NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Kolb H, Fernandez E, Nelson R, editors. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-.

Cover of Webvision

Webvision: The Organization of the Retina and Visual System [Internet].

Show details

Regeneration in the Visual System of Adult Mammals

and .

Created: ; Last Update: June 21, 2007.

Introduction

"...once development was ended, the founts of growth and regeneration of the axons and dendrites dried up irrevocably. In adult centres the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree. Inspired with high ideals, it must work to impede or moderate gradual decay of neurons, to overcome the almost invincible rigidity of their connections, and to re-establish normal nerve paths, when disease has severed centres that were intimately associated." (Santiago Ramon y Cajal, 1913-14).

Over 90 years after Ramon y Cajal's farsighted work (1) (Fig. 1), we are still unable to solve the great mystery of regeneration in the adult mammalian central nervous system (CNS). Retinal degeneration leading to loss of photoreceptors and retinal ganglion cells (RGCs) is still largely untreatable, although recent experimental work is beginning to provide possible solutions to these devastating conditions. Other untreatable pathologies leading to loss of sight involve lesions to the CNS visual centers or projection pathways. There are two fundamental experimental approaches presently used to tackle both these problems. One involves reconstructing lost circuitry by replacement with (usually fetal) neuronal tissue, and the other is attempting to slow the rate of the degeneration.

Figure 1. Santiago Ramon y Cajal at work.

Figure 1

Santiago Ramon y Cajal at work. From the Cajal Institute (http://www.cajal.csic.es/).

Reconstruction of Primary Visual Pathways

Without any experimental intervention, nerve lesions in the adult CNS of mammals produce only a limited and brief period of abortive sprouting and then to the death of axotomized neurons. In sharp contrast, the peripheral nervous system (PNS) and the immature CNS of mammals, as well as the mature CNS of cold-blooded vertebrates, all display varying levels of successful spontaneous regeneration after injury. The development of experimental repair strategies has relied on lessons learned from these systems. Combined with advances in anatomical tracing and immunohistochemical methods, these strategies have revealed the surprising capacity for regeneration and synapse formation in the adult mammalian CNS. For instance, Dr. Albert Aguayo and colleagues have used an experimental approach (2-4) based on the concept that regeneration in the PNS is dependent on the permissive environment provided by Schwann cells present in the nerve tube. They suggested that the absence of this permissive environment in the mature CNS was the reason for failure of regeneration. Thus, they postulate that damaged neurons from the mature CNS might be able to regenerate axons if placed in close proximity to Schwann cells. In fact, this hypothesis was suggested by Ramon y Cajal (1) over a century ago and was later tested by Tello in 1907 (5) (Fig. 2) in a series of experiments on rabbits. There was a suggestion that retinal axons could regenerate after axotomy if the cut optic nerve end was anastomosed to a sciatic nerve graft (5). The lack of anatomical tracers at that time did not allow us to see whether such regenerating axons were indeed of CNS origin, namely from RGCs. The indisputable proof that some CNS neurons do have this regenerative potential had to wait until specific axonal tracing techniques became available in the late 1970s (6, 7). Further work applied to primary visual pathways showed that if directed into the brain (Fig. 3), regenerating RGC axons were able to re-establish connections in visual centers of the brainstem (4). These connections appeared capable of transmitting visual information (8, 9).

Figure 2. Sciatic nerve graft (B) anastomosed on the optic nerve stump (A) in an adult rabbit.

Figure 2

Sciatic nerve graft (B) anastomosed on the optic nerve stump (A) in an adult rabbit. Axons can be seen to cross the anastomosis site (D). A scar has formed at the anastomosis site (C). Letters in lowercase indicate a vein in the optic nerve (a), "neurilema" (more...)

Figure 3. Schematic of peripheral nerve graft bridging the retinofugal pathways.

Figure 3

Schematic of peripheral nerve graft bridging the retinofugal pathways. A, normal optic pathway projecting to superior colliculus (SC), pretectum (PT), and dorsal lateral geniculate nucleus (dLGN). B, regeneration of optic axons through a peripheral nerve (more...)

The concept that neural regeneration depends on a permissive environment does not alone explain why most mature mammalian CNS neurons do not regenerate an axon. For instance, in the absence of axonal myelin-associated growth inhibitors such as Nogo, axonal sprouting itself is not improved (10). The role of axonal growth inhibitors in axonal regeneration remains a controversial issue (11). When developing experimental strategies, other factors have to be considered, such as axotomy-induced cell death and secondary degeneration (12), scar formation (13), and factors intrinsic to neurons themselves. We know that most CNS neurons loose their capacity for axonal regeneration at a specific point in early development, even before myelination (14-16).

The abundant and diverse experiments directed at reconstructing visual circuitry (several will be discussed below) have all uncovered a range of difficulties, such as: 1) establishing a permissive interface between sprouting and/or regenerating axons, or between graft and host; 2) providing the optimal conditions for appropriately directed axon outgrowth; 3) achieving sufficient amount of axon outgrowth for proper function; and 4) limiting or controlling the local neural responses to initial injury, such as cell death, which may in itself mitigate against effective recovery. A central point to all such work is that visual function should be used as the yardstick for success (see Generation of Action Potentials in Target Neurons).

Requirements for Recovery of Function following Lesions of CNS Pathways

The recovery of lost function following axonal interruption in any neuronal system depends on the fulfillment of the following prerequisites:

  • survival of axotomized neurons and prevention of secondary degeneration
  • axonal extension of the neurons surviving axotomy
  • guidance of regenerating axons toward their appropriate target(s)
  • target innervation and synapse formation onto recipient neurons
  • supra-threshold activation in target neurons caused by regenerated afferents
  • restoration of ordered functional connections
  • preservation of local and downstream circuitry

The retinocollicular pathway is particularly suitable for addressing the above-mentioned points for at least three reasons: 1) RGC axons project to the superior colliculus (SC) through the optic nerve, which can be easily lesioned, replaced, and anatomically traced; 2) because RGCs are excited by light, they can be selectively stimulated in a physiological manner without the use of less selective electrical pulses, which would concomitantly excite other pathways; 3) intact RGC axons arborize preferentially in the superficial layers of the SC, onto which they form a point-to-point representation of the retina (17-19) and which allows comparison of the regenerated pathway with those intact, using either morphological or physiological approaches.

We will review the extent to which these requirements can be achieved by using the example of the interrupted retinocollicular pathway and attempts for reconstruction using PN grafts replacing the optic nerve. In brief, the potential for regeneration of optic axons after being damaged was first indicated by studying hamsters in which the optic nerve was cut and a peripheral nerve graft placed in association with the retinal optic fiber layer (3) (Fig. 3). Optic axons grew into this nerve graft, and studies in cat, in this instance, showed that the major classes characterized, both anatomically and physiologically, contribute to this regenerative growth (20). Subsequent experiments (21) refined the approach and were able to show that up to 10% or so of the normal optic projection was able to regenerate into the nerve graft. If the other end of the nerve graft was placed in an appropriate brain region, a proportion of these axons could reach regions normally innervated by them (4, 22). If the central stump was placed in close proximity to a visual center, the axons formed terminal ramifications and synapses within that region (23). If placed at a distance from a visual center, axons were able to grow as much as 6 mm through the brainstem to specific targets of optic input, ignoring in the process other brain regions, including ones that had lost their primary input during the surgical procedure (22). Although an anatomical study of topological representation of the regenerated axons has not been done, physiological experiments (24) have indicated that although the precise map encountered in the normal retinotectal projection was not seen, there was indication of a tendency for the naso-temporal representation of the visual field to be appropriately arrayed along the rostrocaudal SC axis. Whether this would be sufficient for an animal to be able to perform a behavior requiring topographically encoded information, such as head tracking, is not clear. The further possibility that some sort of training regimen might improve the tightness of the map has not been explored either, but this preparation does lend itself to such exploration.

Promoting the Survival of Axotomized RGCs

RGCs Die after Optic Nerve Transection

After a complete intraorbital lesion of the adult mammalian optic nerve, the majority of RGCs are lost within 2 weeks (21, 25-27). Axotomized RGCs start dying after 1 week post-lesion, via programmed cell death. This process, known as apoptosis, is also responsible for the naturally occurring cell death of RGCs during development. Cells undergoing apoptosis, such as axotomized RGCs, are characterized by the condensation of their nucleus, DNA fragmentation, and the formation of apoptotic bodies (25, 28). The pathways responsible for the apoptotic death of axotomized RGCs involve the activation of caspases types 3, 8, 9, and CPP32-like (29-33), and the p38 mitogen-activated protein kinase p38MAPK (34). The inhibition of either or all of these caspases (30, 32, 35, 36) or of p38MAPK (34) enhances the survival of axotomized RGCs. Furthermore, optic nerve transection leads to the elevation of proapoptotic protein Bax and the decrease of the antiapoptotic proteins Bcl-2 and Bcl-X (37). The overexpression of Bcl-2 in transgenic mice has been shown to protect RGCs for axotomy-induced death (38, 39). Finally, transfection of RGCs with the X-linked inhibitor of apoptosis or with the caspase inhibitor p35 can both protect RGCs from axotomy-induced cell death (40). The conclusion from these findings is that axotomy-induced death of RGCs involves the activation of not only one but several apoptotic pathways. Therefore, strategies aimed at preventing the death of axotomized RGCs would have to target multiple pathways.

Strategies to Prevent the Death of Axotomized RGCs

Most strategies developed to prevent RGC death involve the supply of various trophic factors either exogenously, through cell-based therapy, or via gene transfection (for reviews, see Yip and So (41), Cui et al (42), Weishaupt and Bahr (43), and Koeberle and Bahr (44)). The rationale for supplying neurotrophins to axotomized RGCs is that their death might be related to the loss of retrogradely supplied trophic factors, such as brain-derived neurotrophic factor (BDNF), from their targets in the SC (45-47). Axotomized RGCs can be rescued by experimentally supplying the retina with BDNF, either via intravitreal injections (26, 48-50) or via gene transfection of retinal cells (51). Furthermore, transfection of retinal cells with the high-affinity BDNF receptor TrkB also enhances the survival of axotomized RGCs (52). Axotomized RGCs have also been rescued by the experimental addition of several other neurotrophic factors (some of which having additive effects with each other): neurotrophin NT-4/5 (26, 53); NGF (54); GDNF (55, 56); Neurturin (57); and CNTF (50, 58-60). Several growth factors mediate their action by binding to their specific receptors and activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositide-3-kinase (PI3K) transduction cascade pathways. For details on secondary messengers and factors interfering with these cascades, see reviews by Kaplan and Miller (61), Patapoutian and Reichardt (62), and Koeberle and Bahr (44). In brief, neurotrophic factors may prevent axotomy-induced RGC death by interfering with caspase pathways and by promoting the expression of pro-survival genes.

The neurotrophic factors tested to date for their survival effect on axotomized RGCs all have only short-term effects, suggesting that trophic withdrawal is not the only trigger for the apoptosis of axotomized RGCs. Blockade of axonal transport (63) has minimal effects on the death of RGCs in neonatal rats. Other factors have been identified, among them, the up-regulation of inducible nitric oxide synthase (iNOS) by Muller cells after RGC axotomy (64). Inhibition of NOS has been shown to promote the survival of axotomized RGCs (64), and when done in combination with BDNF, it potentiates the effect of this neurotrophin (48). Modulation of microglial cells and macrophage activity has also been shown to have an effect on the survival of axotomized RGCs (65-67).

