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Target recognition and visual maps in the thalamus of achiasmatic mutant dogs

Robert W. Williams, Dale Hogan, and Preston E. Garraghty
Department of Anatomy and Neurobiology, University of Tennessee School of Medicine, 875 Monroe Avenue, Memphis, Tennessee 38163, USA, and Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana 47405, USA
 

Nature 367:637-639

            
brainVision in vertebrates is dependent on ordered neuronal representations or maps of visual space. These maps depend on precise connections between retinal axons and their target cells. In mammals, nerve fibers from right and left eyes produce congruent maps of the contralateral visual space in adjacent layers of the dorsal lateral geniculate nucleus (LGN) (1). We have identified an autosomal recessive mutation in Belgian sheepdogs (2,3) that eliminates the optic chiasm. In these mutants, all retinal axons project into the ipsilateral optic tract, including those originating in the nasal hemiretina that normally cross midline. These animals exhibiyt a pronounced horizontal nystagmus. (4,5). The abnormal ipsilaterally directed nasal fibers innervate the LGN as if they had successfully crossed midline. As a consequence, the LGN contains non-congruent, mirror-image maps of visual space in adjacent layers A and A1 that are aligned in mirror-image fashion. These results show that there is a robust affinity between nasal and temporal retinal axons and specific LGN layers even when all retinal axons originate from a single eye.

 


Link to companion News and Views article by R.W. Guillery


Other than the elimination of the optic chiasm, no other midline abnormalities are evident in mutant dogs. In seven of eight cses, the crossed component of the optic chiasm is absent (Fig 1B). The optic nerves fail to approach midline, and maintain a separation of 5 to 8 mm as they enter the thalamus and midbrain. In one animal (M2), a small contralateral retinal projection was apparent (Hogan and Williams, 1995).

The shape and lamination pattern of the LGN in the normal dog resembles that of other carnivores. In comparison to the cat, the central field representatin in the dog is positioned more rostrally, and the caudal, vertically oriented limb of the nucleus is more prominent (Figu 2a) (1,6). The LGN of the mutant dogs closely resembles that of normal dogs (Fig 2b). A prominent interlaminar zone separates layers A and A1 through the central part of the nucleus. In contrast to normal dogs, the interlaminar zone does not extend to the rostromedial border of the nucleus. In this area, which represents central visual fields, layers A and A1 are fused (Fig. 2b, c). Upper visual fields are located caudomedially, and lower visual fields are located rostrolaterally in the LGN of both normal and mutant dogs. As in other carnivores (7), receptive fields recorded from neighbouring segments of layers A and A1 in normal dogs view the same area of contralateral visual space.

In mutants, as in normal dogs, visual stimuli in the contralateral visual field evoked vigorous responses in layer A1 (Fig. 3). This relatively small, normal ipsilateral temporal projection is unperturbed by the aberrant ipsilateral input of nasal retina to neighbouring layer A (Figs 3, 4). In each mutant, the entire aberrant nasal projection establishes functional connections throughout ipsilateral layer A. These aberrant ipsilateral fields extended to 90-100 degrees of azimuth and included the region occupied by the contralateral monocular segment of layer A in normal dogs. The misconnection of the nasal retina leads to a severe misalignment of visual maps in layers A and A1. Within a large central segment of the mutant LGN, we repeatedly recorded abrupt reversals in receptive field azimuth (Fig. 3, curved arrows). The size of these reversals varied systematically with the mediolateral position of the penetration. In the rostral and medial part of the LGN, small jumps in azimuth were observed. In the caudal and lateral LGN, jumps in azimuth of as much as 35 degrees were encountered (Fig. 3). These reversals across the vertical meridian representations were later correlated with the border between A and A1.

The achiasmatic Belgian sheepdog is the first mutant vertebrate in which the size of the ipsilateral retinal projection is increased. Interestingly, achiasmatic humans have also been described recently (8). The achiasmatic mutation has an effect opposite to that produced by albinism, which increases the size of the contralateral projection. However, the achiasmatic mutation is not a simple anti-albino. In albinism, the line of decussation is shifted toward the temporal edge of the retina and there is almost invariably a residual uncrossed projection from the far temporal retina (9,13). In contrast, in achiasmatic dogs, the phenotype is more extreme and there is usually no residual crossed projection. Although the misrouting of axons in mutant dogs has an opposite patterns to that seen in albinos, the fundamental mapping errors are reminiscent of those observd in the LGN of Siamese cats and albino ferrets (14-17).

