**4. Adaptation of transplanted neural cells to the endogenous host tissue**

It is nearly impossible to distinguish between host-to-transplant and transplant-to-host communication because the interactions between both populations are so intimate. However, for the flow of this review, we decided to first address mechanisms of concern regarding modifications engaged by local host cells such as their growth into the transplant and efforts to exert control. Now, we turn our attention to the manner in which transplanted cells likely recognize what they should do and how they grow into the host with an effort to exert control. As indicated previously, there are certain pro-generative regions such as the olfactory bulb and the hippocampus that are known to accommodate transplantation of new neural cells into their architecture more readily. These structures engage a system already established to continue adding new neurons into their circuits with adjustments according to demand regularly throughout adult mammalian lives, while other structures more commonly experiencing disease-driven deterioration are, unfortunately, less accommodating. Certain practical matters come into play when arranging a protocol for transplantation that limits how developmentally committed the transplant-destined population will be, deviating from the ideal circumstance of, for example, generating pure populations of dopamine and cAMP-regulated phosphoprotein (DARPP-32, marker for the classic resident medium spiny type) expressing GABAergic neurons for striatal transplant in Huntington's disease. While it is often an implicit goal to develop purified populations of only desired cell populations for transplantation, the context of "normal" developmental phenotype adoption seems to be modulated quite handily by local glial cells. If not somehow biochemically prevented from doing so, pure stem cell populations also typically develop into mixtures of neurons and glial cells in a manner approximating that expressed developmentally, with more glial cells than neurons, because the signaling molecules responsible for producing this distribution derive from the manner in which neuronal populations distinguish from epithelial populations with both distal and surface interactions [130]. By comparison, the more purified populations of specific neurons raised *in vitro* by various groups [131], would require considerable artificial manipulations compared with natural development.

Clearly, to adopt a specific neuronal fate with exclusive neurotransmitter-releasing properties, there are specific genes that must be expressed, as each phenotype would require either exclusive gene expression to produce or post-translationally select specific neuropeptides for release, or to process precursors enzymatically to generate classic neurotransmitters. These genes and immediate products have generated a new phenomenology that captures the immunohistochemical characterization of cell types in modern histology. It has, however, become abundantly clear that gene expression responsible for this is controlled by complicated internal processes that, despite early presumptions to the contrary, are not permanent or irreversible. The more prominent of these involve histone manipulations such as acetylation or methylation of DNA. This leads to the DNA source of specific genes becoming buried within inaccessible Gordian-like knots, which may be unwound to allow for DNA transcription under certain contexts. Current technology maintains the clear capacity to take committed cells and reverse this genetic commitment to generate what is now called "induced pluripotency," essentially restoring a precursor status to cells, even after they have become a more standard somatic type. In order for this induced pluripotency to be remotely possible, as well as subsequent guided induction of specific types of neurons from such cells, some genetic propensities must remain, even in cells that have outwardly adopted noticeably distinct fates. Early explorations of neuronal phenotype commitment involved explorations of the bizarre and seemingly extreme tendency of sympathetic neurons that ended up targeting the sweat glands to *convert* from a noradrenergic to a cholinergic phenotype [139]. Considerable controversy surrounded the search for the target-derived factor that was responsible for inducing this switch, which was clearly necessary given the cholinergic receptor population of the gland, and research centered on a cytokine family molecule [140]. The capacity of neurons to switch transmitter expression or take on more complicated forms of expression during development is broader than this [141], but these examples clearly demonstrate that the mechanisms underlying neuronal phenotype determination remain versatile and responsive to external signals, even after neuronal differentiation. This suggests that precursor cells would harbor an even more versatile capacity to properly respond to host signals and, as such, merge into the circuit in a region-

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell…

http://dx.doi.org/10.5772/intechopen.71790

23

The process of becoming a neuron is sensitive to the degree of electrical stimulation in that the corresponding calcium increases tend to facilitate neuronal differentiation [47]. In the case of the earlier stage fetal development following more complex anterior-posterior differentiation of the neural tube and the establishment of prosencephalon, mesencephalon, and rhombencephalon, more distinct neuronal populations begin to emerge due to specific morphogen combinations and temporal sequences of exposure [142, 143], with certain regions producing environmental signals conducive to specific neuronal subtypes. As glutamatergic neurons distinguish from GABAergic neurons within regionally distinct sub-areas of the subventricular source of new neurons, basic helix-loop-helix transcription factors are induced to kick in, such as neurogenins, leading to a glutamatergic fate, and Mash-1 along with the "distal less" homeodomain genes presumably induced into expression by positional signals Dlx1 and Dlx2 that seem to promote a GABAergic fate, with the degree of initial neurogenin or Mash-1 expression a seemingly deciding factor [144]. When cells that are transplanted into the early developing nervous system are evaluated for the expression of regionally specific markers, such as

ally attentive manner.