Finally, the prevention of axotomy-induced RGC death has been explored using a vaccination approach known as "protective autoimmunity" (for a review, see Schwartz (68)). Dr. Michal Schwartz and colleagues recently demonstrated that T cells specific to self-proteins residing in the site of the CNS insult can be neuroprotective. With the aim of boosting autoimmunity for neuroprotection without risking the induction of an autoimmune disease, Dr. Schwartz's group has developed the use of Cop-1 (an FDA-approved drug for the treatment of multiple sclerosis) as an active vaccination for neuroprotection. This approach is currently under investigation as a potential preventive treatment for glaucoma.

Promoting the Growth of Axotomized RGC Axons

Anastomosis of a PN graft onto the optic nerve stump has been shown to have a survival effect on RGCs (21, 69) as well as acting as an environment permissive to RGC axonal regeneration (3, 4). A maximum of 10% of the total RGC population in rodents (10,000 of 100,000 in rats and hamsters) (Fig. 4a, Fig. 4b, Fig. 4c) can regenerate an axon as far as the distal end of an autologous PN graft, covering a distance of up to 2.5 cm. This allows them to reach areas of the primary visual targets, such as the contralateral superior colliculus. The RGCs that have regenerated an axon along the PN graft appear to survive longer than the RGCs that have failed to do so (21). Whether some RGCs have intrinsic survival or axonal regenerative capacities or whether some RGCs simply randomly succeed to regenerate an axon by chance (for instance, proximity to the PN graft stump before retrograde degeneration beyond the optic disc) remains to be clarified.

Figure 4a. Demonstration of hamster RGC axonal regeneration in PN grafts.

Figure 4a

Demonstration of hamster RGC axonal regeneration in PN grafts. Photomicrographic montage of a flattened retinal whole-mount from an animal with a PN graft attached to the ON. The montages were prepared from 24 overlapping photographs printed at a magnification (more...)

Figure 4b. Same retina as in A, incubated with the monoclonal antibody, RT 97, the immunofluorescent axons of retinal ganglion cells converge toward the central optic disk.

Figure 4b

Same retina as in A, incubated with the monoclonal antibody, RT 97, the immunofluorescent axons of retinal ganglion cells converge toward the central optic disk.

Figure 4c. Diagram, drawn from a photographic montage of a flattened retinal whole-mount from a different retina, indicating the location of 9451 neurons (dots) retrogradely labeled with HRP applied to the unconnected, extracranial end of the graft.

Figure 4c

Diagram, drawn from a photographic montage of a flattened retinal whole-mount from a different retina, indicating the location of 9451 neurons (dots) retrogradely labeled with HRP applied to the unconnected, extracranial end of the graft. The montage (more...)

The promotion of RGC axonal regeneration seems to involve different mechanisms than the ones promoting their axonal extension: most trophic factors shown to promote RGC survival fail to promote their axonal regeneration. The discovery of new candidate molecules promoting axonal extension comes in part from the observation that lens scratching induces the production of low molecular weight molecules that can promote both RGC survival and axonal regeneration within the intracranially lesioned optic nerve (70). Furthermore, macrophage stimulation, which is associated with the release of similarly acting molecules (71) can also promote RGC axonal extension within the lesioned optic nerve. The neutralization of myelin-associated growth inhibitors can promote RGC axonal regeneration within lesioned optic nerves, but only if RGCs are in an "active growth state", such as stimulated by the small molecules mentioned above (72).

The ability of RGCs to regenerate an axon does not only depend on their environment but also on their intrinsic state. As mentioned in the introduction, most CNS neurons such as RGCs appear to loose their capacity for axonal regeneration during maturation (15, 16). Some recent experimental manipulations have showed that it might be possible to reverse, at least to some extent, this state. Dr Lisa McKerracher and colleagues have shown that inactivation of the small GTPase Rho can promote RGC axonal regeneration after micro-lesions of the optic nerve in adult rats (for a review, see Ellezam et al. (73). Another approach, investigated by Dr. Mary Filbin and colleagues, involves elevating the intracellular level of cyclic AMP in neurons (74) (for a review, see Spencer and Filbin (75)).

Guidance of Regenerating RGC Axons Toward Their Appropriate Target

On the basis of what we know about developmental events, the challenges for regenerating RGC axons to successfully reach their appropriate targets are severe. First, as during development (for a review, see Oster et al. (76)), regenerating axons have to navigate within the retina, find their way to the optic disc, exit it, and finally enter into the optic nerve. After PN grafting (anastomosed on the intraorbitally cut optic nerve stump) combined with intravitreal BDNF (to increase the survival of axotomized RGCs), a minority of RGC axons do successfully regenerate an axon into a peripheral nerve graft. However, many regenerating RGC axons never actually exit the optic disc (77). Several axons from surviving RGCs appear to turn sharply just before the optic disc, growing in the opposite direction, forming numerous collateral branches and loops, with erratic growing patterns (Fig. 5).

Figure 5. Camera lucida drawings of neurobiotin-labeled RGC axons in flat-mounted retinas 2 weeks after optic nerve (ON) transection alone (A) or with the intravitreal administration of BDNF (B) or NT-3 (C) at the time of transection.

Figure 5

Camera lucida drawings of neurobiotin-labeled RGC axons in flat-mounted retinas 2 weeks after optic nerve (ON) transection alone (A) or with the intravitreal administration of BDNF (B) or NT-3 (C) at the time of transection. The broken lines indicate (more...)

A second challenge facing the regenerating RGC axon consists of navigating across the optic chiasma by crossing or not crossing the midline, again depending on the RGC type and/or location in the retina (for a review, see Williams et al. (78)). After which, regenerating RGC axons, again depending on their types, have to extend all the way into their appropriate target(s); some individual RGCs even have to send collaterals to multiple targets, such as both the SC and the dorsolateral geniculate nucleus (dLGN), and even more as shown in Fig. 6.

Figure 6. Retinal projections to the primary visual centers (white arrows) and their major links with homolateral secondary subcortical areas.

Figure 6

Retinal projections to the primary visual centers (white arrows) and their major links with homolateral secondary subcortical areas. Double arrows indicate reciprocal connectivity. For abbreviations, see later. Cortical connections are given in Fig. 28. (more...)

By using PN grafts, it has been possible to guide regenerating RGC axons into their appropriate targets such as the SC (4, 8, 9, 22, 24, 79), the dLGN (80), the pretectal nuclei (Fig. 7) (23), or deliberately into inappropriate targets such as the inferior colliculus or cerebellum (81).

Figure 7. Light micrographs of 40-μm-thick cryostat coronal sections illustrating CTB-labeled retinal axons in the pretectum 16 weeks after grafting a segment of peripheral nerve between the left retina and the lateral side of the left diencephalon.

Figure 7

Light micrographs of 40-μm-thick cryostat coronal sections illustrating CTB-labeled retinal axons in the pretectum 16 weeks after grafting a segment of peripheral nerve between the left retina and the lateral side of the left diencephalon. A, (more...)

However, in some animals following insertion of the distal end of the PN graft into a chosen target, only a minority or even none of the regenerating RGC axons can enter a target (23). In such cases, several RGC axons (anterogradely labeled with a tracer from the eye) are confined to a neuroma-like formation at the interface between the graft and the CNS target (Fig. 8).

Figure 8. Light micrographs of a 40-μm-thick cryostat coronal section illustrating retinal axons 24 weeks after connecting the left eye and the ipsilateral brainstem with a segment of peripheral nerve and 5 days after intraocular injection of CTB.

Figure 8

Light micrographs of a 40-μm-thick cryostat coronal section illustrating retinal axons 24 weeks after connecting the left eye and the ipsilateral brainstem with a segment of peripheral nerve and 5 days after intraocular injection of CTB. A, interface (more...)

The cause of the formation of the neuroma-like endings is unclear. Three main factors have to be considered: 1) glial reactions that might be associated with the lack of axonal penetration into the CNS target; 2) the presence of inhibitory molecules, which may also be responsible for the curtailed growth observed in CNS targets, and that are known to be expressed in the damaged CNS (82) and at the PNS-CNS interface (83-88); and 3) the perturbation, due to graft insertion procedure, of the tri-dimensional structure of the extracellular matrix that might act as "guiding railways" coated with molecules that have growth-inhibitory or -promoting properties such as laminin, vimentin, and chondroitin sulfate proteoglycans (CSPGs).

In some instances, PN grafts cannot be directly inserted into appropriate targets because of the small size of the nucleus. In the study of Aviles-Trigueros et al. (23), successful innervation of the olivary pretectal nucleus (OPN) and the nucleus of the optic tract (NOT) was achieved by inserting the distal end of a PN graft into the superficial aspect of the midbrain, between these two nuclei, by carefully avoiding touching them. Under such circumstances, some axons were seen crossing the midline to innervate the contralateral nuclei. This led the investigators to insert the nerves some distance further away from the nuclei. Axons, although coursing for long distances through the brainstem, still showed selectivity for optic target regions (Fig. 9, Fig. 10, Fig. 11). This occurred even though some nuclei within their trajectory were deafferented by the surgery associated with graft insertion.

Figure 9. Drawings of alternate 40-μm-thick cryostat coronal sections through the brainstem, from caudal (top left) to rostral (bottom right), of a rat 16 weeks after grafting a peripheral nerve segment between the left retina and the lateral aspect of the left diencephalon.

Figure 9

Drawings of alternate 40-μm-thick cryostat coronal sections through the brainstem, from caudal (top left) to rostral (bottom right), of a rat 16 weeks after grafting a peripheral nerve segment between the left retina and the lateral aspect of (more...)

Figure 10. Drawings of consecutive 40-μm-thick cryostat coronal sections through the brainstem, from caudal (top left) to rostral (bottom right), of a rat 46 weeks after grafting a peripheral nerve segment between the left retina and the dorsal aspect of the left midbrain between the OPN and NOT.

Figure 10

Drawings of consecutive 40-μm-thick cryostat coronal sections through the brainstem, from caudal (top left) to rostral (bottom right), of a rat 46 weeks after grafting a peripheral nerve segment between the left retina and the dorsal aspect of (more...)

Figure 11. Light micrographs of 40-μm-thick cryostat coronal sections illustrating regenerated retinal fibers in the pretectum 46 weeks after grafting a segment of peripheral nerve between the left retina and the dorsal aspect of the left midbrain between the OPN and NOT and 5 days after intraocular injection of CTB.

Figure 11

Light micrographs of 40-μm-thick cryostat coronal sections illustrating regenerated retinal fibers in the pretectum 46 weeks after grafting a segment of peripheral nerve between the left retina and the dorsal aspect of the left midbrain between (more...)

