Yves Sauve and Frederic Gallard
“…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).
Fig.1 Santiago Ramon y Cajal at work (From Cajal Institute; http://www.cajal.csic.es/)
Over 90 years after Ramon y Cajal’s farsighted work, 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 provided 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.
2. 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 following 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 (So and Aguayo, 1985; Vidal-Sanz et al., 1987; Aguayo et al., 1991) 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 over a century ago and was later tested by Tello in 1907 (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 (Tello, 1907). 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 retinal ganglion cells (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 (Richardson et al., 1980; David and Aguayo, 1981). 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 (Vidal-Sanz et al., 1987). These connections appeared capable of transmitting visual information (Keirstead et al., 1989; Sauve et al., 1995).
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 (Kim et al., 2003). The role of axonal growth inhibitors in axonal regeneration remains a controversial issue (Raisman, 2004). When developing experimental strategies, other factors have to be considered, such as axotomy-induced cell death and secondary degeneration (Schwartz, 2004a), scar formation (Rhodes and Fawcett, 2004), 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 (Chen et al., 1995; Shewan et al., 1995; Bouslama-Oueghlani et al., 2003).
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; 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 section 8).
3. 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:
1) Survival of axotomized neurons and prevention of secondary degeneration
2) Axonal extension of the neurons surviving axotomy
3) Guidance of regenerating axons towards their appropriate target(s)
4) Target innervation and synapse formation onto recipient neurons
5) Supra-threshold activation in target neurons caused by regenerated afferents
6) Restoration of ordered functional connections
7) 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) The fact that intact RGC axons arborize preferentially in the superficial layers of the SC onto which they form a point to point representation of the retina (Siminoff et al., 1966; Tiao and Blakemore, 1976; Finlay et al., 1978) allows comparison of the regenerated pathway with the 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 (So and Aguayo, 1985) (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 (Fukuda et al., 1998). Subsequent experiments (Villegas-Perez et al., 1988) 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 (Vidal-Sanz et al., 1987; Carter et al., 1989). If the central stump was placed in close proximity to a visual center, the axons formed terminal ramifications and synapses within that region (Aviles-Trigueros et al., 2000). 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 (Carter et al., 1989). While an anatomical study of topological representation of the regenerated axons has not been done, physiological experiments (Sauve et al., 2001a) have indicated that while 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 rostro-caudal 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.
4. Promoting the survival of axotomized RGCs
a) RGCs die after optic nerve transection
Following a complete intraorbital lesion of the adult mammalian optic nerve, the majority of RGCs are lost within 2 weeks (Villegas-Perez et al., 1988, 1993; Berkelaar et al., 1994; Peinado-Ramon et al., 1996). Axotomized RGCs start dying after one 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 (Berkelaar et al., 1994; Quigley at al., 1995). The pathways responsible for the apoptotic death of axotomized RGCs involve the activation of caspases type 3, 8, 9, and CPP32-like (Kermer et al., 1998, 1999b, 2000a; Weishaupt et al., 2003; Cheung et al., 2004), and the p38 mitogen activated protein kinase p38MAPK (Kikuchi et al., 2000). The inhibition of either or all of these caspases (Chaudhary et al., 1999; Kermer et al., 1998, 1999a, 2000a) or of p38MAPK (Kikuchi et al., 2000) 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 (Isenmann et al., 1997). The overexpression of Bcl-2 in transgenic mice has been shown to protect RGCs for axotomy-induced death (Bonfanti et al., 1996; Chierzi et al., 1998). 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 (Kugler et al., 2000). 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 RGC would have to target multiple pathways.