As described above, previous transplant efforts have utilized populations of cells that have already developed a predisposition toward neuron types that have been responsible for some cells thriving in homotypic versus ectopic target destinations. Thus, when working *in vitro*, complete pre-differentiation and purification of specific neuronal populations requires extensive prior modification, and these efforts seem to benefit from the inclusion of developmentallyconsistent proper local glial cell support [132–134]. *In vivo*, this supporting role seems largely adopted by astrocytes that enhance survival [135]. Neuronal differentiation seems to occur in conjunction with an effort to extend neurites and seek connections; a sensible concept given the previously-described importance of being connected to, and making connections in, the developing organism. After culture, the cells in question need to be lifted from their culture conditions and placed into a delivery mechanism (typically a syringe), for transplantation. It has been pointed out that primary neuron cultures might be particularly sensitive to the trypsin dissociation step and suggestions that more gentle procedures, such as papain, for dissociation of these cells have been made in recent scientific communications [136, 137], along with the notion that extensive floating cultures also face challenges. Therefore, researchers frequently opt for transplantation prior to full neurite extension and interconnectedness, even prior to full neuronal commitment, with the presumption that remaining neuronal commitment will occur *in situ*. Transplants often occur with suspensions of dissociated individual cells or of neurospheres (for review of neural sphere transplant contributions see [138]). If final neuronal commitment occurs after transplantation then, to some extent, this process will be guided by environmental cues within the host tissue.

Clearly, to adopt a specific neuronal fate with exclusive neurotransmitter-releasing properties, there are specific genes that must be expressed, as each phenotype would require either exclusive gene expression to produce or post-translationally select specific neuropeptides for release, or to process precursors enzymatically to generate classic neurotransmitters. These genes and immediate products have generated a new phenomenology that captures the immunohistochemical characterization of cell types in modern histology. It has, however, become abundantly clear that gene expression responsible for this is controlled by complicated internal processes that, despite early presumptions to the contrary, are not permanent or irreversible. The more prominent of these involve histone manipulations such as acetylation or methylation of DNA. This leads to the DNA source of specific genes becoming buried within inaccessible Gordian-like knots, which may be unwound to allow for DNA transcription under certain contexts. Current technology maintains the clear capacity to take committed cells and reverse this genetic commitment to generate what is now called "induced pluripotency," essentially restoring a precursor status to cells, even after they have become a more standard somatic type. In order for this induced pluripotency to be remotely possible, as well as subsequent guided induction of specific types of neurons from such cells, some genetic propensities must remain, even in cells that have outwardly adopted noticeably distinct fates. Early explorations of neuronal phenotype commitment involved explorations of the bizarre and seemingly extreme tendency of sympathetic neurons that ended up targeting the sweat glands to *convert* from a noradrenergic to a cholinergic phenotype [139]. Considerable controversy surrounded the search for the target-derived factor that was responsible for inducing this switch, which was clearly necessary given the cholinergic receptor population of the gland, and research centered on a cytokine family molecule [140]. The capacity of neurons to switch transmitter expression or take on more complicated forms of expression during development is broader than this [141], but these examples clearly demonstrate that the mechanisms underlying neuronal phenotype determination remain versatile and responsive to external signals, even after neuronal differentiation. This suggests that precursor cells would harbor an even more versatile capacity to properly respond to host signals and, as such, merge into the circuit in a regionally attentive manner.

recognize what they should do and how they grow into the host with an effort to exert control. As indicated previously, there are certain pro-generative regions such as the olfactory bulb and the hippocampus that are known to accommodate transplantation of new neural cells into their architecture more readily. These structures engage a system already established to continue adding new neurons into their circuits with adjustments according to demand regularly throughout adult mammalian lives, while other structures more commonly experiencing disease-driven deterioration are, unfortunately, less accommodating. Certain practical matters come into play when arranging a protocol for transplantation that limits how developmentally committed the transplant-destined population will be, deviating from the ideal circumstance of, for example, generating pure populations of dopamine and cAMP-regulated phosphoprotein (DARPP-32, marker for the classic resident medium spiny type) expressing GABAergic neurons for striatal transplant in Huntington's disease. While it is often an implicit goal to develop purified populations of only desired cell populations for transplantation, the context of "normal" developmental phenotype adoption seems to be modulated quite handily by local glial cells. If not somehow biochemically prevented from doing so, pure stem cell populations also typically develop into mixtures of neurons and glial cells in a manner approximating that expressed developmentally, with more glial cells than neurons, because the signaling molecules responsible for producing this distribution derive from the manner in which neuronal populations distinguish from epithelial populations with both distal and surface interactions [130]. By comparison, the more purified populations of specific neurons raised *in vitro* by various groups [131], would require considerable artificial manipulations compared with natural

As described above, previous transplant efforts have utilized populations of cells that have already developed a predisposition toward neuron types that have been responsible for some cells thriving in homotypic versus ectopic target destinations. Thus, when working *in vitro*, complete pre-differentiation and purification of specific neuronal populations requires extensive prior modification, and these efforts seem to benefit from the inclusion of developmentallyconsistent proper local glial cell support [132–134]. *In vivo*, this supporting role seems largely adopted by astrocytes that enhance survival [135]. Neuronal differentiation seems to occur in conjunction with an effort to extend neurites and seek connections; a sensible concept given the previously-described importance of being connected to, and making connections in, the developing organism. After culture, the cells in question need to be lifted from their culture conditions and placed into a delivery mechanism (typically a syringe), for transplantation. It has been pointed out that primary neuron cultures might be particularly sensitive to the trypsin dissociation step and suggestions that more gentle procedures, such as papain, for dissociation of these cells have been made in recent scientific communications [136, 137], along with the notion that extensive floating cultures also face challenges. Therefore, researchers frequently opt for transplantation prior to full neurite extension and interconnectedness, even prior to full neuronal commitment, with the presumption that remaining neuronal commitment will occur *in situ*. Transplants often occur with suspensions of dissociated individual cells or of neurospheres (for review of neural sphere transplant contributions see [138]). If final neuronal commitment occurs after transplantation then, to some extent, this process will be guided by environmental

development.

