immunoreactive neurons in the hypothalamus of the rat. Neurosci Behav Physiol 7:98, 1981 Moore RY, Eichler VB: Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42:201–6, 1972
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THE EYE AS METRONOME OF THE BODY 56. Moore RY, Lenn NJ: A retinohypothalamic projection in the rat. J Comp Neurol 146:1–14, 1972 57. Moore RY, Marchand ER, Riley JN: Suprachiasmatic nucleus afferents in the rat: an HRP-retrograde transport study. Neurosci Abstr 5:232, 1979 58. Moore RY, Speh JC, Card JP: The retinohypothalamic tract originates from a distinct subset of retinal ganglion cells. J Comp Neurol 352:351–66, 1995 59. Moore-Ede MC: The circadian timing system in mammals: two pacemakers preside over many secondary oscillators. Fed Proc 42:2802–8, 1983 60. Mosko SS, Moore RY: Neonatal ablation of the suprachiasmatic nucleus. Effects on the development of the pituitary-gonadal axis in the female rat. Neuroendocrinology 29:350–61, 1979 61. Nagai K, Nagai N, Shimizu K, et al: SCN output drives the autonomic nervous system: with special reference to the autonomic function related to the regulation of glucose metabolism. Prog Brain Res 111:253–72, 1996 62. Nishiwaki T, Okamura H, Kanemasa K, et al: Differences of somatostatin mRNA in the rat suprachiasmatic nucleus under light-dark and constant dark conditions: an analysis by in situ hybridization. Neurosci Lett 197:231–4, 1995 63. Okamoto S, Okamura H, Miyake M, et al: A diurnal variation of vasoactive intestinal peptide (VIP) mRNA under a daily light-dark cycle in the rat suprachiasmatic nucleus. Histochemistry 95:525–8, 1991 64. Orth DN, Besser GM, King PH, Nicholson WE: Free-running circadian plasma cortisol rhythm in a blind human subject. Clin Endocrinol (Oxf) 10:603–17, 1979 65. Orth DN, Island DP: Light synchronization of the circadian rhythm in plasma cortisol (17-OHCS) concentration in man. J Clin Endocrinol Metab 29:479–86, 1969 66. Orth DN, Island DP, Liddle GW: Experimental alteration of the circadian rhythm in plasma cortisol (17-OHCS) concentration in man. J Clin Endocrinol Metab 27:549–55, 1967 67. Pickard GE: Morphological characteristics of retinal ganglion cells projecting to the suprachiasmatic nucleus: a horseradish peroxidase study. Brain Res 183:458–65, 1980 68. Pickard GE, Silverman AJ: Direct retinal projections to the hypothalamus, piriform cortex, and accessory optic nuclei in the golden hamster as demonstrated by a sensitive anterograde horseradish peroxidase technique. J Comp Neurol 196:155–72, 1981 69. Polyak S: The Vertebrate Visual System. Chicago, University of Chicago Press, 1957, pp 288–389 70. Printz RH, Hall JL: Evidence for a retinohypothalamic pathway in the golden hamster. Anat Rec 179:57–65, 1974 71. Raisman G, Brown-Grant K: The suprachiasmatic syndrome: endocrine and behavioural abnormalities following lesions of the suprachiasmatic nuclei in the female rat. Proc R Soc Lond B Biol Sci 198:297–314, 1977 72. Reiter RJ: The effect of pineal grafts, pinealectomy, and denervation of the pineal gland on the reproductive organs of male hamsters. Neuroendocrinology 2:138–46, 1967 73. Reiter RJ, Hester RJ: Interrelationships of the pineal gland, the superior cervical ganglia and the photoperiod in the regulation of the endocrine systems of hamsters. Endocrinology 79:1168–70, 1966 74. Reiter RJ, Sorrentino SD, Hoffmann JC, Rubin PH: Pineal, neural and photic control of reproductive organ size in early androgen-treated male rats. Neuroendocrinology 3:246–55, 1968 75. Reiter RJ, Sorrentino S Jr, Ralph CL, et al: Some endocrine effects of blinding and anosmia in adult male rats with observations on pineal melatonin. Endocrinology 88:895–900, 1971 76. Reuss S, Fuchs E: Anterograde tracing of retinal afferents to the tree shrew hypothalamus and raphe. Brain Res 874:66– 74, 2000 77. Sack RL, Lewy AJ: Melatonin as a chronobiotic: treatment of circadian desynchrony in night workers and the blind. J Biol Rhythms 12:595–603, 1997 78. Sack RL, Lewy AJ, Blood ML, et al: Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab 75:127–34, 1992 79. Sack RL, Lewy AJ, Blood ML, et al: Melatonin administration