b) 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, 1998; Cui et al., 2000; Weishaupt and Bahr, 2001; Koeberle and Bahr, 2004). The rationale for supplying neurotrophins to axotomized RGCs is that their death might be related to the lost of retrogradely supplied trophic factors, such as BDNF, from their targets in the SC (Quigley et al., 2000; Caleo et al., 2000; Spalding et al., 2004). Axotomized RGCs can be rescued by experimentally supplying the retina with BDNF, either via intravitreal injections (Mey and Thanos, 1993; Mansour-Robaey et al., 1994; Peinado-Ramon et al., 1996; Klocker et al., 1998) or via gene transfection of retinal cells (Di Polo et al., 1998). Furthermore, transfection of retinal cells with the high affinity BDNF receptor TrkB also enhances the survival of axotomized RGCs (Cheng et al., 2002). 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 (Cohen et al., 1994; Peinado-Ramon et al., 1996); NGF (Carmignoto et al., 1989); GDNF (Klocker et al., 1997; Koeberle and Ball, 1998; Yan et al., 1999); Neurturin (Koeberle and Ball, 2002); and CNTF (Mey and Thanos, 1993; Weise et al., 2000; Watanabe and Fukuda, 2002; Cui and Harvey, 2000). 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, 2000; Patapoutian and Reichardt, 2001; Koeberle and Bahr, 2004. 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 (Fagiolini et al., 1997) 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 following RGC axotomy (Koeberle and Ball, 1999). Inhibition of NOS has been shown to promote the survival of axotomized RGCs (Koeberle and Ball, 1999), and when done in combination with BDNF, it potentiates the effect of this neurotrophin (Klocker et al., 1998). Modulation of microglial cells and macrophage activity has also been shown to have an effect on the survival of axotomized RGCs (Thanos et al., 1993, Raibon et al., 2002; Koeberle et al., 2004).
Finally, the prevention of axotomy induced RGC death has been explored using a vaccination approach known as “protective autoimmunity” (for a review see Schwartz, 2004b). Dr Michal Schwartz and colleagues recently demonstrated that T cells specific to self-proteins residing in the site of 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.
5. 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 (Villegas-Perez et al., 1988; Bahr et al., 1992) as well as acting as an environment permissive to RGC axonal regeneration (So and Aguayo, 1985; Vidal-Sanz et al., 1987). A maximum of 10% of the total RGC population in rodents (10,000 out of 100,000 in rats and hamsters)(Figs. 4a, b and c) can regenerate an axon as far as the distal end of an autologous PN graft, covering a distance of up to 2.5cm. 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 (Villegas-Perez et al., 1988). 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 prior to retrograde degeneration beyond the optic disc) remains to be clarified.
Fig.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 was prepared from 24 overlapping photographs printed at a magnification of 45 x . S, superior; N, nasal. Bar, 500 um. (from Vidal-Sanz et al., 198)
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 (Leon et al., 2000). Furthermore, macrophage stimulation, which is associated with the release of similarly acting molecules (Yin et al., 2003) 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 (Fischer et al., 2004).
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 (Chen et al., 1995; Shewan et al., 1995). 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 following micro-lesions of the optic nerve in adult rats (for a review see Ellezam et al., 2002). Another approach, investigated by Dr Mary Filbin and colleagues, involves elevating the intracellular level of cyclic AMP in neurons (Cai et al., 2001; for a review see Spencer and Filbin, 2004).
6. Guidance of regenerating RGC axons towards their appropriate target
Based on 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., 2004), regenerating axons have to navigate within the retina, find their way to the optic disc, exit it, and finally enter into the optic nerve. Following 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 (Sawai et al., 1996). 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).
Fig.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 the edge of the ON head. A, An axon in an untreated retina turns at the edge of the ON head, grows toward the periphery of the retina for 824 µm, and then forms a branch that is 445 µm in length. The main axon then turns toward the ON head and ends as a growth cone. Scale bar, 200 um. Inset, Drawn at higher magnification, the axon shown in A also has numerous small branches near the ON head. Scale bar, 50 um. B, An axon in a retina treated with 5 ug of BDNF at the time of ON transection has eight branches that range in length from 11 to 363 um. Scale bar, 100 um. C, An RGC axon in a retina treated with 5 ug of NT-3 ends over the ON head and has many short branches. Scale bar, 50 um. (from Sawai et al., 1996)
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., 2004). 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 superior colliculus (SC) and the dorsolateral geniculate nucleus (dLGN) and even more as shown in Figure 6).