The specificity of innervation of visual and non-visual targets would appear to be at odds with the observation of Zwimpfer et al. (81) showing innervation of the cerebellum by optic axons regenerating through PN grafts. There is, however, a significant difference in experimental design in that in the study of Aviles-Trigueros et al. (23), the axons have a "choice" of optic or non-optic targets, whereas in the cerebellum study, no choice is available. To complicate the issue, there is evidence that when two of the principal targets of retinofugal axons, the SC and dLGN, are ablated in newborn hamsters and the somatosensory (ventrobasal) or auditory (medial geniculate) thalamic nuclei are partially deafferented, the optic axons form permanent, abnormal connections in the latter nuclei (89). The mechanisms responsible for "apparent" preference of appropriate target in studies such as by Aviles-Trigueros et al. (23) are still unclear.

In addition to PN grafting, several studies have reported successful RGC axonal regeneration within the severed optic nerve (70, 73, 90-93). However, it remains unclear as to what is the growth pattern of individual regenerating RGC axons, especially at the level of the optic chiasm, and distally.

Arborization and Synapse Formation by RGC Axons Regenerating into Their CNS Targets

Studies involving PN grafting to bridge the retinofugal pathways have shown that regenerating RGC axons can form distinct arborizations in the target which they reinnervate (4, 23, 94, 95). The study of Aviles-Trigueros et al. (23) suggests that regenerated retinal axons adopt distinctive patterns of terminal arborizations, depending on the target they reinnervate. For instance, while axons entering the OPN show little ramification and swellings reminiscent of the typical retinal innervation of this nucleus, in the NOT axons tend to show more profuse ramifications and arborizations with terminal swellings (Fig. 12 and Fig. 13).

Figure 12. Drawings of retinal fibers 46 weeks after grafting a segment of peripheral nerve between the left retina and the dorsal aspect of the left midbrain between the OPN and NOT and 5 days after intraocular injection of CTB.

Figure 12

Drawings of retinal fibers 46 weeks after grafting a segment of peripheral nerve between the left retina and the dorsal aspect of the left midbrain between the OPN and NOT and 5 days after intraocular injection of CTB. A, retinal fibers divide into fine (more...)

Figure 13. Light micrograph of a 40-μm-thick cryostat coronal section of the midbrain illustrating retinal fibers in the superficial gray 40 weeks after grafting a peripheral nerve segment between the left eye and the lateral aspect of the ipsilateral SC and 5 days after intraocular injection of CTB.

Figure 13

Light micrograph of a 40-μm-thick cryostat coronal section of the midbrain illustrating retinal fibers in the superficial gray 40 weeks after grafting a peripheral nerve segment between the left eye and the lateral aspect of the ipsilateral SC (more...)

These types of terminals are reminiscent of the terminals previously described for such retinorecipient nuclei in another rodent (96). In this context, what is also remarkable, is the similarity of the morphology of the elaborate arborizations found in the superficial layers of the superior colliculus (Fig. 14) with that described in normal animals (96). This indicates further specificity of terminal arborization within the retinorecipient reinnervated target. Thus, it appears that the morphology of the arborization is dictated by the recipient region, more than by the type of retinal fiber arriving to target (80), and that regenerating axons modify their arbors to adapt to the local conditions of the target nucleus.

Figure 14. Light micrographs and drawing illustrating regenerated retinal fibers in the stratum griseum superficiale of 40-μm-thick cryostat sections of the midbrain 48 weeks after grafting a segment of PN between the left eye and the lateral side of the ipsilateral SC and 5 days after intraocular injection of CTB.

Figure 14

Light micrographs and drawing illustrating regenerated retinal fibers in the stratum griseum superficiale of 40-μm-thick cryostat sections of the midbrain 48 weeks after grafting a segment of PN between the left eye and the lateral side of the (more...)

In 1987, Vidal-Sanz et al. (4) provided experimental evidence that regenerating RGC axons were able to re-establish connections in visual centers of the brainstem (Fig. 15). These connections appear to persist for the life span of the rodent, i.e., up to 2 years of age (97). The type of synaptic contacts formed, the ratios of contacts to terminal perimeter, and the domains of the postsynaptic neurons contacted are similar to those of intact retinofugal pathways (22). Therefore, regenerated RGC axons can establish well-differentiated synapses with neurons in the SC. On the basis of their results, Carter et al. (22) concluded that, "The synaptic differentiation attained by such reformed retinocollicular projections suggests that regenerating CNS axons and their target neurons in the adult mammalian brain may retain or reexpress certain molecular determinants of normal connectivity". There are, however, morphological differences between the regenerated and control synapses: 1) larger size of some regenerated terminals; 2) greater mean length of the regenerated synapses; and 3) higher proportion of contacts with dendrites that contain vesicles in regenerated versus intact synapses.

Figure 15. Electron micrographs of presynaptic profiles in the superficial SC (strata zonale and griseum superficiale) lightly labeled with HRP injected in the PN-grafted eyes of group IIb rats.

Figure 15

Electron micrographs of presynaptic profiles in the superficial SC (strata zonale and griseum superficiale) lightly labeled with HRP injected in the PN-grafted eyes of group IIb rats. D, dendrites. The presynaptic terminals contain vesicles that are predominantly (more...)

Generation of Action Potentials in Target Neurons

Dr. Sue Keirstead and colleagues (8) provided electrophysiological evidence that the synapses, such as the ones described at the electron-microscopic level by Vidal-Sanz et al. (4), could mediate the transynaptic activation of neurons in the superior colliculus of adult mammals. Extracellular recordings in the superior colliculus, 15 to 18 weeks after PN graft insertion into the SC, revealed excitatory and inhibitory postsynaptic responses to visual stimulation of the eye that had received PN anastomosis onto its completely cut optic nerve (Fig. 16). Specific stimulation protocols (involving paired electrical stimulation of the PN graft) were used to verify that postsynaptic activity could be elicited in the reinnervated SC.

Figure 16. A, 10 successive responses to light flash (at arrow) recorded at a depth of 250 μm in the SC.

Figure 16

A, 10 successive responses to light flash (at arrow) recorded at a depth of 250 μm in the SC. The large unit responds with a single spike on 4 of 10 iterations. B, the same unit responds erratically with inconsistent latency to (traces 1) single (more...)

Additional studies by Sauve et al. (9), using the same experimental preparation, indicated that each element of a typical bursting response to light (excitatory type of response; Fig. 17) consists of a terminal potential (TP) arising from a regenerated RGC axon terminal arborization, followed by a longer duration focal synaptic potential (FSP) that is selectively blocked by GABA. FSPs are extracellular changes in potential that reflect summation of excitatory postsynaptic potentials (EPSPs) in neurons within the terminal field of the regenerated RGC axon (Fig. 18). In some instances, superimposed on these FSPs are spikes (Fig. 19), which arise after three to four consecutive closely spaced impulses from RGS (as inferred from the TPs).

Figure 17. Unitary response to static illumination of a spot 4" in diameter recorded at a depth of 190 μm in a reinnervated SC 37 weeks after graft insertion.

Figure 17

Unitary response to static illumination of a spot 4" in diameter recorded at a depth of 190 μm in a reinnervated SC 37 weeks after graft insertion. Bandpass 100 Hz to 5 kHz. From Sauve et al. (9).

Figure 18. Successive OFF responses to repetitive light stimuli every 3.

Figure 18

Successive OFF responses to repetitive light stimuli every 3.1 sec from the same unit as in Fig. 1. Traces begin 125 msec after offset of light. Band pass 10 Hz to 5 kHz. After application of GABA between traces 3 and 4, the second component of each unitary (more...)

Figure 19. Spike-like activity arising from FSPs in single sweeps in response to static illumination of a spot.

Figure 19

Spike-like activity arising from FSPs in single sweeps in response to static illumination of a spot. Recordings from units from two different animals. A, an OFF response. Depth, 200 μm. Note increase in baseline noise after closely spaced impulses (more...)

The results from Sauve et al. (9) indicate that terminal arborizations of individual regenerated RGC axons can synapse with multiple neurons in the SC and that convergence of inputs from regenerated RGC axons is not required for activation of SC neurons in response to light.

Finally, in vitro studies by Turner et al. (98) indicate that the deafferentation of the SC, caused by optic nerve cut, and a surgical approach to insert the PN graft into the SC together, lead to ultrastructural changes reflected functionally at the synaptic level in the target structure, even after potential RGC axonal regeneration. Such changes are likely to compromise the ability of the target structure to function normally during information processing. Therefore, although axons regenerating along peripheral nerve grafts can make functional synaptic connections, their efficacy in activating the target structure will probably be compromised by the local changes in synaptic connectivity.

Restoration of Retinotopy

Is Restoration of Retinotopy Needed for Recovery of Function?

Yes it is, for the appropriate execution of visually guided behaviors. We owe the proof to the 1981 Physiology Nobel Prize co-winner Dr. Roger W. Sperry (Fig. 20), who ingeniously took advantage of the spontaneous functional recovery of the retinotectal system in frogs (for a review, see Gaze (99)).

Figure 20. Photograph of Nobelist Roger Sperry.

Figure 20

Photograph of Nobelist Roger Sperry.

Sperry's impressive demonstration involved sectioning a frog's optic nerve and rotating the eye by 180° (100). After spontaneous regeneration of the retinotectal pathway, the frog's attempt to catch a prey resulted in an attack directed to the diametrically opposed direction (Fig. 21). The frog's behavior gave clues as to how the regenerating RGC axons had reconnected in the tectum. Note: the structure equivalent to SC is named "tectum" in lower vertebrates. Sperry inferred that the regenerating axons had returned to their original position in the tectum, regardless of the new position they occupied in the rotated eye. This gave experimental support for his chemo-specificity theory (100), which stipulates that "The connections are governed by intrinsic specificity of the advancing fibre tip plus that of the various cellular elements it encounters in its outgrowth" (101).

Figure 21. When the eye is rotated 180°, the frog's prey-catching behavior is inverted.

Figure 21

When the eye is rotated 180°, the frog's prey-catching behavior is inverted. After Sperry, 1956.

We can learn about the extent to which retinotopic projections have to be re-established to achieve behavioral recovery by comparing species that have various levels of regeneration of their retinotectal system and examining the level of visually guided behavior they can recover. The capacity for RGC axon regeneration in the vertebrate visual pathway is summarized in the study of Dunlop et al. (102). For instance, there is variability between various species of lizards. Some achieve a stable restoration of retinotectal organization (accompanied by restoration of visually guided behaviors), whereas others (Ctenophorus ornatus) fail to maintain a retinotopic ordering of the regenerated projection and lose their capacity to perform visually guided tasks (103). However, training on a visual task has been shown to improve the outcome of optic nerve regeneration in Ctenophorus ornatus lizards (104).

Guidance Cues in the Injured Retinotectal Pathway

The retinotectal system is the model of choice for studying the mechanisms governing the formation of ordered connections in the CNS. In intact mature rodents, axons from RGCs located in the temporal retina project to the rostral (anterior) part of the contralateral SC, whereas axons from RGCs located in the nasal retina project to the caudal (posterior) contralateral SC (17-19). Ventral RGCs project axons medially and dorsal RGCs project axons laterally in the contralateral SC (Fig. 22).

Figure 22. Ventral view schematic of retinotectal projections.

Figure 22

Ventral view schematic of retinotectal projections.