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to blind people: phase advances and entrainment. J Biol Rhythms 6:249–61, 1991 Sadun AA, Johnson BM, Schaechter J: Neuroanatomy of the human visual system: Part III, three retinal projections to the hypothalamus. Neuro-ophthalmology 6:371–9, 1986 Sadun AA, Schaechter JD, Smith LE: A retinohypothalamic pathway in man: light mediation of circadian rhythms. Brain Res 302:371–7, 1984 Sawaki Y: Retinohypothalamic projection: electrophysiological evidence for the existence in female rats. Brain Res 120:336– 41, 1977 Sawaki Y, Nihonmatsu I, Kawamura H: Transplantation of the neonatal suprachiasmatic nuclei into rats with complete bilateral suprachiasmatic lesions. Neurosci Res 1:67–72, 1984 Schaechter JD, Sadun AA: A second hypothalamic nucleus receiving retinal input in man: the paraventricular nucleus. Brain Res 340:243–50, 1985 Shanahan TL, Czeisler CA: Light exposure induces equivalent phase shifts of the endogenous circadian rhythms of circulating plasma melatonin and core body temperature in men. J Clin Endocrinol Metab 73:227–35, 1991 Shibata S, Liou S, Ueki S, Oomura Y: Influence of environmental light-dark cycle and enucleation on activity of suprachiasmatic neurons in slice preparations. Brain Res 302:75–81, 1984 Shiotsuka R, Jovonovich J, Jovonovich JA: In vitro data on drug sensitivity: circadian and ultradian corticosterone rhythms in adrenal organ cultures, in Aschoff J, Ceresa F, Halberg F (eds): Chronobiolocial Aspects of Endocrinology. Stuttgart, Schattauer-Verlag, 1974, pp 255–267 Smith JA, O’Hara J, Schiff AA: Altered diurnal serum melatonin rhythm in blind men. Lancet 2:933, 1981 Sorrentino S Jr, Reiter RJ, Schalch DS: Pineal regulation of growth hormone synthesis and release in blinded and blindedanosmic male rats. Neuroendocrinology 7:210–8, 1971 Sousa-Pinto A, Castro-Correia J: Light microscopic observations on the possible retinohypothalamic projection in the rat. Exp Brain Res 11:515–27, 1970 Stankov B, Reiter RJ: Melatonin receptors: current status, facts, and hypotheses. Life Sci 46:971–82, 1990 Stephan FK, Nunez AA: Elimination of circadian rhythms in drinking, activity, sleep, and temperature by isolation of the suprachiasmatic nuclei. Behav Biol 20:1–61, 1977 Stephan FK, Zucker I: Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA 69:1583–6, 1972 Stephan FK, Zucker I: Circadian rhythms in drinking behavior and locomotor activity are eliminated following suprachiasmatic lesions. Proc Natl Acad Sci USA 54:1521–7, 1972 Stetson MH, Watson-Whitmyre M: Nucleus suprachiasmaticus: the biological clock in the hamster? Science 191:197–9, 1976 Teclemariam-Mesbah R, Kalsbeek A, Pevet P, Buijs RM: Direct vasoactive intestinal polypeptide-containing projection from the suprachiasmatic nucleus to spinal projecting hypothalamic paraventricular neurons. Brain Res 748:71–6, 1997 Tharp GD, Folk GE: Rhythmic changes in rate of the heart and heart cells during prolonged isolation. Comp Biochem Physiol 14:255–73, 1965 Thomas JB, Pizzarello DJ: Blindness, biologic rhythms, and menarche. Obstet Gynecol 30:507–9, 1967 Uhl GR, Reppert SM: Suprachiasmatic nucleus vasopressin messenger RNA: circadian variation in normal and Brattleboro rats. Science 232:390–3, 1986 van der Beek EM: Circadian control of reproduction in the female rat. Prog Brain Res 111:295–320, 1996 van der Beek EM, Horvath TL, Wiegant VM, et al: Evidence for a direct neuronal pathway from the suprachiasmatic nucleus to the gonadotropin-releasing hormone system: combined tracing and light and electron microscopic immunocytochemical studies. J Comp Neurol 384:569–79, 1997 Vandesande F, Dierickx K, DeMey J: Identification of the vasopressin-neurophysin producing neurons of the rat suprachiasmatic nuclei. Cell Tissue Res 156:377–80, 1975 Vrang N, Larsen PJ, Mikkelsen JD: Direct projection from the suprachiasmatic nucleus to hypophysiotrophic corti-
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cotropin-releasing factor immunoreactive cells in the paraventricular nucleus of the hypothalamus demonstrated by means of Phaseolus vulgaris-leucoagglutinin tract tracing. Brain Res 684:61–9, 1995 Vriend J, Richardson BA, Vaughan MK, et al: Effects of melatonin on thyroid physiology of female hamsters. Neuroendocrinology 35:79–85, 1982 Watts AG, Swanson LW: Efferent projections of the suprachiasmatic nucleus: II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunohistochemistry in the rat. J Comp Neurol 258:230–52, 1987 Watts AG, Swanson LW, Sanchez-Watts G: Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J Comp Neurol 258:204–29, 1987 Wehr TA, Sack D, Rosenthal N, et al: Circadian rhythm disturbances in manic-depressive illness. Fed Proc 42:2809–14, 1983 Weitzman ED, Fukushima D, Nogeire C, et al: Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects. J Clin Endocrinol Metab 33:14–22, 1971 Wever RA: The Circadian System of Man: Results of Experiments Under Temporal Isolation. Berlin, Springer, 1979
