Research paper by Jeffrey W. Cummins
(Psy 475 with Dr. Lauren Scharff)
Stephen F. Austin State University
December 19th, 2005
Anybody who has studied the basics of biology understands the concept and importance of adaptation in nature's creatures. Adaptation, at some point in any organism's life, seems inevitable when one considers the static nature of our universe. The concept of neural plasticity is closely related to that of adaptation. Ronald S. Duman defines neural plasticity as "a fundamental process that allows the brain to receive information and form appropriate adaptive responses to the same or similar stimuli" (as cited in Macher, 2004, p.157). Most people alive today understand that the body, especially the brain, is constantly reorganizing itself in order to adapt. The process of neural plasticity, essentially adaptation, is exemplified daily. Whether that be using the non-dominate hand to perform task susually preformed by the dominate hand, or seeing a relative regain use of a limb after years of rehabilitation, neural plasticity is the cause of such events. People who might find themselves pondering why each person's level of cognitive functioning varies to such an extent, should consider the following On the Nature of Human Plasticity:
In the human brain…there are approximately 1 trillion neurons, and each single neuron typically engages in 100-1000 synaptic contacts with other neurons. This means that the number of synapses in the human brain is between 1014 to 1015, or about 1 quadrillion. Yet the number of possible synaptic connections is still greater. "If we assume that each neuron can contact 100 other neurons and then compute all the possible combinations among the 1012 neurons, we end up with a number that is larger than the total number of atomic particles that compose of the entire known universe…as the brain develops, the possibilities for connections among neurons are virtually limitless…suggesting the capacity for the human brain may be almost without limit" (Lerner, 1984, p. 44-45).
While some may realize the importance of our body's plastic nature, nobody, not even those who devote their entire lives to uncovering the mysteries of neural plasticity, completely understands the incredibly complex and variable process. Does the brain have the ability to fully understand something as intricate as itself? The contents of this paper attempt to shed some light on the complexity underlying neural plasticity by reviewing some of its basic principals. Within the last few years, some neural plasticity researches have turned much of their attention towards the apparent promise of stem cells and the profound physiological consequences of stress. For this reason, their application concerning neural plasticity will also be discussed. Finally, this paper also provides information on factors that may influence recovery from neuropsychological impairments.
First, it is best to describe the two basic problems plaguing scientists researching neural plasticity: What prevents the central nervous system (CNS), in adult mammals, from creating new neurons (neurogenesis) with the proficiency of the peripheral nervous system (PNS), and what causes the CNS, in adult mammals, to be such an unreceptive host for PNS cells? Since the beginnings of neural plasticity research, the CNS, especially the aging brain, has repeatedly demonstrated a decreased ability to create neurons and promote their growth. In fact, Ramon and Cajal (1928) were convinced that "Once development [has] ended, the fonts of growth and regeneration of the axons and dendrites dried up irrevocably. In the adult center the nerve paths are something fixed and immutable, nothing may be regenerated" (as cited in Macher, 2004, p.136). Yet, by the 1960's, studies by Raisman, Bjorklund and Aguayo showed that damaged axons could re-grow under certain precise conditions. By the1990's, scientists had clearly proved neurogenesis does indeed occur in certain areas of the adult brain (Macher, 2004). This exciting news sparked a whole new array of questions about the abilities and methods of the CNS with regard to plasticity.
The extraordinarily complex processes involved in neuronal plasticity may cause the basics to appear not so basic, and indeed, they are not. The term neural plasticity encompasses many different ideas and processes. Basically, it refers to the ability of neurons within our bodies to adapt. These methods include but are notlimited to: neural degeneration, neural regeneration, neural reorganization and neural transplantation.