22 Neuroplasticity - Insights of Neural Reorganization

cues within the host tissue.

The process of becoming a neuron is sensitive to the degree of electrical stimulation in that the corresponding calcium increases tend to facilitate neuronal differentiation [47]. In the case of the earlier stage fetal development following more complex anterior-posterior differentiation of the neural tube and the establishment of prosencephalon, mesencephalon, and rhombencephalon, more distinct neuronal populations begin to emerge due to specific morphogen combinations and temporal sequences of exposure [142, 143], with certain regions producing environmental signals conducive to specific neuronal subtypes. As glutamatergic neurons distinguish from GABAergic neurons within regionally distinct sub-areas of the subventricular source of new neurons, basic helix-loop-helix transcription factors are induced to kick in, such as neurogenins, leading to a glutamatergic fate, and Mash-1 along with the "distal less" homeodomain genes presumably induced into expression by positional signals Dlx1 and Dlx2 that seem to promote a GABAergic fate, with the degree of initial neurogenin or Mash-1 expression a seemingly deciding factor [144]. When cells that are transplanted into the early developing nervous system are evaluated for the expression of regionally specific markers, such as these transcription factors, they seem to express themselves as if they pay little heed to their ectopic location. For example, one experiment demonstrated that only about 6% of the transplanted cells that took up residence in the striatum expressed Dlx immunoreactivity, indicating a GABAergic trajectory, while 37% of the transplanted cells residing in the tectum, a region typically devoid of this marker, expressed this marker [145]. Such data suggest that there may be a longer-term set of guidance steps that feed into promoting the regionally specific neuronal phenotypes that include an earlier need for cell juxtaposition interactions that generate homeodomain predilections prior to the final departure of neurons from the cell cycle. The circumstances seem somewhat different in vitro with populations of neural stem cells, because when growth factors are carefully removed from such populations within N2B27 media (conducive of neuronal differentiation), the large majority of neurons (over 80%) produced adopt the GABAergic phenotype [146]. Another informative embryonic-to-embryonic transplant study that broadens the developmental factors associated with phenotype decisions was performed by Magrassi and colleagues [147]. They found that when ganglionic eminencederived neurons clustered together as aggregates, they supported each other in maintaining their GABAergic phenotype fate while, by contrast, neurons that migrate into ectopic locations as individuals may adopt alternative fates guided by local signals. The capacity of cells that are predestined to adopt alternative fates based on responding to positional signals has been demonstrated in that they are able to adopt cortical-like morphologies when they migrate into the cortex, presumably as individual neurons [148]. In fact, at this early point in transplantation evaluation, outcome assessments based largely on the morphology of neurons indicated that transplantation into any region seemed to be guided by local cue phenotype induction toward locally appropriate fates (e.g., [149]). These days such assessments are largely considered insufficient, and a more marker-specific immunocytological phenotype determination is encouraged. When these are evaluated with the subventricular-zone-derived adult neural stem cells and their common migration trajectory into the olfactory bulb, it has been suggested that differential phenotypes or phenotype-restrictions might begin to be established quite early, prior to migration to the destination, given the diversity of expressions despite common local cues within the bulb [150]. However, a more recent hypothesis-driven review compiled by Sequerra and colleagues [151] suggests that the capacity for true phenotype guidance from local cues can be quite extensive, such that environmental circumstances can differentiate between glutamatergic and GABAergic phenotypes and manipulations of morphogen expressions, such as sonic hedgehog, by blocking it in ventral locations or ectopically expressing it in dorsal locations can "dorsalize" neuronal phenotypes in ventral sectors or "ventralize" them in dorsal sectors respectively. Transplantation of small numbers of embryonic stem cells into various regions and subsequent specific tracking of resulting neurons indicates that within the intact mouse brain there is a regionally distinct capacity to promote the incorporation of new neurons that is largely progressively lost with age, but when neurons merge into the circuit during more accommodating developmental periods, they typically adopt regionally appropriate functional contributions.

