The Ventral Lateral Geniculate Nucleus and the Intergeniculate Leaflet: Interrelated Structures in the Visual and Circadian Systems

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NeuroscienceandBiobehavioralReviews,Vol.21,No.5, pp. 705-727, 1997 Copyright01997 Publishedby ElsevierScienceLtd Printedin GreatBritain. AIIrightsreserved 0149-7634/97/$32.00 + ,)0 PII: S0149-7634(96)OO019-X

The VentralLateralGeniculateNucleusandthe IntergeniculateLeaflet:IntenelatedStructuresin the Visual andCircadianSystems MARY E. BARRINGTON* Department of Psychology, Smith College, Northampton, MA 01063, USA

BARRINGTON, M.E. The ventral lateral geniculate nucleus and the intergeniculate leajlet: interrelated structures in the visual and NEUROSCI BIOBEHAV REV21(5)705–7271997.—The ventrallateralgeniculatenucleus(vLGN)andthe summary of researchonthese intergenicuIate leaflet(IGL)areretinorecipient subcorticzd nucIei.Thispaperattemptsa comprehensive thalamicareas,drawingonanatomical, eleetrophysiological, andbehavioral studies.Fromthecurrentperspective, thevLGNandIGL aPI= closelYlinkd inthat~ey sh~em~y neuroehemic~s, projections, ~d physiologic~ properties. Neuroehemicals commonly reportedin thevLGNandIGLarenenropeptide Y,GABA,enkepbalin, andnitricoxidesyntbase(localizedin cells)andserotonin, acetylcholine, histamine, dopamine andnoradrenalin (localized infibers).Afferentandefferentconnections arealsosimilar,withboth areascommonly receivinginputfromtheretina,locuscoreuleus, andraphe,havingreciprocalconnections withsuperiorcolliculus, pretectum rmdhypothrdamus, andalsoshowing comectionstozonaincerta,accessory opticsystem,pats,thecontralateral vLGN/fGL, andotherthatamicnuclei.Physiological studiesindicatespeciesdifferences, withspectrrd-sensitive responses common insomespeeies, andvaryingpopulations ofmotion-sensitive unitsorunitslinkedtooptokinetic stimulation. A highpercentage ofIGLneuronsshow lightintensity-coding responses. Behavioral studiessuggestthatthevLGNandIGLplaya majorrolein mediatingnon-photic phase shiftsofcircadiarr rhythms,largelyvianeuropeptide Y,butmayalsoplaya roleinphoticphaseshiftsandinphotoperiodic responses. ThevLGNandIGLmayparticipatein twomajorfunctionalsystems,thosecontrolling visuomotor responsesandthosecontrolling circadiarr rhythms.Futureresearchshouldbedirectedtowardfurtherintegration ofthesediversefindings. 01997Ek.evierScienceLtd. circadian systems.

leatlet neuropeptide Y pretectnmserotonin subcortical circadiam rhythms GABA hypothalamus intcrgeniculate nucleus ventrallateralgeniculate nucleus visualnuclei superiorcolliculus suprachiasmatic Abbreviations: dLGN,dorsallateralgeniculatenucleusGABA, gammaaminobutyric acid GAD,glutamicaciddecarboxylase leaflet -ir,immunoreactiveNADPH-d, nicotinamide adenosine GHT,geniculo-hypothalamic tract IGL,intergeniculate opticitractus SCN,suprachiasmatic dinucleotide phosphate-diaphorasenMOT,nucleusmarginalis nucleus vLGN,ventral nucleus,externaldivision vLGNi,ventrallateralgeniculate nucleus, lateralgeniculate nucleus vLGNe,ventrallateralgeniculate internaldivision

should be considered in tandem more often than currently is in vogue. One question I will examine is whether the vLGN and/or IGL can be said to serve a unique function. Few brain nuclei appear to control singular functions. For example, the suprachiasmatic nuclei appear to be the mammalian circadian pacemaker (310), but also play an important role in glucose homeostasis (304). Other nuclei seem to partake in one or more functional pathways, and other functions require networks of neurons distributed between many brain areas. I will describe anatomical, electrophysiological, and behavioral studies on the vLGN and the IGL. Both classical cytoarchitectural studies and more modern neurochemical anatomical work will be reviewed. A wide range of electrophysiological work, ranging from responses to whole field illumination to visual receptive field mapping and

INTEREST in the vLGN and IGL has surged recently, largely because of connections with the mammalian circadian clock. This clock input pathway appears to play a role in mediating phase shifts to certain types of environmental stimuli. One neurochemical localized in the vLGN and IGL, neuropeptide Y, appears permanently to reset the phase of circadian rhythms. Other data indicate a role for vLGNIIGL neurons in visuomotor functions. Future research may further detail the visuomotor role and explore possible links between the two functional systems. In this paper, I will attempt a comprehensive review of published research relating to the vLGN and IGL, outlining generalizations possible, given our current state of knowledge, and emphasizing areas where further study is warranted. I will demonstrate that the vLGN and IGL share many anatomical and physiological characteristics and

*Towhomallcorrespondence shouldbe addressed. Tel:413-585-3925; Fax:413-585-3786; E-mail:MHarring@sophia. smith.edu. 705

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modulation by somatosensory stimulation, will be described. Several studies reviewed measured glucose utilization or immediate early gene activation. Behavioral work has focused on either visual function or circadian rhythm modulation and has indicated roles in discrimination of light intensity, spectral discrimination, and both photic and non-photic regulation of circadian rhythms. The work reviewed will demonstrate that the vLGN and IGL are closely linked. They share many neurochemicals, many afferent and efferent projections and show similar physiological properties. These nuclei do not appear to serve one unique function, but they do seem to fit into two major systems of interconnected brain nuclei, those controlling visuomotor functions and those controlling circadian rhythms. It is not yet clear whether separate or overlapping populations of cells serve in these two, presumably distinct, functional pathways. The IGL was defined as an area separate from the vLGN in 1976. While I support the use of this distinction, I will review data indicating that the IGL maybe closely related to the vLGN. Many earlier studies on the “vLGN” also included the IGL. This lack of distinction between IGL and vLGN causes some problems in the incorporation of early results into this review. Whenever possible, I will attempt to describe results using our current anatomical terms; in other cases, when this is not possible, I will refer to the “vLGN/IGL”. With qualifications, I will propose a definition of the IGL as the thalamic area meeting all three of these criteria: (1) receiving bilateral retinal innervation with a diffuse, non-patchy, distribution; (2) projecting to the contralateral IGL and vLGN; and (3) projecting to the SCN. The IGL cells often, but not always, contain neuropeptide Y-immunoreactivity. 1. ANATOMYOF THE IGL ANO VLGN 1.1.

Cytoarchitecture

1.1.1. vLGN An early scheme for cytoarchitectural division of the vLGN (212) proposed two parts: an external division (vLGNe) and an internal division (vLGNi), with the internal division containing smaller cells which are less deeply Nissl stained than those in the external division. These two subdivisions are separated by a group of fine fibers and a neuron-sparse zone. This general scheme has been confirmed in subsequent studies and remains a useful approach. The vLGN appears relatively large in lizards, turtles, rodents, rabbits, and cows, and relatively smaller in bats, blind mole rats, raccoon-dogs, cats and primates (37,49,92,212). Further subdivisions have been described in specific species (hamster: 72; rabbit: 112; ground squirrel: 6). The vLGN in the avian brain is a group of cells adjacent to the optic tract, able to be divided into internal and external subdivisions(54,87). The lateral hypothalamic retinorecipient nucleus in the avian brain may be a continuation of the vLGN (257). In the cat, the cytoarchitecture of the vLGN appears to differ from that of rodents (129,210). The vLGN of the cat is shaped like a question mark, with a broad main part dorsally and a slender stalk which is twisted around the rostrolateral aspect of the optic tract. Five subdivisions of the nucleus were identified by

Jordan and Hollander (129); however, this scheme has not been utilized widely. A scheme for division of the cat vLGN into three zones (medial, intermediate, and lateral) may prove more useful (210). The primate pregeniculate nucleus appears homologous to the vLGN. The pregeniculate nucleus is located dorsomedial and rostral to the dLGN (212). The vLGNe in most primates is merely a small mass of cells, while the vLGNi is more expansive (212). While cytoarchitectural differences between the internal and external populations of vLGN cells are apparent in most species studied, work reviewed below will indicate that, in terms of afferentiefferent connections or localization of neurochemicals, few cross-species generalizations are possible. The one generalization that currently is possible is that the vLGNe receives retinal input. 1.1.2. IGL The IGL encompasses what early studies had referred to as the internal dorsal division of the vLGN or as the dorsal vLGN. These areas first were labeled “intergeniculate leaflet” by Hickey and Spear (108) in the rat. Apparent homologs of the rat IGL have been described in the frog (196), pigeon (94), hamster (97,204), rabbit (272), ground squirrel (6), tree shrew (4), and human (198). In the pigeon, the IGL is a neuronal group located distal to the vLGN. These cells also are referred to as the nucleus marginalis optici tractus (nMOT) and form a “U’ around the nucleus rotundus (88). The cat IGL may correspond to the medial zone of the vLGN as defined by Nakarnura and Kawamura (210). The cat IGL appears to be split by the optic tract, and encompasses cells on both the dorsolateral and ventromedial edges of the dLGN, as well as cells adhering to the ventral edge of the optic tract (210). 1.1.3. Microstructure Several studies have attempted to classify neuron types in the vLGN and IGL on the basis of Nissl and Golgi stains (rat: (31,199,207,267); pigeon and quail: (86,87)). Five classes of neurons were described by Brauer et al. (31). The dominant cell type in the rostral IGL differs from that in the caudal IGL (199). Descriptions of dendritic branching patterns of Golgi-stained neurons in the vLGN and IGL of several species (pigeon, quail, rat, tree shrew) raise the possibility of communication across the subdivisions of the vLGN and into the IGL (47,87,207). Electron microscopic studies of the vLGN have identified four types of synapses (267,268). “Synaptic islands” consisting of three or more synapses are observed throughout the vLGN (267). These differ from the “synaptic glomeruli” found in other thalamic nuclei (128) in that they are not encapsulated by glial processes and the component parts are more variable. In the vLGN, synaptic islands do not appear to include direct cortical input. Many retinorecipient neurons also may receive inhibitory input (as indicated by symmetrical synaptic junctions) close to or on the soma. Some of these input terminals maybe serotonergic (217). Electron microscopic studies of the IGL have identified four types of afferent terminals (199). One type was an unusually large asymmetric terminal in contact with large dendrites in the rostral IGL. Axosomatic contacts were rare in the IGL. In the rat, both neuropeptide Y- and enkephalin-ir fibers form synaptic contacts exclusively with non-ir dendrites in the IGL. The neuropeptide Y-ir fibers form contacts

