Histol Histopathol (2002) 17: 555-590 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review Nonvisual photoreceptors of the deep brain, pineal organs and retina B. Vígh1, M.J. Manzano2, A. Zádori1, C.L. Frank,1 A. Lukáts1, P. Röhlich1, A. Szél1 and C. Dávid1 1Department of Human Morphology and Developmental Biology, Semmelweis University, Budapest, Hungary and 2Occupational Health Service, Hospital dos Capuchos, Lisbon, Portugal Summary. The role of the nonvisual photoreception is to extracranially outgrown groups of deep brain synchronise periodic functions of living organisms to the photoreceptors, pineal organs also contain neurons and environmental light periods in order to help survival of glial elements. Extracranial pineal organs of various species in different biotopes. In vertebrates, the submammalians are cone-dominated photoreceptors so-called deep brain (septal and hy p o t h a l a m i c ) s e n s i t ive to different wavelengths of light, while photoreceptors, the pineal organs (pineal- and parapineal intracranial pineal organs predominantly contain rod-like o rgans, frontal- and parietal eye) and the retina (of the photoreceptor cells and thus scotopic light receptors. "lateral" eye) are invo l ved in the light-based entrain of Vitamin B-based light-sensitive cryptochromes localized endogenous circadian clocks present in various orga n s . i m m u n o cytochemically in some pineal cells may take In humans, photoperiodicity was studied in connection part in both the photoreception and the pacemake r with sleep disturbances in shift work, seasonal function of the pineal organ. depression, and in jet-lag of transmeridional trave l l e r s . In spite of expressing phototransduction cascade In the present rev i ew, experimental and molecular molecules and forming outer segment-like cilia in some aspects are discussed, focusing on the histological and species, the mammalian pineal is considered by most of histochemical basis of the function of nonv i s u a l the authors as a light-insensitive organ. Expression of photoreceptors. We also offer a view about functional phototransduction cascade molecules, predominantly in changes of these photoreceptors during pre- and young animals, is a photoreceptor- l i ke characteristic of postnatal development as well as about its possible pinealocytes in higher vertebrates that may contribute to evolution. Our scope in some points is different from the a light-percepting task in the perinatal entrainment of generally accepted views on the nonv i s u a l rhythmic functions. In adult mammals, adrenergic nerves photoreceptive systems. - mediating daily fluctuation of sympathetic activ i t y The deep brain photoreceptors are hypothalamic and rather than retinal light information as generally septal nuclei of the periventricular cerebrospinal fluid supposed - may sustain circadian periodicity already (CSF)-contacting neuronal system. Already present in entrained by light perinatally. Altogether three phases the lancelet and representing the most ancient type of were supposed to exist in pineal entrainment of internal vertebrate nerve cells ("protoneurons"), CSF-contacting p a c e m a kers: an embryological synchronization by light neurons are sensory-type cells sitting in the wall of the and in viviparous vertebrates by maternal effects (1); a brain ventricles that send a ciliated dendritic process into light-based, postnatal entrainment (2); and in adults, a the CSF. Various opsins and other members of the maintenance of periodicity by daily sympathetic rhythm phototransduction cascade have been demonstrated in of the hypothalamus. telencephalic and hypothalamic groups of these neurons. In addition to its visual function, the lateral ey e In all species examined so far, deep brain photoreceptors retina performs a nonvisual task. Nonvisual retinal light play a role in the circadian and circannual regulation of perception primarily entrains genetically-determined periodic functions. p e r i o d i c i t y, such as rod-cone dominance, EEG rhy t h m s Mainly called pineal "glands" in the last decades, the or retinomotor movements. It also influences the pineal organs actually represent a differentiated form of suprachiasmatic nucleus, the primary pacemaker of the encephalic photoreceptors. Supposed to be intra- and brain. As neither rods nor cones seem to represent the n o nvisual retinal photoreceptors, the presence of Offprint requests to: Prof. Dr. B. Vígh, Laboratory of additional photoreceptors has been supposed. Photoneuroendocrinology, Department of Human Morphology and Cryptochrome 1, a photosensitive molecule identified in Developmental Biology, Semmelweis University, Tüzoltó u. 58. H-1094, retinal nerve cells and in a subpopulation of retinal Budapest, Hungary. Fax: 36-1-215-3064. e-mail: [email protected] photoreceptors, is a good candidate for the nonv i s u a l 556 Nonvisual photoreceptors photoreceptor molecule as