significant growth into the basal ganglia circuitry with the majority of the graft adopting a GABAergic phenotype and projecting *myelinated* axon growth into the host globus pallidus, with only a few projections showing retrograde transport indicating they reached the substantia nigra reticulata. Interestingly in his review, Wictorin [84] also mentions control studies performed in which cerebellar precursor tissue was transplanted into the striatum instead of the ganglionic eminence-derived cells, and that this ectopic transplant resulted in considerably diminished outgrowth and diminished integration with either glutamatergic or dopaminergic host-derived afferent ingrowth. The migration of neurons was even affected when transplants were placed into the developing neonatal striatum in a restricted manner when cerebellar precursor tissue was used instead of striatal precursor tissue, indicating the relevant guidance cues are established early [152]. As might be imagined, hindbrain (rhombencephalon) precursor tissue, transplanted into the adult cerebellum after excitotoxic lesions in that region, adopts several local phenotypes and seems to grow extensively into this region, recapitulating that circuit to an arguably regionally specific, yet similar, degree [153]. This indicates that homotypic versus ectopic concerns are more universal and relevant to multiple regions. Interestingly, human-derived precursor cells transplanted into the rat brain have also been described as growing more extensively into the rat host than do either rat- or mouse-derived precursor cells, though they seemed also to be sensitive to being placed within a homotypic domain (striatal into striatum) versus an ectopic domain (cerebellar into striatum), once again expressing significantly reduced growth into the latter host location [154]. It is intriguing to speculate about how human-derived neural precursors attain a more prominent and extensive host integration into rat host tissue when the signals presumably inspiring growth are likely distinct, though it has been speculated that human cells harbor a propensity to grow for greater distances before target-derived signals are expected while exhibiting a relative insensitivity to growth-inhibiting signals that are produced by the host. The bottom line message of this section is that cell populations seem to acquire, and become limited by, their: (1) neuronal status where they depart from the mitosis cycle, (2) neurotransmitter phenotype that limits their range of influence, and (3) regional predilection that bolsters their contribution to the circuit when they recognize "home" and diminishes contributions from cells delivered elsewhere. This regional predilection has been described above for striatal, or ganglionic eminence-derived neurons, transplanted into the striatum. Apparently, it is also relevant to dopaminergic neuron transplants of fetal ventral mesencephalon, which typically includes both nigral (A9) and ventral tegmental (A10) "type" neurons and for which the ability to successfully re-innervate the striatum is far superior among the nigral type, both anatomically and in terms of behavioral support [155–157]. It seems clear that there are niche components integrated into neuronal phenotypes that extend beyond merely the transmitter they express. So what does this say about the ectopic dopaminergic cell transplantation into the striatum and the idea that transplant contributions will be more successful if placed within their target region? These efforts do require some background explanation. Parkinson's disease has been understood as mainly a loss of forebrain or more specifically striatal dopamine for most of its history. Although the specific temporal and spatial actions of striatal and greater basal ganglia neurons have been better understood for quite some time, there has been a corresponding lack of attention to the temporal dynamics of the dopamine provisions to that system in the clinical world, presumably because the tools available seem to work without a need for such a

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell…

http://dx.doi.org/10.5772/intechopen.71790

25

What about the projection potential of transplanted neurons as they attempt to integrate with the host? As described before, Wictorin and his collaborators [84] explored the placement of presumed striatal-predestined rat embryonic ganglionic eminence-derived grafts into the striatum of adult rats following excitotoxic lesions in this same-target location. They witnessed significant growth into the basal ganglia circuitry with the majority of the graft adopting a GABAergic phenotype and projecting *myelinated* axon growth into the host globus pallidus, with only a few projections showing retrograde transport indicating they reached the substantia nigra reticulata. Interestingly in his review, Wictorin [84] also mentions control studies performed in which cerebellar precursor tissue was transplanted into the striatum instead of the ganglionic eminence-derived cells, and that this ectopic transplant resulted in considerably diminished outgrowth and diminished integration with either glutamatergic or dopaminergic host-derived afferent ingrowth. The migration of neurons was even affected when transplants were placed into the developing neonatal striatum in a restricted manner when cerebellar precursor tissue was used instead of striatal precursor tissue, indicating the relevant guidance cues are established early [152]. As might be imagined, hindbrain (rhombencephalon) precursor tissue, transplanted into the adult cerebellum after excitotoxic lesions in that region, adopts several local phenotypes and seems to grow extensively into this region, recapitulating that circuit to an arguably regionally specific, yet similar, degree [153]. This indicates that homotypic versus ectopic concerns are more universal and relevant to multiple regions. Interestingly, human-derived precursor cells transplanted into the rat brain have also been described as growing more extensively into the rat host than do either rat- or mouse-derived precursor cells, though they seemed also to be sensitive to being placed within a homotypic domain (striatal into striatum) versus an ectopic domain (cerebellar into striatum), once again expressing significantly reduced growth into the latter host location [154]. It is intriguing to speculate about how human-derived neural precursors attain a more prominent and extensive host integration into rat host tissue when the signals presumably inspiring growth are likely distinct, though it has been speculated that human cells harbor a propensity to grow for greater distances before target-derived signals are expected while exhibiting a relative insensitivity to growth-inhibiting signals that are produced by the host. The bottom line message of this section is that cell populations seem to acquire, and become limited by, their: (1) neuronal status where they depart from the mitosis cycle, (2) neurotransmitter phenotype that limits their range of influence, and (3) regional predilection that bolsters their contribution to the circuit when they recognize "home" and diminishes contributions from cells delivered elsewhere. This regional predilection has been described above for striatal, or ganglionic eminence-derived neurons, transplanted into the striatum. Apparently, it is also relevant to dopaminergic neuron transplants of fetal ventral mesencephalon, which typically includes both nigral (A9) and ventral tegmental (A10) "type" neurons and for which the ability to successfully re-innervate the striatum is far superior among the nigral type, both anatomically and in terms of behavioral support [155–157]. It seems clear that there are niche components integrated into neuronal phenotypes that extend beyond merely the transmitter they express.

