A mapping label required for normal scale of body representation in the cortex

Article metrics

Abstract

The neocortical primary somatosensory area (S1) consists of a map of the body surface. The cortical area devoted to different regions, such as parts of the face or hands, reflects their functional importance. Here we investigated the role of genetically determined positional labels in neocortical mapping. Ephrin-A5 was expressed in a medial > lateral gradient across S1, whereas its receptor EphA4 was in a matching gradient across the thalamic ventrobasal (VB) complex, which provides S1 input. Ephrin-A5 had topographically specific effects on VB axon guidance in vitro. Ephrin-A5 gene disruption caused graded, topographically specific distortion in the S1 body map, with medial regions contracted and lateral regions expanded, changing relative areas up to 50% in developing and adult mice. These results provide evidence for within-area thalamocortical mapping labels and show that a genetic difference can cause a lasting change in relative scale of different regions within a topographic map.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Ephrin-A5 RNA expression within motor and sensory areas of the developing rodent neocortex.
Figure 2: Ephrin-A5 graded expression across the developing rodent somatosensory cortex.
Figure 3: The VB complex, the main somatosensory relay to the cortex, displays graded Eph receptor expression, and its axons are differentially repelled by ephrin-A5 in vitro.
Figure 4: Connectivity and pattern of the thalamocortical somatosensory map are grossly normal in ephrin-A5−/− mice.
Figure 5: Expansions and contractions in the cortical somatosensory map of ephrin-A-5−/− mice.

References

  1. 1

    Penfield, W. & Rasmussen, T., The Cerebral Cortex of Man (Macmillan, New York, 1950).

  2. 2

    Woolsey, C. N. in Biological and Biochemical Bases of Behavior (eds. Harlow, H. F. & Woolsey, C. N.) 63–81 (Univ. of Wisconsin Press, Madison, Wisconsin, 1958).

  3. 3

    White, L. E., Lucas, G., Richards, A. & Purves, D. Cerebral asymmetry and handedness. Nature 368, 197–198 (1994).

  4. 4

    Kaas, J. H. in The Cognitive Neurosciences (ed. Gazzaniga, M. S.) 51–71 (MIT Press, Cambridge, Massachusetts, 1995).

  5. 5

    Riddle, D. R. & Purves, D. Individual variation and lateral asymmetry of the rat primary somatosensory cortex. J. Neurosci. 15, 4184–4195 (1995).

  6. 6

    Elbert, T., Pantev, C., Wienbruch, C., Rockstroh, B. & Taub, E. Increased cortical representation of the fingers of the left hand in string players. Science 270, 305–307 (1995).

  7. 7

    Buonomano, D. V. & Merzenich, M. M. Cortical plasticity: from synapses to maps. Annu. Rev. Neurosci. 21, 149–186 (1998).

  8. 8

    Howe, M. J. A., Davidson, J. W. & Sloboda, J. A. Innate talents: reality or myth? Behav. Brain Sci. 21, 399–442 (1998).

  9. 9

    Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).

  10. 10

    Hubel, D. H. & Wiesel, T. N. Early exploration of the visual cortex. Neuron 20, 401–412 (1998).

  11. 11

    Crair, M. C. Neuronal activity during development: permissive or instructive? Curr. Opin. Neurobiol. 9, 88–93 (1999).

  12. 12

    Welker, E. & Van der Loos, H. Is areal extent in sensory cerebral cortex determined by peripheral innervation density? Exp. Brain Res. 63, 650–654 (1986).

  13. 13

    O'Leary, D. D. M., Ruff, N. L. & Dyck, R. H. Development, critical period plasticity, and adult reorganizations of mammalian somatosensory systems. Curr. Opin. Neurobiol. 4, 535–544 (1994).

  14. 14

    Fox, K., Schlaggar, B. L., Glazewski, S. & O'Leary, D. D. M. Glutamate receptor blockade at cortical synapses disrupts development of thalamocortical and columnar organization in somatosensory cortex. Proc. Natl. Acad. Sci. USA 93, 5584–5589 (1996).

  15. 15

    Iwasato, T. et al. NMDA receptor-dependent refinement of somatotopic maps. Neuron 19, 1201–1210 (1997).

  16. 16

    Goodman, C. S. & Shatz, C. J. Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell 72 (Suppl.), 77–98 (1993).

  17. 17

    Molnar, Z. & Blakemore, C. How do thalamic axons find their way to the cortex? Trends Neurosci. 18, 389–397 (1995).

  18. 18

    Killackey, H. P., Rhoades, R. W. & Bennett-Clarke, C. A. The formation of a cortical somatotopic map. Trends Neurosci. 18, 402–407 (1995).

  19. 19

    Sperry, R. W. Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc. Natl. Acad. Sci. USA 50, 703–710 (1963).

  20. 20

    Molnar, Z. & Blakemore, C. Lack of regional specificity for connections formed between thalamus and cortex in coculture. Nature 351, 475–477 (1991).

  21. 21

    Roe, A. W., Pallas, S. L., Hahm, J. O. & Sur, M. A map of visual space induced in primary auditory cortex. Science 250, 818–820 (1990).

  22. 22

    Schlaggar, B. L. & O'Leary, D. D. M. Potential of visual cortex to develop an array of functional units unique to somatosensory cortex. Science 252, 1556–1560 (1991).

  23. 23

    Cheng, H. J., Nakamoto, M., Bergemann, A. D. & Flanagan, J. G. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82, 371–381 (1995).