Fig.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
By using PN grafts, it has been possible to guide regenerating RGC axons into their appropriate targets such as the SC (Vidal-Sanz et al., 1987; Carter et al., 1989; Keirstead et al., 1989; Sauve et al., 1995; Thanos and Mey, 1995; Sauve et al., 2001a), the dLGN (Carter and Jhaveri, 1997), the pretectal nuclei (Fig 7) (Aviles-Trigueros et al., 2000), or deliberately into inappropriate targets such as the inferior colliculus or cerebellum (Zwimpfer et al., 1992).
Fig.7. Light micrographs of 40-um-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, CTB-labeled fibers extend through the dorsal aspect of the midbrain toward the midline. These fibers arborize within the NOT and OPN. Scale bar, 50 mm. B, CTB-labeled fibers show numerous varicosities within the NOT. Scale bar, 20 um. C, PN graft entry zone lateral to the diencephalon. Note the interface between the PN graft and the midbrain and regenerated fibers crossing the interface. Scale bar, 50 um. Insets in A-C are drawings of the respective section of the midbrain, and the red boxes indicate the region photographed. Scale bar, 1 mm. (from Aviles-Trigueros et al., 2000)
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 (Aviles-Trigueros et al., 2000). 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).
Fig.8. Light micrographs of a 40-um-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 between PN graft and diencephalon. Most of the retinal axons do not exit the PN graft and appear within a neuroma-like formation. Scale bar, 47 um. Inset is a drawing of the section, and the box indicates the region photographed. Scale bar, 1 mm. B, Detail from box in A showing CTB-labeled axons that reach the distal end of the PN segment but turn around and do not enter the brainstem. Scale bar, 19 um. (from Aviles-Trigueros et al., 2000)
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 (Dusart et al., 1999) and at the PNS-CNS interface (Liuzzi and Lasek, 1987; Bandtlow et al., 1990; Smith et al., 1990; Davies et al., 1997, 1999; Fawcett, 1997); 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 sulphate proteoglycans (CSPG).
In some instances, PN grafts cannot be directly inserted into appropriate targets due to the small size of the nucleus. In the study of Aviles-Trigueros et al. (2000) 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 (Figs. 9, 10, 11). This occurred even though some nuclei within their trajectory were deafferented by the surgery associated with graft insertion.
Fig. 11. Light micrographs of 40-um-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. A, CTB-labeled retinal axons innervate the OPN extensively (toward the top left) and the rostral limit of the NOT (toward the middle and right). Scale bar, 35 um. B, Extensive innervation of the NOT area with numerous varicosities resembling bouton-like endings in a more caudal section. Scale bar, 28 um. Insets in A and B are drawings of the respective section of the midbrain, and the red boxes indicate the region photographed. Scale bar, 1 mm. (from Aviles-Trigueros et al., 2000)
The specificity of innervation of visual and non-visual targets would appear to be at odds with the observation of Zwimpfer et al. (1992) showing innervation of the cerebellum by optic axons regenerating through peripheral nerve grafts. There is however a significant difference in experimental design in that in the study of Aviles-Trigueros et al. (2000), 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 (Doug, 1986). The mechanisms responsible for “apparent” preference of appropriate target in studies such as by Aviles-Trigueros et al. (2000) are still unclear.
In addition to PN grafting, several studies have reported successful RGC axonal regeneration within the severed optic nerve (Eitan et al., 1994; Berry et al., 1996; Leon et al., 2000; Fischer et al., 2001; Ellezam et al., 2002; Li et al., 2003). 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.
7. 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 (Vidal-Sanz et al., 1987; Carter et al., 1991, 1998; Aviles-Trigueros et al., 2000). The study of Aviles-Trigueros et al. (2000) 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 (Figs. 12 and 13).
These types of terminals are reminiscent of the terminals previously described for such retinorecipient nuclei in another rodent (Ling et al., 1998). 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 (Ling et al., 1998). 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 (Carter and Jhaveri, 1997), and that regenerating axons modify their arbors to adapt to the local conditions of the target nucleus.