these transcription factors, they seem to express themselves as if they pay little heed to their ectopic location. For example, one experiment demonstrated that only about 6% of the transplanted cells that took up residence in the striatum expressed Dlx immunoreactivity, indicating a GABAergic trajectory, while 37% of the transplanted cells residing in the tectum, a region typically devoid of this marker, expressed this marker [145]. Such data suggest that there may be a longer-term set of guidance steps that feed into promoting the regionally specific neuronal phenotypes that include an earlier need for cell juxtaposition interactions that generate homeodomain predilections prior to the final departure of neurons from the cell cycle. The circumstances seem somewhat different in vitro with populations of neural stem cells, because when growth factors are carefully removed from such populations within N2B27 media (conducive of neuronal differentiation), the large majority of neurons (over 80%) produced adopt the GABAergic phenotype [146]. Another informative embryonic-to-embryonic transplant study that broadens the developmental factors associated with phenotype decisions was performed by Magrassi and colleagues [147]. They found that when ganglionic eminencederived neurons clustered together as aggregates, they supported each other in maintaining their GABAergic phenotype fate while, by contrast, neurons that migrate into ectopic locations as individuals may adopt alternative fates guided by local signals. The capacity of cells that are predestined to adopt alternative fates based on responding to positional signals has been demonstrated in that they are able to adopt cortical-like morphologies when they migrate into the cortex, presumably as individual neurons [148]. In fact, at this early point in transplantation evaluation, outcome assessments based largely on the morphology of neurons indicated that transplantation into any region seemed to be guided by local cue phenotype induction toward locally appropriate fates (e.g., [149]). These days such assessments are largely considered insufficient, and a more marker-specific immunocytological phenotype determination is encouraged. When these are evaluated with the subventricular-zone-derived adult neural stem cells and their common migration trajectory into the olfactory bulb, it has been suggested that differential phenotypes or phenotype-restrictions might begin to be established quite early, prior to migration to the destination, given the diversity of expressions despite common local cues within the bulb [150]. However, a more recent hypothesis-driven review compiled by Sequerra and colleagues [151] suggests that the capacity for true phenotype guidance from local cues can be quite extensive, such that environmental circumstances can differentiate between glutamatergic and GABAergic phenotypes and manipulations of morphogen expressions, such as sonic hedgehog, by blocking it in ventral locations or ectopically expressing it in dorsal locations can "dorsalize" neuronal phenotypes in ventral sectors or "ventralize" them in dorsal sectors respectively. Transplantation of small numbers of embryonic stem cells into various regions and subsequent specific tracking of resulting neurons indicates that within the intact mouse brain there is a regionally distinct capacity to promote the incorporation of new neurons that is largely progressively lost with age, but when neurons merge into the circuit during more accommodating developmental periods, they typically adopt regionally appro-

What about the projection potential of transplanted neurons as they attempt to integrate with the host? As described before, Wictorin and his collaborators [84] explored the placement of presumed striatal-predestined rat embryonic ganglionic eminence-derived grafts into the striatum of adult rats following excitotoxic lesions in this same-target location. They witnessed

priate functional contributions.

24 Neuroplasticity - Insights of Neural Reorganization

So what does this say about the ectopic dopaminergic cell transplantation into the striatum and the idea that transplant contributions will be more successful if placed within their target region? These efforts do require some background explanation. Parkinson's disease has been understood as mainly a loss of forebrain or more specifically striatal dopamine for most of its history. Although the specific temporal and spatial actions of striatal and greater basal ganglia neurons have been better understood for quite some time, there has been a corresponding lack of attention to the temporal dynamics of the dopamine provisions to that system in the clinical world, presumably because the tools available seem to work without a need for such a concern. The virtue of the most common pharmaceutical treatment, Levodopa, seems to derive largely from ensuring a more consistent dopamine presence. Dopamine agonists, also used as a pharmacological treatment, likely linger outside any strict temporal parameters in that they are likely removed only by diffusion. Animal models benefit from rudimentary delivery mechanisms that also largely appear to maintain dopamine presence with little to no dynamic shifting according to "need," as might be expected of the phasic attributes of an intact dopamine system. Clearly the previously-mentioned movement tests that reveal the insufficient temporal precision of behavioral control with classic treatment has heightened awareness of the concern [108]. Nevertheless it is readily apparent that dopamine cell transplantation for the Parkinson's patient remains largely conceptualized as a more sophisticated delivery system for dopamine that may become increasingly necessary as the ongoing deterioration of dopaminergic neurons diminishes the patient's capacity to convert Levodopa into dopamine. The enzyme aromatic L-amino acid decarboxylase is necessary to complete this conversion step and experimental animal tests indicate that the effects of Levodopa both depend on this action and that serotonergic neurons within the brain, which also harbor this enzyme, may be capable of supporting continued benefit from the drug [158]. Dopamine neuron transplantation into the striatum likely provides improved benefit beyond this serotonergic neuron involvement in that transplanted cells would be capable of growing into greater proximity, and that their terminals would maintain an improved reuptake transport control of the corresponding dopamine released that serotonergic neurons would lack. Nonetheless, for the reasons mentioned in the previous section, the absence of controlled dynamic modification would develop into a problem over time as the greater circuit compensates, and should be attended to as clinical strategies are formulated.