110. Wilson MM, Rice RW, Critchlow V: Evidence for a free-running circadian rhythm in pituitary-adrenal function in blinded adult female rats. Neuroendocrinology 20:289–95, 1976 111. Wurtman RJ, Axelrod J, Fischer JE: Melatonin synthesis in the pineal gland: effect of light mediated by the sympathetic nervous system. Science 143:1328–9, 1964 112. Yamazaki S, Goto M, Menaker M: No evidence for extraocular photoreceptors in the circadian system of the Syrian hamster. J Biol Rhythms 14:197–201, 1999 113. Zacharias L, Wurtman RJ: Blindness and menarche. Obstet Gynecol 33:603–8, 1969
The authors have no commercial or proprietary interest in any product or concept discussed in this article. They wish to acknowledge Mona Khan, MD, for having persistently questioned and researched many of the issues of light entrainment. Reprint address: Alfredo A. Sadun, MD, PhD, Thornton Professor of Vision, Doheny Eye Institute-DOH 5802, 1450 San Pablo St., Los Angeles, CA 90033-4671.
MAJOR REVIEW
The Eye as Metronome of the Body Virginia Lubkin, MD,1 Pouneh Beizai, MD,2 and Alfredo A. Sadun, MD, PhD3 1
New York Eye and Ear Infirmary, New York, New York; 2Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, California; and 3Doheny Eye Institute, USC School of Medicine, Los Angeles, California, USA Abstract. Vision is much more than just resolving small objects. In fact, the eye sends visual information to the brain that is not consciously perceived. One such pathway entails visual information to the hypothalamus. The retinohypothalamic tract (RHT) mediates light entrainment of circadian rhythms. Retinofugal fibers project to several nuclei of the hypothalamus. These and further projections to the pineal via the sympathetic system provide the anatomical substrate for the neuro-endocrine control of diurnal and longer rhythms. Without the influence of light and dark, many rhythms desynchronize and exhibit free-running periods of approximately 24.2–24.9 hours in humans. This review will demonstrate the mechanism by which the RHT synchronizes circadian rhythms and the importance of preserving light perception in those persons with impending visual loss. (Surv Ophthalmol 47:17–26, 2002. © 2002 by Elsevier Science Inc. All rights reserved.) Key words. circadian rhythms • diurnal rhythms • light entrainment • retinohyopothamic tract • vision
Ophthalmologists, sometimes myopic in their view of the ultra-elegant organ of the body, may have to contend with the realization that the ramifications of vision extend very far. Consequently, the maintenance of vision is an overreaching obligation. The eye controls a panorama of life’s major functions, such as fertility, seasonal gestation, sleep/wake rhythms, adrenal behavior, animal feeding patterns, hibernation, and mood itself. Investigations dating back about 25 years have made it apparent that there is a retino-hypothalamic tract that courses via the optic nerve and chiasm to several hypothalamus nuclei, including the suprachiasmatic nucleus of the hypothalamus. With a few synapses and a circuitous route, this visual information ultimately afferents to that antique remnant of the third eye, the pineal gland. This mysterious organ, belittled for centuries as the “appendix of the nervous system” is the source of the melatonin that may
be involved in or a marker of the sleep/wake rhythms. Disruptions lead to jetlag, problems with shift-work, and sleep impairments. Notwithstanding the thousands of animal experiments of diurnal behavior in dozens of animal species, there remains a dearth of publications in the ophthalmologic or optometric literature concerning these clinical ramifications of blindness. The publications in little-read journals and unpublicized meetings of associations—particularly those of psychologists and physiologists—have failed to gain the attention of the medical world; hence, the lack of dialogue on alterations of circadian rhythm in blindness. However, there is evidence of myriad bodily involvements consequent to blindness. This requires that ophthalmologists investigate the possible multitude of phenomena affecting a million blind patients, many of whom have degrees of retinal destruction. The complete panorama of those impairments, which 17
© 2002 by Elsevier Science Inc. All rights reserved.