Fig. 14. Light micrographs and drawing illustrating regenerated retinal fibers in the stratum griseum superficiale of 40-um-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. A, Single regenerated RGC axon in the SGS of the SC forming many branches that bear multiple varicosities of similar appearance and uniform size. Scale bar, 10 um. Inset illustrates a drawing of the midbrain section and indicates the region photographed. Scale bar, 1 mm. The stem axon is indicated by an arrowhead. B, High-power reconstruction of the terminal arbor in A. Scale bar, 9 um. C, Close interrelation between terminal cluster of bouton-like endings of regenerated retinal projections and SC neurons. Scale bar, 8 um. (from Aviles-Trigueros et al., 2000)
In 1987, Vidal-Sanz et al. provided experimental evidence that regenerating RGC axons were able to re-establish connections in visual centers of the brainstem (Fig. 15) (Vidal-Sanz et al., 1987).
Fig. 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 round or spheroidal. The thickenings of the pre- and postsynaptic membranes at the synaptic contacts are indicated by arrows. a, Characteristic DAB-Co-stabilized TMB reaction product (Lemann et al., 1985) is confined to the presynaptic axon terminal. b, As occasionally occurs with this ‘technique’, the reaction product extends beyond the boundary of the terminal. Bars, 1um. (from Vidal-Sanz et al., 1987)
These connections appear to persist for the life span of the rodent, i.e. up to 2 years of age (Vidal-Sanz et al., 1991). 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 (Carter et al., 1989). Therefore, regenerated RGC axons can establish well-differentiated synapses with neurons in the SC. Based on their results, Carter et al. (1989) 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.
8. Generation of action potentials in target neurons
Dr Sue Keirstead and colleagues provided electrophysiological evidence that the synapses such as the ones described at the electron-microscopic level by Vidal-Sanz et al. (1987) could mediate the transynaptic activation of neurons in the superior colliculus of adult mammals (Keirstead et al 1989). 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 post-synaptic activity could be elicited in the reinnervated SC.
Fig. 16. (A) Ten 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 four of ten iterations. (B) The same unit responds erratically with inconsistent latency to (traces 1) single electrical stimuli (arrow) delivered to the graft and responds at a more constant latency, often with multiple spikes, to (traces 2) paired electrical stimuli (arrows) of the same intensity. This pattern of response is inconsistent with that anticipated from an RGC axon and thus identifies this unit as an SC neuron. All recordings were filtered (band pass 500 Hz to 5 KHz) and stored on magnetic tape. (from Keirstead et al., 1989)
Fig. 17. Unitary response to static illumination of a spot 4″ in diameter recorded at a depth of 190 um in a reinnervated SC 37 weeks after graft insertion. Bandpass 100 Hz to 5 kHz
Further studies by Sauve et al. (1995), 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 (Fig. 18). FSPs are extracellular changes in potential that reflect the summation of excitatory post-synaptic 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 RGCs (as inferred from the TPs).
The results from Sauve et al. (1995) 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. (2001) 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 ultra-structural 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.
9. 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 (reviewed in Gaze, 1970).
Fig. 20. Photograph of Nobelist Roger Sperry
Sperry’s impressive demonstration involved sectioning a frog’s optic nerve and rotating the eye by 180Á (Sperry, 1950). 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 chemospecificity theory (Sperry, 1963), 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” (Sperry, 1965).
Fig. 21. When the eye is rotated 180Á, 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 in order 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. (2004). 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), while others (Ctenophorus ornatus) fail to maintain a retinotopic ordering of the regenerated projection, and lose their capacity to perform visually guided tasks (Dunlop et al., 2003). However, training on a visual task has been shown to improve the outcome of optic nerve regeneration in Ctenophorus ornatus lizards (Beazley et al., 2003).
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 while axons from RGCs located in the nasal retina project to the caudal (posterior) contralateral SC (Siminoff et al., 1966; Tiao and Blakemore, 1976; Finlay et al., 1978). Ventral RGCs project axons medially and dorsal RGCs project axons laterally in the contralateral SC (Fig. 22).