To elucidate the mechanisms involved in axonal guidance, especially with regard to specificity of polarities in the tectum, Dr. Friedrich Bonhoeffer and colleagues developed an in vitro assay, known as the "stripe assay" (105, 106). The basis of this assay involves growing retinal explants on stripes made up of tissues alternating from rostral and caudal parts of the tectum. Results using tissues from developing chicks or rodents show that temporal RGC axons avoid stripes made up of caudal tectal tissue, whereas nasal RGC axons grow equally well on either rostral or nasal tectal tissue stripes (105-108) or show a preference for nasal stripes providing specific pre-treatments (109). This preference appears to be developmentally regulated in a way that is lost in the mature system. However, Dr. Mathias Bahr and colleagues (110-112) showed that this capacity can be partially restored following optic nerve cut in adult rats. Their results indicate that guidance cues might be re-expressed in the deafferented retinotectal system of adult mammals, and that these cues might retain some level of function.

Several axonal guidance molecules and their respective receptors have been identified. Among them, the best studied compose these four classes: netrins, semaphorins, slits, and ephrins (for a review, see Koeberle and Bahr (44)). In the goldfish, in which spontaneous regeneration occurs, Eph/ephrins are upregulated as gradients at the time that topography is restored during optic nerve regeneration (113). Furthermore, the Eph/ephrin system is required to restore topography because blocking their interactions in vivo with fusion proteins results in abnormal topography (114). In rodents, in which spontaneous regeneration does not occur, most of the known guidance molecules have been shown to be modulated after deafferentation. However, although some molecules are up-regulated to levels similar to those achieved in development, some (such as the ephrin receptor EphA5 in the retina and the ephrin-B) are actually down-regulated. Therefore, it remains improbable that these various changes might actually recapitulate developmental events. How experimental manipulations might achieve such recapitulation of developmental events is, for now, a mind-boggling puzzle.

Can RGC axon regenerated through a PN graft resume topological specificity when reinnervating the superior colliculus? See an example from the study of Sauve et al. (24).

The study of Sauve et al. (24) indicates that regenerating mammalian RGC axon terminals do not form a precise retinotopic map (compared with normal intact animals; Fig. 23) when reinnervating the SC (Fig. 24).

Figure 23. A, multiunit receptive fields were recorded from the left eye of a normal hamster, plotted on a tangent screen 20 cm from the eye, and viewed from the side of the screen opposite to the animal.

Figure 23

A, multiunit receptive fields were recorded from the left eye of a normal hamster, plotted on a tangent screen 20 cm from the eye, and viewed from the side of the screen opposite to the animal. The nasotemporal axis of the eye, defined by the position (more...)

Figure 24. Positions of RGCs in the left retina and the projection sites of their respective axon terminals in the contralateral right SC of a grafted animal.

Figure 24

Positions of RGCs in the left retina and the projection sites of their respective axon terminals in the contralateral right SC of a grafted animal. Numbers refer to the recording sites in the SC. Letters indicate multiple receptive fields recorded at (more...)

However, superimposed on the apparent randomness of distribution of RGC terminals, there appears to be a small but nonetheless statistically significant tendency for these terminals to array themselves appropriately within the rostrocaudal axis of the SC. Because the PN graft tip was placed at different locations in different animals, the assessment of topography was of necessity a comparison of the relative positions of reinnervating axon terminals for each animal rather than an identification of the absolute position of each terminal. It must also must be emphasized that the method used by Sauve et al. (24) assessed terminal positions but not trajectories of regenerating RGC axons. Nonetheless, these results suggest that factor(s) may be present in the reinnervated SC, as in the newly innervated SC, that can influence the direction of axonal growth and/or the area within which arborization and synapse formation occur.

Topographic ordering of projections during normal development of retinofugal pathways is thought to reflect at least two processes: 1) an initial pathfinding to the approximately correct area directed by spatially specific molecular cues as first suggested by Sperry (115); and 2) a subsequent phase of refinement of the projection due to activity-dependent processes in which near-simultaneous firing of neighboring RGCs (for a review, see Wong (116)) serves mutually to stabilize the connections of their shared target neurons in the LGN or tectum (117-121). Initial pathfinding of RGC axons in the tectum may be very precise, as in frogs and fish (122, 123), or more exuberant and diffuse, as in rodents (166, 167). Computer simulations suggest that a combination of positional cues and activity-dependent mechanisms gives rise to a very precise retinotectal topology in a variety of experimental situations (124, 125), for example even if a molecular gradient is only transiently expressed during the initiation of innervation of the tectum (126).

During regeneration of the retinotectal pathway in frogs and fish, the initial topography is only roughly organized. Functional synapses are formed indiscriminately by regenerating goldfish RGC axons as they enter the tectum. These may be unstable if inappropriately located (127, 128). Projections become refined into a more precise retinotopic map over a period of several weeks by mechanisms that depend upon ongoing activity in neighboring RGC axons (117, 129).

In vitro experiments have shown that molecules with topological specificity with respect to the rostral and caudal tectum or SC are transiently expressed in the neonatal mammalian SC (105). These topologically specific markers disappear after the retinocollicular pathway is laid down but reappear about 2 weeks after denervation of the SC (112). Such positionally specific markers may be more strongly expressed in deafferented SC than in embryonic SC (130). The experimental results of Sauve et al. (24, 131) are consistent with the possibility that a gradient of such positionally specific markers could serve as an influence on the exploration of the SC by regenerating RGC axons (132-134), either by exerting a repulsive or tropic effect on their axonal growth cones (105, 106, 135-138), or by influencing their branching patterns (108). Positionally specific markers could also influence the deployment of regenerating RGC axons within the nerve graft as they approach the SC (139).

The question arises as to why the effects of these factor(s), if present, are so minimally expressed or so difficult to document in the reinnervated mammalian SC. In the reinnervated SC, the extent of exploration by a regenerated RGC axon is 1 mm or less (140). More extensive exploration of the SC is perhaps limited by the presence of factors inhibitory to axonal growth (141-144) that are present in the adult animal as well as by the developmental down-regulation of growth permissive molecules (145, 146) and receptors (147, 148). This is in contrast to the situation during normal development, where RGC axons from all portions of the retina initially innervate the entire SC (149, 150). In the PN graft regeneration paradigm, no more than 10% of the normal total number of RGCs usually regenerate their axons across the PN graft, and only a portion of these reinnervate the SC (4). Many axons terminate growth immediately after penetrating the CNS (23). One way to increase sprouting of regenerating RGC axons in the SC could be to provide BDNF and chondroitinase ABC (151). However, even in these conditions, with surviving RGCs widely separated in the retina and their axon terminals widely dispersed within the SC, the influence of activity-dependent mechanisms in shaping the topological pattern of innervation would be expected, a priori, to be much more limited than in normal development. Furthermore, with little competition among axons for synaptic sites, it is possible that inappropriately located synapses, once formed, would be much more stable than in the reinnervated frog or goldfish tectum. Such premature formation of synapses could in turn curtail the further exploration of the SC by regenerated RGC axons.

Preservation of Local and Downstream Circuitry

In the study by Turner et al. (98), the local synaptic connectivity in the superficial gray layer of the SC was assessed after RGC axonal regeneration through a PN graft into the rat SC, using in vitro brain slice techniques. Repair was achieved between the ipsilateral eye and SC, after bilateral lesion of optic nerves and ablation of ipsilateral occipital cortex.

Impact of Deafferentation

The normal rat superficial gray layer (SGL) of the SC receives the majority (90%) of its excitatory input from the retina (152) (Fig. 25) and the remainder (10%) from the visual cortex (153).

Figure 25. Details of a vesicle and contact morphology in the normal SC of the rat.

Figure 25

Details of a vesicle and contact morphology in the normal SC of the rat. a, normal S terminal make asymmetric contact (S) and F terminal make symmetric contact (F). b, an F terminal makes symmetric contact. c, an S terminal makes two asymmetric contacts (more...)

Interconnectivity within the SGL appears to be mediated by local GABAergic interneurons (154, 155). Both the GABAergic processes of local circuit interneurons (152, 156) and the axon terminals of other projections proliferate (157, 158) after optic deafferentation. These new neural processes appear to form additional synapses or to take up positions apposed to the postsynaptic densities left vacant by the degenerating retinal afferents in the SC (152). As a result, the synapse-to-neuron ratio stays the same in the SC (159), although it is not known whether these synaptic contacts are functional. Because the subsequent repair of retinal afferents is also going to alter the balance between excitatory and inhibitory inputs, the connectivity between restored retinal afferents and target neurons is likely to be very different from that in the normal SGL (Fig. 26).

Figure 26. Partial occupation of postsynaptic contacts.

Figure 26

Partial occupation of postsynaptic contacts. a, the contact (arrow) has a degenerate terminal (D) and an F terminal (F) adjacent to it. b, the contact (arrow) is shared by an F terminal (F) and an unidentified profile (U). Magnification ×50,000. (more...)

There is as yet no evidence for local excitatory connections in the SGL. Electrophysiological studies are consistent with the anatomical organization, in that retinal input to the SGL is monosynaptic and there is no evidence for local network-related activity, even when inhibition is blocked (160). In addition, contralateral enucleation 14 days before recording is sufficient to result in a complete loss of excitatory inputs to the SGL in vitro after intracollicular stimulation (161). However, the study by Turner et al. (98) suggests that this is not always the case: optic tract stimulation 3–9 months after optic nerve transection leads to excitation in the SC, and this is likely attributable to the recruitment of corticocollicular projections, which run close to the optic tract (162). Indeed, anatomical studies have shown that 30–45 days after contralateral enucleation, there is a reactive synaptogenesis of corticocollicular terminals (157). The nature of this responsiveness also suggests that this cortical input recruits local recurrent excitatory connections that have been formed as part of the reactive process to retinal deafferentation.

Evidence of New Inputs after PN Graft Repair

After combined retinal and cortical deafferentation (as part of the surgery for PN bridging the retinocollicular pathway), all normal excitatory inputs to the SGL are abolished. However, there is evidence from the study by Turner et al. (98) for the presence of both spontaneous and evoked EPSP-like events in SC slices from the PN graft repair preparation. This suggests that excitatory inputs can form new synaptic contacts on neurons within the SGL. These connections are likely to be attributable to reactive sprouting of excitatory neurons, either in the SGL itself or the deeper layers of the SC, such as the intermediate gray layer (IGL). Because both the SGL and IGL contain neurons that have dendrites that extend across the SO, this could provide a substrate on which such reactive synaptogenesis could form a recurrent excitatory network. Certainly, the delay (20–30 ms) in the onset of the network depolarizations after electrical stimulation (reported by Turner et al. (98)) suggests that sprouted excitatory input is polysynaptic, resulting from the recruitment of a relatively remote population of neurons, as may be located in the IGL. Indeed, the structure of the IGL is conducive to bursting activity because IGL neurons form a recurrent collateral network in normal animals and produce long-lasting synaptic responses in the presence of bicuculline (160). The network reorganization in the PN graft preparation (recorded in vitro (98)) is not that surprising, in view of the impact of deafferentation in other structures, e.g., cerebral cortex (163) or the dentate gyrus of the hippocampus (164). In both cases, this process leads to sprouting of excitatory axons to form new recurrent excitatory connections. One consequence of the reactive events found in most SC slices (from PN graft repair preparation) is that they are likely to obscure efficacy of regenerated RGC axons that had established monosynaptic connections of retinorecipient neurons.

