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. 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. 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. 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

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. 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 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. 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. 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. 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. 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 (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 (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 (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. 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 (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 (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. 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. 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. Bandpass 100 Hz to 5 kHz. From Sauve et al. (9).

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. 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.

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. 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.

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. 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. 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. 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. 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 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

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