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affect a variety of bodily functions in our blind patients, must be first understood, then considered and then dealt with.
synchronized endogenous circadian rhythms, whereas bilateral transsection of the optic tract did not.33,93 Therefore, it was proposed that a retinofugal pathway exists which entrains the endogenous circadian rhythms. Later, through neuroanatomical methods employing autoradiography,53 horseradish peroxidase,68 and electrophysiology23 in animals, and paraphenylene-diamine in humans,80,81 the pathways mediating light/ dark entrainment of endogenous circadian rhythms were found and collectively named the retinohypothalamic tract. With input from the environment, such as the light/dark cycle, the endogenous period is entrained to 24 hours. If the external stimulus is removed by creating a “constant” environment, the organism would continue to show circadian rhythms, but it would have a free-running period consistent with its own internal clock; in humans this is approximately 24.2 to 24.9 hours, which is probably the intrinsic period of the endogenous pacemaker (which, intriguingly, is about the length of the earth’s rotation 100– 200 million years ago).11,45,51,77 For example, Ebling and his colleagues found that when normal rams were subjected to constant darkness or constant light, their melatonin rhythms were eliminated.13 It should be noted, however, that in most animals vision is not the important sense; yet in humans, it is the predominant sense. For example, in humans, blindness alone can alter the diurnal rhythm of serum melatonin, whereas studies in rats suggest that it takes the combination of blindness and anosmia to produce this complete effect.9,75,88 Hence, blindness has a more devastating effect on the circadian rhythm in humans. The circadian rhythms in blind persons with no light perception have been studied extensively.26,45,108 These individuals exhibit changes in their circadian rhythms with respect to cortisol,27,35,37,51,64,65 melatonin,88 growth hormone,32 and gonadotropins.4 Hence, behavioral abnormalities in sexual maturation, fertility, menopause, and sleep/wake cycle are seen.108 This may even impact longevity.42 Therefore, it appears very important that clinicians remain aware of the critical role that visual pathways play in subserving circadian rhythms and the neuroendocrine implications that exist for blind persons. Ophthalmologists should be cognizant of the problems that may arise with loss of light perception and try to salvage this sense even though otherwise useful visual perception may be lost.
I. Circadian Rhythms Every day at approximately 6:00 a.m. our serum cortisol level peaks.35 How does our body control the spurt of cortisol release so that it occurs at the same time and amount every day? It is thought that our body has an internal clock with a free-running period of about 25 hours51,98 and that this endogenous rhythm is entrained to the 24-hour (solar) period.24 In addition to cortisol,24,35,37,51,108 other hormones such as growth hormone,36 melatonin,33,45 folliclestimulating hormone, and testosterone12,15 have daily rhythmical levels. Blood pressure and core body temperature also vary predictably day by day, with both values rising during the day and falling during sleep. In fact, in vitro studies have shown that certain tissues, such as the adrenal gland,1,87 heart,97 gut, and liver,23 can independently maintain rhythmical activity with different periods and phases. The periods and phases of these physiological parameters must be synchronized with respect to each other and the environment in order for them to have the most benefit and effective advantage on organs and systems in the body. The current theory is that multiple independent oscillators exist in the body and that their periods are locked together with different phases by a pacemaker system, thus generating coherent circadian rhythms. Any physiological or psychological process with a period in the range of 20–28 hours may be described as having a circadian rhythm (circa, about; dies, a day). This circadian pacemaker system has three major components: 1) the suprachiasmatic nucleus of the hypothalamus (SCN), generator of circadian rhythms; 2) neuronal inputs or entrainers into the SCN from other parts of the brain, the most important one being the retinohypothalamic tract (RHT); and 3) output fibers from the SCN to target tissues which couples their internal rhythmicity to that of the SCN. The result of all this is a stable, predictable, and coherent system of circadian rhythms. Circadian rhythms are entrained by factors termed zeitgebers (zeit, time; geber, to give). Zeitgebers synchronize our internal clocks with the environment. In humans, zeitgebers are thought to be rhythmic changes in the environment, such as social factors, lighting, feeding, and activity. The light/dark cycle, however, seems to be the most important factor in synchronization of the endogenous circadian rhythms in animals and humans.2,64 What is the mechanism by which the light/dark cycle entrains endogenous circadian rhythms? Bilateral transsection of the optic nerve in the rat resulted in de-
II. Retinohypothalamic Tract The retinohypothalamic tract (RHT) is a direct afferent pathway from the retina to several hypothalamic nuclei. This tract sends visual signals, including those from the light/dark cycle, to the hypothalamus,
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which in turn uses this information to pace its clock and synchronize the endogenous circadian rhythm. The RHT has been described in humans80–82,84 as well as several experimental animal models, such as the rat,69,90,94 guinea pig,69 golden hamster,10,70,75,95 and other rodents.76 It has yet to be established which class of photoreceptors in the retina subserve the RHT. However, there is some evidence that this information is not mediated by the dominant threecone system.6 It is known that there is great buffering against the loss of irradiance detection; that is, even if there is sufficient loss of photoreceptors to induce visual loss, detection of light and dark still remains intact.48 It remains to be determined if the photoreceptors that mediate the RHT are different from those used for other aspects of vision, whether they have a very low threshold or if there is simply upregulation of input to the surviving