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Nonlagged relay cells and interneurons in the cat lateral geniculate nucleus: Receptive-field properties and retinal inputs

Published online by Cambridge University Press:  02 June 2009

David N. Mastronarde
Affiliation:
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder

Abstract

Simultaneous recording in the cat's retina and lateral geniculate nucleus (LGN) was used to find excitatory inputs to LGN cells. These recordings, correlated with measurements of LGN cell receptive-field properties, suggested new functional subdivisions of LGN cells. Distinctions between lagged and nonlagged cells were described before (Mastronarde, 1987a,b; Mastronarde et al., 1991), classification of nonlagged cells is examined here.

The Xs-type relay cells described before (Mastronarde, 1987a,b) each had detectable excitatory input from only one retinal X cell. Cells that received significant input from more than one retinal X cell were of three kinds: relay cells with pure X input (XM); relay cells with mixed X and Y input (X/Y); and cells that could not be antidromically activated from visual cortex (XI). In the series of relay cells, XS-XM-X/Y-Y, cells had progressively larger receptive-field centers, lower spatial resolution, and faster and more Y-like responses to various stimuli. XI cells resembled XM and X/Y cells in some respects but tended to have higher maintained firing rates, more sustained responses, and weaker surround suppression of the center response.

The distinctness of XS, XM, X/Y, XI, and Y from each other was examined with a modification of discriminant analysis that allowed cells to lack measurements for some parameters. Any given pair of categories could be distinguished reliably with only three parameters, although less so for X/Y-Y. In particular, XI cells were distinguishable from relay cells by properties other than the results of cortical stimulation, thus supporting the identity of XI cells as a separate class of X interneurons.

Two discontinuities in the behavior of retinal input suggest that XM cells are a separate class from XS and X/Y cells: (1) LGN X cells received either no detectable input from any of the retinal X cells adjacent to their main input, or an easily detectable amount from several such cells; and (2) cells received either no Y input or a certain minimum amount. No such discontinuity in input underlies the distinction between X/Y and Y cells.

LGN Y cells were also heterogeneous. Those with substantial input from more than one retinal Y cell had larger receptive fields and a greater preference for fast-moving stimuli than did Y cells dominated by a single input. Three Y cells could not be antidromically activated. They tended to differ from Y relay cells and resemble X interneurons in several ways. These shared properties, and the general reliability of cortical stimulation for nonlagged cells, indicate that the cells were Y interneurons.

The strength of excitatory input extrapolated to zero at a separation between LGN and ganglion cell receptive fields equivalent to the radius of a retinal X axonal arbor for X input to XM, XI, and X/Y cells, or to the radius of a Y arbor for Y input to X/Y and Y cells. Thus, a retinal axon appears to be selective in providing input primarily to cells with somata within its arbor, rather than to all cells with overlapping dendrites.

Coverage, the number of receptive-field centers overlapping a single point, was estimated for each kind of LGN cell described here. Each had a coverage of at least 6, comparable to that of retinal Y cells; most kinds had coverages of 15–35. These estimates support the idea that these subdivisions of LGN cells are functionally significant.

XM and X/Y cells fill in the functional gap that is present between retinal X and Y cells and make the distribution of spatial properties more continuous, while multiple-input Y cells broaden the range of spatial properties. One role of LGN circuitry might thus be to provide a substrate for the correspondingly broad and continuous range of spatial-frequency tuning in the visual cortex.