VENTRAL LATERAL GENICULATE NUCLEUS AND THE INTERGENICULATE LEAFLET

which are almost always asymmetrical, while the enkephalinir fibers form exclusively symmetrical synapses (274). A large blood vessel often is prominent in the IGL. Histaminergic mast cells cluster around arterioles in the cat IGL (165). In the rat IGL, the endothelial lining of blood vessels appears attenuated (199). Further studies should examine the possibility of alterations in the blood–brain barrier in this area. 1.1.4. The dorsal cap An additional nuclear group in this area has been described in the ground squirrel and tree shrew. This retinorecipient area, termed the “dorsal cap”, is sandwiched between the IGL and the rostral vLGN (6). The dorsal cap may be homologous to the nucleus lateralis anterior in pigeons (88; Karten, personal communications). 1.1.5. The medial vLGN A medial reticulated group of cells adjacent to the reticular nucleus of the thalamus was identified as part of the vLGN in the tree shrew (47). This area may be present in more species, but may usually be confused with the thalamic reticular nucleus. The medial nucleus is not retinorecipient. It can be distinguished from the thalamic reticular nucleus by the scarcity of glutamic acid decarboxylase (GAD)-ir neurons. In subsequent text, when I refer to the vLGN of the tree shrew, I do not refer to the medial vLGN unless specifically noted. 1.2. Neurochemistry 1.2.1. Neurochemistry of the vLGN Neurochernical studies have indicated the presence of several putative neurotransmitters and receptor binding sites in the vLGN. Cells in the vLGN are irnmunoreactive for neuropeptide Y (bat: (144); hamster: (204); rat: (41); ground squirrel: (4); cat: (51,284); sheep: (9); tree shrew: (4)), enkephalin (rat: (167); hamster: (204)), gamma-aminobutyric acid (GABA) and/or its synthetic enzyme GAD (bird: (82,247); rat: (214); ground squirrel: (5); rabbit: (224); tree shrew: (4,47)), nicotinamide adenosine dinucleotide phosphate-diaphorase (NADPH-d), a marker for nitric oxide synthase (rat: (74,80,192)), and substance P (ground squirrel: (4)). Other studies indicate fibers, but not cell bodies, immunoreactive for neuropeptide Y (bird: (14,88,93); rat: (167)), serotonin (lizard: (179); bird: (88); rat: (218,285); hamster: (204); cat: (59,193,285); primate: (285,302)), choline acetyltransferase (lizard: (179); bird: (88,70); tree shrew: (47)), histamine (rat: (26)), dopamine and norepinepbrine (rat: (218)), tyrosine hydroxylase, the rate-limiting enzyme for synthesis of dopamke, norepinephrine and epinepluke (bird: (131); rat: (143)), substance P (bird: (14,88); rat: (167,204); cat: (15)), enkephalins (rat: (3); ground squkrel: (5,47,69)), GAD (opossum, cat, Galago: (224); primate: (106)), and vasoactive intestinal polypeptide-ir (rat: (167)). Various lines of research indicate the vLGN contains binding sites for nicotine, acetylcholine and alpha-bungarotoxin (bird: (34,206,296); rat: (45,60,95); cat, dog, rabbit, squirrel, guinea pig, other rodents: (73)), GABA and benzodiazepines (cat: (265)), melatonin (chick: (240); Japanese quail: (52)), serotonin (rat: (202)), somatostatin

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(rat: (27)) and cholesytokinin (guinea pig: (307)). Several lines of research indicate that the nicotinic receptors in the avian vLGN may be presynaptic on retinal afferents (34,177). 1.2.2. Neurochemistry of the IGL The IGL is characterized most clearly by cells immunoreactive for neuropeptide Y and, in some cases, researchers have attempted to define the IGL by detailing the extent of neuropeptide Y-ir neurons in this area. Neuropeptide Y-ir cells have been demonstrated in the IGL of the rat (41,167), hamster (97,204), mouse (145), ground squirrel (5), chipmunk (284), cat (284), pigeon (14,88,93), and tree shrew (4,146). However, such cells have not been observed in all species studied. No neuropeptide Y-ir cells are observed in the IGL of the frog, hedgehog, or sheep (9,283a). Similarly, no neuropeptide Y-ir cells were observed in the IGL of the little brown bat, although some neuropeptide Y-ir cells were noted in the vLGN of this species (144). No neuropeptide Yir cells were observed in the IGL of three different primates (Macaca fuscata: 84; squirrel monkey: 263; lemur: 28); however, an extensive group of neuropeptide Y-ir cells were identified adjacent to the cerebral peduncle and the zona incerta in what may correspond to the IGL of a monkey (Macaca mulatta) and in the human brain (198). An even more abundant neurotransmitter in the IGL may be GABA. In fact, Moore and Speh (201) conclude that virtually all of the IGL neurons are GAD-ir in rats. Cell bodies immunoreactive for GABA and GAD are reported in the IGL of the rat (201,214), ground squirrel (5), and tree shrew (4). Both neuropeptide Y and enkephalin-ir have been colocalized with GAD-ir. Other reports indicate IGL cells are also irnmunoreactive forenkephalin (rat: 167,201; hamster: 204; cat: Itoh, as cited in Nakamura and Kawamura 210; tree shrew:48), [Met]enkephalin–Arg-Gly -Leu (rat: 3), substance P (rat: 275) and for the nitric oxide synthase marker NADPH-d (rat: 80; ground squirrel: 5; tree shrew: 4). Antisera raised against VGF, a protein regulated by nerve growth factor, labels cells in the rat IGL (289). The IGL cells are calcitonin generelated peptide-ir in the mouse, but not in the rat, guinea pig, or rabbit (219,220). Fibers in the IGL show immunoreactivity for serotonin (rat: (53,167,218); hamster: (204)), norepinephrine (rat: (143,217)), enkephalin (ground squirrel: (5)), histamine (rat: (286)), choline acetyltransferase (tree shrew: (47)) and substance P (rat: (15,167); hamster: (204); ground squirrel: (5)). Sparse fibers immunoreactive for gastrin releasing peptide also have been reported in the rat (190) and hamster (97) IGL. Binding sites for cholesytokinin (guinea pig: (307)), somatostatin (rat: 27), substance P (rat: 166), and bungarotoxin (rat: 45; chick: 34) have been described in the IGL. It is likely that serotonin fibers in the IGL come from neurons in the raphe nuclei (222), noradrenaline from the locus coeruleus (143), and histamine from the tuberomarnmillary complex (216). In the pigeon, the IGL (nMOT) can be divided into two subdivisions based on neurochemical features. While both areas contain neuropeptide Y- and GAD-ir cells and fibers, as well as enkephalin- and serotonin-ir fibers, only the rostrodorsal area also contains cells and fibers immunoreactive for substance P and cholesytokinin as well as tyrosine hydroxylase-ir fibers (88).

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TABLE 1 NEUROCHEMICALS ASSOCIATED WITHCELLSORFIBERSINTHEVENTRAL LATERAL GENICULATE NUCLEUS (vLGN)ORTHE INTERGENICULATE LEAFLET (IGL)*

Nerrropeptide Y GABA Enkephalins Substance P Nitricoxide(NADPH-d) Serotonin Acetylcholine (cholineacetyltransferase) Histamine Dopamine, noradrenatin, tyrosinehydoxylase Vasoactive intestinalpolypeptide VGF Gastrin-releasing peptide Calcitoningene-related peptide Cholesytokinin

vLGN Cells

IGLCells

vLGNFibers

IGLFibers

x x x x x

x x x x x

x x x x

x x x x

x x x x x

x x x x

x

x x x x

x x

*Notethehighdegreeof similaritybetweentheneurchernical markersfoundinthevLGNandIGL.Seetextfordetails

The dorsal cap is characterized by the presence of many neuropeptide Y-ir fibers, but few neuropeptide Y-ir cells (4,5). An abundant population of GABA-ir cells and fibers are observed in the ground squirrel and the tree shrew, and the ground squirrel dorsal cap also is noted to contain enkephalin-ir and substance P-ir fibers (4,5). 1.2.3. Summary The vLGN and IGL contain very similar neurochemicals (see Table 1). Cells in both vLGN and IGL may contain neuropeptide Y, GABA, enkephalin, nitric oxide synthase, and substance P. These results are common across most species studied with these notable exceptions: (1) reports of substance P-ir vLGN and IGL cells are relatively rare, while substance P-ir fibers are more commonly observed; (2) neuropeptide Y-ir fibers, but no neuropeptide-ir cells, are reported in the bird vLGN; (3) several species (frog, bat, hedgehog, sheep, some primates) do not show neuropeptide Y-ir cells in the IGL. Fibers in both vLGN and IGL may contain serotonin, acetylcholine, histamine, dopamine and noradrenaline, results common across many species studied. Acetylcholine receptors may differ between these areas, with the IGL containing mainly alpha-bungarotoxin binding sites, while the vLGN has both nicotine and alpha-bungarotoxin binding sites in many species. Although from Table 1 it appears the vLGN and IGL differ in localization of vasoactive intestinal polypeptide, gastrin-releasing peptide, calcitonin gene-related peptide, and cholecystokinin, these results are from one or two species only. I would like to emphasize the one report of VGF-ir in rat IGL cells. As it is similar to the Drosophila clock protein PER, VGFmight be a protein specificallyrelated to the circadian clock (289). Future research should examine a greater variety of species for VGF-ir in the IGL, with careful control of the state of the circadian clock. 1.3. A#erent and efferent connections 1.3.1. Retinal afferents to the IGL and vLGIV A major source of afferent input to the vLGN and IGL is the retina. This projection has been described in detail for

many species (turtle: 92,140; lizard: 36,179; chick: 54; pigeon: 257; rat: 108,271; hamster: 72,97; honey possum: 96; 13-lined ground squirrel: 6,136; rabbit: 272,112; cat: 113; tree shrew: 4; rhesus monkey: 105). Most reports agree that the IGL and the vLGNe receive binocular retinal input; the vLGNi has been reported to receive either binocular, solely contralateral, or no retinal input. An exception to this is the pigeon, where all vLGN/IGL retinal input is contralateral 88. Retinal input to the vLGNi typically is much more sparse than that to the vLGNe. Retinal terminal fields in the vLGN often are described as having a “patchy” appearance, with patches of input observed on one side possibly corresponding to patches of reduced input on the other side after monocular tracer injections (4,47,108). The apparent separation of retinal input from the two eyes in these areas should be confirmed with more appropriate material, such as that from an animal with different anterograde tracers placed in each eye. The retinal projection to the vLGNe is organized topographically in the rabbit (112), hamster (125), and chick (54,67). The IGL, on the other hand, shows no evidence of a topographic organization to its retinal input (112). A subpopulation of retinal afferents to the vLGN in pigeon may be immunoreactive to either tyrosine hydroxylase or substance P (33,135), while substance P-ir does not appear to label vLGN/IGL retinal afferents in the rat (184) or rabbit (32). Retinal afferents terminate on neuropeptide Y- and/or enkephalin-ir neurons in rat (274) and probably on neuropeptide Y-ir cells in pigeon IGL (88). Removal of the eyes increases serotonergic innervation of the hamster vLGN and IGL (236). Studies of the retinal afferents to vLGN and IGL highlight the close links between these cells and those in superior colliculus, pretectum, and suprachiasmatic nucleus. Retinal ganglion cells projecting to the vLGN of the cat are morphologically similar to those projecting to the pretectum or the superior colliculus showing smaller soma and thinner axons than alpha or beta cells (155). Rat pups administered the selective neurotoxin capsaicin demonstrated degeneration of a subpopulation of retinal afferents to the SCN, vLGN and IGL, as well as to the olivary and medial pretectal nuclei (239). Approximately 90% of all

