Why Aren’t We More Like Fish and Frogs?
The question of why the mammalian central nervous system does not regenerate after injury is of extra-ordinary interest at many levels. In terms of descriptive biology, it is remarkable how great the discrepancy is between nerve cells that can, and cannot repair their connections after their axons have been lesioned.
In an invertebrate such as the leech, in fishes and in frogs the central nervous system does show effective regeneration and restoration of function after complete transection. Thus, a leech can swim again after it’s nervous system has regenerated after being cut in two, and a frog can catch flies with it’s tongue after it’s optic nerve has grown back to the tectum(the dorsal portion of the midbrain, containing the superior colliculus and inferior colliculus).
In these “simple” animals the wiring is far more complex than in any man-made circuit, yet somehow fibres grow to find their targets and form effective synapses upon them. In this they resemble their counterparts in the mammalian peripheral nervous system.
What makes the mammalian central nervous system so different in this regard?
At the cellular and molecular level, differences between non-regenerating and regenerating neurons and the satellite cells that surround them are the focus of intense research. Detailed information is accumulating about molecules that enhance or inhibit growth, as well their receptors. And at the level of clinical medicine, there is the essential question about whether and when treatments can be devised for patients with central nervous system injuries so that functions can be restored.
Recent experiments at all of these levels have provided unexpected new findings and insights. Yet one of the most striking features of the field of regeneration today is how many key questions remain. For example, while we have clues, the mechanisms that prevent regeneration in mammalian CNS are still not fully known.
Why is the proportion of axons, that actually elongate, so small, even when the application of suitable techniques does give rise to successful growth across a lesion?
What changes in molecular mechanisms of growth occur in immature mammals during development, that later prevent regeneration in the adult?
While it seems reasonable to guess that understanding of growth promoting and inhibiting mechanisms will continue to proceed rapidly, a baffling question remains. It arises from our ignorance about normal development of the nervous system.
At present it is not known how specific synapses form, so that one type of cell is selected as a target while another one sitting just next door is ignored.
If hope is to be offered to patients with spinal cord lesions, axons must not only grow (obviously a prerequisite for repair) but they must reform useful connections with the appropriate targets. In the best of all possible worlds no errors would be made. One also can imagine a scenario in which incorrect connections are formed and subsequently tuned by use; pain fibres would, one hopes, not re-form connections in patients.
All the neuroscientists who work on these problems have to face inevitable and quite natural questions about prospects for therapy.
A convenient analogy seems to me to be the repair of a watch. A desirable requirement would surely be to have an understanding of how the watch works and what the various components are doing. Without that knowledge one can still hope for some new insight or fluke that will allow the repair to be made. It would, however, be dangerous to promise how soon the watch will work again until the failure has been diagnosed and only one or two parts remain to be replaced. Because we are not even remotely at this stage in our knowledge of the nervous system, predictions about how and when seem unrealistic. (This analogy is of course flawed: the nervous system has to do the job on it’s own once one has provided the appropriate conditions).
In contrast to the plasticity of the brain, in the spinal cord the degree of plasticity is much less, although perhaps currently underestimated. Once the long tracts are severed or compressed to the point of axotomy, they will not recover and there is usually insufficient overlap in function in the spinal cord for the missing functions to be taken over by surviving tracts, should there indeed be any. The spinal cord is such a narrow structure, normally well protected by the bone forming the spinal canal, that any injury sufficient to damage it in part, may well be severe enough to damage it completely.
In the general strategy of devising spinal repair procedures that could eventually be applied in patients, there are at least four problems to be overcome:
- Central nervous system neurons show a variable response in their ability to produce neurites in response to injury, in contrast to peripheral nervous system, which show a consistent ability to do this.
- Following damage to the CNS, as for example in a spinal cord injury, any neurites that do appear at the site of injury are unable to cross it, which in patients may involve a substantial length of spinal cord.
- Once methods for promotion of growth of axons across the site of injury are available in a clinically applicable form, the axons may have to grow considerable distances to reach appropriate targets and may require specific guidance cues to direct them to functionally appropriate targets.
- Having reached appropriate targets, effective functional re-innervation of the targets should occur.
It is not entirely clear how separable are these four components of successful repair. There is increasing evidence that they may indeed be substantially separate processes and that achievement of one will not automatically lead to success with the others.
Thus the work described by Beazley & Dunlop on regeneration in the lizard shows clearly that while axotomised fibres can regrow to the appropriate targets in the visual systems in this species, no functionally effective innervation occurs.