Type
Research Articles
Copyright
Copyright © Cambridge University Press 1992

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References

AhlsÉN, G., Grant, K. & LindstrÖM, S. (1982). Monosynaptic excitation of principal cells in the lateral geniculate nucleus by corticofugal fibers. Brain Research 234, 454458.CrossRefGoogle ScholarPubMed
Arkin, M.S. & Miller, R.F. (1988). Mudpuppy retinal ganglion cell morphology revealed by an HRP impregnation technique which provides Golgi-like staining. Journal of Comparative Neurology 270, 185208.CrossRefGoogle ScholarPubMed
Bowling, D.B. & Michael, C.R. (1984). Terminal patterns of single, physiologically characterized optic tract fibers in the cat's lateral geniculate nucleus. Journal of Neuroscience 4, 198216.CrossRefGoogle ScholarPubMed
Bowling, D.B. & Wieniawa-Narkiewicz, E. (1987). Differences in the amplitude of X-cell responses as a function of depth in layer A of lateral geniculate nucleus in cat. Journal of Physiology (London) 390, 201212.Google Scholar
Boycott, B.B. & WÄSsle, H. (1974). The morphological types of ganglion cells of the domestic cat's retina. Journal of Physiology (London) 240, 397419.Google Scholar
Bullier, J. & Norton, T.T. (1977). Receptive-field properties of X-, Y- and intermediate cells in the cat lateral geniculate nucleus. Brain Research 121, 151156.CrossRefGoogle Scholar
Bullier, J. & Norton, T.T. (1979a). X and Y relay cells in cat lateral geniculate nucleus: Quantitative analysis of receptive-field properties and classification. Journal of Neurophysiology 42, 244273.CrossRefGoogle ScholarPubMed
Bullier, J. & Norton, T.T. (1979b). Comparison of receptive-field properties of X and Y ganglion cells with X and Y lateral geniculate cells in the cat. Journal of Neurophysiology 42, 274291.CrossRefGoogle ScholarPubMed
Chan, L.S., Gilman, J.A. & Dunn, O.J. (1976). Alternative approaches to missing values in discriminant analysis. Journal of the American Statistical Association 71, 842844.CrossRefGoogle Scholar
Cleland, B.G., Dubin, M.W. & Levick, W.R. (1971). Sustained and transient neurones in the cat's retina and lateral geniculate nucleus. Journal of Physiology (London) 217, 473496.Google Scholar
Cleland, B.G., Harding, T.H. & Tulunay-Keesey, U. (1979). Visual resolution and receptive field size: Examination of two kinds of cat retinal ganglion cell. Science 205, 10151017.CrossRefGoogle ScholarPubMed
Cleland, B.G., Levick, W.R., Morstyn, R. & Wagner, H.G. (1976). Lateral geniculate relay of slowly conducting retinal afferents to cat visual cortex. Journal of Physiology (London) 255, 299320.Google Scholar
Cleland, B.G., Levick, W.R. & WÄSsle, H. (1975). Physiological identification of a morphological class of cat retinal ganglion cells. Journal of Physiology (London) 248, 151171.Google Scholar
Cooley, W.W. & Lohnes, P.R. (1962). Multivariate Procedures for the Behavioral Sciences. New York: Wiley.Google Scholar
Dreher, B. & Sefton, A.J. (1979). Properties of neurons in cat's dorsal lateral geniculate nucleus: A comparison between medial interlaminar and laminated parts of the nucleus. Journal of Comparative Neurology 183, 4764.CrossRefGoogle ScholarPubMed
Dubin, M.W. & Cleland, B.G. (1977). Organization of visual inputs to interneurons of lateral geniculate nucleus of the cat. Journal of Neurophysiology 40, 410427.CrossRefGoogle ScholarPubMed
Elgeti, H., Elgeti, R. & Fleischhauer, K. (1976). Postnatal growth of the dorsal lateral geniculate nucleus of the cat. Anatomy and Embryology 149, 113.CrossRefGoogle ScholarPubMed
Famiglietti, E.V. Jr., & Peters, A. (1972). The synaptic glomerulus and the intrinsic neuron in the dorsal lateral geniculate nucleus of the cat. Journal of Comparative Neurology 144, 285334.CrossRefGoogle ScholarPubMed