VENTRAL LATERAL GENICULATE NUCLEUS AND THE INTERGENICULATE LEAFLET

retinal ganglion cells projecting to vLGN also project to optic tectum in pigeon (33). Some retinal ganglion cells which project to the area of the vLGN/IGL also project to the SCN in the hamster (226). The retinal ganglion cells projecting to the IGL and to the SCN may form a distinct class. These cells can be infected selectively by strains of an alpha-herpes virus (42) and were resistant to monosodium glutamate-induced toxicity (230). Their terminals may cover only a portion of the retinorecipient SCN (2,282). These retinal ganglion cells may project to pretectal areas in addition to the vLGN/IGL ador SCN. 1.3.2. Non-retinal afferents and efferents to the IGL and vLGN 1.3.2.1. Superior colliculus. The superior colliculus has reciprocal connections with both the vLGN and IGL. Neurons in the superior colliculus project to the vLGN (17,48,50,84,210,222,273) and IGL (183,277). This projection appears to arise primarily from neurons in the stratum griseum superficial (rat: (50,222); tree shrew: (48)) and the stratum opticum (tree shrew: 48). In birds, the superior colliculus projection to the vLGN arises from layer 10 and appears topographically organized (54,120,235). A topographic projection has been reported from cells in the presumed homologous structures in the frog brain, the optic tectum and the corpus geniculatum (195). Tectal projections to the vLGN also are found in lizards (35,197), turtles (92,233a) and snakes (56). The superior colliculus neurons terminate within the vLGNe in rats and tree shrews (48,273) and in both vLGNi and vLGNe in birds (87). This projection is at least in part substance P-ir in rats (184). Neurons in the vLGN and IGL project back to the superior colliculus. In fact, Matute and Streit (171) suggest that, in the rat, the vLGN may provide the greatest thalamic source of afferents to the superior colliculus. The projection of the vLGN to the superior colliculus appears to be entirely ipsilateral and all layers of the superior colliculus receive at least some fibers from the vLGN (48,65,84,148,237,271). The reticulated nucleus medial to the vLGN appears selectively to innervate deep layers of the superior colliculus in the tree shrew (48). In the cat, some of the vLGN neurons projecting to the superior colliculus are GABAergic (10) while, in rats or rabbits, probably they do not contain glutamate, aspartate or GABA (171). In the rat, some vLGN neurons afferent to the superior colliculus are NADPH-d-positive (80). The IGL projection to the superior colliculus has been observed both in rat (80,277) and pigeon (88). This projection originates from IGL neuropeptide Y-ir cells in the pigeon. The location of vLGN neurons afferent to the superior colliculus has been described in the cat (66,132), tree shrew (48) and rat (30,104). In the rat, such neurons are found only in the vLGNe, while in the tree shrew, they are found in the vLGNi. The superior colliculus is important in guiding visual attention and orientation (181), and may mediate rapid approach/withdrawal responses (58). 1.3.2.2. Pretectum. The pretectum has reciprocal connections with IGL and vLGN. Pretectal input has been

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described for the frog IGL (nucleus of Bellonci–anterior thalamic nucleus complex; 196). The pigeon IGL (nMOT) receives projections from the n. lentifonnis mesencephalis (301), an area thought to be homologous to the mammalian nucleus of the optic tract (303). The projection from the pretectum to the vLGN originates from neurons in the olivary pretectal nuclei (rat, cat), the nuclei of the optic tract (bird [lentiformis mesencephali], rat, cat), the anterior pretectal nuclei (rat, tree shrew) and the posterior pretectal nuclei (rat: (19,39,50,159,210,301,306)). There is scant information on what subdivisions of the vLGN receive pretectal input. The fibers from the anterior pretectal nucleus appear to terminate in the vLGNi in the rat (39), while in the tree shrew, both vLGNi and vLGNe receive pretectal input (48). In the cat, afferents from the nucleus of the optic tract and the olivary pretectal nucleus terminate largely in the vLGNb (19). Cells in the IGL and vLGN reciprocate the pretectal projection. To my knowledge, the retinorecipient olivary pretectal nuclei receive vLGN afferents in all species studied (in pigeon, the ‘‘area pretectalis’ probably homologous to the olivary pretectal nuclei; (75). Other projections are less consistent across species. Afferents from the vLGN are observed in the anterior pretectal nucleus (rat, cat, tree shrew), the nucleus of the optic tract (rat, cat), the posterior pretectal nucleus (tree shrew, cat), the suboptic pretectal nucleus (cat), the medial pretectal nucleus (pigeon, cat), the lentiform nucleus (primate), and the principal precommissural nucleus (pigeon) (pigeon: (234); rat: (39,149); cat and rat: (84,271); cat: (65,210); tree shrew: (47,48); monkey: (18,106)). In the rat, the pretectal projection originates from cells in the vLGNe and IGL (31,39), while reports differ as to the location of these neurons in the cat vLGN (19,132). In both rat and cat, vLGN neurons projecting to either the superior colliculus or the pretectum have similar morphology and location. There is electrophysiological evidence (90) indicating that some vLGN neurons in the cat project to both superior colliculus and pretectum. This suggestion should be confirmed with a double-labeling anatomical study. The vLGN/IGL-pretectum connections suggest a role in diverse visuomotor functions. The nucleus of the optic tract is thought to be important in generation of optokinetic nystagmus in response to movement of a large visual stimulus (253). Reciprocal connections with the nucleus of the optic tract suggest a role for vLGN/IGL neurons in optokinetic nystagmus. Olivary pretectal nucleus neurons show tonic ‘‘on” responses and provide signals for pupillary constriction to neurons of the oculomotor nucleus in rats (281). Thus, it is possible that the connections of the vLGN and the olivary pretectal nucleus may modulate the pupillary light reflex or may provide feedback about pupil diameter to other areas of the visual system. Finally, neurons responding to quick shifts (“jerks”) of visual stimuli are observed in many pretectal nuclei of the cat (253). These neurons might be involved in circuits allowing shifts of visual attention to rapidly moving objects in the peripheral visual field. 1.3.3. Hypothalamus 1.3.3.3. Suprachiasmatic nuclei. The suprachiasmatic nuclei are the site of the mammalian circadian pacemaker (244a). Cells in the vLGN and IGL contribute to a

710 projection to the hypothalamic suprachiasmatic nuclei (SCN) in rats, cats, gerbils, hamsters, and frogs. This projection is commonly called the geniculo-hypothalamic tract (GHT). The GHT arises from GABA-ir neurons, some of which are also neuropeptide Y-ir (41,97,98,199,201,204). Neuropeptide Y-ir GHT neurons in the rat also contain the C-flanking peptide of the neuropeptide Y precursor (41). The GHT cells also maybe met-enkephalin-ir. Lesions of the hamster GHT lead to a loss of met-enkephalin-ir fibers in the SCN (204). Work done in the rat is contradictory, with one report indicating that ablation of the IGL leads to a reduction in enkephalin-ir fibers in the SCN (275), while another group reports that GHT neurons do not appear to show immunoreactivity to met-enkephalin (41,199). Further research is required to determine reasons for these discrepancies. Substance P-ir neurons do not appear to contribute to the GHT, since destruction of the IGL did not alter density of substance P-ir fibers in the SCN of the rat (274). Curiously, studies of neuropeptide Y binding sites generally have indicated low levels in the SCN and vLGN (77,158), although relatively high levels of binding of the related peptide YY in the SCN have been reported (215). Levels of peptide YY binding may vary with circadian time (269a). Interactions between several neurochemicals within the SCN have been studied. Glutamic acid decarboxylase (GAD, the synthetic enzyme for GABA)-ir is colocalized with neuropeptide Y-ir in SCN terminals in the rat with both symmetric and asymmetric synaptic contacts observed (71). Some neuropeptide Y-ir terminals in the rat SCN make synaptic contact with vasoactive intestinal polypeptide-ir neurons (109). while generally isolated from each other, neuropeptide Y- and serotonin-ir terminals in the rat SCN occasionally form synaptic contacts on the same target cell and may also form direct axo-axonal appositions (89). Destmction of the serotonergic innervation of the SCN did not have any apparent effect on SCN neuropeptide Y-ir (89), and GHT ablation does not alter appreciably SCN serotonin-ir (Barrington and Pyun, unpublished observations). While injections of retrograde tracers into the rat SCN labeled IGL cells only (41,199), similar injections into the hamster SCN labeled neurons in both the IGL and in anterior sections of vLGNe (98). One paper proposes to redefine the hamster IGL on the basis of the location of cells afferent to the SCN, to rename the hamster anterior vLGNe as IGL (204). This argument also is based on staining patterns for several peptides, none of which are located exclusively in the IGL. I prefer to retain use of the more widely accepted terminology, to continue to distinguish anterior vLGNe from the more caudal IGL. The pattern of retinal innervation and physiological responses of cells in the anterior vLGNe differ from those in the IGL. The species difference in location of GHT neurons may help to explain species differences in behavioral effects of GHT lesions, as will be discussed later. A very interesting case for further study is the avian brain, since, in the pigeon, neuropeptide Y-ir cells in the IGL have been shown to project to extra-SCN sites. Research should clarify if these cells also project to the SCN; this would add to the discussion of whether the location of cells afferent to the SCN can be used to define the IGL. In the gerbil, lateral parts of the IGL project to ventromedial SCN, while cells in medial parts of the IGL project

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to a wider extent of the SCN (187). Work in the rat also suggests two subdivisions, one rostral and one caudal (199). Cat GHT neurons appear to be more restricted in extent than IGL neurons retrogradely labeled from the contralateral LGN (210,230a). Further comparative work is necessary to determine if it would be helpful to define subdivisions within the IGL based upon patterns of connectivity. Geniculate fibers travel to the hypothalamus by several routes. In the rat and gerbil, it appears that most GHT fibers descend along the optic tract (149,186,187,237), while smaller numbers of fibers either course through the zona incerta (274) or travel medially to the periventricular thalamus and then ventrally to the hypothalamus along the third ventriculm wall (186,187). In the hamster, a greater proportion of fibers may follow routes distal to the optic tracts, since cuts severing the optic tracts do not appear to reduce neuropeptide Y-ir in the SCN (126). In the hamster, the SCN may receive neuropeptide Y-ir afferents from an extra-geniculate site (97,126). The site of origin of these fibers has not yet been determined, although it is possible that they may arise from the retina (121). 1.3.3.4. The SCN, peri-SCN and retrochiasmatic area. A small population of neurons in and around the SCN project to the IGL. This was reported first by Watts and Swanson (297) and has been described further in rats (41,199), hamsters (204,205) and frogs (196). Most of these neurons are not located in the SCN; the largest percentage of these neurons are found in the retrochiasmatic area. Some neurons also are found in the anterior hypothalamic area. They do not appear to stain for vasoactive intestinal polypeptide, peptide histidine isoleucine, neuropeptide Y, enkephalin, or vasopressin (41,204). 1.3.3.5. Other hypothalamic nuclei. While IGL and vLGN cells share projections to the hypothalamus, these are largely to non-overlapping nuclei. The IGL projects to many ventral hypothalamic nuclei, while the vLGN projects to several areas in the dorsal hypothalamus (186,187). Cat vLGN receives input from dorsal hypothalamus (210). 1.3.4. Pineal The pineal gland plays an important role mediating seasonal reproductive responses. Following injections of anterograde tracer into the IGL of the Mongolian gerbil, fibers were labeled in the rostral part of the deep pineal gland, where they arborized among the endocrine cells (191). 1.3.5. Contralateral vLGN/IGL A projection from IGL neurons to the contralateral vLGN/IGL has been observed in many species (31,50,84, 159,188,196,210,221,225,226,271). It is unusual for a thalamic cell group to show direct interthalarnic connections (128). These fibers follow one of two routes in rats: either rostrally into the optic tract, or medially via the posterior commissure (188). Rostral areas of the vLGN are especially densely innervated by this projection in the rat (188). The neurons which project to the contralateral vLGN/IGL appear to be a population largely distinct from those which project to the SCN (41,308). Many of the IGL neurons projecting to the contralateral vLGN/IGL are enkephalin-ir (41,199,276), while some neurons forming this projection