Impact of PN Graft Repair Surgery on the SGL Function: The Future for Repair Strategies

It is clear from the work of Turner et al. (98) that intrinsic changes in response patterns will impact the way the SGL will function during visual stimulation. Keirstead et al. (8) demonstrated that, in comparison with normal controls, restoration of functional retinal inputs into the SC, using the PN-graft method, had delays in the onset of post-synaptic action (165). This delay probably reflects the fact that the underlying synaptic responses involve the recruitment of recurrent excitatory connections. It may also reflect the profound impact that GABAergic inhibition has in controlling this network. The impact of visual deafferentation needs to be assessed throughout the SC to identify the locus/loci of the reactive changes that underlie(s) altered network behavior. In addition, for improvements in the current strategies of pathway repair, there is the need to limit or reverse these deafferentation-induced changes because: 1) this would allow a better assessment of the efficacy of new connections; and 2) it would probably improve system function.

In conclusion, axonal regeneration to a target alone clearly does not guarantee functional recovery. The study by Turner et al. (98) highlights the fact that the functional state of the target area is of fundamental importance for whether normal function can be restored, once axonal reinnervation has been achieved.

Evidence for Some Level of Recovery of Function in the PN-bridged Retinofugal Pathways

The question of whether visual functions can be mediated by regenerated axons has been explored by looking at: 1) the pupillary light reflex, a conditioned response; 2) EEG desynchronization; and 3) behavioral arousal. It was found that the regenerated pathway could mediate pupillary constriction to light (166). Additional studies (167) showed that at best, the response amplitude and latency could be within normal range, but one noticeable difference was that although in normals, repetitive stimulation gave repeated responses of similar amplitude, regenerated pathways showed substantially reduced amplitudes with successive stimulation. The conditioned response studied, i.e., escape from a shuttle box in response to a light flash as a predictor of an electric shock, showed that this task could be performed in rats with regenerated optic input (168). Finally, animals were tested to demonstrate whether the regenerated pathways could mediate EEG desynchronization behavior to light (169). This depended on the fact that, under normal conditions, rats show a slow wave sleep pattern. A sensory stimulus, such as a flash of light or auditory signal, desynchronizes this high-amplitude slow wave activity, replacing it with low-amplitude, high-frequency activity. When presented with a light flash, blinded rats do not show this response, but animals with nerve grafts connected into the SC do. Associated with this, the rats also show a range of behavioral arousals.

Visual Function Assessment

Visual function runs at many levels from unconscious responses to perception. These various functions are generally mediated through specific primary visual centers. Unconscious responses include driving circadian rhythms (relayed through the suprachiasmatic nucleus), photophobic responses (not specifically localized to any specific visual center), pupillary light reflex (mediated by the olivary pretectal nucleus), orienting responses (involving the SC), and head tracking to moving stripes (involving the SC also, but requiring cortical input for higher spatial frequencies). Perception requires elaborate decoding and integration of a set of visual signals to achieve a representational image at the level of the cortex.

For some visually driven functions, such as circadian rhythms and photophobia, all that is needed is to recognize a gradient, either temporal or spatial, of light and dark. For the pupillary light reflex, ability to encode the light intensity is also important, because the amount of pupillary constriction depends on brightness. For orienting responses and head tracking, some level of topographic encoding must be present. For perception, a much more elaborate degree of encoding must be achieved. In any attempt to reconstruct the damaged visual system, or indeed to limit its deterioration, the ideal is to recreate or preserve exactly the normal substrates of the various visually driven behaviors. This is rarely possible and indeed may not always be necessary. The CNS can sometimes adapt to an imperfect sensory input and demonstrate a level of adaptation sufficient to achieve a normal response (170-173): even in an intact animal, the system is able to operate over a wide range of luminance and contrast sensitivity (174). It is also apparent, especially in conditions involving re-establishment of connections, that specific visual responses can be modulated by associated events and may be interdependent.

To reconstruct a particular function, therefore, it is necessary for axons to innervate the appropriate brain region, subserving that function. Beyond this, it may also be necessary for a topological representation of the retina to be resumed within the region. Despite the likely neural circuit remodeling in a retinorecipient nucleus previously devoid of visual inputs, information processing within this particular nucleus should be relatively normal, and this becomes particularly important when cortical functions are involved. Finally, the information must have "significance" to the animal so that it can elaborate a suitable response strategy or develop a percept.

About the Authors

Image regeneration1fu1.jpg
Dr. Yves Sauve was born in Montreal, Canada. He attended the University of Montreal where he received his B.Sc. in Biochemistry in 1983 and his M.Sc. in Neuroscience in 1988 with Dr. Thomas Reader, focusing on the neurochemistry of catecholamines and their receptors in the CNS. He then obtained his Ph.D. in Physiology under Dr. Michael Rasminsky at McGill University in 1995, where his research focused on the electrophysiological evaluation of reformed synapses between regenerating RGC axons and neurons in the superior colliculus, using the preparation developed in Dr. Albert Aguayo's group. Dr. Sauve subsequently undertook postdoctoral studies with Dr. Raymond Lund at the Institute of Ophthalmology (University College London), where he developed electrophysiological approaches to evaluate visual responsiveness in rodent models of retinal degeneration. In 2001, he became assistant professor of Ophthalmology and Visual Sciences at the Moran Eye Center (University of Utah), where he is currently evaluating rod and cone function following retinal degeneration, transplant therapies, and regeneration in the adult mammalian visual pathways.

Image regeneration1fu2.jpg
Dr. Frederic Gaillard was born in Tours, France. He attended the University of Poitiers, where he received his B.Sc. (1969) and his M.Sc. (1971) in physiology. He then obtained a Ph.D. (1975) and a Doctorates-Sciences (1984) in neurophysiology. Until recently, most of his studies focused on aspects of binocular information processing in the amphibian visual system, mainly on the functional properties of the crossed isthmo-tectal pathway. He is now examining host-graft relationships in the adult mammalian visual system. Since 1977, Dr. Gaillard has been a senior investigator (Charge de recherches) of the Centre National de la Recherche Scientifique (CNRS) at the Institut de Physiologie et Biologie Cellulaires (UMR 6187), Poitiers, France.

