Injury to the adult central nervous system (CNS) is devastating because of the inability of the central nervous neurons to regenerate correct axonal and dendritic connections. Injury can lead to neuron degeneration and cell death. Raymon y Cajal 1928 and Tello 1911 showed that adult CNS neurons could re-grow if they have access to the permissive environment of a conditioned sciatic nerve.
Further studies were replicated with new methods by Aguayo and colleagues and confirmed that the adult CNS neurons the ability to regenerate.
As the CNS could not regenerate it was not due to intrinsic deficits of the neurons, but rather a characteristic feature of the damaged environment that either did not support or prevented regeneration.
There are several strategies for regeneration in the adult CNS. Firstly, the injured neuron must survive, and then damaged axon must extend its cuts processes to its original neuronal targets. Once contact has been made, the axon needs to be remyelinated and function synapse need to form on the surface of the targeted neurons.
Degenerative disease where a defined phenotype is lost, such as Parkinson’s disease are also good targets, but may be more challenging because of the potential for continued cells loss or axonal degeneration.
Recovery after brain damage is a very limited area, which have been vaguely studies in the area of neuroscience. The reason because it is difficult to conduct controlled experiment on population of brain damaged patients. The second reason being is that the nervous system damage may result in a variety of outcomes in to conclude as to whether or not it is the true result of the recovery.
Neural regeneration is though to be lost once they have reached maturity, which is virtually non-existent in the CNS of the adult mammals. However, research has shown that PNS neurons are regenerated in the mammalian and CNS are not capable of doing so. However, research provided has proved this view as being wrong. The CNS is capable of regeneration only if they are transmitted to the PSN. However, the factors that affect this could be the environment of the PNS that promotes regeneration and something that is not available in the CNS. (Goldberg and Barres, 2000).
In most CNS trauma and disease, both neurons and glia are lost. In addition, spared systems cannot supplant the function of lost cells. Injury to the spinal cord has provided example of loss motor neurons. The motor neurons that project to the muscles are irrevocably lost.
Stem cells are a good source for introducing new neurons or glial cells to the damaged CNS. Neural stem cells have a key potential as they are multipotent and can be propagated in vitro. Once transplanted into the brain, neural stem cells can adopt to the region of engraftment by differentiating into the appropriate neuronal and glial subpopulations.
Several studies have found that stem cells can lead to neurogenesis in animal model of degeneration. Such as cortical neurons that are undergoing damage-induced apoptosis, which replaced morphologically by, transplanting embryonic stem cells which resemble pyramidal cells.
Research in the area of neurogenesis has recent discovery bearing on Huntington's Disease. By studying post-mortem brains of people with HD, researchers evidence suggesting that HD-affected brains produce new neurons throughout the course of the disease. Moreover, there is a correlation between the rate of neurogenesis and the severity of the illness. The brains of individuals at the most severe stages of HD showed the most neurogenesis. It appears that the brain is attempting to compensate for the neural damage resulting from the disease. Unfortunately, however, brains damaged by HD seem to be unable to generate new neurons quickly enough to replace the dying ones. Another problem may be that the new neurons are unable to migrate to the areas where they are needed.
Research as to whether strokes, which occur because of gradule loss of neural functions around the core of the brain, are able to recover after the incident has been phenomenal. Research by Nudo and colleagues produced small ischemic lesion in the hand area of the motor cortex of monkeys. Over 3 to 4 weeks the program that the monkeys were initiated to do was visible in their behaviour. The monkeys that had received the rehabilitative training also showed greater recovery in the use of their affected hand. Based on the principal that neurons compete with each other in the synaptic site, Weiller and Rijnjes 1999 designed a rehabilitation program. It was tested on unilateral stroke patients and monkeys. Result showed there was remarkable recover in the affected arm and there was an increase in the area of motor cortex controlling that arm.
The phantom of the limbs is a breakthrough into neuroscience. It assesses the ability of the adults brains ability to recover any loss or damaged sense in the limbs that they have lost by stroke or had amputated, has raised many interesting facts about the capabilities of the human brain. Ramachandran study on monkey’s provide the key evidence that even after that a limb has lost its ability to function properly sensory input from the face activates the area of the Penfield homunculus. Eighteen patients had participated in the study either in which each subject had a case of a limb amputated or that they had brachial vision. Result showed that sensation could be felt in the phantom limb from the face on eight of the patient’s. Also one amputee felt that his phantom arm extended straight out from the shoulder, as a result of this her always turned sideways whenever he passes through doorways. (Melzack 1992 [1])
Ramachandran went on to produce the ‘’remapping hypotheses’’ Ramachandran p. which states that because there was a direct change in topography following differentiation.
The remapping hypothesis also predicts that after trigeminal nerve section, one should observe a map of the face on one hand and shown in the remarkable study by Clarke et al 1996.The study conducted on a patient whose mandibular and maxillary parts of right trigeminal ganglion removed experienced referred sensations after stimulation of the right hand and right forehead. She described them either as parallel to the perception at the actual stimulation site or as coming uniquely from a (non-existent) stimulation of denervated territory.