  24. 24

    Drescher, U. et al. In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 82, 359–370 (1995).

  25. 25

    Nakamoto, M. et al. Topographically specific effects of ELF-1 on retinal axon guidance in vitro and retinal axon mapping in vivo. Cell 86, 755–766 (1996).

  26. 26

    Frisen, J. et al. Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20, 235–243 (1998).

  27. 27

    Feldheim, D. A. et al. Topographic guidance labels in a sensory projection to the forebrain. Neuron 21, 1303–1313 (1998).

  28. 28

    Castellani, V., Yue, Y., Gao, P. P., Zhou, R. & Bolz, J. Dual action of a ligand for Eph receptor tyrosine kinases on specific populations of axons during the development of cortical circuits. J. Neurosci. 18, 4663–4672 (1998).

  29. 29

    Gao, P. P. et al. Regulation of thalamic neurite outgrowth by the Eph ligand ephrin-A5: implications in the development of thalamocortical projections. Proc. Natl. Acad. Sci. USA 95, 5329–5334 (1998).

  30. 30

    Donoghue, M. J. & Rakic, P. Molecular evidence for the early specification of presumptive functional domains in the embryonic primate cerebral cortex. J. Neurosci. 19, 5967–5979 (1999).

  31. 31

    Mackarehtschian, K., Lau, C. K., Caras, I. & McConnell, S. K. Regional differences in the developing cerebral cortex revealed by ephrin-A5 expression. Cereb. Cortex 9, 601–610 (1999).

  32. 32

    Agmon, A., Yang, L. T., O'Dowd, D. K. & Jones, E. G. Organized growth of thalamocortical axons from the deep tier of terminations into layer IV of developing mouse barrel cortex. J. Neurosci. 13, 5365–5382 (1993).

  33. 33

    Cheng, H. J. & Flanagan, J. G. Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cell 79, 157–168 (1994).

  34. 34

    Flanagan, J. G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309–345 (1998).

  35. 35

    Paxinos, G. The Rat Nervous System (Academic, San Diego, California, 1995).

  36. 36

    Walter, J., Henke-Fahle, S. & Bonhoeffer, F. Avoidance of posterior tectal membranes by temporal retinal axons. Development 101, 909–913 (1987).

  37. 37

    McCasland, J. S., Bernardo, K. L., Probst, K. L. & Woolsey, T. A. Cortical local circuit axons do not mature after early deafferentation. Proc. Natl. Acad. Sci. USA 89, 1832–1836 (1992).

  38. 38

    Chiaia, N. L. et al. Evidence for prenatal competition among the central arbors of trigeminal primary afferent neurons. J. Neurosci. 12, 62–76 (1992).

  39. 39

    Renehan, W. E., Crissman, R. S. & Jacquin, M. F. Primary afferent plasticity following partial denervation of the trigeminal brainstem nuclear complex in the postnatal rat. J. Neurosci. 14, 721–739 (1994).

  40. 40

    Killackey, H. P., Chiaia, N. L., Bennett-Clarke, C. A., Eck, M. & Rhoades, R. W. Peripheral influences on the size and organization of somatotopic representations in the fetal rat cortex. J. Neurosci. 14, 1496–1506 (1994).

  41. 41

    Fox, K. A critical period for experience-dependent synaptic plasticity in rat barrel cortex. J. Neurosci. 12, 1826–1838 (1992).

  42. 42

    Gao, W. Q. et al. Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, Rek7/EphA5, and its ligand, AL-1/ephrin-A5. Mol. Cell. Neurosci. 11, 247–259 (1998).

  43. 43

    Rakic, P. Specification of cerebral cortical areas. Science 241, 170–176 (1988).

  44. 44

    O'Leary, D. D. M. Do cortical areas emerge from a protocortex? Trends Neurosci. 12, 400–406 (1989).

  45. 45

    Miyashita-Lin, E. M., Hevner, R., Wassarman, K. M., Martinez, S. & Rubenstein, J. L. R. Early neocortical regionalization in the absence of thalamic innervation. Science 285, 906–909 (1999).

  46. 46

    Crair, M. C., Gillespie, D. C. & Stryker, M. P. The role of visual experience in the development of columns in cat visual cortex. Science 279, 566–570 (1998).

  47. 47

    Crowley, J. C. & Katz, L. C. Development of ocular dominance columns in the absence of retinal input. Nat. Neurosci. 2, 1125–1130 (1999).

  48. 48

    Winslow, J. W. et al. Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation. Neuron 14, 973–981 (1995).

  49. 49

    Wong-Riley, M. Changes in the visual system of monocularly sutured or enucleated cats demonstrable with cytochrome oxidase histochemistry. Brain Res. 171, 11–28 (1979).

  50. 50

    Schlaggar, B. L., De Carlos, J. A. & O'Leary, D. D. M. Acetylcholinesterase as an early marker of the differentiation of dorsal thalamus in embryonic rats. Dev. Brain Res. 75, 19–30 (1993).

Download references

Acknowledgements

We thank David Feldheim, Michael Hansen, Verne Caviness, David Van Vactor, Rick Born, Gerard Dallal, Sonal Jhaveri, Clay Reid and Michael Belliveau for help and advice. This work was supported by grants from the US NIH and NSF, the Swedish MRC, the Klingenstein foundation, the NATO/Belgian-American Educational Foundation and the Belgian FNRS.

Author information

Correspondence to John G. Flanagan.

Rights and permissions

Reprints and Permissions

About this article

Further reading