Wesley, and all:
Ok.......regarding axon "regeneration" in the ADULT CNS. I found a terrific LENGTHY article.
I'll post some of it here, but what it basically is saying is what Wesley alluded to earlier here, and what the original discussion I posted first in this thread is talking about. Axon regeneration in the adult CNS is somehow inhibited. This is what researchers are now working on. How to "trigger" or activate the regeneration process in the adult (i.e. postnatal) CNS.
These excerpts below are talking about how to activate "in vivo" (key words there) axonal regeneration in the CNS. The thought is it takes not only growth factors and neurotrophins, but ALSO an elevation in cAMP at the same time in order for CNS regeneration to result.
I propose to go one step farther (based on prior research of mine). If you can also block PKC activity, inhibit Nogo-A/NgR (which is a protein that has been found to impair regeneration in the CNS after injury), and also enhance GAP-43 at the same time as increasing neurotrophins and elevating cAMP, what have you got
then? The possibility or even probability of activating axonal regeneration in the adult CNS in vivo?? I'd say YES!
Here are some interesting findings. I'll warn you, they are lengthy. The whole article can be found at
http://www.genesdev.org/cgi/content/full/17/8/941
Quote:
Control of neuronal responsiveness to trophic peptides
An interesting difference between the ability of trophic peptides to promote axon growth by CNS and PNS neurons has been identified. Peptide trophic factors, such as neurotrophins, are sufficient to induce axon growth by purified PNS neurons in culture. In contrast, to elicit axon growth from CNS neurons in culture, peptide trophic signals alone are insufficient. For instance, retinal ganglion cells (RGCs) fail to survive in the presence of such trophic signals as BDNF or CNTF unless their cAMP levels are elevated, either pharmacologically or by depolarization (Meyer-Franke et al. 1995 ). cAMP elevation and depolarization do not promote axon growth on their own. Similarly, RGCs kept alive with Bcl-2 overexpression extend axons only poorly in response to BDNF, but this axon growth is greatly potentiated by cAMP elevation or by physiological levels of electrical activity, either from endogenous retinal activity or from direct electrical stimulation when cultured on a silicon chip (Goldberg et al. 2002a )....
…. This trophic dependence contrasts with PNS neurons, which survive and regenerate their axons in response to trophic peptides in the absence of cAMP elevation or electrical activity, raising the hypothesis that the trophic signaling of axon growth may differ between CNS and PNS neurons. Could this difference contribute to their different abilities to regenerate in vivo? Previous studies have suggested that trophic factor delivery alone or electrical stimulation alone do not induce CNS axonal regeneration. If axon growth normally depends on activity in vivo, and if damaged cells are less active, or elevate cAMP less effectively in response to activity, a CNS neuron's ability to regenerate its axon could be impaired. Therefore it may be crucial to provide trophic peptides as well as signals such as cAMP elevation to ensure an optimal axon growth response (Shen et al. 1999 ; Goldberg and Barres 2000 ). Although cAMP elevation has been implicated in overcoming inhibitory signals at the growth cone (Ming et al. 2001 ), it is interesting to speculate whether some of the effect of cAMP in promoting regeneration in vivo is actually attributable to improving the neurons' response to trophic or other positive peptide signals (Neumann et al. 2002 ; Qiu et al. 2002 )....
…. Intrinsic growth ability of CNS neurons is developmentally regulated
Is the rate and extent of axon growth dependent purely on extracellular signals and substrates, or does it also depend on the intrinsic state of the neuron? This is a critical, though largely unanswered, question in research on axon growth and regeneration. Embryonic CNS neurons can regenerate their axons quite readily, but they lose their capacity to regenerate with age (Schwab and Bartholdi 1996 ; Fawcett 1997 ). For example, in the spinal cord, axons lose the ability to regenerate between P4 and P20 (Kalil and Reh 1982 ; Reh and Kalil 1982 ; Saunders et al. 1992 ). This developmental loss of regenerative ability has generally been attributed to the maturation of CNS glial cells, both astrocytes and oligodendrocytes, and to the production of CNS myelin, all of which strongly inhibit regenerating axons after injury (Schwab and Bartholdi 1996 ). Embryonic neurons also develop responsiveness to myelin-associated inhibitors through this period (Bandtlow and Loschinger 1997 ). In experiments in which a PNS nerve graft (David and Aguayo 1981 ; Bray et al. 1987 ) or anti-myelin neutralizing antibodies (Huang et al. 1999 ) or removal of proteoglycans associated with reactive astrocytes (Moon et al. 2001 ) allow axons to circumvent contact with these inhibitory CNS glia, however, only a few percent of axons regenerate, and functional recovery typically proceeds remarkably slowly. For example, RGCs take 2 mo to regenerate through a peripheral nerve graft (Aguayo et al. 1987 ; Bray et al. 1987 ). These experiments indicate that an inhibitory environment is likely only part of the explanation.
Are the neurons themselves partly responsible? Axons from P2 or older hamster retinas have lost the ability to reinnervate even embryonic tectal explants (Chen et al. 1995 ). Purkinje cells in cerebellar slices show a similar age-related inability to re-extend axons out of cultured slices (Dusart et al. 1997 ). This suggests that changes in a CNS neuron's intrinsic ability to grow could also explain this developmental loss of regenerative ability. The lack of postnatal neurons to re-extend their axons might also be explained by the development of glial cells, however, which are largely generated postnatally. Therefore the ability to separate neurons from CNS glia remains critical to determining whether CNS neurons actually change in their intrinsic axon growth ability during development.
By purifying neurons away from nearby glia at various developmental stages, we recently showed that neonatal RGCs undergo a profound, irreversible loss in their intrinsic ability to regenerate their axons (Goldberg et al. 2002b ). When cultured in strongly trophic environments in the complete absence of CNS glia and at clonal density, embryonic RGCs extend axons up to 10 times faster than postnatal RGCs. The evidence for this decreased growth ability being intrinsically maintained is twofold. First, we found that embryonic RGCs grew at a faster rate than postnatal RGCs in a variety of environments that should facilitate growth, including in media containing neurotrophic factors, in media conditioned by cells from the embryonic visual pathway, and after transplantation into developing pathways in vivo. In all cases, embryonic RGCs extended their axons at rates substantially higher than did the postnatal RGCs, suggesting that any extrinsic growth-promoting environment is dependent on an intrinsically set maximal growth rate. Second, we found that RGCs purified from either embryonic or postnatal ages, and cultured away from all of the other cell types with which they normally interact, retained their faster or slower growth phenotypes, respectively. Therefore the difference in the abilities of embryonic and postnatal RGCs to elongate axons is not dependent on continued signaling by neighboring cell types, but is intrinsically maintained. ....
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In one part, they induced brain lesions in mice and saw that Olig1 proteins were located in the nucleus of cells (as opposed to the cytoplasm of those cells) around the lesions that were being remyelinated. They also found this nuclear Olig1 pattern in post-mortem examinations of brains of MS patients. So I guess this is supposed to suggest that the mechanism may be similar for mice and people. They then compared the remyelination efficiency of induced lesions in mice populations with and without the gene for Olig1. Several weeks after the induced lesions, the mice with Olig1 had less severe demyelination than the mice without Olig1. This would support the notion that Olig1 is important for remyelination.