Thumb stimulations localized on the right side of the face, stimulations of right forehead, middle and ring fingers more precisely on right cheek. Referred sensations were present on postoperative day 7 and had a more real-like quality than 5 days later.
After amputation of the index finger in one of the patient, a map of the index finger found neatly draped across the ispuateral cheek. (Aglioti et al 1994)
Barsook et al 1994 found that even a few hours after amputation the pre-existing connection other than the sprouting receives support that there is sensation from the face to the phantom limb.
Using his ingenuity and previous knowledge from the finding from his previous research, he invented a special tool to help his patients who suffer from mobility whether due to stroke or disease.
V.S Ramachandran’s (1998) [1] and his box invention
The remapping hypotheses has received immense support from the finding from other researchers who reached the same conclusion according to the remapping hypotheses. We can say that we are now able to track the time course of perceptual changes in humans of which therefore systematically related to the anatomy. Due to topography and modality specificity it rules out any possibility of the refer as being due to non-specific arousal.
Studies dedicated to finding out whether or not there is sensation in phantom limbs have a more clear understanding of the complexity of the adult brain, mainly because these finding suggest the importance of topography. The adult brain has shown that even in its short periods massive re organisation of the brain can occur and these findings provide the basis of how plastic the adult brain can be. Secondly, these findings allow us to relate perceptual subjective sensation (qualia) to the activity of brain maps.
Muller’s law of specific never energies,’ pattern coding’ vs. ‘placing coding’ where it depends on the particular neuron fibre rather than the overall pattern of activity. Even after a limb has been amputated patients have dual sensations i.e. both in the arm and the phantom limb. Findings from these studies suggest that we have two separate points in our brain, which activate, on our cortical map.
Hebb 1949 postulated that by simply strengthening synapse without adding new neurons would achieve nervous system plasticity.
Understanding of plastic process such as learning, memory, mood and other features of adult behaviour is entrenched in this concept of fixed neurons in the adult brain. Although it has been thought that the reproduction of constant neural replacement is not the logic of the nervous system function, several functions are also affected.
Memory is one of many functions that has been affected by neural replacement in the brain, and has changed our perspective of the way we think about the biology of memory. The reason being is that neuronal replacement is likely to have an impact on what a brain remembers and what it learns.
New cells in the dentate gyrus may play a role in hippocampal modulation of the HPA axis response to stress (Herman et al., 1989). The hippocampus has also been implicated in certain learning and memory functions. There is evidence that the new hippocampal cells may play a role in such functions (Barnea and Nottebohm, 1994 Gross, 2000). Learning has been shown to increase the number of new neurons in the hippocampus by altering cell survival or cell proliferation (Gould et al., 1999a Lemaire et al., 2000). Running increases both the number of new dentate gyrus cells and performance on a hippocampal-dependent task (van Praag et al., 1999a). Moreover, decreasing the number of new granule neurons is correlated with impairment on such a task (Shors et al., 2001).
Studies using the newly introduced methods of 3Hthymidine autoradiography challenged this view. 3H-thymidine is taken up by cells undergoing DNA synthesis in preparation for mitosis, and thus can be used as a marker for proliferating cells and their progeny. Altman (1962, 1963, 1966, 1967, 1969) and Altman and Das (1965, 1966) reported new neurons in a variety of structures in the adult rat and cat including the olfactory bulb, hippocampus, and cerebral cortex.
Researcher Kaplan examined the ultra structure of 3H-thymidine-labeled cells in the olfactory bulb, hippocampus, and neo-cortex of adult rats and confirmed that they were neurons .Further support that the cells added to the dentate gyrus were neurons came from studies by Stanfield and Trice (1988) and Gue´neau et al. (1982). In contrast, demonstrations of adult neurogenesis in no mammalian vertebrates such as fish, reptiles, and birds appear to have been more readily accepted (Anderson and Waxman, 1985) but their potential relevance to mammals generally not acknowledged. ((9)
A major source of difficulty in early adult neurogenesis studies was uncertainty as to whether the adult brain generated cells were the glia or neurons. Recent evidence suggests that these categories may not be as fixed as previously believed. In the adult brain, some glia may be a source of neurons, and some progenitors give rise to both neurons and glia (Alvarez-Buylla et al., 2001) were then assumed applicable to studies of the adult brain.
Adult neurogenesis must be accompanied by cell death, because the total number of neurons in the adult brain does not dramatically increase. The presence of pyknotic cells in the regions that add new neurons provides evidence that this is the case (Gould et al., 2001). There reason to believe that this degeneration predominantly represents turnover of the adult generated population, instead of death of older cells produced during development. This decline appears to be caused by cell death rather than label dilution (Cameron et al., 1993; Gould et al., 1999a).