In order to understand how neurons and axons grow, it is first necessary to understand how they die. Neural degeneration occurs in two ways: Anterograde degeneration and retrograde degeneration. Anterograde refers to the degeneration of the distal segment, or the section of a cut axon between the cut and the synaptic terminals. Retrograde refers to degeneration of the proximal segment, or the portion of a cut axon between the cut and the cell body. Anterograde degeneration occurs rather rapidly because the segment of the cut axon has been cut off from its heart, the cell body. Conversely, in retrograde degeneration, the cut segment gradually progresses to the cell body. Natural neural regeneration in the CNS of adult mammals is rare, and in the PNS, it is essentially a shot in the dark. Regeneration of a damaged proximal segment in the PNS will generally start two or three days after the damage occurred. From here, there are three possibilities. First, "if the original Schwann cell myelin sheaths remain intact, the regenerating axons grow through them to their original targets…" (Pinel, 2003, p.257). It should be noted that Schwann cells, cells that myelinate axons, are found only in the PNS. Secondly, "if the peripheral nerve is severed and the cut ends become separated by a few millimeters, regenerating axon tips often grow into incorrect sheaths and are guided by them to incorrect destinations" (Pinel, 2003, p.257). Thirdly, if a large section of the cut nerve is damaged or the cut ends are widely separated, there is likely to be no functioning regeneration because the regenerating axons end up growing in a twisted heap surrounding the proximal stump (Pinel, 2003). There are currently three theories as to how neurons and axons grow and reorganize themselves with their respective position. The Blueprint Hypothesis states that the correct location is found by following "chemical landmarks" along the path. The Topographic Gradient theory proposes that neurons and axons grow and essentially travel in a group to their correct location. The Chemoaffinity Hypothesis states that chemical signals at the target zone attract neurons and axons to their proper location. Each of the above theories has been tested experimentallyand proven to occur. However, it appears that the "chosen" method of re-organization may be dependent on the type of system, be that visual or tactile, that needs to be reorganized. The fundamental key allowing PNS plasticity, in this case, regeneration, is the Schwann cells. These cells, which myelinate PNS axons, promote plasticity and regeneration by producing neurotrophic growth factors (NGFs) and cell-adhesion molecules (CAMs). In contrast, the cells that form myelin for the CNS, oligodendroglia, not only fail to produce NGFsand CAMs, but also actively inhibit regeneration. The fact that CNSneurons are capable regenerating within the PNS and PNS neurons are not able to regenerate in the CNS, except under very specific conditions, provides substance to the idea of active inhibitory features in the CNS (Pinel, 2003).
As a neuron attempts to regenerate, it produces receptors that "interact with cues present in the micro environment of the growing nerve fib[er]…these cues can include molecules on neuronal and glial cell surfaces, molecules of the extra cellular matrix and diffusible molecules that affect neuronal growth (Ferrett & Geraudie, 1998, p. 356). In fact, there is currently a rapidly expanding list of molecules like the ones described above and have subsequently been divided into three broad classes: ECM (Extra Cellular Matrix) molecules and their receptors, diffusible molecules and cytokines, and molecules that inhibit neuron growth. CAMs, lumped in with ECMs, promote adhesion between cells by interacting with the same molecule (homophilic interaction) or with cell surface receptors (heterophillic interaction). The molecules that comprise the ECM have "profound effects on [neuron] outgrowth and act via specific receptors. Diffusible molecules and cytokines bind to neuronal receptors and are involved in the regulation of neuronal survival and differentiation, but also strongly stimulate [neuron] outgrowth" (Ferrett & Geraudie, 1998, p. 356). The interesting, yet frustrating, aspect of these recent developmentsstems from the fact that researches have yet to decided if these molecules "simply provide a growth-permissive environment for the outgrowing nerve fibers and migrating neurons, or whether they are also involved in specific path finding decisions of outgrowing fibers"(Ferrett & Geraudie, 1998, p. 356). Following a lesion, the CAMsN-CAM and L1 are expressed by Schwann cells close to the lesion. Laminin and tenascin are then secreted by Schwann cells in to the ECM. These molecules are known to facilitate neuron growth but the methods by which they promote this growth is still unknown (Ferrett & Geraudie, 1998).