on to the ventrolateral and ventromedial thalamus, understood to form the basis of motor program selection provided by the basal ganglia [169]. These GABAergic transplants into the nigra also may contribute benefit by increasing the local suppression of noise as described previously for the seemingly noisy striatum. As efforts expanded, it became clear that considerable neurotrophic support was necessary and this was either provided by "bridge" tissue grafts that might be likely to release such compounds, such as Schwann cell type cells, or the local cells were induced to release these compounds by viral transgenic expression (e.g., [82, 160, 170]). This strategy renders the CNS territory through which the new dopaminergic fibers must grow more hospitable, presumably also providing retrograde support signals, inspiring continued growth, and staving off the previously-described cell death that results from the lack of con-

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell…

http://dx.doi.org/10.5772/intechopen.71790

27

It is notable that while many of these strategies were being tested, a well-recognized age dependency was revealed in that even significant dopamine-depleting lesions performed on young and neonatal animals yielded only mild or dramatically diminished behavioral deficits [171, 172]. At the same time, these animals, when grown to adults, still depended upon dopamine for their locomotor behavior, albeit in an altered way [173], and produced sufficient but diminished levels of striatal dopamine to accomplish this [174]. Perhaps the enhanced plasticity supporting this maintenance of dopamine-dependent behavioral control was derived from the natural expression of neurotrophic factors that maintain a higher presence during early postnatal periods of development [175]. A general protection of dopaminergic neurons has been shown to derive from glial-derived neurotrophic factor (GDNF) in particular [176]. In fact, it has been determined that developing nigral dopaminergic neurons depends considerably on GDNF for their survival and maintenance by the establishment of a conditional GDNF knock-out mouse that exhibits clear dopaminergic disruption-related hypokinesia and diminished tyrosine hydroxylase among dopaminergic neurons once GDNF production is blocked during adulthood [177]. The age-dependency factor, regarding the dopamine system, has also been demonstrated in the ability to incorporate dopaminergic transplants. Efforts to unilaterally transplant dopaminergic fetal grafts into the substantia nigra on postnatal days 3, 10, and 20 into rats that had received bilateral 6-OHDA lesions on postnatal day 1 resulted in the intriguing finding that transplants given on postnatal days 3 and 10 showed evidence of nigrostriatal regrowth or fuller incorporation into that circuit, while those receiving transplants on postnatal day 20 did not [178]. It seems GDNF and BDNF may cooperate, to some extent, in supporting dopaminergic cells, as BDNF has also been used successfully to promote a sparse re-innervation of the striatum from a nigral-targeted graft [179]. The neurotrophic factors that seem to play supportive roles expand considerably when observed in the light of what supports the original production of the medial forebrain bundle during development [180]. Coaxing the growth-trajectory environment to also express adhesion molecules that new growth cones might grow along has also been considered (e.g., [170]). The sorts of glial cells or other tissue, which are often added to the equation of a "bridge," are generally not those known to be disruptive to axon growth such as astrocytes and oligodendrocytes. In fact when the medial forebrain bundle pathway is observed for regrowth following axotomy, sprouting of new axons is considerably enhanced by removing glial cells from the growth path by use of

nectedness during this growth journey.

Presumably behavioral support would be improved if derived from dopamine release from more fully reconstructed dopaminergic projections from a grafted nigra into the striatum as there would be improved potential for dynamic temporal control by more "appropriate" afferents. Despite the fact that most reviews of transplants for PD mention this point (e.g., [155]), to our current knowledge, despite several apparent successes in establishing nigra-to-striatum re-innervation from nigral dopaminergic grafts [159–165], there have been no systemic assessments of the afferent control of these grafts established by the host. Clearly the main interest at present with such a grafting strategy is to ensure the dopaminergic reconstruction extends across the inhospitable terrain of the adult brain from the nigra to the striatum. Likely due to the expression of considerable disruptive signals within the adult CNS and the need for more continual support during the growth process, initial efforts to coax this reconstruction from homotypic nigral-placed grafts were unsuccessful in breaching the divide, though even these relatively nigral-restricted grafts did provide some behavioral support [166], likely due to the importance of dendritic dopamine release within the nigra [167]. In fact, the neuronal populations upon which the dendritic dopamine release likely plays its role are GABAergic neurons in the reticulata, and efforts to transplant GABA-producing neurons into this region have also demonstrated some behavioral benefit, presumably by somehow expanding the repertoire of this basal ganglia output region [83, 168]. Such an effect speaks volumes, questioning the precision of the disinhibitory feedback loop formed by striatal efferents to the nigra reticulata and on to the ventrolateral and ventromedial thalamus, understood to form the basis of motor program selection provided by the basal ganglia [169]. These GABAergic transplants into the nigra also may contribute benefit by increasing the local suppression of noise as described previously for the seemingly noisy striatum. As efforts expanded, it became clear that considerable neurotrophic support was necessary and this was either provided by "bridge" tissue grafts that might be likely to release such compounds, such as Schwann cell type cells, or the local cells were induced to release these compounds by viral transgenic expression (e.g., [82, 160, 170]). This strategy renders the CNS territory through which the new dopaminergic fibers must grow more hospitable, presumably also providing retrograde support signals, inspiring continued growth, and staving off the previously-described cell death that results from the lack of connectedness during this growth journey.