The novel pattern of misrouting of retinal fibers in achiasmatic mutants provides a challenging natural experiment that can be used to study processes responsible for generating visual maps and LGN lamination (Fig. 4). In the achiasmatic dog, a single retina innervates a structure that normally receives input from two retinae. A single input that projects to a single nucleus might be expected to produce a single map in an unlaminated nucleus. This is a pattern found in the LGN after unilateral enucleation early in development (18-20) (Fig. 4d) and also found normally in another retinal target—the superior colliculus (21). In fact, the LGN of mutants is laminated and nasal reintal fibres terminate in ipsilateral layer A with the same anatomical polarity normally seen in the contralateral LGN—the central nasalpart of retina projects into the rostral and medial part of the LGN and the peripheral nasal part of the retina projects inot the caudal and lateral part of the nucleus. As these fibres have not corssed midline, the physiological poloarity of the projection is reversed, both with respect to that in normal dogs and with respect to that in the relatively normal layer A1 of mutant dogs. This results in mirror-image maps in layers A and A1 that cover the entire visual space and which are congruent only at the representation of the vertical meridian (Fig. 4b). It is possible that the vertical meridian is duplicated in A and A1 and that thesee layers contain independent, but fused map. It is also possible that there is a single map wrapped around on itself at the vertical meridian representation. The well-ordered mirror-image maps in the mutant LGN indicate that genes that control the crossing of retinal axons at the chiasm differ from those that regulate the formation of maps in the LGN.

Despite its monocular innervation, three relatively normal characteristics of the mutant LGN are surprising. It is not obvious why the so-called binocular segment of layers A and A1 would be preserved in mutants (Fig. 2), why nearly symmetrical receptive field positions would be recorded across the A/A1 border (Fig. 3), or why the point at which the layers are fused would correspond to the vertical meridian. All three features can be explained if positional specificity between retinal axons and LGN cells is rigidly preserved, despite the misrouting of nasal axons at the chiasm. The preservation of target recognition in mutants most probably reflects a fixed chemoaffinity between subsets of retinal axons and LGN neurons (22, 24). This mutation shows that the selection of a target site in the LGN is not controlled by the eye of origin (namely, ipsilateral or contralateral), but rather that the criticial factors are the retinal position from which axons originate and positional specifity within the LGN.

 

ACKNOWLEDGEMENTS. This work was supported by NIH and the National Eye Institute. Our thanks to A. de LaHunta and J. Cummings and M. Young for their help in starting this project. We thank B. Belton and T. Mandrell for animal care; T. Kimble for technical help; J. Kaas for sharing his facilities at Vanderbilt University with us, and N. Berman, E. Geisert, L. Dell'Osso, and D. Goldowitz for discussion.

References

    Kaas, J. H., Guillery, R. W. & Allman, J. M. Brain Behav. Evol 6, 253-299 (1972).

  1. Williams, R.W., Garraghty, P.E. & Goldowitz, D. Soc. Neurosci. Abstr. 17, 187 (1991).
  2. Hogan, D., Garraghty, P. E., & Williams R. W. Soc. Neurosci. Abstr. 19, 524 (1993).
  3. Dell'Osso, L.F. Curr. Neuro. Ophthalmol. 1, 139-172 (1988).
  4. Williams, R.W. & Dell'Osso, L.F. Invest. Ophthalmol. Vis. Sci. 34, 1125 (1993).
  5. Rioch, D.M. J. comp. Neurol. 49, 1-119 (1929).
  6. Sanderson, K.J. J. comp. Neurol. 143, 101-118 (1971).
  7. Apkarian, P., Barth, P.G., Wenniger-Prick, L. & Bour, Eur. J. Neurosci. XX, XX-XX (1994).
  8. Guillery, R.W. Trends in Neurosci. 9, 364-367 (1986).
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  10. Cooper M.L. & Pettigrew, J.D. J. Comp. Neurol. 187, 313-348 (1979).
  11. Leventhal, A.G. & Creel, D.J. J. Neurosci. 5, 795-807 (1985).
  12. Balkema, G.W. & Drager U.C. Vis. Neurosci. 4, 595-604 (1990).
  13. Hubel, D.H & Wiesel, T.N. J. Physiol. 218, 33-62 (1971).
  14. Guillery, R.W. & Kaas, J.H. J. comp. Neurol. 143, 73-00 (1971).
  15. Huang, K. & Guillery, R.W. Dev. Brain Res. 20, 213-220 (1985).
  16. Gulliery R.W., Lamantia, A.S., Robson, J.A. & Huang, K. J. Neurosci. 5, 1370-1379 (1985).
  17. Rakic, P. Science 214, 928-931 (1981).
  18. Chalupa, L.M. & Williams, R.W. Human Neurobiol. 3, 103-107 (1984).
  19. Garraghty, P.E., Shatz, C.J. & Sur, M. Vis. Neurosci. 1, 93-102 (1988).
  20. Berman, N. & Cynader, M. J. Physiol. 224, 363-389 (1972).
  21. Walsh, C., Polley, E.H., Hickey, T.L. & Guillery, R.W. Nature 302, 611\0xD0614 (1983).
  22. Sperry, R.W. Proc. natl. Acad. Sci. USA 50, 703-710 (1963).
  23. Bonhoeffer, F. & Huf, F. Nature 315, 409—410 (1985).

Legends

Figure 1. Ventral views of Belgian sheepdog brains showing the normal (A) and mutant achiasmatic phenotypes (case M3) (B). A. In the normal dog, the two optic nerves meet at midline, and 80-85% of the retinal fibers from each nerve cross midline to enter the contralateral optic tract. B. In most mutants, the chiasm is eliminated entirely, and all fibers extend into the ipsilateral tract. The minimum distance separated the two retinal projections is about 5 mm. The arrowhead points to the lamina terminalis of case M3. This structure is normally covered ventrally by the optic chiasm. The pituitary has been removed in B, exposing the floor of the third ventricle at the midline. Scale bar = 5 mm.