photoreceptors for light/dark detection in blind persons.112 In animals and probably humans, light transduction of photoreceptors leads to activation of a subset of ganglion cells, mainly W type cells. These cells have axons that run with fibers of other types of retinal ganglion cells to compose the optic nerve. Therefore, fibers of the RHT begin in the retina, course through the optic nerve and branch off at the level of the optic chiasm to project to various nuclei in the hypothalamus. Based on anatomical studies in rats, the RHT has been divided into a medial and lateral component. The medial component contains ganglion fibers from cells distributed across the entire retina and projects bilaterally to the hypothalamic SCN,57,58,67 anterior hypothalamus, and retrochiasmatic areas.31,55 The lateral component, on the other hand, receives input mostly from ganglion cells located in the superior temporal quadrant of the retina38 and projects contralaterally to the lateral hypothalamus and supraoptic nucleus (SON).31,43,44,49 There is also a bidirectional internuclear pathway between the (two hypothalamic centers) SCN and the paraventricular nucleus (PVN).109 Animal experiments, for example, enucleation,86 optic nerve transsection,33,93 or destruction of suprachiasmatic nuclei,71,92 have shown that lesions anywhere in the RHT result in altered circadian rhythms, such as abnormally timed locomotor activity, melatonin secretion, and estrous period. Lesions in the optic tracts will not result in circadian rhythm abnormalities because the RHT has already branched off from the optic chiasm. This indicates also that fibers controlling conscious vision (via the lateral geniculate nucleus) and those mediating circadian rhythm entrainment are two of perhaps as many as six separate systems. How does the RHT system, with inputs to the SCN, SON, and perhaps other hypothalamic nuclei, synchro-
nize endogenous circadian rhythms? It is important to consider the functions of the RHT target tissues in order to understand how entrainment of circadian rhythms occur. Many of the effector functions of the RHT target tissues are still being investigated.
III. Target Areas of the RHT A. HYPOTHALAMUS
When the SCN is destroyed in rats, circadian rhythms of hormonal release55 and the sleep-wake cycle disappear.28 Transplantation of fetal SCN into the same host restores rhythmical behavior according to the donor’s activity.39,83 The SCN is proposed to be one and perhaps the only pacemaker of the multioscillator system.59 After ablating the SCN in rats, Stephan and Zucker93 demonstrated a loss of circadian rhythm in the rats’ drinking behavior and locomotor activity. In a similar study, Moore and Eichler55 found a loss of circadian corticosterone rhythm. These lesion experiments, coupled with electrophysiological studies showing the diurnal multiunit activity in the SCN after surgical isolation, demonstrate that the SCN acts as the primary circadian oscillator.29 In primates, it is thought that at least two circadian pacemakers exist, the SCN being one of them.19,59 The SCN has higher neuronal activity in the light period and lower activity in the dark period,29 which probably reflects the effect of light/visual inputs via the RHT afferents directly into this nucleus. Thus, the SCN generates its own rhythmical activity, and input from the RHT entrains its activity to the lightdark cycle. Therefore, SCN projections to other nuclei serve to synchronize their functions with the light/dark cycle as well. The neuroanatomy of the SCN has been studied extensively in the rat.22,56 The SCN is located superior to the optic chiasm and lateral to the third ventricle. Three subdivisions of the SCN exist: 1) the rostral area and the caudal area, the latter consisting of 2) a dorsomedial division, and 3) a ventrolateral division. Most of the retinal afferents are confined to the ventrolateral region, whereas the rostral area receives none. The SCN contains three types of peptide hormones: vasopressin (VP), vasoactive intestinal peptide (VIP), and somatostatin (SOM). These peptides and their mRNA show diurnal rhythmicity;63 neuronal inputs from retinal ganglion cells during the daytime reduce VIP mRNA and VIP levels,13 whereas levels of VP99 and SOM62 mRNA and peptides are increased. Vasopressin-containing neurons are located in the rostral and dorsomedial regions,102 and VIP in the ventrolateral area and SOM is present throughout the nucleus.54,96 Hence, based on these observations, the SCN is the primary circadian pacemaker. It receives and in-
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tegrates afferent visual information regarding the light/dark cycle to entrain endogenous rhythms via the RHT. Although numerous independent oscillators exist, it is the SCN of the hypothalamus that maintains phase control over those rhythms. The efferent connections of the SCN may play a role in its ability to control rhythmic hormonal release and autonomic function.8 Lesions of the SCN produce an increase in basal and stress-induced corticosterone levels in rats.32 When VP is infused into the hypothalamic paraventricular (PVN) region of these same animals, the serum corticosterone levels decrease.96 Therefore, it was concluded that VP-sensitive cells in the SCN contributed fibers to the paraventricular cells. These PVN cells contain corticotropin-releasing hormone (CRH), and control the circadian rhythm of corticosterone release through the hypothalamic– pituitary–adrenal axis. It is hypothesized that the SCN modulates the release of other pituitary hormones, as most pituitary-controlling neuroendrcrine neurons are located in the medial hypothalamus, where the SCN sends numerous projections. In addition, because the SCN projects to the PVN of the hypothalamus and the latter has fiber connections to brain stem and spinal cord preganglionic sympathetic neurons, the SCN could, potentially, affect autonomic functions such as blood pressure, body temperature, and serum glucose levels.61 Anatomical studies have also shown direct connections from the SCN to the preoptic area.13,101 Further experiments are needed to examine the role of the SCN in controlling rhythmical motor activity, appetite, and sexual activity through its connections to the hypothalamic paraventricular nucleus, hypothalamic dorsomedial nuclei,105,106 and gonadotropin-releasing hormone neurons in the preoptic area,101 respectively.