In the monkey, there is a similar decline after 5 weeks in the dentate gyrus and after 2 weeks in cortex (Gould et al., 2001). These results have important implications for reviewing the existing studies on adult neurogenesis; long survival times after BrdU injection may result in failure to find adult generated cells if they surpass the life span of most new cells. Cell proliferation in the dentate gyrus, which decreased by the gluco-corticoids, which in response to stress are released, suggesting that stress-induced inhibition of cell proliferation, is mediated by gluco-corticoids.
The rate of neurogenesis in adulthood is still low when compared with the rate during development. If the adult generated cells, have the same relative influence as those generated in early life. If, these cells have unique properties that increase their impact relative to more mature neurons, then it is possible that their constant incorporation into the existing circuitry would be important.
Perhaps the immature neurons form more new connections in a given period than mature neurons. This likelihood indicates that new neurons, because they are structurally plastic, are highly susceptible to changes in the environment and to different life experiences. The unique properties of immature granule cells suggest that adult neurogenesis is important because it results in a continual influx of neurons that are, at least temporarily, immature.
The concept that decreased neurogenesis might be the cause of depression is supported by the effects of stress on neurogenesis and the demonstration that neurogenesis seems to be necessary for antidepressant action. Based on these findings, the neurogenesis might play a subtle role in depression but that it is not the primary factor in the final common pathway leading to depression.
Research P Rakic (4) researched based on macaque monkeys, which showed that the brain develops as dendrites and synapses grow around a fixed number of neurons after birth. Between pre-existing components the brain showed signs that it continues to form new. However, it has appeared that a person with fixed allotment of neurons at birth will invariably decline with age. The fact that many people do not recover the ability to speak or walk after strokes or other brain injury also seems to support the view that adult brains do not add new cells.
From a mechanistic point of view, one of the main reasons why this dogma has not received the sufficient amount of investigation required as to whether or neurogenesis actually exists in the adult brain was because the adult brain was, considered highly complex. Most neurons with their highly branded dendrites and polysynaptic axonal combination are considered terminally differentiated and therefore unable to re-enter the cell cycle.
The conceptual argues that if the neurons were able to divide in the adult brain, what would be the likely chance of them adapting to the existing mechanism of the brain. It therefore did not seem logical that neurogenesis could occur in the adult brain.
However, several methodological problems in its quantitative study remain. One is the use of low doses of the exogenous marker of cell proliferation, bromodeoxyuridine (BrdU). Secondly is the transient lifetime of most of the adult-generated cells. Thirdly is that the survival of new neurons may depend on stimuli that are lacking in standard laboratory conditions. A fundamental aspect of this stability was that no new neurons were added to the brain in adulthood (Gross, 2000).(8)
In conclusion as to whether or not the adult brain is plastic still remains a controversial debate, however the findings to suggest that there is some activity of neurogenesis within the adult brain is outstanding. The dogma of neuroscience has always been that new neurons were not capable to reproduce in the adult mammalian brain. However, the acceptance of adult neurogenesis has shifted our view of the plasticity and stability of the adult brain.
Due to the complexity of the brain and its complex function, it did not occur to researchers that the brain was in fact able to regenerate its damaged cells in certain conditions. This is a remarkable finding in the world of neuroscience because it means that we are able to get, yet better understanding of the human brain and its function. It has always been thought that the brain would stop producing until maturity and it would remain fixed in this critical stage. Because of this, it was thought that nerve cells could not regenerate, and that the functions controlled by the specific area of the brain would be lost forever.
However, studies have shown remarkable evidence, which has proved this long held dogma down. Study by Ramachandran and colleagues result clearly showed that the brain was capable of reproducing new neurons, which is remarkable finding in terms of the complexity of the brain. This means that the brain has the ability to repair any damaged cells that may occur, which was always thought impossible because of the complexity of the central nervous system.
However although we cannot say that the brain is fully plastic because there are some restriction for instance those whose suffer from disease such as Parkinson disease.
Nevertheless, it should be taken into consideration that new research in the future could provide a better explanation required to help give a clearer understanding of adult neurogenesis and their potential to regenerate in the adult brain. Word count 3,675
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BIBLIOGRAPHY
References
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Reynolds BA, Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707
Richards LJ, Kilpatrick TJ, Bartlett PF (1992) De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci USA 89:8591-8595
GAGE, F.H. Mammalian neural stem cells. Science 287(5457):1433–1438, 2000
CAMERON, H.A., and MCKAY, R.D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. Journal of Comparative Neurology 435(4):406–417, 2001.
GOULD, E. Serotonin and hippocampal neurogenesis. Neuropsychopharmacology 21(Suppl. 2):46S–51S, 1999.
DUMAN, R.S.; MALBERG, J., and NAKAGAWA, S. Regulation of adult neurogenesis by psychotropic drugs and stress. Journal of Pharmacology and Experimental Therapeutics 299(2):401–407, 2001.
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