Figure 2. Lamination of the LGN in normal and achiasmatic mutant dogs. A. In this parasagittal plane, the A layer of the LGN of a normal dog appears S-shaped, with its caudal (left) and rostral (right) parts wrapping dorsally and ventrally, respectively. Layer A1 is separated from layer A by a cell-sparse interlaminar zone. The magnocellular C layer (Cm) follows the S-shape caudally and extends beneath both layers A and A1 in the rostral, binocular portion of the nucleus. Unlike cats, there is no interlaminar zone between layer Cm and layer A1 in the dog (8). The parvicellular C layers (Cp) are located in the most caudal and ventral portions of the LGN. These layers are thinner than Cm and are separated from Cm by a narrow interlaminar zone. B. Parasagittal section through the LGN of mutant M3. The overall shape and size of the nucleus is similar to that of normal dogs. However, the interlaminar zone between layers A and A1 is only present in the mid and caudal portions of the nucleus. In the rostral LGN, layers A and A1 are tightly apposed or fused in the mutant. Similar lamination defects may be present in the C layers, but they are not obvious in Nissl-stained material. Cell size does not differ from that of normal animals. C. Photomicrograph of a coronal section through the LGN of mutant M1. Fusion of A and A1 is evident on the medial (left) side of the nucleus. The asterisk indicates the location of an electrolytic lesion made along penetration P6 at the junction of A1 with Cm, and corresponds in position to the double asterisk in Figure 3. Scale bar on each photomicrograph equals 1 mm.

Figure 3. Receptive field discontinuities in the achiasmatic mutant. These data are taken from case M1. Note the large receptive field discontinuities (long curved arrows) along each of three penetrations through the LGN (P6\0xD0P8). The large, nearly symmetrical shifts in azimuth across the vertical meridian representation (VM) is larger in the more lateral penetrations (P7 and P8). Electrolytic lesions (*) were used to verify that the jumps occurred at the borders between layers. Double asterisk marks a lesion along P6 that is also marked in Fig. 2C. Penetrations P7 and P8 were so far caudal in the LGN that the electrode initially traversed layer A1, before finally entering layer A. In contrast, more rostral penetrations initially traversed layer A and then passed into A1. The most lateral penetration (P5) extended through the far peripheral representation that would represent the monocular segment of the LGN in a normal dog. The progression of fields from high to low elevation is normal, and is caused by the dorsoventral orientation of geniculate layers. Small inset is a schematic plan view of the four electrode penetrations. (HM, the approximate horizontal meridian representation; VM, the approximate vertical meridian representation).

METHODS. We recorded from three mutant dogs ranging in age from 3 months to 1 year (M1, M2 and M3; 5\0xD022 kg). As controls, we recorded from one behaviorally normal Belgian and three normal adult mongrels (8-24 kg). Dogs were sedated with ketamine hydrochloride (7 mg/kg) and xylazine (0.4 mg/kg). Anesthesia was induced with sodium pentobarbital (15\0xD020 mg/kg). During the course of the experiments, anesthesia was maintained by infusing sodium pentobarbital (3 mg/kg/hr). Paralytic agents were not used. Heart rate was monitored. The eyes were protected with contact lenses, stabilized by suturing to eye rings, and focused on a tangent screen 57 cm from the dogs' eyes. A craniotomy was made over the thalamus. Low-impedance tungsten microelectrodes (1 MOhm) were used to record from visually responsive cells in the LGN. Whenever possible, receptive fields were plotted every 100\0xD0200 um along penetrations through the LGN, and small electrolytic lesions were made to facilitate electrode track identification and reconstruction. At the conclusion of the experiment, animals were given an overdose of pentobarbital (30\0xD040 mg/kg, i.v.) and perfused transcardially with fixative. The brain, eyes, and optic nerves were dissected free from the cranium. Brains were sectioned at 50 um on a freezing microtome and stained with cresyl violet.

Figure 4. Simple schemes of lamination and the representation of visual space in layers A and A1 of the carnivore LGN. The horizontal meridian of the visual field is represented as a numbered semicircle. In the schematics of the right LGN, the dark areas represent abnormal representations of the ipsilateral visual field A. The pattern of lamination, retinotopy, and visuotopy of normal dogs is comparable to that seen in other carnivores. The area of contralateral visual space viewed by the two eyes are aligned in precise register across layers A and A1. B. The achiasmatic pattern in which the entire ipsilateral hemifield (numbers on dark blocks) is represented in layer A. These ipsilateral fields in layer A are out of register with the contralateral fields in layer A1. C. The common pattern in the LGN of Siamese cat and albino ferret in which lamination abnormality affects only the medial part of layer A1. D. The pattern following prenatal or early postnatal enucleation in carnivores (13, 19). Contralateral to the remaining eye, layers A and A1 have formed a composite layer A/A1.

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