Fitzpatrick, D., Penny, G.R. & Schmechel, D.E. (1984). Glutamic acid decarboxylase-immunoreactive neurons and terminals in the lateral geniculate nucleus of the cat. Journal of Neuroscience 4, 18091829.CrossRefGoogle ScholarPubMed
Flury, B.W. (1989). Understanding partial statistics and redundancy of variables in regression and discriminant analysis. American Statistician 43, 2731.Google Scholar
Friedlander, M.J., Lin, C.-S., Stanford, L.R. & Sherman, S.M. (1981). Morphology of functionally identified neurons in lateral geniculate nucleus of the cat. Journal of Neurophysiology 46, 80129.CrossRefGoogle ScholarPubMed
Friedlander, M.J., Martin, K.A.C. & Vahle-Hinz, C. (1985). The structure of the terminal arborizations of physiologically identified retinal ganglion cell Y axons in the kitten. Journal of Physiology (London) 359, 293313.Google Scholar
Fukuda, Y., Hsiao, C.-F., Watanabe, M. & Ito, H. (1984). Morphological correlates of physiologically identified Y-, X-, and W-cells in cat retina. Journal of Neurophysiology 52, 9991013.CrossRefGoogle Scholar
Garraghty, P.E. (1985). Mixed cells in the cat lateral geniculate nucleus: Functional convergence or error in development? Brain, Behavior, and Evolution 26, 5864.CrossRefGoogle ScholarPubMed
Geisert, E.E. Jr. (1980). Cortical projections of the lateral geniculate nucleus in the cat. Journal of Comparative Neurology 190, 793812.CrossRefGoogle ScholarPubMed
Ginsburg, A.P. (1984). Visual form perception based on biological filtering. In Sensory Experience, Adaptation and Perception, ed. Spillmann, L. & Wooten, W.R., pp. 5372. Hillsdale, New Jersey: Lawrence Erlbaum Associates.Google Scholar
Glezer, V.D., Yakovlev, V.V. & Gauzelman, V.E. (1989). Harmonic basis functions for spatial coding in the cat striate cortex. Visual Neuroscience 3, 351363.CrossRefGoogle ScholarPubMed
Guillery, R.W. (1966). A study of Golgi preparations from the dorsal lateral geniculate nucleus of the adult cat. Journal of Comparative Neurology 128, 2150.CrossRefGoogle ScholarPubMed
Hamori, J., Pasik, P. & Pasik, T. (1983). Differential frequency of P-cells and I-cells in magnocellular and parvocellular laminae of monkey lateral geniculate nucleus. An ultrastructural study. Experimental Brain Research 52, 5766.CrossRefGoogle ScholarPubMed
Hamos, J.E., Van Horn, S.C., Raczkowski, D. & Sherman, S.M. (1987). Synaptic circuits involving an individual retinogeniculate axon in the cat. Journal of Comparative Neurology 259, 165192.CrossRefGoogle ScholarPubMed
Hand, D.J. (1981). Discrimination and Classification. Chichester, UK: Wiley.Google Scholar
Hoffmann, K.-P., Stone, J. & Sherman, S.M. (1972). Relay of receptive-field properties in dorsal lateral geniculate nucleus of the cat. Journal of Neurophysiology 35, 518531.CrossRefGoogle ScholarPubMed
Hughes, A. (1975). A quantitative analysis of the cat retinal ganglion cell topography. Journal of Comparative Neurology 163, 107128.CrossRefGoogle ScholarPubMed
Hughes, A. (1981). Cat retina and the sampling theorem; the relation of transient and sustained brisk-unit cut-off frequency to α and β-mode cell density. Experimental Brain Research 42, 196202.CrossRefGoogle ScholarPubMed
Humphrey, A.L. & Weller, R.E. (1988 a). Functionally distinct groups of X-cells in the lateral geniculate nucleus of the cat. Journal of Comparative Neurology 268, 429447.CrossRefGoogle ScholarPubMed
Humphrey, A.L. & Weller, R.E. (1988 b). Structural correlates of functionally distinct X-cells in the lateral geniculate nucleus of the cat. Journal of Comparative Neurology 268, 448468.CrossRefGoogle ScholarPubMed
Illing, R.-B. & WÄSsle, H. (1981). The retinal projection to the thalamus in the cat: A quantitative investigation and a comparison with the retinotectal pathway. Journal of Comparative Neurology 202, 265285.CrossRefGoogle Scholar
Jones, H.E. & Sillito, A.M. (1990). A specific subgroup of non-length tuned relay cells in the feline dorsal lateral geniculate nucleus. Experimental Brain Research 82, 3339.CrossRefGoogle ScholarPubMed