Based on the plethora of experiments preformed to date, it has been determined that regeneration of CNS axons is possible under very specific experimental conditions. Currently, there are three possible experimental conditions that enable the re-growth of CNS axons. The first of these conditions involves the transplantation of peripheral nerves or Schwann cells into the CNS. A summary of the experiments preformed using this method follows. In 1980, experiments preformed by Richardson and Aguayo demonstrated that CNS nerve fibers are capable of regeneration provided the transplantation process supplies them with a micro environment similar to that of thePNS, that being one that is dominated by Schwann cells. Subsequent experiments by Aguayo, in 1981 and 1985, involved transplanting pieces of sciatic nerve into the thoracic spinal cord and the medulla oblongata. Their tracing techniques revealed that CNS neurons had penetrated the graft tissue for several millimeters. Although thepossibility of growth is now realized, the growth that did occur ceased soon after re-entering the spinal cord tissue (Ferrett & Geraudie, 1998). The researchers postulated a very important question: Would the regenerating CNS axons be able to form synapses if they actually reached their appropriate tissue? This is a crucial thought because without the formation of synapses and their features, communication among neurons is impossible. To test this, Vidal-Sanzet al. (1987) and Aguayo et al. (1990) performed another set of experiments on the visual system by replacing a section of the optic nerve with a long sciatic nerve transplant and replacing it into the superior colliculus. The optic fibers grew the entire length of the transplant and re-entered the CNS. Vidal-Sanz et al. (1991) and Carter et al. (1989) found that not only did they form synapses similar to retinotectal synapses, but a few of the connections were actually functional, indicated by the presence of postsynaptic potentials after stimulation of the retina (as cited in Ferrett & Geraudie, 1998). More recently, experiments in rats demonstrated "improvement of motor function and regeneration of supraspinal nerve fibers after complete spinal cord transactions wherein the lesion cavity was bridged with multiple intercostals nerve grafts" (Ferrett & Geraudie, 1998, p. 359). As mentioned earlier, Schawnn cells may be the key to successful regeneration. After injection, these cells integrate into the CNS tissue and may migrate over a considerable distances. According to Brook, Li and Raisman, (1994) injection of Schawnn cells into the spinal cord promoted growth of CNS fibers along Schwann cell surfaces (as cited in Ferrett & Geraudie, 1998). Experiments by Li (1997) reported the regenerative growth of corticospinal tract chord lesions. After injections of Schwann cells into the fornix, hippocampal axons that were lesioned close to the mamillary body of the hypothalamus body regenerated and reconnected to their target, the hippocampus (Ferrett & Geraudie,1998). Schwann cells have recently been used to craft guidance channels, which do exactly what their name suggests. Guidance channels consist of a matrix which is then coated with Schwann cells and grown in a culture. After implantation into the spinal cord, researchers discovered that CNS fibers were able to grow into the guidance channels (as cited in Ferrett & Geraudie, 1998). According to recent research, guidance channels play a very active role in nerve damage repair. Apparently, "the material and growth factor combinations within a nerve guidance channel influence the type of regeneration achieved" (Raymer, 2005). If the materials of the guidance channels are varied, so are the neurons and parts of the brain that regenerate. All of these experiments, taken together, demonstrate the elevated ability of Schwann cells to elicit growth from a variety of CNS neurons in various experimental designs.
The second experimental condition found to promote neuron regeneration involves the transplantation of embryonic neurons into the CNS. Wictorin (1991) indicated that when early embryonic human striatal neuroblasts were transplanted into the stratum of adult rats, extensive outgrowth from these transplants was recorded (as cited in Ferrett & Geraudie, 1998). Neuroblasts are the embryonic cells from which nerve cells develop. When similar experiments were preformed by Wictorin in 1991 using embryonic ratneurons, a marked reduction in outgrowth was noticed. Based on this finding, it seems that the growth potential of embryonic human neurons is larger than that of rat neurons, possibly because of the longer distances that human neurons must travel during embryonic development (Ferrett & Geraudie, 1998). In a number of somewhat recent studies long-distance fiber growth has been observed. "After transplantation of embryonic rodent CNS neurons into the fimbriafornix (Davis et al. 1993), the spinal cord (Li and Raisman 1993), orother fiber tracts of the adult rat (Davis et al. 1993) long-distance outgrowth from the transplanted embryonic neurons was observed"(Ferrett & Geraudie, 1998). It should be noted that in these studies only a small number of cells were injected into the rat. Regardless of that fact, it is apparent that the CNS environment is not completely unresponsive to axonal re-growth.