well as for a member of endogenous circadian and circannual timeke e p i n g pacemaker molecules in the retina. system and by this, influence seasonal functions like When comparing various visual and nonv i s u a l breeding, migration, moulting or colour change, and in photoreceptors, transitory, "semivisual" (directional) humans, among others, circadian sleep- and seasonal light-perceptive cells can be detected among them, such a ff e c t ive - p e r i o d i c i t y. The endogenous circadian rhy t h m as those in the parietal eye of reptiles. Measuring diffuse of several organs also persists in constant light light intensity of the environment, semiv i s u a l conditions with a period being nearly, but not ex a c t l y, photoreceptors also possess some directional light 24 h. Environmental stimuli - first of all light - adjusts p e r c e p t ive capacity aided by complementary lens-like this endogenous circadian clock to astrologic periods. structures, and screening pigment cells. Semiv i s u a l The suprachiasmatic nucleus of the hypothalamus has photoreception in aquatic animals may serve for been shown to be the primary pacemaker of the brain identifying environmental areas of suitable illumination, that drives physiological and behavioral rhy t h m s . or in poikilotermic terrestrial species for measuring Besides the suprachiasmatic master pacemaker, there are direct solar irradiation for thermoregulation. As " s l ave" oscillators in several other organs including the directional photoreceptors were identified among retina and pineal organs. Photic information from the nonvisual light perceptive cells in the lancelet, but eyes retina is conveyed to the suprachiasmatic nucleus by the are lacking, an early appearance of semivisual function, r e t i n o hypothalamic tract and, indirectly, by the prior to a visual one (nonvisual ® semivisual ® visual?) g e n i c u l o hypothalamic tract (Illnerova et al., 2000; in the vertebrate evolution was supposed. Moore et al., 2000; Shanan and Czeisler, 2000). The pineal organ of higher ve r t e b r a t e s Key words: Photoreceptor ultrastructure, Opsin p hylogenetically develops from two epithalamic ey e s , i m m u n o cy t o c h e m i s t r y, Phototransduction cascade, the "third" and the "fourth eye" of the supposed four- Efferent of terminal photoreceptors, Photoperiods Introduction In contrast to several body areas including skin, retinal pigment epithelium, iris, or chromatophores k n own to show light sensitivity, specialized p h o t o receptor cells are only present in the lateral ey e retina (to avoid confusion with pineal eyes, we use the expression "lateral eye"), in the pineal organs and in the so-called deep brain (septal and hy p o t h a l a m i c ) photoreceptor areas of vertebrates. These photoreceptor cells may have visual, locator-type functions, as in the lateral eye, or n o nv i s u al, photodensitometer-type light perception, like the pineal organs and deep brain photoreceptors. Besides their visual, image-decoding function, the lateral eyes also have a nonv i s u a l , photoperiodic light-perceptive function. The earliest evidence for the existence of "deep encephalic photoreceptors" was provided in the first half of the last century. Young (1935) described that blinded and pinealectomised larval lampreys react to illumination of the head, a result that may be explained by the presence of some photosensitive brain areas. Benoit and Ott (1944) reported that illumination of the hypothalamus resulted in testicular growth of blind ducks. Recent studies show that deep brain photoreceptors are represented by the so-called cerebrospinal fluid (CSF)-contacting neurons of some septal and anterior hypotahalamic nuclei (Foster et al., 1994; Garcia-Fernandez and Fo s t e r, 1994; Grace et al., 1996; Garcia-Fernandez et al., 1997; Wada et al., 1998, 2000; Vígh et al., 2001). The main task of both the nonvisual and semivisual photoreceptors is to inform the organism of the ambient Fig. 1. a. Scheme on the hypothetic four-eyed protovertebrate. light conditions. These receptors regulate the b. Scheme on the photoreceptor cells of the lancelet brain. 557 Nonvisual photoreceptors eyed protovertebrate (Fig. 1a). Correspondingly, in the photoreceptors in the central nervous system (Fig 1b). In cyclostome lamprey, representing one of the most simple the dorsal portion of the brain and the rostral ve n t r a l recent craniate vertebrates, and in bony fishes two pineal spinal cord, three types of photoreceptor cells were o rgans are present: the pineal and parapineal orga n . found: Joseph cells and Hesse cells, both supplied with a Besides the pineal organ, frogs have a frontal eye and rhabdome composed by microvilli, further, Satir cells some reptiles possess a parietal eye (Vigh and Ví g h - displaying ciliary photoreceptor lamellae, thus being Teichmann, 1988, 1989b, 1992b, 1999). similar to light-sensitive cells of vertebrates.