References

1.
>Cajal SR. (1913–1914). Estudios Sobre la Degeneraci—n y Regeneraci—n del Sistema Nervioso. Madrid: Moya. Translated into English as Degeneration and Regeneration of the Nervous System (R. M. May, tran. and Ed.). London: Oxford University Press, 1928. Reprinted and edited with additional translations by J. DeFelipe and E. G. Jones (), Cajal's Degeneration and Regeneration of the Nervous System. New York: Oxford University Press;1991.
2.
Aguayo AJ, Rasminsky M, Bray GM, Carbonetto S, McKerracher L, Villegas-Perez MP, Vidal-Sanz M, Carter DA. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci. 1991;331:337–343. [PubMed: 1677478]
3.
So KF, Aguayo AJ. Lengthy regrowth of cut axons from ganglion cells after peripheral nerve transplantation into the retina of adult rats. Brain Res. 1985;328:349–354. [PubMed: 3986532]
4.
Vidal-Sanz M, Bray GM, Villegas-Perez MP, Thanos S, Aguayo AJ. Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J Neurosci. 1987;7:2894–2909. [PubMed: 3625278]
5.
Tello F. La regeneration dans les voies optiques. Trab Lab Invest Biol Univ Madr. 1907;5:237–248.
6.
David S, Aguayo AJ. Axonal elongation into peripheral nervous system "bridges" after central nervous system injury in adult rats. Science. 1981;214:931–933. [PubMed: 6171034]
7.
Richardson PM, McGuinness UM, Aguayo AJ. Axons from CNS neurons regenerate into PNS grafts. Nature. 1980;284:264–265. [PubMed: 7360259]
8.
Keirstead SA, Rasminsky M, Fukuda Y, Carter DA, Aguayo AJ, Vidal-Sanz M. Electrophysiologic responses in hamster superior colliculus evoked by regenerating retinal axons. Science. 1989;246:255–257. [PubMed: 2799387]
9.
Sauve Y, Sawai H, Rasminsky M. Functional synaptic connections made by regenerated retinal ganglion cell axons in the superior colliculus of adult hamsters. J Neurosci. 1995;15:665–675. [PubMed: 7823170]
10.
Kim JE, Li S, GrandPre T, Qiu D, Strittmatter SM. Axon regeneration in young adult mice lacking Nogo-A/B. Neuron. 2003;38:187–199. [PubMed: 12718854]
11.
Raisman G. Myelin inhibitors: does NO mean GO? Nat Rev Neurosci. 2004;5:157–161. [PubMed: 14735118]
12.
Schwartz M. Optic nerve crush: protection and regeneration. Brain Res Bull. 2004;62:467–471. [PubMed: 15036559]
13.
Rhodes KE, Fawcett JW. Chondroitin sulphate proteoglycans: preventing plasticity or protecting the CNS? J Anat. 2004;204:33–48. [PMC free article: PMC1571240] [PubMed: 14690476]
14.
Bouslama-Oueghlani L, Wehrle R, Sotelo C, Dusart I. The developmental loss of the ability of Purkinje cells to regenerate their axons occurs in the absence of myelin: an in vitro model to prevent myelination. J Neurosci. 2003;23:8318–8329. [PubMed: 12967994]
15.
Chen DF, Jhaveri S, Schneider GE. Intrinsic changes in developing retinal neurons result in regenerative failure of their axons. Proc Natl Acad Sci U S A. 1995;92:7287–7291. [PMC free article: PMC41324] [PubMed: 7638182]
16.
Shewan D, Berry M, Cohen J. Extensive regeneration in vitro by early embryonic neurons on immature and adult CNS tissue. J Neurosci. 1995;15:2057–2062. [PubMed: 7891152]
17.
Finlay BL, Schneps SE, Wilson KG, Schneider GE. Topography of visual and somatosensory projections to the superior colliculus of the golden hamster. Brain Res. 1978;142:223–235. [PubMed: 630383]
18.
Siminoff R, Schwassmann HO, Kruger L. An electrophysiological study of the visual projection to the superior colliculus of the rat. J Comp Neurol. 1966;127:435–444. [PubMed: 5968989]
19.
Tiao YC, Blakemore C. Functional organization in the superior colliculus of the golden hamster. J Comp Neurol. 1976;168:483–503. [PubMed: 939819]
20.
Fukuda Y, Watanabe M, Sawai H, Miyoshi T. Functional recovery of vision in regenerated optic nerve fibers. Vision Res. 1998;38:1545–1553. [PubMed: 9667019]
21.
Villegas-Perez MP, Vidal-Sanz M, Bray GM, Aguayo AJ. Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. J Neurosci. 1988;8:265–280. [PubMed: 2448429]
22.
Carter DA, Bray GM, Aguayo AJ. Regenerated retinal ganglion cell axons can form well-differentiated synapses in the superior colliculus of adult hamsters. J Neurosci. 1989;9:4042–4050. [PubMed: 2479728]
23.
Aviles-Trigueros M, Sauve Y, Lund RD, Vidal-Sanz M. Selective innervation of retinorecipient brainstem nuclei by retinal ganglion cell axons regenerating through peripheral nerve grafts in adult rats. J Neurosci. 2000;20:361–374. [PubMed: 10627613]
24.
Sauve Y, Sawai H, Rasminsky M. Topological specificity in reinnervation of the superior colliculus by regenerated retinal ganglion cell axons in adult hamsters. J Neurosci. 2001;21:951–960. [PubMed: 11157081]
25.
Berkelaar M, Clarke DB, Wang YC, Bray GM, Aguayo AJ. Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats. J Neurosci. 1994;14:4368–4374. [PubMed: 8027784]
26.
Peinado-Ramon P, Salvador M, Villegas-Perez MP, Vidal-Sanz M. Effects of axotomy and intraocular administration of NT-4, NT-3, and brain-derived neurotrophic factor on the survival of adult rat retinal ganglion cells. A quantitative in vivo study. Invest Ophthalmol Vis Sci. 1996;37:489–500. [PubMed: 8595949]
27.
Villegas-Perez MP, Vidal-Sanz M, Rasminsky M, Bray GM, Aguayo AJ. Rapid and protracted phases of retinal ganglion cell loss follow axotomy in the optic nerve of adult rats. J Neurobiol. 1993;24:23–36. [PubMed: 8419522]
28.
Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36:774–786. [PubMed: 7706025]
29.
Cheung ZH, Chan YM, Siu FK, Yip HK, Wu W, Leung MC, So KF. Regulation of caspase activation in axotomized retinal ganglion cells. Mol Cell Neurosci. 2004;25:383–393. [PubMed: 15033167]
30.
Kermer P, Klocker N, Labes M, Šhr MB. Inhibition of CPP32-like proteases rescues axotomized retinal ganglion cells from secondary cell death in vivo. J Neurosci. 1998;18:4656–4662. [PubMed: 9614240]
31.
Kermer P, Klocker N, Labes M, Thomsen S, Srinivasan A, Bahr M. Activation of caspase-3 in axotomized rat retinal ganglion cells in vivo. FEBS Lett. 1999;453:361–364. [PubMed: 10405176]
32.
Kermer P, Ankerhold R, Klocker N, Krajewski S, Reed JC, Bahr M. Caspase-9: involvement in secondary death of axotomized rat retinal ganglion cells in vivo. Brain Res Mol Brain Res. 2000;85:144–150. [PubMed: 11146116]
33.
Weishaupt JH, Diem R, Kermer P, Krajewski S, Reed JC, Bahr M. Contribution of caspase-8 to apoptosis of axotomized rat retinal ganglion cells in vivo. Neurobiol Dis. 2003;13:124–135. [PubMed: 12828936]
34.
Kikuchi M, Tenneti L, Lipton SA. Role of p38 mitogen-activated protein kinase in axotomy-induced apoptosis of rat retinal ganglion cells. J Neurosci. 2000;20:5037–5044. [PubMed: 10864961]
35.
Chaudhary P, Ahmed F, Quebada P, Sharma SC. Caspase inhibitors block the retinal ganglion cell death following optic nerve transection. Brain Res Mol Brain Res. 1999;67:36–45. [PubMed: 10101230]
36.
Kermer P, Klocker N, Bahr M. Long-term effect of inhibition of ced 3-like caspases on the survival of axotomized retinal ganglion cells in vivo. Exp Neurol. 1999;158:202–205. [PubMed: 10448432]
37.
Isenmann S, Wahl C, Krajewski S, Reed JC, Bahr MB. Up-regulation of Bax protein in degenerating retinal ganglion cells precedes apoptotic cell death after optic nerve lesion in the rat. Eur J Neurosci. 1997;9:1763–1772. [PubMed: 9283831]
38.
Bonfanti L, Strettoi E, Chierzi S, Cenni MC, Liu XH, Martinou J-C, Maffei L, Rabacchi SA. Protection of retinal ganglion cells from natural and axotomy-induced cell death in neonatal transgenic mice overexpressing bcl-2. J Neurosci. 1996;16:4186–4194. [PubMed: 8753880]
39.
Chierzi S, Cenni MC, Maffei L, Pizzorusso T, Porciatti V, Ratto GM, Strettoi E. Protection of retinal ganglion cells and preservation of function after optic nerve lesion in bcl-2 transgenic mice. Vision Res. 1998;38:1537–1543. [PubMed: 9667018]
40.
Kugler S, Straten G, Kreppel F, Isenmann S, Liston P, Bahr M. The X-linked inhibitor of apoptosis (XIAP) prevents cell death in axotomized CNS neurons in vivo. Cell Death Differ. 2000;7:815–824. [PubMed: 11042676]
41.
Yip HK, So KF. Axonal regeneration of retinal ganglion cells: effect of trophic factors. Prog Retin Eye Res. 2000;19:559–575. [PubMed: 10925243]
42.
Cui Q, So KF, Yip HK. Major biological effects of neurotrophic factors on retinal ganglion cells in mammals. Biol Signals Recept. 1998;7:220–226. [PubMed: 9730581]
43.
Weishaupt JH, Bahr M. Degeneration of axotomized retinal ganglion cells as a model for neuronal apoptosis in the central nervous system - molecular death and survival pathways. Restor Neurol Neurosci. 2001;19:19–27. [PubMed: 12082226]
44.
Koeberle PD, Bahr M. Growth and guidance cues for regenerating axons: where have they gone? J Neurobiol. 2004;59:162–180. [PubMed: 15007834]
45.
Caleo M, Menna E, Chierzi S, Cenni MC, Maffei L. Brain-derived neurotrophic factor is an anterograde survival factor in the rat visual system. Curr Biol. 2000;10:1155–1161. [PubMed: 11050383]
46.
Quigley HA, McKinnon SJ, Zack DJ, Pease ME, Kerrigan-Baumrind LA, Kerrigan DF, Mitchell RS. Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest Ophthalmol Vis Sci. 2000;41:3460–3466. [PubMed: 11006239]
47.
Spalding KL, Rush RA, Harvey AR. Target-derived and locally derived neurotrophins support retinal ganglion cell survival in the neonatal rat retina. J Neurobiol. 2004;60:319–327. [PubMed: 15281070]
48.
Klocker N, Cellerino A, Bahr M. Free radical scavenging and inhibition of nitric oxide synthase potentiates the neurotrophic effects of brain-derived neurotrophic factor on axotomized retinal ganglion cells in vivo. J Neurosci. 1998;18:1038–1046. [PubMed: 9437024]
49.
Mansour-Robaey S, Clarke DB, Wang YC, Bray GM, Aguayo AJ. Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc Natl Acad Sci U S A. 1994;91:1632–1636. [PMC free article: PMC43217] [PubMed: 8127857]
50.
Mey J, Thanos S. Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res. 1993;602:304–317. [PubMed: 8448673]
51.
Di Polo A, Aigner LJ, Dunn RJ, Bray GM, Aguayo AJ. Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Muller cells temporarily rescues injured retinal ganglion cells. Proc Natl Acad Sci U S A. 1998;95:3978–3983. [PMC free article: PMC19948] [PubMed: 9520478]
52.
Cheng L, Sapieha P, Kittlerova P, Hauswirth WW, Di Polo A. TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J Neurosci. 2002;22:3977–3986. [PubMed: 12019317]
53.
Cohen A, Bray GM, Aguayo AJ. Neurotrophin-4/5 (NT-4/5) increases adult rat retinal ganglion cell survival and neurite outgrowth in vitro. J Neurobiol. 1994;25:953–959. [PubMed: 7964706]
54.
Carmignoto G, Maffei L, Candeo P, Canella R, Comelli C. Effect of NGF on the survival of rat retinal ganglion cells following optic nerve section. J Neurosci. 1989;9:1263–1272. [PubMed: 2467970]
55.
Klocker N, Braunling F, Isenmann S, Bahr M. In vivo neurotrophic effects of GDNF on axotomized retinal ganglion cells. Neuroreport. 1997;8:3439–3442. [PubMed: 9427303]
56.
Koeberle PD, Ball AK. Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res. 1998;38:1505–1515. [PubMed: 9667015]
57.