concern. The virtue of the most common pharmaceutical treatment, Levodopa, seems to derive largely from ensuring a more consistent dopamine presence. Dopamine agonists, also used as a pharmacological treatment, likely linger outside any strict temporal parameters in that they are likely removed only by diffusion. Animal models benefit from rudimentary delivery mechanisms that also largely appear to maintain dopamine presence with little to no dynamic shifting according to "need," as might be expected of the phasic attributes of an intact dopamine system. Clearly the previously-mentioned movement tests that reveal the insufficient temporal precision of behavioral control with classic treatment has heightened awareness of the concern [108]. Nevertheless it is readily apparent that dopamine cell transplantation for the Parkinson's patient remains largely conceptualized as a more sophisticated delivery system for dopamine that may become increasingly necessary as the ongoing deterioration of dopaminergic neurons diminishes the patient's capacity to convert Levodopa into dopamine. The enzyme aromatic L-amino acid decarboxylase is necessary to complete this conversion step and experimental animal tests indicate that the effects of Levodopa both depend on this action and that serotonergic neurons within the brain, which also harbor this enzyme, may be capable of supporting continued benefit from the drug [158]. Dopamine neuron transplantation into the striatum likely provides improved benefit beyond this serotonergic neuron involvement in that transplanted cells would be capable of growing into greater proximity, and that their terminals would maintain an improved reuptake transport control of the corresponding dopamine released that serotonergic neurons would lack. Nonetheless, for the reasons mentioned in the previous section, the absence of controlled dynamic modification would develop into a problem over time as the greater circuit compensates, and should be attended to as clinical

Presumably behavioral support would be improved if derived from dopamine release from more fully reconstructed dopaminergic projections from a grafted nigra into the striatum as there would be improved potential for dynamic temporal control by more "appropriate" afferents. Despite the fact that most reviews of transplants for PD mention this point (e.g., [155]), to our current knowledge, despite several apparent successes in establishing nigra-to-striatum re-innervation from nigral dopaminergic grafts [159–165], there have been no systemic assessments of the afferent control of these grafts established by the host. Clearly the main interest at present with such a grafting strategy is to ensure the dopaminergic reconstruction extends across the inhospitable terrain of the adult brain from the nigra to the striatum. Likely due to the expression of considerable disruptive signals within the adult CNS and the need for more continual support during the growth process, initial efforts to coax this reconstruction from homotypic nigral-placed grafts were unsuccessful in breaching the divide, though even these relatively nigral-restricted grafts did provide some behavioral support [166], likely due to the importance of dendritic dopamine release within the nigra [167]. In fact, the neuronal populations upon which the dendritic dopamine release likely plays its role are GABAergic neurons in the reticulata, and efforts to transplant GABA-producing neurons into this region have also demonstrated some behavioral benefit, presumably by somehow expanding the repertoire of this basal ganglia output region [83, 168]. Such an effect speaks volumes, questioning the precision of the disinhibitory feedback loop formed by striatal efferents to the nigra reticulata and

strategies are formulated.

26 Neuroplasticity - Insights of Neural Reorganization

It is notable that while many of these strategies were being tested, a well-recognized age dependency was revealed in that even significant dopamine-depleting lesions performed on young and neonatal animals yielded only mild or dramatically diminished behavioral deficits [171, 172]. At the same time, these animals, when grown to adults, still depended upon dopamine for their locomotor behavior, albeit in an altered way [173], and produced sufficient but diminished levels of striatal dopamine to accomplish this [174]. Perhaps the enhanced plasticity supporting this maintenance of dopamine-dependent behavioral control was derived from the natural expression of neurotrophic factors that maintain a higher presence during early postnatal periods of development [175]. A general protection of dopaminergic neurons has been shown to derive from glial-derived neurotrophic factor (GDNF) in particular [176]. In fact, it has been determined that developing nigral dopaminergic neurons depends considerably on GDNF for their survival and maintenance by the establishment of a conditional GDNF knock-out mouse that exhibits clear dopaminergic disruption-related hypokinesia and diminished tyrosine hydroxylase among dopaminergic neurons once GDNF production is blocked during adulthood [177]. The age-dependency factor, regarding the dopamine system, has also been demonstrated in the ability to incorporate dopaminergic transplants. Efforts to unilaterally transplant dopaminergic fetal grafts into the substantia nigra on postnatal days 3, 10, and 20 into rats that had received bilateral 6-OHDA lesions on postnatal day 1 resulted in the intriguing finding that transplants given on postnatal days 3 and 10 showed evidence of nigrostriatal regrowth or fuller incorporation into that circuit, while those receiving transplants on postnatal day 20 did not [178]. It seems GDNF and BDNF may cooperate, to some extent, in supporting dopaminergic cells, as BDNF has also been used successfully to promote a sparse re-innervation of the striatum from a nigral-targeted graft [179]. The neurotrophic factors that seem to play supportive roles expand considerably when observed in the light of what supports the original production of the medial forebrain bundle during development [180].