Kalil, R.E. (1978). Development of the dorsal lateral geniculate nucleus in the cat. Journal of Comparative Neurology 182, 265292.CrossRefGoogle ScholarPubMed
Kratz, K.E., Webb, S.V. & Sherman, S.M. (1978). Studies of the cat's medial interlaminar nucleus: A subdivision of the dorsal lateral geniculate nucleus. Journal of Comparative Neurology 181, 604614.Google ScholarPubMed
Lachenbruch, P.A. & Mickey, M.R. (1968). Estimation of error rates in discriminant analysis. Technometrics 10, 111.CrossRefGoogle Scholar
Levay, S. & Ferster, D. (1979). Proportion of interneurons in the cat's lateral geniculate nucleus. Brain Research 164, 304308.CrossRefGoogle ScholarPubMed
Leventhal, A.G. (1982). Morphology and distribution of retinal ganglion cells projecting to different layers of the dorsal lateral geniculate nucleus in normal and Siamese cats. Journal of Neuroscience 2, 10241042.CrossRefGoogle ScholarPubMed
Levick, W.R. (1972). Another tungsten microelectrode. Medical and Biological Engineering 10, 510515.CrossRefGoogle ScholarPubMed
Levick, W.R., Cleland, B.G. & Dubin, M.W. (1972). Lateral geniculate neurons of cat: Retinal inputs and physiology. Investigative Ophthalmology 11, 302311.Google ScholarPubMed
LindstrÖM, S. (1983). Interneurones in the lateral geniculate nucleus with monosynaptic input from retinal ganglion cells. Acta Physiologica Scandinavica 119, 101103.CrossRefGoogle Scholar
Little, R.J.A. (1978). Consistent regression methods for discriminant analysis with incomplete data. Journal of the American Statistical Association 73, 319322.CrossRefGoogle Scholar
MadarÁSz, M., Gerle, J., Hajdu, F., Somogyi, G. & TÖMbÖL, T. (1978). Quantitative histological studies on the lateral geniculate nucleus in the cat. II. Cell numbers and densities in the several layers. Journal fur Hirnforschung 19, 159164.Google ScholarPubMed
MadarÁSz, M., Somogyi, J., Silakov, V.L. & Hamori, J. (1983). Residual neurons in the lateral geniculate nucleus of adult cats following chronic disconnection from the cortex. Experimental Brain Research 52, 363374.CrossRefGoogle ScholarPubMed
Marr, D. (1982). Vision. San Francisco, California: W.H. Freeman.Google Scholar
Mastronarde, D.N. (1983a). Correlated firing of cat retinal ganglion cells. I. Spontaneously active inputs to X- and Y-cells. Journal of Neurophysiology 49, 303324.CrossRefGoogle Scholar
Mastronarde, D.N. (1983b). Interactions between ganglion cells in cat retina. Journal of Neurophysiology 49, 350365.CrossRefGoogle ScholarPubMed
Mastronarde, D.N. (1987a). Two types of single-input X-cells in cat lateral geniculate nucleus. I. Receptive-field properties and classification of cells. Journal of Neurophysiology 57, 357380.CrossRefGoogle Scholar
Mastronarde, D.N. (1987b). Two types of single-input X-cells in cat lateral geniculate nucleus. II. Retinal inputs and the generation of receptive-field properties. Journal of Neurophysiology 57, 381413.CrossRefGoogle Scholar
Mastronarde, D.N. (1988). Divergence of retinal input into functionally different cell classes in the cat's lateral geniculate nucleus. Ph.D. Thesis, University of Colorado.Google Scholar
Mastronarde, D.N., Humphrey, A.L. & Saul, A.B. (1991). Lagged Y cells in the cat lateral geniculate nucleus. Visual Neuroscience 7, 191200.CrossRefGoogle ScholarPubMed
Mastronarde, D.N., Thibeault, M.A. & Dubin, M.W. (1984). Nonuniform postnatal growth of the cat retina. Journal of Comparative Neurology 228, 598608.CrossRefGoogle ScholarPubMed
Montero, V.M. & Zermpel, J. (1985). Evidence for two types of GABA-containing interneurons in the A-laminae of the cat lateral geniculate nucleus: A double-label HRP and GABA-immunocytochemical study. Experimental Brain Research 60, 603609.Google ScholarPubMed