The third experimental condition that allows the re-growth of CNSneurons is the neutralization of myelin-associated neuron growth inhibitors. The first piece of evidence that hinted at the existence these inhibitors was seen in the experiments by Schwab and Thoenen in1985. In these experiments, it was determined that neonatal rat sympathetic neurons failed to extend neurites into explanted sections of the optic nerve even in the presence of high amounts of NGF (Ferrett & Geraudie, 1998). Subsequent studies reported that inhibition of the neurite growth was attributed to the presence of oligodendrocytes, the myelin forming cells of the CNS. Biochemical studies by Schwab and Caroni (1998) identified two protein factions derived from CNS myelin with molecular weights of 35,000 and 250,000 (as cited in Ferrett & Geraudie, 1998). Advances in biochemical technology have allowed scientists to extract and purify these proteins in order to use them in ensuing experiments. Experiments using frozen sections of nervous tissue as a substrate showed that CNS myelin is a terrible candidate for cell attachment, sprouting and neurite outgrowth (Ferrett & Geraudie, 1998). A number of studies reported that oligodendrocytes in culture were shown to cause growth cone collapse (Stem Cell Basics, 2005). Recently, a specific myelin protein found within the CNS and PNS, MAG, was shown to have properties that inhibit outgrowth of neurites. A monoclonal antibodynamed IN-1 was created with the purpose of counteracting some of the inhibitory properties found within the CNS (Ferrett & Geraudie,1998). In the experiments, IN-1 was tested in conjunction with the inhibitory protein with a molecular weight of 250,000. The results showed that IN-1 had successfully neutralized the inhibitory properties of the protein mentioned above. In addition, Caroni andSchwab (1988b) found that injections of IN-1 into the explanted optic nerve caused sympathetic neurons to extend fibers into the explants for considerable distances. In experiments involving lesions to the fimbria-fornix, preformed by Cadelli and Schwab (1991), re-growth was enhanced and accelerated in the presence of the IN-1 antibody. Schnell et al. (1994) showed that long-distance regeneration of nerve fivers was only observed in situations where the IN-1 antibody was present (Ferrett & Geraudie, 1998). However, in these animal experiments involving the manipulation of IN-1, the antibody was effective only in very high concentrations. The high levels of concentration were achieved by transplantation of hybridoma cells which secrete the antibody. These transformed cells essentially create a tumor with in the host that constantly generates a supply of the IN-1 antibody. For ethical and health reasons, this approach cannot be applied to human patients.
An approach that has promise involves manifesting small peptides that would block the function of any inhibitory molecules (Ferrett & Geraudie, 1998). These studies reviewed above indicate that the absence of myelin and the myelin-associated growth inhibitors enhances regeneration of damaged axons and neurites. Based on all the research conducted to date, it seems that CNS axons, neurons and neurites have the inherent ability to regenerate. However, there is something within the CNS that does not allow such re-growth. Current studies are aimed at uncovering this mysterious variable(s) that has been eluding researchers for decades. These studies may be hampered because of the current technical limitations involving the tracing techniques used to identify areas of regeneration. The fact of the matter is that neurogenesis could be occurring in a number of sites but has not yet been detected because of the limitations of our current tracing techniques. Our knowledge of the mechanisms of plasticity should expand rapidly as our tracing techniques develop and evolve allowing researchers to gather superior information.
Although there have been many studies that claim neurogenesis occurs in multiple regions in the brain, there have only been a few reports that have been substantiated. The substantiated reports showing neurogenesis in the brain state that it only occurs robustly in two areas of the brain: the forebrain and the hippocampus. It appears a significantly large number of neurons migrate from the forebrain to the olfactory bulb using ventricles positioned on the forebrain. The evidence pointing to neurogenesis in the hippocampus states that it occurs within the denate gyrus of the hippocampus (Macher, 2004). The olfactory bulb is involved in our interpretation of smell, and the hippocampus plays a crucial role in forming new memories. The fact that both of these structures are essentially forced to adapt, be it because of a combination of new smells or memories, leads to a general theory regarding plasticity, specifically neurogenesis. The theory states that the possible significance of neurogenesis could be that it provides the plasticity necessary to process and code the novel information processed by the olfactory bulb and hippocampus (Macher, 2004). A study by Emory University researchers in 2001 produced results, in adult rats, that showed newly generated neurons in several forebrain structures,"including the parenchyma (gray mater) of the striatum, septum, thalamus and hypothalamus"; areas that serve a multitude of cognitive and vital neurological functions" (Growth factor, 2001, p.1). Researchers were able to generate these results by inducing the growth factor BDNF (brain-derived neurotrophic growth factor) into the lateral ventricle of adult rat brains for a period of two weeks. They waited for two weeks before examining the brains. Previous studies had detected only a very limited level of neurogenesis in the thalamus, septum and striatum. This study also produced some interesting evidence involving the unique existence of progenitor cells in a region of the subventricular zone and therostal migratory stream (Growth factor, 2001). These results are important because these progenitor cells are able to divide and produce progeny, also known as daughter cells. In every other part of the brain the neurons appear to be post-mitotic, cells that are unable to divide. The presence of these progenitor cells leads researchers to believe that the adult forebrain has a more profound capacity for neurogenesis than previously thought (Growth factor, 2001). A study preformed by the Yale University School of Medicine and cited in the May 11th, 1999 issue of Neurobiology provided insight into the existence of neurogenesis in the hippocampus of adult macaque monkeys. These researchers estimate that theprevalence of neurogenesis in these monkeys is about ten times lessthan that reported in adult rodent dentate gyrus. However, this study indicated the adult primate hippocampus has the capacity to produce multipotent neural stem cells that survive for at least seventy-five days, the longest survival period tested. "It is unknown whether the new neurons, oligodendrocytes, and astrocytes in the macaque monkey granule cell layer (GCL) are each generated from a distinct committed progenitor, or whether all are derived from a multipotent progenitor" (Kornack & Rakic, 1999, p.5). Because of the "macaque's phylogenetic proximity to humans, long life span and elaborate cognitive abilities…", the macaque is the preferred animal to study in the hopes of generalizing results to humans (Kornack & Rakic, 1999, p.1). Before this study, it was assumed because of previous experiments, that neurogenesis did not occur in mature monkeys. Monkeys are considered to be mature after reaching five years of age (Kornack & Rakic, 1999).