Fig. 1 demonstrates the retinal hypothalamic fiber projection that terminates in the paraventricular nucleus. Fibers destined for the supraoptic and suprachiasmatic nuclei split off earlier from the optic tract near the optic chiasm. B. PINEAL GLAND
The pineal gland secretes melatonin in a rhythmical fashion. Melatonin levels are low during the day and high at night.88 The circadian rhythm of melatonin production and release has been shown to be dependent on the light portion of the light/dark cycle. Exposure to bright light during the night when melatonin levels are highest quickly causes suppression of further melatonin production.46 In addition, phase shifts in the light/dark cycle in humans produce phase shifts in melatonin rhythm.85 Therefore, the RHT and its connections in the hypothalamus also play a critical role in entrainment of melatonin circadian rhythm.3,30 The synchronization of circadian rhythms is accomplished via a long and circuitous multi-synaptic pathway by which light input from the RHT leads to entrainment of melatonin circadian rhythm (Fig. 2). Retinofugal visual projections via the RHT arrive at the SCN, which, in turn, generates a circadian signal. This signal is transmitted to the parvocellular autonomic component of the PVN of the hypothalamus. PVN efferent axons project to the upper thoracic intermediolateral cell column of the autonomic nervous system. Preganglionic sympathetic fibers (neuron II) project to the superior cervical ganglion behind the mandible of the jaw, which synapses on postganglionic sympathetic fibers that, in turn, go to the pineal gland.52 Ophthalmologists are quite familiar with the latter three segments of this pathway which, if interrupted,
Fig. 1. Coronal section through optic chiasm and hypothalamus demonstrating retinofugal projections to the paraventricular nucleus. PVN: paraventricular nucleus. POT: paraventricular optic tract. SON: supraoptic nucleus. OT/OX: optic tract/optic chiasm junction. 3V: IIIrd ventricle.
THE EYE AS METRONOME OF THE BODY
21 Fig. 2. Pathway from retina to pineal through hypothalamus and spinal cord sympathetic neurons for the light/dark entrainment of diurnal and longer rhythms.
leads to Horner’s syndrome.16 Would a child with bilateral Horner’s syndrome also have a deafferented and hence desynchronized pineal? Would this alter the timing of developmental milestones such as puberty? Studies in enucleated hamsters demonstrated that superior cervical ganglionectomy and pinealectomy are equivalent; in that the normal gonadal evolution seen with the absence of light perception was prevented.72,73 Even if the pineal tissue was grafted in a ganglionectemized hamster, the inhibitory substance (thought to be melatonin) was not released because of the absence of sympathetic innervation. In a different study performed in ganglionectemized nonblinded rats, neither the pineal weight nor the enzymes used to make melatonin showed any reduction after exposure to light.111 Therefore, these researchers concluded that an intact sympathetic nervous system is needed for light/dark entrainment of the pineal gland. Thus, bilateral denervation of the pineal gland has the potential to result in clinical abnormalities. Due to the abundance of melatonin-binding sites in the median eminence and anterior pituitary gland, the pineal gland is thought to be the coupler of circadian rhythms and endocrine functions. Melatonin-binding sites have been identified in the pars tuberalis of the anterior pituitary gland, the median eminence as well as the SCN of rats21 and hamsters.91
For over 30 years,98,113 scientists have thought that both the human neuroendrocrine axis and that of other polyestrous mammals is influenced by environmental lighting. Now, we have two mechanisms that may explain this phenomenon: 1) the output of the SCN to the PVN of the hypothalamus and medial hypothalamus, whose cells contain many of the hormone-releasing factors of the neuroendocrine axis; and 2) the indirect output of the SCN to the pineal gland whose product, melatonin, has massive amounts of binding sites in the median eminence and anterior pituitary. These anatomical data support the findings of the earlier scientists. Melatonin circadian rhythms modulate the hypothalamic–pituitary–gonadal system. Male hamsters, when deprived of light—either by removing their eyes or keeping them in constant darkness—undergo atrophy of the gonads.25 In both cases this is prevented by pinealectomy. In another study, seminal vesicle weight, and serum leuteinizing hormone(LH) and follicle-stimulating hormone (FSH) were reduced in the golden hamster on shorter days.12 This response was blocked when the hamsters were exposed to a periodic light stimulus during the night. These experiments along with similar studies in rats7,74 illustrate the importance of light input, the pineal gland, and circadian rhythms in the reproductive functioning and sexual maturation of animals.34