Fig. 22. Ventral view schematic of retinotectal projections
In order 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” (Walter et al., 1987a,b). 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 while nasal RGC axons grow equally well on either rostral or nasal tectal tissue stripes (Walter et al., 1987a,b; Godement and Bonhoeffer, 1989; Roskies and O’Leary, 1994), or show a preference for nasal stripes providing specific pre-treatments (von Boxberg et al., 1993). This preference appears to be developmentally regulated in a way that is lost in the mature system. However, Dr Mathias Bahr and colleagues showed that this capacity can be partially restored following optic nerve cut in adult rats (Bahr and Eschweiler, 1991, 1993; Wizenmann et al., 1993). 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 comprise these four classes: netrins, semaphorins, slits and ephrins (for a review see Koeberle and Bahr, 2004). 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 (King et al, 2003). Furthermore, the Eph/ephrin system is required to restore topography since blocking their interactions in vivo with fusion proteins results in abnormal topography (Rodger et al., 2004). In rodents, in which spontaneous regeneration does not occur, most of the known guidance molecules have been shown to be modulated following deafferentation. However, while 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? (Example from the study of Sauve et al., 2001a)
The study of Sauve et al. (2001a) indicates that regenerating mammalian RGC axon terminals do not form a precise retinotopic map (compared to normal intact animals, Fig. 23) when reinnervating the SC (Fig. 24).
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. (2001a) 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 occurs.
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 (1963), 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, 1999) serves mutually to stabilize the connections of their shared target neurons in the LGN or tectum (Shatz, 1990, Cline 1991; Penn et al., 1998; Debsky and Cline, 2002; Schmidt, 2004). Initial pathfinding of RGC axons in the tectum may be very precise as in frogs and fish (Holt and Harris, 1983; Stuermer et al., 1992), or more exuberant and diffuse, as in rodents (Simon and O’Leary, 1992a, b). 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 (Fraser and Perkel, 1990; Honda, 1998), for example even if a molecular gradient is only transiently expressed during the initiation of innervation of the tectum (Hua et al., 1993).
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 (Matsumoto et al., 1987; Meyer and Kageyama, 1999). 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 (Udin and Fawcett, 1988; Cline 1991).
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 (Walter et al., 1987a). These topologically specific markers disappear after the retino-collicular pathway is laid down, but reappear about 2 weeks after denervation of the SC (Wizenmann et al., 1993). Such positionally specific markers may be more strongly expressed in deafferented SC than in embryonic SC (Bahr and Wizenmann, 1996). The experimental results of Sauve et al. (2001) 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 (Baier and Bonhoeffer, 1992; Wizenmann and Bahr, 1997, 1998).: either by exerting a repulsive or tropic effect on their axonal growth cones (Walter et al., 1987a,b; Boxberg et al., 1993; Nakamoto et al., 1996; Ichijo and Bonhoeffer, 1998, Davenport et al., 1998), or by influencing their branching patterns (Roskies and O’Leary, 1994). Positionally specific markers could also influence the deployment of regenerating RGC axons within the nerve graft as they approach the SC (Goodhill, 1998).
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 (Carter et al. 1994). More extensive exploration of the SC is perhaps limited by the presence of factors inhibitory to axonal growth (Caroni and Schwab, 1988; McKerracher et al. 1994; Smith-Thomas et al., 1994; Ghosh and David, 1997) that are present in the adult animal as well as by the developmental down-regulation of growth permissive molecules (McLoon et al., 1988; Rager et al., 1996) and receptors (Cohen et al., 1986; de Curtis and Reichardt, 1993). This is in contrast to the situation during normal development, where RGC axons from all portions of the retina initially innervate the entire SC (Simon and O’Leary, 1992a,b). 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 (Vidal-Sanz et al., 1987). Many axons terminate growth immediately after penetrating the CNS (Aviles-Trigueros et al. 2000). One way to increase sprouting of regenerating RGC axons in the SC could be to provide brain-derived neurotrophic factor (BDNF) and chondroitinase ABC (Tropea et al., 2003). 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.