Although the above study indicates that a mature macaque is able to perform neurogenesis, it also indicates that this ability is dramatically reduced as the organism becomes more mature. The researchers postulated that this could be related to their prolonged period of adolescence and longer life span. With this in mind, researchers supposed that neurogenesis would be greater in"…short-lived early-maturing mammals than in longer-living late-maturing Old World primates" (Kornack & Rakic, 1999, p. 9). Their hypothesis appears to be consistent with evidence of substantial levels of neurogenesis in the dentate gyrus of fast-maturing mammals. Despite the evidence of neurogenesis, cell counting studies indicate that the number of neurons in the normal human GCL remains relatively stable throughout postnatal life (Kornack & Rakic, 1999). The fact there seems to be no"significant net accumulation of neurons in the primate GCL implies that the rate of neuronal production in adulthood is balanced by an equal rate of apoptosis and cell removal" (Kornack & Rakic, 1999, p. 9). Questioning the possible consequences of unbalancing the equation, leading to an increase of neurons, leads one to ponder how our cognitive abilities might be enhanced by such a change. Now that researchers have proven that the adult human brain does engage in neurogenesis, they have another problem to solve. For researchers to understand the complex dynamics of neurogenesis, they must uncover the factors that control cell proliferation, their creation, cell migration, moving to where they are needed, and cell differentiation, turning into the type of cell that is needed. When scientists have a true in-depth understanding of these three processes, only then will they begin to understand the true possibilities of neurogenesis.
With the tremendous amount of research aimed at revealing the mysteries of neurogenesis, there was an unexpected finding: Not only does the brain engage in neurogenesis, but it also appears to have a small reserve of stem cells located in various tissues of the body. Stem cells come in two varieties: embryonic and adult. As their first names imply, embryonic stem cells are retrieved from embryos and adult stem cells derive from adults. Basically, stem cells, regardless of their original source, have three general properties that make them unique. First, stem cells are capable of dividing and renewing themselves for long periods. Secondly, they are unspecialized, meaning that they are not confined to becoming only acertain type of cell. Finally, and arguably most important, stem cells posses the ability to become any type of mature cell, called totipotental. Stem cells have the capacity to"…give rise to itself (self-renewal) and can also give rise to any or all of the three main cell lineages of the brain: neurons, astrocytes, and oligodendrocytes" (Macher, 2004, p. 136). Astrocytes, as with all glial cells, are important because they provide multiple levels necessary support to neurons and their actions. In 2002 astrocytes received some notoriety because research preformed by the Howard Hughes Medical Institute suggested they might play a much larger role in the maturation of neural stem cells than previously thought (Stevens, 2002). Traditionally, astrocytes have been thought to only play a supportive role in maturation and proliferation. The research suggested that astrocytes may actually be instructing stem cells about which developmental pathway to follow. Apparently, the astrocytes either "instruct the progenitors [daughter stem cells] to adopt a neuronal fate or form an environment that induces or permits that fate" (Stevens, 2002, p. 2). At some point during a stem cell's life, it loses the ability of being totipotent. When it loses this ability, it becomes a pluripotent stem cell. This means that although the stem cell's morphing abilities have diminished, it can still become multiple types of cells.