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Darkness, or the absence of light perception, stimulates the pineal gland to synthesize and secrete melatonin, which, in turn, inhibits the reproductive system. Rats housed in constant darkness or made blind suffer a delay in sexual maturation, whereas rats kept under constant light undergo premature ovulation.17 After some time, the experimental rats maintained the same reproductive activity as the control rats.100 During the experiments on the reproductive activity of rats, researchers noted that rats subjected to constant darkness or prepubertal blinding also exhibited a lag in bodily growth.6 Consequently, the regulation of growth hormone by the pineal gland was studied.89 It was concluded that rats blinded before puberty had lower amounts of growth hormone and a smaller pituitary size when compared to normal rats. When these blinded rats were pinealectemized, the growth hormone levels were normal. Therefore, it was concluded that the pineal gland plays an inhibitory role in the production and release of growth hormone by the pituitary. More recently, it has been hypothesized that melatonin circadian rhythms may play a role in thyroid gland physiology. Melatonin inhibits the synthesis and release of hypothalamic thyrotropin-releasing hormone through its actions in the median eminence. In a study performed on female hamsters, the levels of thyroxin (T4), triiodothyronine (T3), and thryotropin (TSH) were all decreased after highdose administration of melatonin in the light period.104 In addition, shortening the photoperiod resulted in reduced levels of these hormones in rats and hamsters.78 Interestingly, pinealectomy restored thyroid hormones to normal. Thus, free-running melatonin rhythms may impact many different systems and cycles, such as sleep, reproductive systems, and even growth.
neal gland. As indicated previously, both these areas are important regulators of the neuroendocrine system, activity, sleep/wake cycle, and more. It should be kept in mind, however, that even though a blind person has no light perception, he or she may indeed have a functioning RHT pathway because the level of light needed to stimulate the system and synchronize the SCN may be very low. Minimal vision, even light perception and perhaps the intact eye in clinically no-light perception, and, hence, the RHT system should be preserved in individuals with eye disease in order to avoid disturbances in circadian rhythms and clinical symptoms related to gonadal dysfunction, sexual maturation, infertility, mood disorders, sleep/wake cycles, and so on. Sack and colleagues measured serum cortisol and melatonin levels in 20 blind patients and found that half of them had free-running rhythms with a period of about 25 hours.78 Although Migeon and colleagues found no difference in the diurnal variation of cortisol between normal and blind persons,50 Krieger and Rizzo,37 along with many other researchers, found desynchronization of the cortisol circadian rhythm in blind persons.64 However, it was debated whether abnormal sleep/wake cyles and activity or absence of the light/dark cycle was the culprit.37 Orth and colleagues66 concluded that some stimulus other than the sleep/wake cycle entrains the cortisol rhythm in humans, as deprivation or prolongation of sleep in a normal individual did not change the cortisol circadian rhythm. In another experiment, they showed that increasing the time a normal individual spent in the dark shifted the peak plasma cortisol level from the time of awakening to the time of illumination.62 These studies show the importance of the light/dark cycle in synchronization of cortisol circadian rhythms in humans. There is also strong evidence in rats that the eyes and the light-dark cycle are important for entrainment of the hypothalamic– pituitary–adrenal function.110 When the rats were blinded by optic enucleation, their cortisol secretion demonstrated a free-running rhythm. Furthermore, the melatonin circadian rhythms are more often abnormal in blind persons without light perception than those who are blind with light perception.47 In addition, the melatonin circadian secretory rhythms vary from one blind person to another.45 The melatonin circadian rhythm free-runs with a periodicity of 24.1 to 24.9 hours. Therefore, endogenous rhythms drift later and later every 24 hours; and in 2 to 3 weeks’ time, will be 180 degrees out of phase with the light/dark cycle. This may result in abnormal sleep/wake cycles, as the individual’s sleep propensity is highest in the daytime. Therefore, the blind may experience daytime sleepiness as well as nightime insomnia. Appropriately
IV. Circadian Rhythm Abnormalities in Blind Persons Environmental cues, such as social interactions, clocks, regular activity, and feeding, might provide the cues necessary to establish normal circadian rhythms in blind individuals. However, fixed-interval feeding in blind rats did not entrain the circadian pacemaker.20 Likewise, many blind persons without light perception exhibit free-running temperature,18 cortisol, and melatonin levels,45,47 despite having a daily routine.35,51 Circadian rhythm abnormalities occur and there is a difference between blind persons with and without light perception. Most blind persons without light perception are not able to activate their RHT pathway, which leads to desynchronization of the SCN and its target tissues, such as the PVN of the hypothalamus and pi-
23