Beazley and Dunlop describe different features of a wide range of species from cold-blooded vertebrates to mammals. Particularly with respect to effectiveness of target re-innervation, there appears to be a spectrum of regeneration. This goes from amphibia and lampreys (with particular respect to the underlying subcellular structures that may be responsible for regenerative outgrowth of injured axons) which can regenerate not only new axons but also functional connections with appropriate targets, through lizards that show excellent axonal growth, but inappropriate target innervation, to mammals in which neither regenerative axon growth nor appropriate target innervation normally occur. The evolutionary significance of this progressive loss of regenerative ability (an ability which is even more marked in invertebrates) through the animal kingdom is unclear.
The central nervous system of adult mammals, including humans, recovers only poorly from injury. Once severed, major axon tracts (such as those in the spinal cord) never regenerate. The devastating consequences of these injuries—e.g., loss of movement and the inability to control basic bodily functions—has led many neuroscientists to seek ways of restoring the connections of severed axons. There is no a priori reason for this biological failure, since “lower” vertebrates—e.g., lampreys, fish, and frogs—can regenerate a severed spinal cord or optic nerve.
Even in mammals, the inability to regenerate axonal tracts is a special failing of the central nervous system; peripheral nerves can and do regenerate in adult animals, including humans.
Why, then, not the central nervous system?
At least a part of the answer to this puzzle apparently lies in the molecular cues that promote and inhibit axon outgrowth.
In mammalian peripheral nerves, axons are surrounded by a basement membrane (a proteinaceous extracellular layer composed of collagens, glycoproteins, and proteoglycans) secreted in part by Schwann cells, the glial cells associated with peripheral axons. After a peripheral nerve is crushed, the axons within it degenerate; the basement membrane around each axon, however, persists for months.
One of the major components of the basement membrane is laminin, which (along with other growth promoting molecules in the basement membrane) forms a hospitable environment for regenerating growth cones. The surrounding Schwann cells also react by releasing neurotrophic factors, which further promote axon elongation.
This peripheral environment is so favourable to regrowth that even neurons from the central nervous system can be induced to extend into transplanted segments of peripheral nerve.
Albert Aguayo and his colleagues at the Montreal General Hospital found that grafts derived from peripheral nerves can act as “bridges” for central nervous system neurons (in this case, retinal ganglion cells), allowing them to grow for over a centimeter (Figure
A); they even form a few functional synapses in their target tissues (Figure B).
These several observations suggest that the failure of central neurons to regenerate is not due to an intrinsic inability to sprout new axons, but rather to something in the local environment that prevents growth cones from extending.
This impediment could be the absence of growth-promoting factors— such as the neurotrophins—or the presence of molecules that actively prevent axon outgrowth.
Studies by Martin Schwab and his colleagues point to the latter possibility. Schwab found that central nervous system myelin contains an inhibitory component that causes growth cone collapse in vitro and prevents axon growth in vivo. This component, recognized by a monoclonal antibody called IN-1, is found in the myelinated portions of the central nervous system but is absent from peripheral nerves.
IN-1 also recognizes molecules in the optic nerve and spinal cord of mammals, but is missing in the same sites in fish, which do regenerate these central tracts.
Nogo-A, the primary antigen recognized by the IN-1 antibody, is secreted by oligodendrocytes(they are present in central nervous system), but not by Schwann cells in the peripheral nervous system. Most dramatically, the IN-1 antibody increases the extent of spinal cord regeneration when provided at the site of injury in rats with spinal cord damage. All this implies that the human central nervous system differs from that of many “lower” vertebrates in that humans and other mammals present an unfavourable molecular environment for regrowth after injury.
Why this state of affairs occurs is not known.
One speculation is that the extraordinary amount of information stored in mammalian brains puts a premium on a stable pattern of adult connectivity.
At present there is only one modestly helpful treatment for CNS injuries such as spinal cord transection. High doses of a steroid, methylprednisolone, immediately after the injury prevents some of the secondary damage to neurons resulting from the initial trauma.
Although it may never be possible to fully restore function after such injuries, enhancing axon regeneration, blocking inhibitory molecules and providing additional trophic support to surviving neurons could in principle allow sufficient recovery of motor control to give afflicted individuals a better quality of life than they now enjoy. The best “treatment,” however, is to prevent such injuries from occurring, since there is now very little that can be done after the fact.
- Degeneration and Regeneration in the Nervous System edited by Norman Saunders, Katarzyna Dziegielewska; Anatomy and Physiology, The University of Tasmania, Australia©2000, OPA (Overseas Publishers Association)
Neuroscience, 3rd edition. Editors: Dale Purves, George J Augustine, David Fitzpatrick, Lawrence C Katz, Anthony-Samuel LaMantia, James O McNamara, and S Mark Williams. Sunderland (MA): Sinauer Associates; 2004. ISBN 0-87893-725-0
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