As mentioned previously, a reserve of stem cells have been identified in various tissues in the body. Hematopoietic stem cells are responsible for producing every type of blood cell. Bone marrowstromal cells give rise to a variety of cell types: bone cells (osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes) and assorted types of connecting tissue. Epithelial stem cells manufacture the differing types of cells needed for the digestive tract to function properly. Finally, skin stem cells create the cells which produce our hair and also protect our skin (Stem Cell Basics, 2005). Until recently, most of the evidence from experiments with these stem cells indicated that they once they have been employed by their respective tissues, they lack the ability to become cells of a differing tissue. However, recent research indicates that this may not be true for some of the cell types (Stem Cell Basics, 2005). Hematopoietic stem cells appear to also have the ability to differentiate into the three major brain cell types, skeletal muscle cells, cardiac muscle cells and liver cells. Bone marrow stromal cells may differentiate into cardiac muscle cells and skeletal muscle cells. Brain stem cells may differentiate into blood cells and skeletal muscle cells (Stem Cell Basics, 2005). This discovery hints at their apparent capacity to be plastic.
During the twenty years of research on these unique cells, scientists have learned how to essentially direct embryonic stemc ells towards a specific resting place within a given tissue. Stem cells grown in a laboratory are referred to as cell cultures. Scientists essentially take the heart of these cells and transplant them into a culture dish containing a "nutrient broth known as a culture medium" that facilitates the growth of the stem cells (Stem Cell Basics, 2005, p. 5). The culture dish is also coated with a layer of cells named a "feeder layer" (Stem Cell Basics, 2005, p. 5).This layer of cells typically consists of mouse cells that provide the stem cells a sticky surface to attach to. The fact that mouse cells are used in the genetic modification of human stem cells has raised questions of the possible transfer of defects and viruses. Although most research states that this process is safe, scientists are developing methods of stem cell culture that does not employ the use of mouse cells. After several days in a culture, the stem cells begin to proliferate. When the culture dish becomes "crowded," some of the cells are removed and placed into a fresh batch of culture dishes. As long as the embryonic stem cells are reared under specific conditions, they continue to be unspecialized. However, if the cells are allowed to cluster together forming embryoid bodies, they "begin to differentiate spontaneously" (Stem Cell Basics, 2005, p. 6). Obviously, this is not the desired outcome of these experiments because the scientists are not able to control the differentiation. Scientists have learned they are able to control differentiation and generate multiple cultures of specific types of differentiated cells. By changing the chemical composition of the culture medium, altering the surface of the culture dish or inserting specific genes into the cells, scientists have established some very basic "recipes for directed differentiation" (Stem Cell Basics, 2005, p. 7). This idea of "directed differentiation" may tackle some of the problems scientists are faced with when using stem cells.
When doctors attempt to asses the regenerative properties of stem cells, they must use stem cells that are specialized to a degree in accordance with their experiment's goals. The problem with adult stem cells is that not only is there a limited number, but many are too mature and do not withstand the isolation and transportation procedures involved in cell culturing (Turksen, 2004). With fetal stem cells, not only do their small numbers present a problem, but there are only a few cells available that are just the right age and location. For their use to be conceivable either a large number of fetus must be used or the cells must be placed in culture (Macher, 2005). As scientists begin to unravel the underlying process of cell differentiation and perfect their methods for this process, they will have an increased ability to combat a host of diseases and problems faced by millions of people worldwide. For instance, an article written by Lauran Neergaard in 2005 for SFGate.com summarized the results of an experiment that suggested stem cells may repair spinal cord damage. This information came from an experiment that analyzed how the transplantation of human fetal neural stem cells into paralyzed mice may facilitate recovery of walking ability. The fetal neural cells are slightly more advanced; meaning more specialized, and are destined to become neurons in the CNS. Although this is not the first article suggesting stem cells may repair cord damage, it is the first to postulate that it is the connections the stem cells make that may be the key to recovery from a damaged spinal cord. Results indicated that the stem cells did not just form new nerve cells but that they also manufactured the myelin that allows rapid communication between neurons. The fanatical pursuit of knowledge and constant progression of science will hopefully one day result in our complete understanding of stem cells and their intriguing possibilities related to plasticity.