VENTRAL LATERAL GENICULATE NUCLEUS AND THE INTERGENICULATE LEAFLET

are neuropeptide Y-ir in the rat (41,275), but not in the hamster (204). Rat neuropeptide Y-ir cells also project extensively within the ipsilateral IGL (199). While, presumably, GAD would be localized in these neurons (201), IGL cells immunoreactive for either GABA or substance P did not appear to participate in the projection to the contralateral vLGN/IGL (276). In the mouse, some IGL cells projecting to the contralateral IGL contain calcitonin gene-related peptide-ir (219). 1.3.6. Neocortex The vLGN receives a projection from larnina V pyramidal cells in various visual cortical areas. In most species studied, the cortical projection is limited to the vLGN, although the IGL receives projections from the Wulst in owls (43). In the rat, this projection originates from visual cortical areas 17, 18, and 18a (50,252,254). In the cat, this projection originates from areas 17, 18, 19, 20, 21, and the antero-medial lateral suprasylvian area (118). In primates, vLGN afferents arise from various areas: striate cortex (squirrel monkey: (213)), middle temporal extrastriate cortex (macaque monkey: (173,287); owl monkey: (81), preoccipital cortex (rhesus monkey: 153a), dorsomedial, medial and posterior parietal areas (owl monkey: (81)), lateral intraparietal area, and dorsal prelunate gyms (cynomolgus monkey: (12)). Species differ in the distribution of afferents from specific cortical areas within the vLGN, with both the vLGNi and afferents (43,48 cortical the vLGNe receiving 130,154,252,264,273,288). The cortical projection to the vLGN appears to be organized topographically (78,154, 288), with a columnar or reticular organization observed in the rabbit (78). These cortical afferents support a visuomotor role for vLGN/IGL cells. The middle temporal area, the cells of which show responses to visual motion, appears to play a role in both smooth pursuit and saccadic eye movements (172,249). Cells in the antero-medial lateral suprasylvian area show both velocity- and direction-selective responses to visual motion, with some cells responding best to threedimensional cues simulating proximal approaching motion (280). The preoccipital cortical area functions in pupillary constriction, accommodation, and convergence (153a). The dorsal prelunate gyros and lateral intraparietal areas project to three major targets of vLGN efferent projections: zona incerta, anterior pretectal nucleus and superior colliculus (12). Studies directly examining vLGN function in the absence of cortical input would help to clarify the exact role of these afferents. 1.3.7. Zona incerta The zona incerta is a somatosensory integration area with connections to neocortex, superior colliculus and pretectum (10,156). This area has been hypothesized to play a role in shifts of attention in response to somatosensory and visual stimuli. The IGL receives input from the zona incerta (221,294). Neurons of the vLGN and IGL project to the zona incerta in gerbil, rat and cat (31,65,149,186,187, 210,237,271). Both subdivisions of the vLGN contribute to this projection (255). The zona incerta has a rough cortico-topic organization (156); further research should determine the overlap of vLGN input onto this cortical map.

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1.3.8. Accessory optic system The function of accessory optic nuclei may be to play a role in analysis of optical flow fields. This may aid in directing gaze and in detection of self- vs object-motion (83). Two of the three accessory optic system nuclei receive vLGN afferents in rat and cat. A projection from the vLGN to the lateral terminal nucleus and to the medial terminal nucleus has been described in both the rat and the cat (65,84,148,237,271), while a projection to the medial terminal nucleus was observed in the rabbit (79). Neuropeptide Y-ir IGL cells, as well as some vLGNi cells, project to the sole accessory optic system nucleus in pigeons, the nucleus of the basal optic root (94). Cells in the lateral terminal nucleus may project to the vLGN in the cat (210). 1.3.9. Vestibular nuclei and thalamic intralaminar nuclei A pathway from the vestibular nuclei to the vLGN and then to the thalamic intralaminar nuclei could be involved in integrating vestibular and oculomotor information with early levels of motor processing (76). Magnin and Kennedy (162) placed small injections of a retrograde tracer into the vLGN of cats where vestibular-related unit activity had been recorded. Many vestibular nuclei neurons were labeled retrogradely. This projection has been confirmed using electrophysiological techniques (169). A similar projection from the vestibular nuclei to the vLGN is found in rats (221) and tree shrews (48). The projection from the vLGN to the thalamic intralaminar nuclei has been shown by several techniques, largely in cats (132,162,210,241,291). This projection may be reciprocated (242). A projection from the reticulated nucleus just medial to the vLGN to the central lateral nucleus of the thalamic intralaminar group was described in the tree shrew (48); a similar projection maybe observed in the cat (210). 1.3.10. Pens and cerebellum Input from the cerebellum and projections to an area of the pens afferent to the cerebellum further indicate a role for the vLGN and IGL in the generation and/or control of eye movements. The lateral cerebella nucleus in the pigeon, cat and tree shrew sends afferents to the vLGN (11,48,84). The rabbit vLGN receives input from the cerebella posterior interposed nucleus (309). Cells in the vLGN and IGL project to a small terminal field along the midline of the rostral pens in rats and cats (31,65,84,149,237,251,299). This may be the medio-dorsal pontine nucleus, implicated in control of optokinetic eye movements. Cells in this nucleus respond to horizontal motion of the visual field (134). Cells in this area of the pens project to the cerebellum (84) indicating a possible route for visual information relayed via the vLGN/IGL to reach the cerebellum. The cells of origin for this projection are located in the IGL and various subdivisions of the vLGN across species (cat: 1; rat: 185; rabbit: 299). In the tree shrew, both vLGN and medial reticulated nucleus neurons project to the reticular tegmental pontine nucleus, which in turn projects to the cerebellum (48). Cells in the reticular tegmental pontine nucleus are implicated in regulation of both optokinetic nystagmus and saccadic eye movements (248). 1.3.11. Other afferents and efferents The vLGN and IGL have connections with many brainstem nuclei. Afferents to the vLGN arise from the dorsal

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raphe and parabigeminal nuclei (rat, cat), locus coeruleus (rat, cat, pigeon), the mesencephalic reticular formation, periaqueductal gray, dorsal tegmental nuclei (rat) and nucleus of the posterior comrnissure (rat) (50,84,118,138, 159,210,222,295,306). Cells just dorsolateral to the red nucleus are afferent to the vLGN in cats (210). Cells in the IGL receive afferents from dorsal raphe, locus coeruleus and midbrain central gray (64,143,183,199). Several brainstem afferents to vLGN may be related to oculomotor control. The mesencephalic reticular formation is an area important for the control of eye movements; stimulation here can produce saccades (133). The nucleus prepositus hypoglossi projects to the vLGN (142,162, 176). The nucleus prepositus has been hypothesized to provide an efference copy of eye movements (176). One report of a reciprocal projection from the vLGN to the nucleus prepositus hypoglossi (160) was not confirmed in a subsequent study (176). Efferent projections of the vLGN terminate in the perirubral fields in the rat, cat and tree shrew (48,65,148,210, 237, 271). Thalamic connections have been reported in several studies. Reciprocal connections of the vLGN with the subthalamus have been described (65,84). Both vLGN and IGL contribute to a small projection to the dLGN (48,188). A

projection from the vLGN to the pulvinar was observed in both tree shrew and cat (48,210). The lateral posterior thalamic nucleus projects to the rat vLGN (222) and vLGN efferents to this nucleus were seen in the cat (210). The anterior thalamic nucleus of the rat may receive projections from neurons in the rostral IGL (260). The IGL may receive afferents from the caudal thalamic reticular nucleus in rats (199) while the cat vLGN has reciprocal connections with the rostral thalamic reticular nucleus (210). The IGL cells in the rat may project to the subcommissural organ, precommissural nucleus, and nucleus of the posterior comrnissure (189). Additional connections were noted in several papers. The cat vLGN has been reported to receive input from the interstitial nucleus of Cajal and to project to the field of Forel (210). In the tree shrew, afferents from the facial motor nucleus were described (48). 1.4. Conclusions based on anatomical studies The vLGN has widespread connections with subcortical visual centers. Swanson et al. (271) commented that, with few exceptions, every brain area which receives a direct projection from the retina also receives a projection from the vLGN. The afferent and efferent connections described

TABLE 2

AREASIDENTIFIED ASAFFERENT OREFFERENT TOTHEVENTRAL LATERAL GENICULATE NUCLEUS (vLGN)ORTHEINTERGENICULATELEAFLET (IGL)INSTUDIES REVIEWED INTHETEXT*

Retina Superiorcolliculus Pretectum Suprachiasmatic nucleus Extra-SCN hypothafarmrs Contralateral IGL Neocortex Zonaincerta Accessory opticsystem ‘flrafarnic reticularnucleus Nucleusoftheposteriorcomrnissure Perirrrbral fields Subthalannrs Lateralposteriorthafarrric nucleus Vestibulm nuclei Lateralcerebellanuclei Parabigerninal nuclei Mesencephalic reticularformation Periaqueductal gray Dorsaltegmentaf nuclei Nucleusprepositus hypoglossi InterstitialnucleusofCajal Facialmotornucleus Raphe Locuscoerrdeus Anteriorthafarnicnucleus Midbraincentralgray Tfmlamic intrrdamimu nucleus Prdvinar Pens dLGN Subcornmissural organ Precommisora.1 nucleus Pineal

AfferentvLGN

AfferentIGL

x x x

x

x x x x x x x x x x x x x x x x x x x x

x x x x x x x

EfferentvLGN

EfferentIGL

x x x x

x x x x x

x x x

x x x

x x x

x x x x

*Notethemanyneoronalconnections sharedbythesetwobrainareas.Seetextfordetails.