Koeberle PD, Ball AK. Neurturin enhances the survival of axotomized retinal ganglion cells in vivo: combined effects with glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. Neuroscience. 2002;110:555–567. [PubMed: 11906793]
58.
Cui Q, Harvey AR. CNTF promotes the regrowth of retinal ganglion cell axons into murine peripheral nerve grafts. Neuroreport. 2000;11:3999–4002. [PubMed: 11192617]
59.
Watanabe M, Fukuda Y. Survival and axonal regeneration of retinal ganglion cells in adult cats. Prog Retin Eye Res. 2002;21:529–553. [PubMed: 12433376]
60.
Weise J, Isenmann S, Klocker N, Kugler S, Hirsch S, Gravel C, Bahr M. Adenovirus-mediated expression of ciliary neurotrophic factor (CNTF) rescues axotomized rat retinal ganglion cells but does not support axonal regeneration in vivo. Neurobiol Dis. 2000;7:212–223. [PubMed: 10860786]
61.
Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000;10:381–391. [PubMed: 10851172]
62.
Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001;11:272–280. [PubMed: 11399424]
63.
Fagiolini M, Caleo M, Strettoi E, Maffei L. Axonal transport blockade in the neonatal rat optic nerve induces limited retinal ganglion cell death. J Neurosci. 1997;17:7045–7052. [PubMed: 9278540]
64.
Koeberle PD, Ball AK. Nitric oxide synthase inhibition delays axonal degeneration and promotes the survival of axotomized retinal ganglion cells. Exp Neurol. 1999;158:366–381. [PubMed: 10415143]
65.
Koeberle PD, Gauldie J, Ball AK. Effects of adenoviral-mediated gene transfer of interleukin-10, interleukin-4, and transforming growth factor-beta on the survival of axotomized retinal ganglion cells. Neuroscience. 2004;125:903–920. [PubMed: 15120851]
66.
Raibon E, Sauve Y, Carter DA, Gaillard F. Microglial changes accompanying the promotion of retinal ganglion cell axonal regeneration into peripheral nerve grafts. J Neurocytol. 2002;31:57–71. [PubMed: 12652088]
67.
Thanos S, Mey J, Wild M. Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro. J Neurosci. 1993;13:455–466. [PubMed: 7678855]
68.
Schwartz M. Vaccination for glaucoma: dream or reality? Brain Res Bull. 2004;62:481–484. [PubMed: 15036561]
69.
Bahr M, Eschweiler GW, Wolburg H. Precrushed sciatic nerve grafts enhance the survival and axonal regrowth of retinal ganglion cells in adult rats. Exp Neurol. 1992;116:13–22. [PubMed: 1559562]
70.
Leon S, Yin Y, Nguyen J, Irwin N, Benowitz LI. Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci. 2000;20:4615–4626. [PubMed: 10844031]
71.
Yin Y, Cui Q, Li Y, Irwin N, Fischer D, Harvey AR, Benowitz LI. Macrophage-derived factors stimulate optic nerve regeneration. J Neurosci. 2003;23:2284–2293. [PubMed: 12657687]
72.
Fischer D, He Z, Benowitz LI. Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J Neurosci. 2004;24:1646–1651. [PubMed: 14973241]
73.
Ellezam B, Dubreuil C, Winton M, Loy L, Dergham P, Selles-Navarro I, McKerracher L. Inactivation of intracellular Rho to stimulate axon growth and regeneration. Prog Brain Res. 2002;137:371–380. [PubMed: 12440379]
74.
Cai D, Qiu J, Cao Z, McAtee M, Bregman BS, Filbin MT. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J Neurosci. 2001;21:4731–4739. [PubMed: 11425900]
75.
Spencer T, Filbin MT. A role for cAMP in regeneration of the adult mammalian CNS. J Anat. 2004;204:49–55. [PMC free article: PMC1571233] [PubMed: 14690477]
76.
Oster SF, Deiner M, Birgbauer E, Sretavan DW. Ganglion cell axon pathfinding in the retina and optic nerve. Semin Cell Dev Biol. 2004;15:125–136. [PubMed: 15036215]
77.
Sawai H, Clarke DB, Kittlerova P, Bray GM, Aguayo AJ. Brain-derived neurotrophic factor and neurotrophin-4/5 stimulate growth of axonal branches from regenerating retinal ganglion cells. J Neurosci. 1996;16:3887–3894. [PubMed: 8656282]
78.
Williams SE, Mason CA, Herrera E. The optic chiasm as a midline choice point. Curr Opin Neurobiol. 2004;14:51–60. [PubMed: 15018938]
79.
Thanos S, Mey J. Type-specific stabilization and target-dependent survival of regenerating ganglion cells in the retina of adult rats. J Neurosci. 1995;15:1057–1079. [PubMed: 7869083]
80.
Carter DA, Jhaveri S. Retino-geniculate axons regenerating in adult hamsters are able to form morphologically distinct terminals. Exp Neurol. 1997;146:315–322. [PubMed: 9270040]
81.
Zwimpfer TJ, Aguayo AJ, Bray GM. Synapse formation and preferential distribution in the granule cell layer by regenerating retinal ganglion cell axons guided to the cerebellum of adult hamsters. J Neurosci. 1992;12:1144–1159. [PubMed: 1556590]
82.
Dusart I, Morel MP, Wehrle R, Sotelo C. Late axonal sprouting of injured Purkinje cells and its temporal correlation with permissive changes in the glial scar. J Comp Neurol. 1999;408:399–418. [PubMed: 10340514]
83.
Bandtlow C, Zachleder T, Schwab ME. Oligodendrocytes arrest neurite growth by contact inhibition. J Neurosci. 1990;10:3837–3848. [PubMed: 2269887]
84.
Davies SJA, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J. Regeneration of adult axons in white matter tracts of the central nervous system. Nature. 1997;390:680–684. [PubMed: 9414159]
85.
Davies SJA, Goucher DR, Doller C, Silver J. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci. 1999;19:5810–5822. [PubMed: 10407022]
86.
Fawcett JW. Astrocytic and neuronal factors affecting axon regeneration in the damaged central nervous system. Cell Tissue Res. 1997;290:371–377. [PubMed: 9321700]
87.
Liuzzi FJ, Lasek RJ. Astrocytes block axonal regeneration in mammals by activating the physiological stop pathway. Science. 1987;237:642–645. [PubMed: 3603044]
88.
Smith GM, Rutishauser U, Silver J, Miller RH. Maturation of astrocytes in vitro alters the extent and molecular basis of neurite outgrowth. Dev Biol. 1990;138:377–390. [PubMed: 2318341]
89.
Frost DO. Development of anomalous retinal projections to nonvisual thalamic nuclei in Syrian hamsters: a quantitative study. J Comp Neurol. 1986;252:95–105. [PubMed: 3793977]
90.
Berry M, Carlile J, Hunter A. Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J Neurocytol. 1996;25:147–170. [PubMed: 8699196]
91.
Eitan S, Solomon A, Lavie V, Yoles E, Hirschberg DL, Belkin M, Schwartz M. Recovery of visual response of injured adult rat optic nerves treated with transglutaminase. Science. 1994;264:1764–1768. [PubMed: 7911602]
92.
Fischer D, Heiduschka P, Thanos S. Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats. Exp Neurol. 2001;172:257–272. [PubMed: 11716551]
93.
Li Y, Sauve Y, Li D, Lund RD, Raisman G. Transplanted olfactory ensheathing cells promote regeneration of cut adult rat optic nerve axons. J Neurosci. 2003;23:7783–7788. [PubMed: 12944507]
94.
Carter DA, Aguayo AJ, Bray GM. Retinal ganglion cell terminals in the hamster superior colliculus: an ultrastructural study. J Comp Neurol. 1991;311:97–107. [PubMed: 1719046]
95.
Carter DA, Bray GM, Aguayo AJ. Regenerated retinal ganglion cell axons form normal numbers of boutons but fail to expand their arbors in the superior colliculus. J Neurocytol. 1998;27:187–196. [PubMed: 10640178]
96.
Ling C, Schneider GE, Jhaveri S. Target-specific morphology of retinal axon arbors in the adult hamster. Vis Neurosci. 1998;15:559–579. [PubMed: 9685208]
97.
Vidal-Sanz M, Bray GM, Aguayo AJ. Regenerated synapses persist in the superior colliculus after the regrowth of retinal ganglion cell axons. J Neurocytol. 1991;20:940–952. [PubMed: 1809272]
98.
Turner JP, Sauve Y, Lund RD, Salt TA. Retinotectal synaptic transmission in vitro after the repair of cut optic nerve with a peripheral nerve graft. Soc Neurosci Abstr. 2001;27
99.
Gaze RM. The formation of nerve connections. New York: Academic Press; 1970.
100.
Sperry RW. Neural basis of the spontaneous optokinetic response produced by visual inversion. J Comp Physiol Psychol. 1950;43:482–489. [PubMed: 14794830]
101.
Sperry RW. (1965) Embryogenesis of behavioral nerve nets. In: DeHann RL, Ursprung H, editors. Organogenesis. New York: Holt, Rinehart and Winston. p.161-186.
102.
Dunlop SA, Tee LB, Stirling RV, Taylor AL, Runham PB, Barber AB, Kuchling G, Rodger J, Roberts JD, Harvey AR, Beazley LD. Failure to restore vision after optic nerve regeneration in reptiles: interspecies variation in response to axotomy. J Comp Neurol. 2004;478:292–305. [PubMed: 15368531]
103.
Dunlop SA, Stirling RV, Rodger J, Symonds AC, Bancroft WJ, Tee LB, Beazley LD. Failure to form a stable topographic map during optic nerve regeneration:abnormal activity-dependent mechanisms. Exp Neurol. 2003;184:805–815. [PubMed: 14769373]
104.
Beazley LD, Rodger J, Chen P, Tee LB, Stirling RV, Taylor AL, Dunlop SA. Training on a visual task improves the outcome of optic nerve regeneration. J Neurotrauma. 2003;20:1263–1270. [PubMed: 14651812]
105.
Walter J, Henke-Fahle S, Bonhoeffer F. Avoidance of posterior tectal membrane by temporal retinal axons. Development. 1987;101:909–913. [PubMed: 3503703]
106.
Walter J, Kern-Veitis B, Huf J, Stolze B, Bonhoeffer F. Recognition of position specific properties of tectal cell membranes by retinal axons in vitro. Development. 1987;101:685–696. [PubMed: 3503693]
107.
Godement P, Bonhoeffer F. Cross-species recognition of tectal cues by retinal fibers in vitro. Development. 1989;106:313–320. [PubMed: 2591317]
108.
Roskies AL, O'Leary DDM. Control of topographic retinal axon branching by inhibitory membrane-bound molecules. Science. 1994;265:799–803. [PubMed: 8047886]
109.
von Boxberg Y, Deiss S, Schwarz U. Guidance and topographic stabilization of nasal chick retinal axons on target-derived components in vitro. Neuron. 1993;10:345–357. [PubMed: 8461131]
110.
Bahr M, Eschweiler GW. Regenerating adult rat retinal axons reconnect with target neurons in-vitro. Neuroreport. 1991;2:581–584. [PubMed: 1661620]
111.
Bahr M, Eschweiler GW. Formation of functional synapses by regenerating adult rat retinal ganglion cell axons in midbrain target regions in vitro. J Neurobiol. 1993;24:456–473. [PubMed: 8515251]
112.
Wizenmann A, Thies E, Klostermann S, Bonhoeffer F, Bahr M. Appearance of target-specific guidance information for regenerating axons after CNS lesions. Neuron. 1993;11:975–983. [PubMed: 8240818]
113.
King CE, Wallace A, Rodger J, Bartlett C, Beazley LD, Dunlop SA. Transient up-regulation of retinal EphA3 and EphA5, but not ephrin-A2, coincides with re-establishment of a topographic map during optic nerve regeneration in goldfish. Exp Neurol. 2003;183:593–599. [PubMed: 14552900]
114.
Rodger J, Vitale PN, Tee LB, King CE, Bartlett CA, Fall A, Brennan C, O'Shea JE, Dunlop SA, Beazley LD. EphA/ephrin-A interactions during optic nerve regeneration: restoration of topography and regulation of ephrin-A2 expression. Mol Cell Neurosci. 2004;25:56–68. [PubMed: 14962740]
115.
Sperry RW. Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc Natl Acad Sci U S A. 1963;50:703–709. [PMC free article: PMC221249] [PubMed: 14077501]
116.
Wong RO. Retinal waves and visual system development. Annu Rev Neurosci. 1999;22:29–47. [PubMed: 10202531]
117.
Cline HT. Activity-dependent plasticity in the visual systems of frogs and fish. Trends Neurosci. 1991;14:104–111. [PubMed: 1709534]