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timed exogenous administration of melatonin in the blind has been widely investigated and found to curb their sleeping difficulties.18,79 Melatonin plays a role in many physiological and behavioral processes, such as aging, calcium homeostasis, neuroendocrine, and immune and reproductive regulation; any changes in its circadian rhythms could potentially cause clinical symptoms in any of these areas.107 Even though the experimental data prove that light input to the SCN and the pineal gland modulates gonadal structure and function in rats6,60 and hamsters,25 there are conflicting data with respect to humans. Neonatal ablation of the SCN nucleus, prior to the development of the RHT system, produces constant vaginal estrous in female rats.12 This demonstrates the importance of circadian rhythms in reproductive functioning. Bellastella and colleagues noted a decreased plasma level of LH, FSH, testosterone, and subnormal plasma LH, FSH, PRL response to GnRH-TRH in prepubertal blind boys.4 This may result in delayed maturation of the hypothalamic-pituitary gonadal axis and delayed pubertal development. In contrast, Bodenheimer5 conducted a study measuring the same hormones in blind men (total quantities) and found no differences in hormone levels between sighted men and blind men with no light perception. However, in the Bodenhemier study, the blind men lost their sight after puberty. There is also much controversy regarding the influence of light perception on the female reproductive system. Rats who have been kept in constant darkness or those that have undergone optic enucleation show a delay in sexual maturation.17 Zacharias and Wurtman113 also concluded that sexual maturation in humans is dependent on environmental light perception. With use of a questionnaire, they compared the age of menarche between blind and nonblind girls; they found that blind girls without light perception underwent menarche 7 months earlier than their nonblind counterparts. Thomas and Pizzarello,98 on the other hand, found no significant difference in the age of menarche between blind and nonblind girls living in an institution. They conluded that any stimulus, not just light stimulus, with a 24-hour periodicity can entrain the circadian rhythms. Institutions that have fixed daily schedules may help set the periodicity in blind persons. Lehrer also postulated that blindness has no impact on fertility,40,41 even though many years earilier, Elden14 had thought otherwise because fewer blind women were becoming pregnant than the national birth rate predicted. Furthermore, Lehrer found a negative linear correlation between age at loss of light perception and age at menopause,41 which could imply that pineal stimulation and production of melatonin can lengthen life span.
Bodily growth may be stunted in blind persons without light perception. Krieger and Glick measured growth hormone levels in five blind persons.34 The normal peak plasma growth hormone level seen following the onset of sleep was absent. Growth hormone levels were also lower in blinded rats; however, the blinded pinealectemized rats displayed normal levels of growth hormone.86 Hence, the abnormal pineal circadian rhythms in blind persons could lead to deficient growth.
V. Conclusion The importance of light entrainment of circadian rhythms is becoming more and more apparent as further information is unraveled regarding the role of SCN in other neuroendocrine functions, such as thyroid hormone, growth hormone, and GnRH. Controversies regarding the critical nature of light/dark cycle input to neuroendocrine systems such as fertility remain unresolved. Future studies comparing large clinical populations with different degrees of vision will be important. Circadian rhythms are vital to physiological and behavioral processes in animals and especially in humans. Light entrainment of the circadian rhythms to the 24-hour solar period is important as studies in blinded rats and humans have proven to us. Freerunning circadian rhythms can cause problems with sleep/wake cycles, mood,103 growth, reproductive functioning and other endocrine systems, and aging. Circadian rhythms may also impact maturation, developmental milestones, and longevity. Therefore, it is incumbent upon the clinician to recognize the importance of preserving even minimum vision, such as light perception, especially in the setting of profound bilateral visual loss.
Method of Literature Search A Medline/Ovid search was conducted for all database years (1968–present). Search words were: circadian and vision, diurnal and vision, retino-hypothalamic, circadian rhythms, retinohypothalamic tract, diurnal rhythms, visual entrainment, hypothalamus. These searches were limited to English journals and abstracts. From this bibliography we proceeded with a classical search of primary sources. On two occasions we obtained help in translating from the German.
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The authors have no commercial or proprietary interest in any product or concept discussed in this article. They wish to acknowledge Mona Khan, MD, for having persistently questioned and researched many of the issues of light entrainment. Reprint address: Alfredo A. Sadun, MD, PhD, Thornton Professor of Vision, Doheny Eye Institute-DOH 5802, 1450 San Pablo St., Los Angeles, CA 90033-4671.