x x x x

x x x x x

VENTRAL LATERAL GENICULATE NUCLEUS AND THE INTERGENICULATE LEAFLET

above, however, suggest more than a purely visual role. It is obvious that the vLGN is in a position to be a major visuomotor integration center. The anatomy of the vLGN and IGL appears quite similar. Both structures share many neurochemicals, most commonly neuropeptide Y, GABA, enkephalin, and nitric oxide synthase (localized in cells) and serotonin, acetylcholine, histamine, doparnine and noradrenalin (localized in fibers). Afferent and efferent connections are also similar, with both areas commonly receiving input from retina, locus coreuleus and raphe, having reciprocal connections with superior colliculus, pretectum and hypothalamus, and also showing connections to zona incerta, accessory optic system, pens, the contralateral vLGN/IGL and other thalamic nuclei (see Table 2). Several anatomical findings suggest a role for the IGL and vLGN in circadian rhythm regulation. Most notably, many cells in the IGL, and some in the vLGN, project to the SCN, an area very important for circadian rhythm generation in mammals. The IGL cells also project to the pineal, and hypothalamic areas near the SCN project back to the geniculate. Some retinal ganglion cells afferent to the vLGN/IGL also project to the SCN. A visuomotor role for vLGN and IGL neurons is supported strongly by the anatomical data available. Many vLGN cells receive photic afferents, at least three of which are topographically organized — those from the retina, visual cortical areas, and superior colliculus. Many vLGN neurons also may receive detailed information on both self- and object-motion, and on eye movements via inputs from the vestibular nuclei, the lateral cerebella nuclei, the mesencephalic reticular formation, and the nucleus prepositus hypoglossi. Connections with accessory optic system nuclei may aid these areas in determinations of self- vs object-motion. Optokinetic nystagmus, a response to movements of the head and/or body, helps to maintain stability and clarity of vision. The vLGN and IGL are in a good position to play a role in the optokinetic system, most notably by their reciprocal connections with the nucleus of the optic tract. The vLGN may play some role in the saccadic eye movement system, used to shift the visual focus from one object to another, given the input from the middle temporal and antero-medial lateral suprasylvian cortical areas and the mesencephalic reticular formation, as well as the projection of vLGN cells to the reticular tegmental pontine nucleus. Other connections suggest a role in pupilkuy control (the olivary pretectal nucleus and the middle preoccipital cortical area) or somatosensory integration (zona incerta). The vLGN/IGL maybe especially closely associated with the superior colliculus and pretectum. Retinal ganglion cells projecting to the vLGN/IGL also project to the superior colliculus or pretectum. Some individual vLGN neurons project to both the superior colliculus and the pretectum. Neuropeptide Y-ir cells in the IGL project to the superior colliculus and accessory optic system in pigeons. Further research should determine the functional significance of these close anatomical links. The association of neuropeptide Y with the geniculate fibers afferent to the SCN has been exploited profitably in behavioral studies reviewed below. Future anatomical work on the IGL should determine neurotransmitters associated with other afferent and efferent pathways. Several unresolved issues deserve highlighting. Exactly

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which cells constitute the vLGN remains controversial. Some studies support the inclusion of a non-GABAergic cell group linked with the thalamic reticular nucleus. Recent work using avian brains suggests the lateral retinorecipient hypothalamic nucleus may be a part of the vLGN. While one study (198) suggested that only a small portion of the primate pregeniculate nucleus may be homologous to the vLGN, this conclusion was based largely on neuropeptide Y-ir results (see below). Further work is necessary to resolve these issues. There appear to be great species differences as to the location of various subgroups of vLGN neurons within the cytoarchitecturally defined vLGN subdivisions. While this could be a focus of further research, at this time there is little consistency in the literature to guide such research. The only cross-species generalization possible at this time is that retinal input generally is densest in the vLGNe. The question of the anatomical borders of the IGL is even more unsettled than that of the vLGN. At this point, a working definition of the IGL may be: the thalamic area meeting all three of these criteria: (1) receiving bilateral retinal innervation with a diffuse, non-patchy, distribution; (2) projecting to the contralateral IGL; and (3) projecting to the SCN. As an exception, in the pigeon retinal input to the IGL is solely contralateral. The IGL is identified by neuropeptide Y-ir cells in some, but not all, species. Other peptides and neurotransmitters are also commonly, but not consistently, present. Most of the same substances also are found in vLGN cells and fibers. Thus, at present, there is no neurochemical label for the IGL common to all species. It is possible that further comparative work might identify a useful neurochemical label able to identify the IGL in many species. An alternative way to identify this nucleus is via its cytoarchitecture, especially using Golgi preparations. Another way to define the IGL is by its projections. In many species, IGL neurons have been shown to receive diffuse bilateral retinal input and to project to the SCN and the contralateral IGL. The IGL cells also project to the zona incerta, the superior colliculus, the pretectum, and the pens. It should be kept in mind that some work suggests that the IGL consists of at least two subdivisions, distinguished both by neurochernical markers and by their patterns of connectivity. Comparative work should be carried out to allow localization and description of this nucleus in more species and to aid our understanding of its evolution. A major problem in this area is “species myopia”, where researchers attempt to define the area based on results from only one species. Future research should be directed toward several promising “stains” (e.g. VGF, alpha-herpes virus) which, to my knowledge, have been tested on few species. 2. PHYS1OLOGYOF THE VLGNAND IGL 2.1. Electrophysiological recordings of vLGN cells The visual response characteristics of vLGN neurons vary rather dramatically across species. Therefore, I will discuss work on each species separately. 2.1.1. Studies using birds Relative to results from other species, an unusually high percentage of motion-sensitive units was found in the chick

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vLGN (63% of the total sample; 223). Most of these units had uniform receptive fields. Approximately 40% of the motion-sensitive units were direction selective. The most effective movements were those with a forward and a downward component. Cells responded to a wide range of stimulus velocities, with target velocity usually related to firing rate by a log–log function. A subpopulation of cells showed an exceptionally high rate of sustained firing and responses to low target velocities in a large receptive field. These cells might function in stabilization of gaze (223). Spectral responses were studied in the quail vLGN (170). The exact proportion of vLGN cells showing such responses is ambiguous, since the authors did not systematically tabulate cells not showing spectral responses; however, they note that the units they describe (80% of which were clearly spectral-sensitive) constitute ‘‘roughly half of the units encountered”. Thus, “roughly” 40% of quail vLGN units show spectral responses. Similar to work in the cat (119), most units responded optimally to short wavelength (blue) light. All spectral units had uniform receptive fields, many of which were large, with indistinct boundaries. All cells showing a preferred wavelength also had an optimum wavelength for inhibition. A small proportion (1IYo)of units were both spectral- and movement-sensitive. The retinotopic organization was similar to that described by Crossland and Uchwat (54), Interestingly, there seemed to be “chromatic regions’ in the vLGN, the most striking of which was a tendency for cells with receptive fields in the anterior visual field showing stronger preferences for blue wavelengths. To my knowledge, there have been no studies directed toward recordings from IGL neurons in the avian brain. 2.1.2. Studies using rats Most visually responsive neurons in the vLGN/IGL of the rat appear to have sustained ‘‘on’ responses to light. Two studies (104,270) sampled only vLGN/IGL units responding orthodromically to both optic tract and visual cortex stimulation. Since presumably not all vLGN/IGL units receive visual cortex input, it must be assumed that this is a rather selective sample of vLGN/IGL units. These two studies found a slightly higher percentage of sustained “on” type responses than the studies (56a,85,91) that sampled vLGN/ IGL units less discriminatively. Units in the vLGN/IGL not showing sustained “on’ responses fell into a variety of categories. Transient “on’ or “off” responses and lightinhibited cells were observed, as well as a small number of movement-sensitive units (56a,85,91,104,270). While very few vLGN/IGL units showed direct responses to electrical stimulation of the tail, such stimulation facilitated subsequent responses to light in 10 out of 16 neurons tested (56a). Thus, somatosensory stimulation can modulate photic responses in the vLGN/IGL. No vLGN/IGL units showed active suppressive surrounds; however, a silent suppressive surround was apparent in about one-half of the sustained-type units in one study (91). Thus, increasing the size of the stimulus so that it extended beyond the receptive field center decreased the response of these cells, although stimulation of the receptive field surround alone did not alter the firing-rate. The rest of the sustained-type units lacked a suppressive surround and all these units varied their discharge rates as the intensity of

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ambient illumination was varied. Similar light intensitycoding responses were seen in another study (270). The range of retinal afferent conduction velocities measured indicates that both the dLGN and vLGN/IGL are innervated by retinal fibers from all three conduction velocity groups (3, 6, and 13 m/s); but the vLGN/IGL appears to be innervated by a higher proportion of the slowly conducting group (270,91). The mean size of the receptive field centers of vLGN/IGL units (91: 14°; 270: 22.3°) was larger than those of dLGN units. No visually responsive units were found in the vLGNi (270). Very few responses of vLGN/ IGL units to stimulation of the ipsilateral eye were observed. No binocular facilitation or inhibition was observed (209,270). Most vLGN/IGL units tested showed a smooth recovery when tested for the response to double stimuli applied to the optic tract at varied intervals (91,270). These results indicate that a recurrent inhibitory input probably is not common in the vLGN/IGL. Hayashi and Nagata (104) used a stimulating electrode to identify those vLGN/IGL units projecting to the superior colliculus. They sampled only those vLGN/IGL units responding to visual cortex and optic chiasm stimulation. Most units sampled (125/136) responded to stimulation of the superior colliculus, and fifty units were antidromically activated, indicating a direct projection to the superior colliculus. The visual responses of vLGN/IGL units projecting to the superior colliculus were similar to those of the vLGN/IGL as a whole. Sustained “on’ responses were the most common (8170),while a sizable minority (14’ZO) of the units were movement sensitive. Groos and Rusak (85) used a similar stimulation technique to identify vLGN/IGL cells projecting to the SCN. Of 12 units antidromically activated by electrical stimulation of the SCN, seven showed sustained “on” responses to light. Two units showed sustained “off” responses, one unit gave phasic responses and two units did not respond to retinal illumination. The rat vLGNe is organized visuotopically (194,209), with the nasal visual field represented more dorsally, and the lower field represented medially. Units in the rostral vLGN have receptive fields located in the upper temporal visual field. The very rostral vLGN is unique in having a representation of the extreme upper visual field (20–60° above the horizontal meridian), an area that is not represented in the rest of the vLGN. The nasal field is not well represented in the rostral vLGN relative to its representation in the remainder of the vLGN (209). The studies reviewed above did not distinguish the IGL from the vLGN. This should be done in further electrophysiological work on the rat. It would be advisable also for future investigators to conduct a more thorough search for movement-sensitive and spectral-coding units in order to confirm or refute the species differences suggested below. Integration of arousal andlor somatosensory stimulation should be studied further since one study (56a) indicates possible modulatory effects. 2.1.3. Studies using hamsters Cells in the IGL, as distinct from the vLGN, have been studied most extensively in the hamster. These studies all involved the exclusive use of whole eye illumination; receptive fields have not been mapped. Despite these limitations,