Scientists researching the methods of neural plasticity have recently turned some of their attention towards stress, its causal role in depression, and both their roles in regard to plasticity. Scientists have long pondered what causes depression and have subsequently determined that stress may be the most significant casual agent, with the exception of genetic predisposition. It seems that nerve cells near the hippocampal region are the most sensitive to the debilitating effects of stress (Macher, 2004). Using the MRI, researches at Washington University studied the hippocampus of women with recurrent major depression (2000). Their results showed smaller left and right hippocampal volumes in these women even though they were currently in remission. A follow up study by the same researches reported that the amount of decreased hippocampal volume was correlated with "…total lifetime duration of depression and not with age" (Depression and the birth, 2000, p. 7). As stated previously, the hippocampus is one of the two brain areas known to engage in a significant amount of neurogenesis. What causes a structure that readily creates new neurons to decrease in size? Researchers found that repeated stress alters the structure of the hippocampus by causing "…atrophy of the dendrites of CA3 pyramidal neurons…measured by a decrease in the number and length of apical dendrites" (Macher, 2004, p. 159). Some recent studies may show that while stress causes atrophy of the hippocampus, it causes hypertrophy in the amygdale (Macher, 2004). Remember that the amygdale is thought to be primarily responsible for the emotional component to memories. This hypertrophy in the amygdale could serve as a partial explanation for the relationship between levels of emotional arousal and stress related disorders, including anxiety disorders, PSTD and depression (Macher, 2004). When stress is experienced, the hallmark response by the body is "…activation of the hypothalamic-pituitary-adrenal (HPA) axis, which includes increases circulating levels of adrenal glucocorticoids" (Macher, 2004, p. 161). Glucocorticoids have been experimentally tested and they appear to cause atrophy and decreased levels of neurogenesis. The fact that the hippocampus possesses such a large number of glucocorticoids receptors may explain why it is so significantly impacted by stress.
The treatment of depression usually involves prescription of anti-depressants, typically SSRI's. These medications frequently fall a bit short of their desired effects and usually produce unwanted side effects ranging from dry mouth to sleep disturbances. However, because depression is so common, creating wide-spread use of anti-depressants, researches have compiled a wealth of information about how these medications affect neurogenesis. "Different classes of antidepressants, including serotonin and noradrenalin reuptake inhibitors, and electroconvulsive seizures are reported to increase adult neurogenesis" (Macher, 2004, p. 162). Serotonin is known to"stimulate cell division in a variety of peripheral tissues and triggers neurogenesis in the central nervous system during development" (Depression and the birth, 2000, p. 7). Some research on adult rats has been done employing a drug that discharges serotonin throughout the CNS, d, l-fenfluramine. The results showed that systematic administration of the drug resulted in a two to threefold increase in cell division in the dentate gyrus. Other studies using Prozac, an SSRI, reported a seventy percent increase in the number of cells produced in the dentate gyrus (Depression and the birth, 2000). The effects of antidepressants may be caused by the fact that they actively inhibit atrophy caused by CA3 apicaldendrites (Macher, 2004). One of the flaws with anti-depressant medication being used to treat depression is that they typically havesome therapeutic lag: they usually take about three to six weeks to become effective. This lag could be explained by taking into account the amount of time a new neuron requires to become fully mature and functional (Depression and the birth, 2000).
When the brain becomes injured a complex cascade of events takes place affecting both the brain and body in a vast variety of ways. Even if the damage to the brain is limited to only a small section of tissue, the effects of this damage could be very widespread and noticed in a variety of bodily functions. When the brain is traumatically injured, whether that be by a stroke or a bat to the skull, a dramatic change in the "anatomy and physiology" of the brain occurs (Stein, 1995, p. 41). This change is witnessed in the blood-brain-barrier, otherwise known as the BBB. "In a healthy individual, the BBB protects the brain from potentially harmful substances that may circulate in the blood, such as antibodies that cause inflammation, or blood itself, which is actually toxic toneurons" (Stein, 1995, p. 41). The BBB ensures protection of the brain by selectively filtering out substances that are toxic to thebrain and its neurons thereby ensuring equilibrium. However, because the brain must have a steady supply of food and nutrients, it must be only semi-permeable in order to allow the passage of certain necessities. When the BBB becomes disturbed by trauma or injury, blood cells, which are toxic to the brain's neurons, proteins and other toxic substances may bypass the BBB. The glial cells found within the BBB attempt to absorb any toxins but eventually become overwhelmed and swell up because they are essentially "full." When they die, they release all the toxins back into cerebral circulation. These toxins may kill neurons or produce a state of shock for others. When neurons enter a state of shock, they release their entire store of neurotransmitters and the calcium ions needed to activate them. The unusually high levels of these substances damage and kill already weakened neurons. Eventually, the collateral damage is minimized and the brain attempts to return to its original state of equilibrium. Glial cells that have congregated to clean up any left-over debris may begin to form scar tissue becoming a permanent part of the brain. In some cases these scars may inhibit the re-growth and regeneration of neuronal connections (Stein, 2004). The ability of the brain to regenerate, re-grow or reorganize to its original state depends solely on the remaining structure of the damaged neurons. This "remaining structure" refers to the condition of the cell membrane and axons used for communication.