118.
Debski EA, Cline HT. Activity-dependent mapping in the retinotectal projection. Curr Opin Neurobiol. 2002;12:93–99. [PubMed: 11861170]
119.
Penn AA, Riquelme PA, Feller MB, Shatz CJ. Competition in retinogeniculate patterning driven by spontaneous activity. Science. 1998;279:2108–2112. [PubMed: 9516112]
120.
Schmidt JT. Activity-driven sharpening of the retinotectal projection: the search for retrograde synaptic signaling pathways. J Neurobiol. 2004;59:114–133. [PubMed: 15007831]
121.
Shatz CJ. Impulse activity and the patterning of connections during CNS development. Neuron. 1990;5:745–756. [PubMed: 2148486]
122.
Holt CE, Harris WA. Order in the initial retinotectal map in Xenopus: a new technique for labelling growing nerve fibres. Nature. 1983;301:150–152. [PubMed: 6823290]
123.
Stuermer CA, Bastmeyer M, Bahr M, Strobel G, Paschke K. Trying to understand axonal regeneration in the CNS of fish. J Neurobiol. 1992;23:537–550. [PubMed: 1431836]
124.
Fraser SE, Perkel DH. Competitive and positional cues in the patterning of nerve connections. J Neurobiol. 1990;21:51–72. [PubMed: 2181067]
125.
Honda H. Topographic mapping in the retinotectal projection by means of complementary ligand and receptor gradients: a computer simulation study. J Theor Biol. 1998;192:235–246. [PubMed: 9637060]
126.
Hua SE, Massone LL, Houk JC. Model of topographic map development guided by a transiently expressed repulsion molecule. Neuroreport. 1993;4:1319–1322. [PubMed: 8260613]
127.
Matsumoto N, Kometami M, Nagano K. Regenerating retinal fibers of the goldfish make temporary and unspecific but functional synapses before forming the final retinotopic projection. Neuroscience. 1987;22:1103–1110. [PubMed: 3683848]
128.
Meyer RL, Kageyama GH. Large-scale synaptic errors during map formation by regeneration of optic axons in the goldfish. J Comp Neurol. 1999;409:299–312. [PubMed: 10379922]
129.
Udin SB, Fawcett JW. Formation of topographic maps. Annu Rev Neurosci. 1988;11:289–327. [PubMed: 3284443]
130.
Bahr M, Wizenmann A. Retinal ganglion cell axons recognize specific guidance cues present in the deafferented adult rat superior colliculus. J Neurosci. 1996;16:5106–5116. [PubMed: 8756440]
131.
Sauve Y, Girman SV, Wang S, Lawrence JM, Lund RD. Progressive visual sensitivity loss in the Royal College of Surgeons rat: perimetric study in the superior colliculus. Neuroscience. 2001;103:51–63. [PubMed: 11311787]
132.
Baier H, Bonhoeffer F. Axon guidance by gradients of a target-derived component. Science. 1992;255:472–475. [PubMed: 1734526]
133.
Wizenmann A, Bahr M. Growth characteristics of ganglion cell axons in the developing and regenerating retinotectal projection of the rat. Cell Tissue Res. 1997;290:395–403. [PubMed: 9321703]
134.
Wizenmann A, Bahr M. Growth preferences of adult rat retinal ganglion cell axons in retinotectal cocultures. J Neurobiol. 1998;35:379–387. [PubMed: 9624620]
135.
von Boxberg Y, Deiss S, Schwarz U. Guidance and topographic stabilization of nasal chick retinal axons on target-derived components in vitro. Neuron. 1993;10:345–357. [PubMed: 8461131]
136.
Davenport RW, Thies E, Zhou R, Nelson PG. Cellular localization of ephrin-A2, ephrin-A5, and other functional guidance cues underlies retinotopic development across species. J Neurosci. 1998;18:975–986. [PubMed: 9437019]
137.
Ichijo H, Bonhoeffer F. Differential withdrawal of retinal axons induced by a secreted factor. J Neurosci. 1998;18:5008–5018. [PubMed: 9634566]
138.
Nakamoto M, Cheng HJ, Friedman GC, McLaughlin T, Hansen MJ, Yoon CH, O'Leary DD, Flanagan JG. Topographically specific effects of ELF-1 on retinal axon guidance in vitro and retinal axon mapping in vivo. Cell. 1996;86:755–766. [PubMed: 8797822]
139.
Goodhill GJ. Mathematical guidance for axons. Trends Neurosci. 1998;21:226–231. [PubMed: 9641531]
140.
Carter DA, Bray GM, Aguayo AJ. Long-term growth and remodeling of regenerated retino-collicular connections in adult hamsters. J Neurosci. 1994;14:590–598. [PubMed: 7507980]
141.
Caroni P, Schwab ME. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron. 1988;1:85–96. [PubMed: 3272156]
142.
Ghosh A, David S. Neurite growth-inhibitory activity in the adult rat cerebral cortical gray matter. J Neurobiol. 1997;32:671–683. [PubMed: 9183745]
143.
McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron. 1994;13:805–811. [PubMed: 7524558]
144.
Smith-Thomas LC, Fok-Seang J, Stevens J, Du J-S, Muir E, Faissner F, Geller HM, Rogers JH, Fawcett JW. An inhibitor of neurite outgrowth produced by astrocytes. J Cell Sci. 1994;107:1687–1695. [PubMed: 7962209]
145.
McLoon SC, McLoon LK, Palm SL, Furcht LT. Transient expression of laminin in the optic nerve of the developing rat. J Neurosci. 1988;8:1981–1990. [PubMed: 3385486]
146.
Rager G, Morino P, Schnitzer J, Sonderegger P. Expression of the axonal cell adhesion molecules axonin-1 and Ng-CAM during the development of the chick retinotectal system. J Comp Neurol. 1996;365:594–609. [PubMed: 8742305]
147.
Cohen J, Burne JF, Winter J, Bartlett P. Retinal ganglion cells lose response to laminin with maturation. Nature. 1986;322:465–467. [PubMed: 2874498]
148.
de Curtis I, Reichardt LF. Function and spatial distribution in developing chick retina of the laminin receptor alpha 6 beta 1 and its isoforms. Development. 1993;118:377–388. [PMC free article: PMC2758228] [PubMed: 8223267]
149.
Simon DK, O'Leary DDM. Responses of retinal axons in vivo and in vitro to position-encoding molecules in the embryonic superior colliculus. Neuron. 1992;9:977–989. [PubMed: 1419004]
150.
Simon DK, O'Leary DDM. Development of topographic order in the mammalian retino collicular projection. J Neurosci. 1992;12:1212–1232. [PubMed: 1313491]
151.
Tropea D, Caleo M, Maffei L. Synergistic effects of brain-derived neurotrophic factor and chondroitinase ABC on retinal fiber sprouting after denervation of the superior colliculus in adult rats. J Neurosci. 2003;23:7034–7044. [PubMed: 12904464]
152.
Lund RD, Lund JS. Synaptic adjustment after deafferentation of the superior colliculus of the rat. Science. 1971;171:804–807. [PubMed: 5549304]
153.
Harvey AR, Worthington DR. The projection from different visual cortical areas to the rat superior colliculus. J Comp Neurol. 1990;298:281–292. [PubMed: 2212104]
154.
Mize RR. Immunocytochemical localization of gamma-aminobutyric acid (GABA) in the cat superior colliculus. J Comp Neurol. 1988;276:169–187. [PubMed: 3220979]
155.
Pinard R, Benfares J, Lanoir J. Electron microscopic study of GABA-immunoreactive neuronal processes in the superficial gray layer of the rat superior colliculus: their relationships with degenerating retinal nerve endings. J Neurocytol. 1991;20:262–276. [PubMed: 1646864]
156.
Houser CR, Lee M, Vaughn JE. Immunocytochemical localization of glutamic acid decarboxylase in normal and deafferented superior colliculus: evidence for reorganization of gamma-aminobutyric acid synapses. J Neurosci. 1983;3:2030–2042. [PubMed: 6619922]
157.
Garcia del Cano G, Gerrikagoitia I, Martinez-Millan L. Plastic reaction of the rat visual corticocollicular connection after contralateral retinal deafferentiation at the neonatal or adult stage: axonal growth versus reactive synaptogenesis. J Comp Neurol. 2002;446:166–178. [PubMed: 11932934]
158.
Gerrikagoitia I, Garcia Del Cano G, Martinez-Millan L. Changes of the cholinergic input to the superior colliculus following enucleation in neonatal and adult rats. Brain Res. 2001;898:61–72. [PubMed: 11292449]
159.
Smith SA, Bedi KS. Unilateral eye enucleation in adult rats causes neuronal loss in the contralateral superior colliculus. J Anat. 1997;190:481–490. [PMC free article: PMC1467634] [PubMed: 9183672]
160.
Isa T, Endo T, Saito Y. The visuo-motor pathway in the local circuit of the rat superior colliculus. J Neurosci. 1998;18:8496–8504. [PubMed: 9763492]
161.
Miyamoto T, Sakurai T, Okada Y. Masking effect of NMDA receptor antagonists on the formation of long-term potentiation (LTP) in superior colliculus slices from the guinea pig. Brain Res. 1990;518:166–172. [PubMed: 1975212]
162.
Bourassa J, Deschenes M. Corticothalamic projections from the primary visual cortex in rats: a single fiber study using biocytin as an anterograde tracer. Neuroscience. 1995;66:253–263. [PubMed: 7477870]
163.
Salin P, Tseng GF, Hoffman S, Parada I, Prince DA. Axonal sprouting in layer V pyramidal neurons of chronically injured cerebral cortex. J Neurosci. 1995;15:8234–8245. [PubMed: 8613757]
164.
Laurberg S, Zimmer J. Lesion-induced sprouting of hippocampal mossy fiber collaterals to the fascia dentata in developing and adult rats. J Comp Neurol. 1981;200:433–459. [PubMed: 7276246]
165.
Fortin S, Chabli A, Dumont I, Shumikhina S, Itaya SK, Molotchnikoff S. Maturation of visual receptive field properties in the rat superior colliculus. Brain Res Dev Brain Res. 1999;112:55–64. [PubMed: 9974159]
166.
Thanos S. Adult retinofugal axons regenerating through peripheral nerve grafts can restore the light-induced pupilloconstriction reflex. Eur J Neurosci. 1992;4:691–699. [PubMed: 12106313]
167.
Whiteley SJ, Sauve Y, Aviles-Trigueros M, Vidal-Sanz M, Lund RD. Extent and duration of recovered pupillary light reflex following retinal ganglion cell axon regeneration through peripheral nerve grafts directed to the pretectum in adult rats. Exp Neurol. 1998;154:560–572. [PubMed: 9878191]
168.
Sasaki H, Inoue T, Iso H, Fukuda Y, Hayashi Y. Light-dark discrimination after sciatic nerve transplantation to the sectioned optic nerve in adult hamsters. Vision Res. 1993;33:877–880. [PubMed: 8506630]
169.
Sasaki H, Coffey P, Villegas-Perez MP, Vidal-Sanz M, Young MJ, Lund RD, Fukuda Y. Light induced EEG desynchronization and behavioral arousal in rats with restored retinocollicular projection by peripheral nerve graft. Neurosci Lett. 1996;218:45–48. [PubMed: 8939477]
170.
Gilbert CD. Adult cortical dynamics. Physiol Rev. 1998;78:467–485. [PubMed: 9562036]
171.
Kaas JH, Merzenich MM, Killackey HP. The reorganization of somatosensory cortex following peripheral nerve damage in adult and developing mammals. Annu Rev Neurosci. 1983;6:325–356. [PubMed: 6340591]
172.
Merzenich MM, Nelson RJ, Stryker MP, Cynader MS, Schoppmann A, Zook JM. Somatosensory cortical map changes following digit amputation in adult monkeys. J Comp Neurol. 1984;224:591–605. [PubMed: 6725633]
173.
Xerri C, Merzenich MM, Peterson BE, Jenkins W. Plasticity of primary somatosensory cortex paralleling sensorimotor skill recovery from stroke in adult monkeys. J Neurophysiol. 1998;79:2119–2148. [PubMed: 9535973]
174.
MacEvoy SP, Paradiso MA. Lightness constancy in primary visual cortex. Proc Natl Acad Sci U S A. 2001;98:8827–8831. [PMC free article: PMC37520] [PubMed: 11447292]
175.
Lemann W, Saper CB, Rye DB, Wainer BH. Stabilization of TMB reaction product for electron microscopic retrograde and anterograde fiber tracing. Brain Res Bull. 1985;14:277–281. [PubMed: 2581677]

Views

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...