10. Preservation of local and downstream circuitry
In the study of Turner et al. (2001), the local synaptic connectivity in the superficial gray layer of the superior colliculus (SC) was assessed following RGC axonal regeneration through a peripheral nerve graft into the rat SC, using in vitro brain slice techniques. Repair was achieved between the ipsilateral eye and SC, following 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 (Lund and Lund 1971, Fig 25) and the remainder (10%) from the visual cortex (Harvey and Worthington, 1980).
Fig. 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 (arrows); only one contact has vesicles aggregated to it. (d) Myelin lamellae make asymmetric contact. Scale indicates 0.1 um. (from Lund and Lund, 1971)
Interconnectivity within the SGL appears to be mediated by local GABAergic interneurons (Mize, 1988; Pinard et al., 1991). Both the GABAergic processes of local circuit interneurons (Lund and Lund, 1971; Houser et al., 1983) and the axon terminals of other projections proliferate (Gerrikagoitia et al., 2000; Garcia del Cano et al., 2002) following 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 (Lund and Lund, 1971). As a result, the synapse to neuron ratio stays the same in the SC (Smith and Bedi, 1998), although it is not known whether these synaptic contacts are functional. Since 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 superficial gray layer (SGL).
Fig. 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 X 50,000. (from Lund and Lund, 1971)
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 (Isa et al., 1998). In addition, contralateral enucleation 14 days prior to recording is sufficient to result in a complete loss of excitatory inputs to the SGL in vitro following intracollicular stimulation (Miyamoto et al 1990). However, the study of Turner et al. (2001) suggest 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 due to the recruitment of corticocollicular projections, which run close to the optic tract (Bourassa and Deschenes, 1995). Indeed, anatomical studies have shown that 30-45 days after contralateral enucleation there is a reactive synaptogenesis of corticocollicular terminals (Garcia del Cano et al., 2002). 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 following PN-graft repair
Following 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 of Turner et al., (2001) 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 due 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). Since 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 (20-30ms) in the onset of the network depolarizations following electrical stimulation (reported by Turner et al., 2001) suggests that sprouted excitatory input is poly-synaptic, 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 since IGL neurons form a recurrent collateral network in normal animals and produce long lasting synaptic responses in the presence of bicuculline (Isa et al., 1998). The network reorganization in the PN graft preparation (recorded in vitro, (Turner et al., 2001) is not that surprising, in view of the impact of deafferentation in other structures, e.g. cerebral cortex (Salin et al., 1995) or the dentate gyrus of the hippocampus (Laurberg and Zimmer 1981). 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 Turner et al.’s work (2001) that intrinsic changes in response patterns will impact the way the SGL will function during visual stimulation. Keirstead et al. (1989) demonstrated that, in comparison to normal controls, restoration of functional retinal inputs into the SC, using the PN-graft method, had delays in the onset of post-synaptic action (Fortin et al., 1999). 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, in order to identify the locus/loci of the reactive changes that underlie(s) altered network behavior. In addition, for improvements in current strategies of pathway repair, there is the need to limit or reverse these deafferentation-induced changes because firstly, this would allow a better assessment of the efficacy of new connections, and secondly it would probably improve system function.
In conclusion, axonal regeneration to a target alone clearly does not guarantee functional recovery. The study of Turner et al. (2001) 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.
11. 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 (Thanos, 1992). Further studies (Whiteley et al., 1998) showed that at best, the response amplitude and latency could be within normal range, but one noticeable difference was that while 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 (Sasaki et al., 1993). Finally, animals were tested to demonstrate whether the regenerated pathways could mediate EEG desynchronization behavior to light (Sasaki et al., 1996). 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.
12. 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 superior colliculus, 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, since 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 (Kaas et al., 1983; Merzenich et al., 1984; Gilbert, 1998; Xerri et al., 1998): even in an intact animal the system is able to operate over a wide range of luminance and contrast sensitivity (MacEvoy and Paradiso, 2001). 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.
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