VENTRAL LATERAL GENICULATE NUCLEUS AND THE INTERGENICULATE LEAFLET

one can make reasonable guesses about the receptive field organization of these units. For instance, work using other species indicates that vLGN/IGL units with uniform receptive fields respond more vigorously to whole eye illumination than to spots (119,223), while cells with concentric receptive fields give “on/off’ responses to whole eye illumination (223). It is obvious, none the less that receptive field mapping work should be done in the hamster as well. Units in the hamster IGL are more likely to show sustained “on” responses to whole eye illumination than are vLGN units (102). Phasic visual responses with no sustained component were observed in 46% of vLGN units and only 8% of IGL units. Units sampled from all parts of the vLGNe did not differ in their responses to illumination; however, units in the vLGNi were more likely to show ‘‘on/off” responses than units in other vLGN subdivisions. Most phonically responsive IGL cells show light intensity coding properties. Both monotonic and non-monotonic responses to increasing and decreasing light intensity were observed (103). A subpopulation of IGL neurons code only increasing light intensity. Cells in the IGL identified as projecting to either the contralateral IGL or the SCN showed photic response characteristics similar to the total sample of IGL units (308). While most cells projected to only one of these targets, one cell was identified as projecting to both the contralateral IGL and the SCN. Binocular responses were observed in most IGL and rostral vLGNe cells tested. In many instances, binocular illumination produced a weaker response than illumination of the contralateral eye alone due to a suppressive effect of ipsilateral eye illumination (102). Such inhibitory effects may arise from projections from the contralateral IGL (308) as well as from the direct binocular retinal innervation. Light intensity coding properties of IGL cells can be altered dramatically by binoculm vs contralateral eye illumination (103). Both serotonin and melatonin may play an inhibitory role in the vLGN/IGL. In the majority of largely sustained-on IGL neurons sampled in hamsters, both spontaneous firing rate and photic response were suppressed by iontophoretic administration of serotonin, a serotonin-lA agonist, or melatonin (305). Chronic treatment with the antidepressant clorgyline, a type A monoamine oxidase inhibitor, alters serotonin levels and causes changes in circadian rhythms of hamsters in many respects similar to those observed after IGL lesions (63). While chronic clorgyline treatment did not appreciably alter light intensity coding properties of hamster IGL cells, firing rates of IGL cells were lower in both light and dark conditions in clorgyline-treated animals (103). On the other hand, chronic treatment with the antidepressant imipramine does not alter circadian responses of hamsters (233), although it does alter firing characteristics in the vLGN and SCN (180). Specific depletion of serotonergic input to the IGL and not the SCN did not alter circadian rhythm parameters in one study (183). 2.1.4. Studies using rabbits There has been only one report of a survey of visual response types of units in the vLGN/IGL in rabbits (168). The visuotopic organization of the rabbit vLGN is similar to that of the vLGN of the rat (209). Most vLGN/IGL neurons in the rabbit had concentric receptive fields (39%), while a

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sizable minority (14$%0) had uniform receptive fields. No visual response was apparent in 1470 of units sampled. Approximately 28Y0of rabbit vLGN/IGL units responded to light, but receptive field boundaries were unclear, or in some instances the units responded only to whole eye illumination. A very small number of motion- and direction-sensitive units were found in this study. 2.1.5. Studies using cats In contrast to the sustained responses predominant in other species, most cat vLGN/IGL neurons gave only a transient response at light onset (266). Many units had uniform or concentric receptive fields, with very few showing active surrounds (117,119,266). Some neurons were movement-sensitive, and direction-selectivity was observed in a subgroup of these (119,266). Approximately 10Yoof units sampled appeared to signal the level of ambient illumination (119,266). These units were characterized by an unusually regular maintained discharge. These units required very large stimuli to respond (typically 10° in diameter or more) and had very large receptive fields (30° in diameter or more) with poorly defined boundaries (266). The receptive fields of some units covered the entire contralateral visual field (119). None of these units had receptive field surrounds, so that the level of full-field illumination was as effective in controlling the discharge of the unit as was stimulation of the mapped receptive field. All units increased firing rate to an increased level of illumination. In one study, the response of all units to light of various wavelengths was assessed with broad band filters ( >600, 430–460, and 520–540 nm) matched for luminance with white light (119). Wavelength-selective responses were seen in 10Yoof the units sampled. Most units responded primarily to blue light (430–460 rim). Other units showed opponent spectral responses. All but one of these units responded with “on” to blue light, “off” to red light and variably to green. A relatively large proportion of units (20–40Yo) gave indefinite or no responses to light (119,266). Spear and colleagues noted that more than one-half of the cells classified as indefinite did give consistent visual responses to whole eye illumination, but no receptive field could be mapped. These units probably should be placed into a separate category called ‘‘whole field” rather than ‘‘indefinite”. Most vLGN/IGL units were driven only by the contralateral eye, but 30Y0were binocularly driven and 1390were driven only by the ipsilateral eye (266). A visuotopic organization was noted, with the lower visual field represented anteriorly and the upper visual field posteriorly. It appeared that the vertical meridian was represented along the dorsomedial border of the vLGN while the temporal periphery was represented ventrolaterally. Visual receptive field sizes for vLGN/IGL units generally were larger than those for dLGN units at all visual field eccentricities. Hada et al. (90) used stimulating electrodes to identify neurons projecting to the superior colliculus and pretectum while recording from the vLGN/IGL in cats. The receptive field characteristics of vLGN/IGL units in this study do not differ from those reported in previous studies except that a very high (58%) percentage of units were not visually responsive. Visual responses of units projecting to the

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metectum or stmerior colliculus differed from other vLGN/ ~GL units only’in that a smaller percentage of sustained “on’ units was observed in the group of projection neurons. Nine units could be activated antidromicallv. from stimulation in both sites, indicating that these neurons projected to both the pretectum and the superior colliculus. In two studies, responses of vLGN/IGL neurons to paired visual and vestibular stimuli were measured (163,232). Units were found to respond to horizontal vestibular andl or optokinetic stimulation, many in a direction-selective manner. This effect ~ersisted in comrdete darkness. The firing rate appeared to-map the changes-in angular velocity. Many units fired in fixed relation with saccadic or slow phase nystagmic eye movements; most of these units did not respond to light or to a moving spot. A few units responded to light, but no receptive field could be mapped. Most of these units were located in the medial vLGN/IGL. 2.1.6. Primates The pregeniculate nucleus of the primate is thought to be the homologue to the vLGN. An early ‘study of visual responses of units in this nucleus (61) reported that many units responded to visual stimulation of either eye. All units gave sustained “on” responses. Later studies indicated that other units in this area respond to saccadic eye movements in the dark, but not to vestibulm stimulation or pursuit eye movements (38,161). 2.2. Glucose utilization and immediate-early gene expression Close links between the SCN and the vLGN/IGL are shown by studies of metabolic activity. Electrical stimulation of the vLGN/IGL produced an increase in the relative metabolic activity of many brain areas, as assessed by the uptake of [14C]2-deoxyglucose (175). Most areas showing increased activity are connected directly with either the vLGN/IGL or the SCN. Metabolic activity in the vLGN/IGL could be increased by SCN stimulation (175). Lesions of the vLGN/lGL did not alter SCN metabolism (174). While early reports on light-induced expression of the immediate early gene fos in the IGL were contradictory (see 141 for review), a more recent paper reports that cells in the rat IGL show increased Fos-ir after sustained light exposure of at least 2 h (220). These cells were concentrated in the caudal IGL. Scattered vLGN cells also showed Fos-ir. This effect was observed following light exposure in the light or dark phase of the animal’s light:dark cycle. High doses of MK-801 blocked the light-induced increase of Fosir in the IGL (220). Another treatment which may increase Fos-irin the IGL is exposure to a novel running wheel (122). Many Fos-ir neurons are observed in the vLGN after light exposure in dark-reared kittens (16). Cells in the lateral hypothalamic retinorecipient nucleus in the avian brain show increased fos expression in response to novel motion (293). This area may be a subdivision of the vLGN (257). Cells in the rat vLGN show increased Fos-ir following acoustic stimulation (246). In a study explicitly pairing a conditioned stimulus (20 min air puff,) with a light pulse (unconditioned stimulus), increased Fos-ir was observed in the IGL/vLGN of trained rats following the conditioned stimulus alone (8). Since the conditioned stimulus was capable of phase-shifting circadian rhythms, the data

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suggest that the IGL/vLGN might integrate photic and non-photic inputs related to resetting the circadian clock. 2.3. Conclusions based on physiological studies In general, the vLGN/IGL may be distinguished from surrounding retinorecipient nuclei in several respects. Retinal input appears to originate mainly from retinal ganglion cells with relatively slow conduction velocities. Sustained “on” units were common in all animals except cats, where transient responses were more common. Some units appear to code light intensity by their level of maintained discharge. Spectral-opponent responses are seen in birds and in cats. Varying proportions of movement-sensitive units are seen in all species tested. At least in the cat and primate, some vLGN/IGL units are responsive to vestibular and optokinetic stimulation and to nystagmic and saccadic eye movements. It appears that there is a good deal of variation in visual receptive field characteristics of vLGN/IGL units across species, although in some instances even more variation exists across studies using the same species. Further research is needed before we can determine whether the role of the vLGN/IGL in functional systems varies with species. A general problem is “hypothesis myopia” (68), leading researchers to find only the types of responses they set out to find. Studies using various species should examine vestibular and optokinetic responses and motion- or spectral-sensitive responses. An effort should be made to correlate with anatomical and behavioral results electrophysiological studies. Units with uniform receptive fields always appear to predominate over those with a concentric organization. The rat, rabbit and cat all seem fairly similar in the percentage of movement-sensitive units, while studies using birds differ dramatically in their estimates of the proportion of movement-sensitive units. It maybe significant that the one study reporting a high percentage of motion-sensitive units in the vLGN was conducted using a young animal (the chick). A high percentage of IGL cells show light intensity coding responses; these are probably related to the projections of these cells to the circadian clock and the pineal gland. Some IGL cells code only increasing light intensity; these cells may be important in signaling “dawn”. It is difficult to correlate these electrophysiological results with results from behavioral studies of this nucleus, as will be discussed later. Recordings from unanesthetized animals at various circadian phases would be useful, since other studies suggest that the responses of vLGN/IGL neurons to light might be altered by circadian phase or by activity. Especially interesting would be studies of electrophysiological responses of cells following cross-modality conditioning (8). Some studies have identified subpopulations of vLGN/ IGL neurons on the basis of afferent or efferent connections. Small differences were noted. For example, cells receiving visual cortex and retinal input were slightly more likely to show sustained “on” responses. Cells projecting to the superior colliculus or pretectum were slightly less likely to show sustained on responses. On the whole, however, few dramatic differences in photic responses were observed in subpopulations of vLGN/IGL neurons. Many studies indicate that a subpopulation of vLGN/IGL neurons show spectral-sensitive responses. The vLGN may