Mooney, R.D., Dubin, M.W. & Rusoff, A.C. (1979). Interneuron circuits in the lateral geniculate nucleus of monocularly deprived cats. Journal of Comparative Neurology 187, 533544.CrossRefGoogle ScholarPubMed
Movshon, J.A. (1981). Functional architecture in the cat's lateral geniculate nucleus. Investigative Ophthalmology and Visual Science (Suppl.) 20, 14.Google Scholar
Movshon, J.A., Thompson, I.D. & Tolhurst, D.J. (1978). Spatial and temporal contrast sensitivity of neurones in areas 17 and 18 of the cat's visual cortex. Journal of Physiology (London) 283, 101120.Google Scholar
Palkovits, M., Magyar, P. & Szentagothai, J. (1971). Quantitative histological analysis of the cerebellar cortex in the cat. I. Number and arrangement in space of the purkinje cells. Brain Research 32, 113.CrossRefGoogle ScholarPubMed
Peichl, L. & WÄSsle, H. (1979). Size, scatter and coverage of ganglion cell receptive field centres in the cat retina. Journal of Physiology (London) 291, 117141.Google Scholar
Peichl, L. & WÄSsle, H. (1981). Morphological identification of on and off-center brisk transient (Y) cells in the cat retina. Proceedings of the Royal Society B (London) 212, 139156.Google Scholar
Pollen, D.A. & Feldon, S.E. (1979). Spatial periodicities of periodic complex cells in the visual cortex cluster at one-half octave intervals. Investigative Ophthalmology and Visual Science 18, 429434.Google ScholarPubMed
Robson, J.G. (1983). Frequency domain visual processing. In Physical and Biological Processing of Images, ed. Braddick, O.J. & Sleigh, A.C., pp. 7387. Berlin: Springer-Verlag.CrossRefGoogle Scholar
Rodieck, R.W. & Brening, R.K. (1983). Retinal ganglion cells: Properties, types, genera, pathways and trans-species comparisons. Brain, Behavior, and Evolution 23, 121164.CrossRefGoogle ScholarPubMed
Rowe, M.H. & Stone, J. (1980). The interpretation of variation in the classification of nerve cells. Brain, Behavior, and Evolution 17, 123151.CrossRefGoogle ScholarPubMed
Saito, H.-A. (1983). Morphology of physiologically identified X-, Y-, and W-type retinal ganglion cells of the cat. Journal of Comparative Neurology 221, 279288.CrossRefGoogle Scholar
Sanderson, K.J. (1971a). The projection of the visual field to the lateral geniculate and medial interlaminar nuclei in the cat. Journal of Comparative Neurology 143, 101118.CrossRefGoogle Scholar
Sanderson, K.J. (1971b). Visual field projection columns and magnification factors in the lateral geniculate nucleus of the cat. Experimental Brain Research 13, 159177.CrossRefGoogle ScholarPubMed
Saul, A.B. & Humphrey, A.L. (1990). Spatial and temporal response properties of lagged and nonlagged cells in the cat lateral geniculate nucleus. Journal of Neurophysiology 64, 206224.CrossRefGoogle ScholarPubMed
Schein, S.J. & De Monasterio, F.M. (1987). Mapping of retinal and geniculate neurons onto striate cortex of macaque. Journal of Neuroscience 7, 9961009.CrossRefGoogle ScholarPubMed
Shapley, R. & Lennie, P. (1985). Spatial frequency analysis in the visual system. Annual Review of Neuroscience 8, 547583.CrossRefGoogle ScholarPubMed
Shapley, R. & So, Y.T. (1980). Is there an effect of monocular deprivation on the proportions of X and Y cells in the cat lateral geniculate nucleus? Experimental Brain Research 39, 4148.CrossRefGoogle ScholarPubMed
Sherman, S.M. (1985). Functional organization of the W-, X-, and Y-cell pathways in the cat: A review and hypothesis. In Progress in Psychobiology and Physiological Psychology, Vol. II, ed. Sprague, J.M. & Epstein, A.N., pp. 233314. New York: Academic Press.Google Scholar
Sherman, S.M. & Friedlander, M.J. (1988). Identification of X versus Y properties for interneurons in the A-laminae of the cat's lateral geniculate nucleus. Experimental Brain Research 73, 384392.CrossRefGoogle ScholarPubMed