Recovery of function following brain trauma has been well documented throughout history but remains to be understood. In his book Brain Repair, Stein discusses four strategies employed by the brain that lead to recovery of function. First is his discussion of vicariance which implies that "…different areas of the brain have the potential to take over and mediate the specific functions of damaged tissue" (Stein, 1995, p. 48). The second strategy mentioned is centered on the idea of redundancy. Basically, this theory assumes that the brain has some sort of backup or fail-safe system that takes over in the event of damage. Evidence for this method was presented by Patrick Wall in the 1970's when he demonstrated that"…previously silent fiber pathways in the brainstem could become immediately active when the primary sensory fibers in the spinal cord were cut" (Stein, 1995, p. 48). Wall hypothesized that these secondary pathways have always been present but that they were"masked" or inhibited by the primary pathways. The third strategy mentioned by Stein, functional substitution, states that a"…part of the brain not normally associated with a certain function can be 'reprogrammed' to take charge of the functions of the damaged area" (Stein, 1995, p. 48). Even though the reprogrammed areas of the brain may not be as efficient as the previous master, this recovery allows patients to function as well as possible given the circumstances. Finally, Stein offers insight into one of the oldest explanations of recovery, Diaschisis, which was originally proposed by Constantin von Monakow. This possible explanation has been receiving quite a bit of attention from researchers as of late. Monakow's theory is best described in terms of the amount of shock experienced by certain parts of the brain. Monakow believed that the uninjured brain exists in a very delicate balance among its parts. When a section is inured by trauma or disease, this trauma may also affect other parts of the brain located a considerable distance from the damaged area. "Diaschisis was thought to be the temporary block of function (or inhibition) produced by the shock of damage orirritation to the brain tissue" (Stein, 1995, p. 49). Even though each strategy mentioned is grounded with experiment research, it is vital that one remains aware that in actuality it is probably a combination of these methods that leads to the recovery of function following brain damage.
When one considers the rehabilitation that is usually required for any recovery of lost functioning, there could be said to be two broad goals of intervention: one of restitution and one of amelioration. Restitution implies the "…full or partial regaining of lost functional capacities and therefore involves recovery of functions as means" (Miller, 1984, p. 78). Amelioration, on the other hand, is concerned with "…assisting the afflicted person to function as well as possible despite [any] handicaps" (Miller, 1984, p.78). The bulk of research implies that complete restitution of lost abilities is very rare. In his book Recovery and Management of Neuropsychological Impairments, Miller contends that amelioration is much more sensible approach even though it is inherently more limited (p. 79). Any goal directed at amelioration is likely to be situation-specific because the overall approach of amelioration is to facilitate the daily living of afflicted persons. This means that as problems arise in a handicapped person's life, these problems are tackled with solutions that are specifically designed for only that situation, hence the more limited approach. However, because complete recovery of function is rare, it seems more desirable to help a patient recovery in as many ways as possible (Miller, 1984). This may involve the patient learning new coping strategies for old problems or placing the patient in an environment more suited to their unique needs. The intrinsic problem with either of these approaches is recovery of function is dependent on the interaction of a huge number of variables. These variables complicate the convoluted nature of functional recovery and thereby thwart our understanding of the big picture.
Within the past thirty or so years, great strides have been made in the field of Neuroscience. These great strides have also provided an increased understanding of plasticity. As with most incredibly complex problems, our increased knowledge has given rise to yet more questions concerning the processes underlying neural plasticity. Researchers now know that neurogenesis is possible in the CNS given the perfect experimental conditions. Yet they have yet to pin down the exact conditions that permit re-growth in multiple tissues. Research on stem cells indicates that they have a profound potential to help millions of people in a variety of ways. However, our current level of knowledge and comprehension on these issues prevents us from using them to their greatest potential. As thousands of hours and millions of dollars are thrown into research on the body's plastic capabilities, there is still a tremendous quantity that we do not yet understand. But most logical people appreciate that without some level of plasticity, they would have died long ago. As our knowledge concerning the copious underlying factors that cause aging and debilitation expands, it could be proposed that the both the quality and duration of humans' natural lives will also lengthen.
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