VENTRAL LATERAL GENICULATE NUCLEUS AND THE INTERGENICULATE LEAFLET

be organized into “chromatic regions’ Many cells seem especially responsive to blue wavelengths. Neurons in the nucleus of the optic tract show directionselective responses in the rabbit (46). Input from the nucleus of the optic tract modifies the direction selectivity of neurons in the accessory optic system of rats (211). A similar role for input to the vLGN might be investigated using chicks, where a sizable proportion of vLGN cells show direction-selective responses (223). 3. BEHAVIORALSTUDIES 3.1. Visual finction Several studies have examined the effects of vLGN/IGL lesions on general visual capabilities. An unambiguous role for the vLGN/IGL area in visual functions has not yet been determined, although perhaps the most consistent finding is a deficit in visual intensity discrimination after vLGN/IGL ablation in the rat. One difficulty in interpreting the studies below is that vLGN/IGL ablation in the rat usually is confounded with incidental damage to the primary optic tract and the dorsal lateral geniculate nucleus, due to the proximity of these structures to the vLGN. Control animals with only dorsal lateral geniculate and primary optic tract damage, as well as animals with neurotoxin-produced vLGN lesions, are required for more firm conclusions about visual deficits attributable specifically to the vLGN and/or the IGL. Studies showing visual intensity discrimination deficits in rats point toward a variety of responsible pathways. Lesion of the vLGN/IGL and/or projections from the vLGN toward the zona incerta impair both acquisition and retention of black–white (intensity) but not horizontal-vertical (orientation) discrimination in rats (115,116,150,151). A similar pattern of deficits is observed in animals with lesions in the lateral and posterior portions of the zona incerta (149). It is possible that visual intensity information is relayed to the zona incerta either from vLGN/IGL cells or via fibers passing through the vLGN area. Results from a small number of animals with varied degrees of vLGN/IGL damage suggests that rats with vLGN/IGL lesions have elevated relative brightness thresholds (150). A connection between the vLGN and the posterior thalamus may be critical for the formation and maintenance of some visual discriminations in the rat (278). Deficits in contrast and flicker sensitivity following vLGN/IGL lesions appear to be attributable to damage to extra vLGN/IGL structures (152,153), illustrating the need for caution in interpretation of results from lesions in this area. Effects of vLGN/IGL lesions on the pupillary light reflex (147) could very well be due to destruction of the retinal input to the pretectum. Using knife cuts of the optic tract fibers running along the lateral edge of the vLGN, Schneider and Jhaven (250) showed that the optic tract fibers that course through the main body of the vLGN project specifically to the pretectum. Distinguishing vLGN from IGL function by behavioral studies can be better performed in the bird, since the vLGN can more easily be damaged separately. One study reports deficits in color but not pattern discrimination after vLGN damage in the pigeon (292). Unfortunately, this conclusion is based on a single subject; however, similar results were referred to in another

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report (87). Other studies report no deficits in intensity or pattern discrimination or luminance difference thresholds after vLGN damage in the pigeon (110,111). Oddly, vLGN damage appeared able to ameliorate deficits observed following nucleus rotundus damage; damage to the subpretectal nucleus reduced this effect (110,111). Rat vLGN cells show mainly sustained “on” responses to retinal illumination; these animals show vLGN lesioninduced deficits in visual discrimination. Bird vLGN cells show many spectral-coded responses; vLGN lesions in birds may lead to color-discrimination deficits. While it is tempting to form generalizations about species differences in vLGN/IGL function, clearly much more behavioral work on the function of the vLGN and IGL is required. A greater variety of species should be utilized in studies using comparable behavioral tasks. It seems odd that none of the studies reviewed here measured visuomotor functions after vLGN/IGL lesions. Such work is essential given the connections of the vLGN/IGL with visuomotor area (superior colliculus, vestibular nuclei, nucleus of the optic tract, etc.) and responses of some vLGN/IGL cells to eye movements or to visual motion. 3.2. Circadian rhythms Studies of the role of the vLGN/IGL in circadian rhythms have utilized animals with destruction of either the geniculo-hypothalamic tract (GHT) or the primary optic tracts posterior to the chiasm. Here, the lesions are referred to as “GHT” lesions instead of “vLGN/IGL” lesions, since the goal is to destroy the cells of origin of the GHT. Thus, parts of the vLGN may be left intact in animals with complete GHT lesions. Ablation of the primary optic tracts would involve destruction of primary and seconday visual afferents to the vLGN (as well as those to other brain areas), but would presumably leave the retinohypothalamic tract to the SCN intact. There are several major drawbacks to the lesion technique, especially in these areas. Some retinal ganglion cells project to both the SCN and the vLGN/IGL; lesions of the optic tracts or the GHT might alter properties of these fibers. In addition, depending on the placement, primary optic tract lesions may damage neurons in the vLGN/IGL or the lateral hypothalamic area. The lateral hypothalamic area receives direct retinal innervation (137,164,238). The projection of hypothalamic cells to the vLGN/IGL might also be interrupted. Thus, changes in the responsiveness of circadian rhythms to lighting conditions following primary optic tract or GHT lesions may not always be attributable to the loss of GHT function. Fortunately, electrical stimulation and neurochemical studies have been conducted to complement the lesion approach. The GHT appears to play a role in both photic and nonphotic phase-shifting. Phase shifts to brief light pulses, utilizing non-parametric effects of light (55) provide a mechanism for entrainment of circadian rhythms to a light–dark cycle. Light also may have effects on the period of the underlying circadian oscillation (parametric effects of light) which also could aid entrainment. Nonphotically induced phase shifts, associated with stimuli such as dark pulses, increased activity, or benzodiazepine injections, do not yet have a clear functional role. This phaseshifting pattern might function to allow animals to shift their

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behavioral rhythms so as to exploit a newly available food source or to avoid a predator. 3.2.1. Primary optic tract lesions Lesions of the primary optic tract do not appear to disrupt daily rhythms of pineal hydroxyindole-O-methyl-transferase activity (44), adrenal corticosterone levels (200), or pineal N-acetyl-transferase activity (139). Rats with large primary optic tract lesions, including extensive damage to the LGN and to surrounding areas, did not show obvious changes in photic entrainment of drinking rhythms although suppression of water intake in response to continuous illumination was enhanced (269). Effects of primary optic tract lesions were quite variable in studies using hamsters (243,244). Under a light:dark cycle, some animals showed an increase in the duration of their active phase. Most hamsters showed an increase in the period of their rhythm in constant darkness, usually accompanied by a lengthening of the duration of the active phase. Under constant light, some animals showed a dramatic lengthening of their rhythm’s period. An effect of the lesions which seemed to be unrelated to the lighting condition was an increase in total wheel-running activity seen in some animals. The most dramatic circadian effects of primary optic tract lesions were observed in a study of the sleep patterns of rats housed under 1 h (light:dmk 0.5:0.5) lighting cycles (261). Under light:dark 0.5:0.5, the control rats confined almost all of their rapid eye movement sleep to the dark phases. The rats with primary optic tract lesions, on the other hand, showed only slightly more rapid eye movement sleep in the dark periods than in the light periods. The primary optic tract may play a role in mediating direct (i.e. “masking”) effects of light on rapid eye movement sleep distribution. Further behavioral studies on the role of the GHT in both masking effects of light and on sleep patterns might be helpful. 3.2.2. Lesions of the GHT The GHT may be primarily involved in mediating responses of hamster circadian rhythms to stimuli causing phase-shifts in the non-photic pattern. Ablation of the GHT alters phase shift responses following 6 h dark pulses in animals housed under continuous illumination. Phase shifts to dark pulses starting at circadian times 5–7 and 14–16 were blocked by GHT ablation; shifts at other phases were unaffected (100). Benzodiazepines induce phase shifts in circadian rhythms of some species and these shifts show a phase response curve similar to that for dark pulses [for review, see Morin (203)]. Phase shifts induced by the benzodiazepines triazolam and chlordiazepoxide at a variety of circadian phases were blocked by GHT ablation (21,127,182). Exposure to a novel running wheel can phase shift in a similar pattern and these phase shifts are blocked by GHT ablation (123,300). It is important to consider activity levels when studying responses to non-photic stimuli. Phase shifts elicited by triazolam injections, novel wheels, or dark pulses may be mediated by the associated increased activity in hamsters (208,283,290). Since hamsters with GHT ablation show a slight reduction in levels of wheel-nmning activity in their home cages (123,126), could this hypoactivity explain their reduced response to triazolam, dark pulses, or novel wheels? This appears unlikely, for two reasons. First, GHT-ablated

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hamsters can be induced to show higher levels of activity and they still do not phase shift (123). Second, unlike triazolam, chlordiazepoxide induces phase shifts which are not dependent on increased activity and these shifts also are blocked by GHT ablation (24,182). These results indicate that effects of GHT ablation on non-photic phase shifting are not due to changes in activity levels. Ablation of the GHT in hamsters alters phase shift responses to light pulses as well as responses of circadian rhythms to continuous lighting. Phase advance shifts to light pulses in the late subjective night are decreased following GHT ablation in hamsters housed under continuous darkness, while phase delay shifts after light in the early subjective night were either unaffected (100) or increased (229). Circadian rhythm responses to continuous illumination were altered bv GHT ablation in several wavs: . the incidence of free-ruining activity rhythms splitting into two components was reduced (100,101); splitting was eliminated in animals already showing stable split rhythms (101); free-mnning periods under constant illumination were often shorter in GHT-ablated hamsters compared to controls (100,101); and the usual effect of increasing illumination causing increasing free-running periods was greatly reduced (229). Changes in photic phase shifting and in the ability of light to alter the clock’s period would be expected to alter entrainment to light:dark cycles. Ablation of the GHT does appear to alter entrainment patterns of hamsters but not rats. The rate at which wheel running re-entrained following a reversal of a 12:12 light:dark cycle was slowed in hamsters with vLGN/IGL lesions (310). Entrainment to light:dark 14:10 was not altered following GHT ablation in hamsters in two studies (101,229), while one study reported GHT-ablated hamsters showed slight phase delays (123). Entrainment to shorter photoperiods may be more dramatically altered (126) (Barrington, Lee, and Rahmani, unpublished). The phase angle of entrainment to a sinusoidal light cycle where the intensity of a blue–green light was varied gradually from 5 to 10 IUXevery 24 h was altered variably in GHT-ablated hamsters, with five animals showing more positive and two more negative phase angles (227). Hamsters with GHT ablation re-entrained at a slightly slower rate than did control animals when the sinusoidal light cycle was delayed by 6 h. On the other hand, a study exposing rats to shifted light:dark cycles found no differences between intact and GHT-ablated rats (62). Reports of changes in free-running periods of animals housed in constant darkness have been variable. Mice show increased period in constant dark (but no alteration under light:dark or constant light) following GHT ablation (228). One report indicated hamsters showed lengthened periods following GHT ablation (229), while another report indicates no alterations relative to control animals (100). Hamsters with GHT damage show altered responses to changing photoperiods (126,262). For example, control hamsters switched from a long photoperiod (light:dark 14:10) to a short photoperiod (Iight:dark 8:16) advanced the phase of their activity onsets, while animals with GHT damage showed no chmges in activity onset phase during 35 days under the short photoperiod. These studies involved small numbers of animals and should be continued and expanded to determine if the GHT actually plays a role in photoperiodic responses.