Singer, W. & Bedworth, N. (1973). Inhibitory interaction between X and Y units in the cat lateral geniculate nucleus. Brain Research 49, 291307.CrossRefGoogle ScholarPubMed
Snappin, S.M. & Knoke, J.D. (1989). Estimation of error rates in discriminant analysis with selection of variables. Biometrics 45, 289299.CrossRefGoogle Scholar
So, Y.T. & Shapley, R. (1979). Spatial properties of X and Y cells in the lateral geniculate nucleus of the cat and conduction velocities of their inputs. Experimental Brain Research 36, 533550.CrossRefGoogle Scholar
So, Y.T. & Shapley, R. (1981). Spatial tuning of cells in and around lateral geniculate nucleus of the cat: X and Y relay cells and perigeniculate interneurons. Journal of Neurophysiology 45, 107120.CrossRefGoogle Scholar
Stanford, L.R., Friedlander, M.J. & Sherman, S.M. (1981). Morphology of physiologically identified W-cells in the C laminae of the cat's lateral geniculate nucleus. Journal of Neuroscience 1, 578584.CrossRefGoogle Scholar
Stanford, L.R. & Sherman, S.M. (1984). Structure/function relationships of retinal ganglion cells in the cat. Brain Research 297, 381386.CrossRefGoogle ScholarPubMed
Sur, M., Esguerra, M., Garraghty, P.E., Kritzer, M.F. & Sherman, S.M. (1987). Morphology of physiologically identified retinogeniculate X- and Y-axons in the cat. Journal of Neurophysiology 58, 132.CrossRefGoogle ScholarPubMed
Sur, M., Weller, R.E. & Sherman, S.M. (1984). Development of X and Y-cell retinogeniculate terminations in kittens. Nature 310, 246249.CrossRefGoogle ScholarPubMed
Thompson, I.D. & Tolhurst, D.J. (1979). Optimal spatial frequencies of neighboring neurones in the cat's visual cortex. Journal of Physiology (London) 300, 5758P.Google Scholar
Tolhurst, D.J. & Thompson, I.D. (1981). On the variety of spatial frequency selectivities shown by neurons in area 17 of the cat. Proceedings of the Royal Society B (London) 213, 183199.Google Scholar
Tusa, R.J., Rosenquist, A.C. & Palmer, L.A. (1979). Retinotopic organization of areas 18 and 19 in the cat. Journal of Comparative Neurology 185, 657678.CrossRefGoogle Scholar
WÄSsle, H., Boycott, B.B. & Illing, R.-B. (1981a). Morphology and mosaic of on- and off-beta cells in the cat retina and some functional considerations. Proceedings of the Royal Society B (London) 212, 177195.Google Scholar
WÄSsle, H., Levick, W.R. & Cleland, B.G. (1975). The distribution of the alpha type of ganglion cells in the cat's retina. Journal of Comparative Neurology 159, 419438.CrossRefGoogle ScholarPubMed
WÄSsle, H., Peichl, L. & Boycott, B.B. (1981b). Morphology and topography of on- and off-alpha cells in the cat retina. Proceedings of the Royal Society B (London) 212, 157175.Google Scholar
Weber, A.J. & Kalil, R.E. (1983). The percentage of interneurons in the dorsal lateral geniculate nucleus of the cat and observations on several variables that affect the sensitivity of horseradish peroxidase as a retrograde marker. Journal of Comparative Neurology 220, 336346.CrossRefGoogle Scholar
Weber, A.J., Kalil, R.E. & Behan, M. (1989). Synaptic connections between corticogeniculate axons and interneurons in the dorsal lateral geniculate nucleus. Journal of Comparative Neurology 289, 156164.CrossRefGoogle ScholarPubMed
Williams, R.W., Bastiani, M.J. & Chalupa, L.M. (1983). Loss of axons in the cat optic nerve following fetal unilateral enucleation: An electron microscopic analysis. Journal of Neuroscience 3, 133144.CrossRefGoogle ScholarPubMed
Wilson, J.R., Friedlander, M.J. & Sherman, S.M. (1984). Fine structural morphology of identified X- and Y-cells in the cat's lateral geniculate nucleus. Proceedings of the Royal Society B (London) 221, 411436.Google Scholar
Wilson, P.D., Rowe, M.H. & Stone, J. (1976). Properties of relay cells in cat's lateral geniculate nucleus: A comparison of W-cells with X- and Y-cells. Journal of Neurophysiology 39, 11931209.CrossRefGoogle ScholarPubMed