VENTRAL LATERAL GENICULATE NUCLEUS AND THE INTERGENICULATE LEAFLET

In humans, it is possible that the GHT plays an important role in mediating the expression of circadian rhythmicity. One case report indicates a loss of circadian rhythms in body temperature, heart rate, and vaxious hormones associated with degeneration in the anterior and dorsomedird thalamic nuclei (157). 3.2.3. Electrical stimulation or neurochemical studies Studies using stimulation techniques support a primary role for the vLGN/IGL in non-photic phase-shifting of circadian rhythms. Electrical stimulation of the vLGN/IGL induced phase shifts in wheel-running rhythms of hamsters housed under either continuous light or darkness (245). Similar shifts were observed following injections of an excitotoxin into the vLGN/IGL (126). These phase shifts varied with circadian phase of stimulation in a manner similar to that seen after dark pulses (29). The association of the GHT with neuropeptide Y has been exploited in several studies implicating the GHT in nonphotic phase shifting. Phase shifts in the non-photic pattern were observed following microinjections of neuropeptide Y into the SCN of hamsters (7). Phase shifts to novel wheel access were reduced if preceded by microinjections of neuropeptide Y antisemm into the area of the SCN (23). Neuropeptide Y applied to a rat SCN brain slice preparation shifts the succeeding peak in spontaneous firing rate with a generally non-photic type pattern (79a,178,256). Measurements of neuropeptide Y-ir in the SCN indicate changes with photic conditions. Levels of neuropeptide Y-ir in the SCN show a circadian rhythm, with a peak at circadian time (CT) 12, the projected phase of dark onset under a light:dmk cycle (258,259). This rhythm was altered dramatically by photic stimulation. When rats were studied under a light:dark cycle, peaks in neuropeptide Y-ir were seen at the transitions of the lighting cycle (40,124,258). Such peaks were observed only when those transitions occurred at the usual phases (258). Transitions at inappropriate phases were associated with a smaller increase or no increase in neuropeptide Y-ir. Levels of phonically induced neuropeptide Y-ir did not appear to depend on either levels of light intensity varied between 3 and 300 IUXor on the duration of light pulses greater than 5 min. Shinohara et al. (258) suggest that the GHT may contribute to stabilization of the phase relationship between the light:dark cycle and the circadian pacemaker. The GHT might oppose effects of light. Phase advances to light in the late subjective night were enhanced by treatment with antiserum to neuropeptide Y (20) and reduced by microinjection of neuropeptide Y (298). Since light can oppose the phase-shifting effects of neuropeptide Y (25), a general model might be that light and neuropeptide Y have opposite effects on circadian clock cells. This model can be tested in vitro (22,107). 3.3. Summary of behavioral studies Behavioral work on visual functions of vLGN/IGL neurons may still be in its infancy. While some studies point to a role of these neurons in visual discrimination in rats, studies using pigeons indicate only color discrimination to be altered. Future research should explore the possible role of these nuclei in visuomotor functions such as optokinetic nystagmus or saccadic eye movements. Studies using

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approaches other than lesion methodology also are required. Of course, it is possible that the vLGN/IGL does not play a significant role in the visual or visuomotor systems, but results from anatomical and physiological studies make this appear unlikely. More work has been conducted on the role of vLGN/IGL neurons projecting to the SCN (GHT neurons). The GHT appears to play a small role in phase shifts of circadian rhythms induced by photic stimuli, but its major role may be in mediating non-photic phase shifts. Phase shifts following light pulses are partially reduced, while phase shifts to novel wheel access or benzodiazepines may be totally blocked following GHT ablation. Neuropeptide Y induces non-photic phase shifts, while neuropeptide Y antiserum can block such shifts. Neuropeptide Y and light may oppose each other’s actions on the circadian clock. The IGL/vLGN may be involved in learned associations between photic and non-photic stimuli (8). The circadian clock is important for responses of animals to changing seasons. Several studies using small numbers of animals indicate that GHT ablation alters entrainment to short, but not long, photoperiods. Future work should examine this possibility more systematically. Neuropeptide Y-ir levels in the SCN appear to signal transitions in a previous light:dark cycle. During a short photoperiod, this pattern may allow neuropeptide Y to induce a daily phase shift. Light-induced phase shifts are altered dramatically by the previous photoperiod (231). While no one has yet studied light-induced phase shifts in GHT-ablated animals previously housed under a short photoperiod, this might be expected to yield more dramatic effects of GHT ablation on the light pulse phase-response curve. Studies of the GHT should be extended to a greater variety of species. It appears that the GHT may play a more important role in the hamster circadian system as compared to the rat. No obvious differences between rats and hamsters in GHT anatomy and physiology can yet account for these behavioral differences. Perhaps it is relevant that the hamster is photoperiodically responsive while the rat is not. Hamsters, but not rats, show GHT neurons located in the anterior vLGN. These cells may play a role in photic control of circadian rhythms. Ablation of anterior vLGN cells was associated with increased duration activity phase and circa 12 h phase shifts to light pulses in late subjective night in hamsters (Barrington and Rusak, unpublished observations). The anterior vLGN cells do not appear to be important or as important in non-photic control of circadian rhythms, since block of non-photic phase shifts is seen even when lesions spare this area. Effects of neuropeptide Y application mirror those of GHT stimulation. The GHT neurons also contain GABA and probably other neurochemicals. These results suggest that GHT neurons mediate non-photic phase shifts via release of neuropeptide Y. Several studies indicate that GABA agonists can induce similar phase shifts; however, these may be attributable to GABA intrinsic to the SCN as well. 4. HYPOTHESES While many experimental hypotheses have been suggested throughout the text, I would like to summarize by proposing several conclusions more strongly. First, I

720 hypothesize that the vLGN and IGL are closely related structures. This is suggested especially by the anatomical data reviewed, showing extensive overlap and similarity in connections and neurochemicals of the vLGN and the IGL across species (see Tables 1 and 2). Electrophysiological studies also highlight the similarities between these areas. Light intensity coding properties of cells in the vLGN/IGL suggest how similar cells might be involved in separate functions. Light intensity-coding cells may be connected with similar cells in the olivary pretectal nucleus and thus may play a role in pupillary constriction. They may also project to the SCN where intrinsic cells show similar, although less brisk, light intensity coding properties. As described below, I believe these two structures may both participate in two neural systems: that controllingvisuomotor functions and that regulating circadian rhythms. While researchers tend to emphasize a visuomotor role for vLGN cells and a circadian rhythm role for IGL cells, at the moment there is little empirical reason for such a firm separation, especially when considering more than one species. This is not to imply that these areas are identical. This hmothesis mav. serve to stimulate .. avenues of research in which possible links between visuomotor and circadian systems are explored. 1hypothesize also that vLGN/IGL cells play a visuomotor or optovestibular role, most likely in mediating optokinetic nystagmus. While there is, as yet, no direct evidence in support of this hypothesis, several lines of research provide supporting indirect evidence. Anatomical studies show that cells in the vLGN/IGL are particularly closely linked with the pretectum. The pretectum, in particular the nucleus of the optic tract, may play a role in horizontal optokinetic nystagmus. The IGL is unusual among thalamic nuclei by virtue of its direct commissural connections. These might play a role in binocular interactions in the optokinetic system. Links between the vLGN and other visual and vestibular nuclei may indicate function in a variety of visuomotor and optovestibular contexts, perhaps detection of selfmotion orobject-motion, orinitiating or monitoring eye movements. Do neurophysiological studies on the vLGN/IGL support the hypothesized roles in visuomotor and optovestibular pathways? In general, only by the exceptions. A minority of vLGN/IGL cells in most species are motion-sensitive ordirection-selective. The bird is an exception in that one study found a fairly high percentage of motion-sensitive units. Several studies in the cat indicate vLGN/IGL units firing in fixed relation to saccadic ornystagmic eye movements. The majority of vLGN/IGL units in most animals studied show fairly simple visual responses, generally an ‘‘on’ response, with a fairly large, uniform receptive field. Could these be the “simple cells” providing input to areas such as the nucleus of the optic tract or the accessory optic system nuclei, where cells show more complex responses? Lateral terminal nucleus neurons in the cat have very large receptive fields and only respond to movement covering approximately two-thirds of the receptive field (83). This is an effective mechanism for responding to self-motion, since self-motion would stimulate the entire visual field, while moving objects rarely cover such a large percentage of the visual field. Perhaps these accessory optic s-ystem neurons receive primary input from large receptive field vLGN neurons. My third hypothesis is that cells of the vLGN/IGL play a major role in mediating non-photic phase shifts of circadian rhythms. There is good evidence for this in hamsters. The

BARRINGTON vLGN/IGL neurons send a major projection to the circadian pacemaker in the SCN. A smaller projection from areas surrounding the SCN reciprocates. Neuropeptide Y, one of the neurochemicals localized to the projection from vLGN/ IGL to the circadian clock, can mimic the non-photic pattern of phase shifts when applied to the SCN both in vivo and in vitro, and antiserum to neuropeptide Y can block nonphotic phase shifts induced by a novel wheel. Ablation of the GHT blocks most non-photic phase shifts. Whether the neurons mediating non-photic phase shifts respond to photic stimuli or stimulation via some other sensory system is unclear. The close connections between superior colliculus cells and vLGN/IGL neurons may be significant here. The superior colliculus may function in the detection of and orientation toward objects in the peripheral visual field (181) allowing approach (prey)/avoidance (predator) decisions (58). Largely anecdotal evidence indicates animals phase shift circadian rhythms in order to avoid a predator. Perhaps the superior colliculus provides input relevant to non-photic phase shifting under natural conditions. It is interesting to note that, while attention focuses on the IGL as playing a role in circadian rhythms, the one species for which extensive behavioral data supports this hypothesis (hamster) has many SCN afferent neurons in the vLGN. A fourth hypothesis is that vLGN/IGL cells play a role in photic entrainment, perhaps only under short photoperiods. At least some of the vLGN/IGL neurons projecting to the SCN are phonically responsive, and many of these appear to code light intensity by maintained firing rate. Levels of neuropeptide Y-ir in the SCN vary with photic stimulation. A fairly common finding in neurophysiological studies of the vLGN/IGL is spectral-sensitive units, at least, in studies using quail or cat. Most units respond primarily to blue, with some units showing spectralopponent responses. This result might indicate some special role for blue light in modulation of visuomotor or circadian rhythm responses. Color may be used to assess time of day (twilight vs midday). Lesion studies suggest vLGN/IGL cells play a minor role in mediating phase shifts and entrainment to photic stimuli; however, these studies are of uncertain value due to the many difficulties interpreting effects of lesions in this area. It should be noted, however, that one lesion study found a major effect on photic masking of sleep. Few studies have examined the role of the vLGN/IGL in photic entrainment under various photoperiods. Further research on a functional level is critical in order to resolve these issues. The plethora of anatomical studies on this nucleus can only point toward possible functions. I hope that this review has indicated what may be the more fruitful avenues for further research on the function of the vLGN and IGL, leading to further progress toward our understanding of these areas. ACXNOWLEDGEMENTS

I would like to thank Stephany Biello and Ben Rusak for many helpful discussions and also for their comments on an earlier version of this manuscript. I would also like to thank Don Mitchell, R. Rodieck, and Jens Mikkelsen for helpful comments and suggestions on earlier versions. This work was supported partially by NIH grant NS26496.

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