Coaxing the growth-trajectory environment to also express adhesion molecules that new growth cones might grow along has also been considered (e.g., [170]). The sorts of glial cells or other tissue, which are often added to the equation of a "bridge," are generally not those known to be disruptive to axon growth such as astrocytes and oligodendrocytes. In fact when the medial forebrain bundle pathway is observed for regrowth following axotomy, sprouting of new axons is considerably enhanced by removing glial cells from the growth path by use of a glial toxin [181]. Among the putative interfering variables to this sort of existing cell regrowth are heparan sulfate proteoglycans, chondroitin sulfate proteoglycans, and keratan sulfate proteoglycans that are derived from activated astrocytes that surround lesions [182]. Developing dopaminergic neurons of the substantia nigra must sprout axons that grow anteriorly for substantial lengths to reach their target termination zones. Also, anatomists have recognized a substantial formation of synapses *en passant* among these and other monoaminergic neuron types, suggesting multiple way stations occur within target structures prior to establishing classic terminal boutons, each subject to various degrees of local control [183]. Their extensive growth trajectory requires growth-promoting and cell-death-diminishing signal molecules during axon extension, particularly when transplants are placed during adulthood when the road is longer. Thus, regrowth from such posterior-ventral origins likely depend on the presence of cellular *guideposts* along the way that might break up the full growth required of the nigrostriatal tract into growth stints that are supported by retrograde feedback signals, as well as the removal of potentially interfering substances derived from activated glia. The involvement of glia in the diminished propensity to grow extensive connections from posterior regions may also depend on the manner in which the original lesion is created. It may be that the neurotoxins used in animal models to induce dopamine-depleting lesions (e.g., 6-OHDA, MPTP) exacerbate glia, resulting in more activation of astrocytes and thereby interfering with regrowth (see [184, 185]). However in most idiopathic cases of Parkinson's disease, there is a distinct lack of reactive astrocytes during the course of deterioration or afterward [186, 187], indicating that the contributions of chondroitin sulfate and other growth-interfering responses might be lower in this condition, despite a clear insufficiency of dopaminergic regrowth. Nevertheless, the indication that reactive astrocytes may linger for up to 90 days following 6-OHDA administration [185] is intriguing when the rat 6-OHDA treated model system is considered because usually transplantation is performed prior to that time in those animal models.

cell to cell contact information and signal gradients that get established during the course of progressive commitment in gene expression. Specifically, inducing the transcription factor known as Wnt5a via transfection, following sonic hedgehog and FGF-8 exposure, seems to generate greater dopaminergic phenotype yields than sonic hedgehog and FGF-8 alone [191]. In addition, bone marrow derived stem cells seem to require a neuronal-enhancing, region-specific environment characterized by low oxygen, retinoic acid, and continuous neurotrophin-3 stimulation, as these in combination with the aforementioned sonic hedgehog and FGF-8 stimulation seem to enhance dopaminergic phenotype expression further [192]. All this indicates that there are specific local environments that would induce phenotype commitment based on regionally-specific combinations of factors that are provided in the appropriate sequence during development, and these remain in a sort of residual form still capable of supporting, albeit at a more limited degree of commitment, in the adult structure. The capacity of dopaminergic neurons grafted into the nigra to acquire afferent control remains understudied, but this capacity would likely be higher than that of ectopic transplants into the striatum. If gap junction connections could also be established with the local endogenous dopamine neurons of the nigra, this could enhance temporal pattern production substantially. Of course, if there are ongoing deterioration-inducing challenges among the Parkinsonian endogenous dopamine neurons this could induce the closure of gap junction connections, due to sensed pH or calcium changes, as a protective response [193]. However, given the circumscribed positioning of the dopaminergic neurons within the nigra following the transplant, it would seem a far more straightforward incorporation process regarding afferent stimulation in general than what would otherwise be required within the striatum.

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell…

http://dx.doi.org/10.5772/intechopen.71790

29

Multiple placement transplants have been performed using animal models that have shown more substantial support for behavior. Experiments performed by Mukhida and colleagues showed considerable improvement in behavioral control with dopaminergic-destined fetal ventral mesencephalic transplants into the striatum, substantia nigra, and subthalamic nucleus that seemed to improve behavioral recovery better than the typical single transplant alone [194]. Clearly there may be a benefit to such extended transplantation but there are two major issues drawing the practicality of such strategies into question. First, transplantation of cells into one area in human patients is already a significant procedure, fraught with considerable risk and expense. The idea of multiple sites of transplantation would need to be justified by not only significant movement restoration but also in long-term viability beyond the 5-week, post-transplantation assessments commonly used. Second, given the concerns raised in this review, each ectopic transplant performed is likely to both provide some distortion in the temporal dynamics of delivery and also would perhaps block the more successful growth and penetration of the homotypic aspect. How well would new nigrostriatal terminals grow into the striatum if there are already local striatal dopaminergic terminals competing for CNS real estate in the same region? Given the clinical limitations and the likely extended growth time that would be required for nigrostriatal restoration, it may be prudent to consider formulating temporary neurons that could be progressively eliminated as fibers reach the striatum that could maintain a "substitute" dopamine presence. The concern with dual transplants (both in the nigra and the striatum) is that striatal transplants would likely diminish the growth or synaptogenesis drive among incoming nigrostriatal growth cones in a manner similar to what seems to occur among striatal neurons transplanted into the intact

Homotypic transplant placement may also be promoted in the context of dopaminergic cells, given that their qualities may be guided more substantially by local cues, as well as gaining from local afferent control. During development, the local ventral midbrain environment seems to contribute considerable epigenetic guidance to newly generated neurons in the form of morphogens. One of these morphogens that has been classically associated with ventral development beginning at the neural tube stage is sonic hedgehog (for review see [188]). The two prominent locally secreted factors that drive dopaminergic phenotype development are fibroblast growth factor 8 (FGF-8) and sonic hedgehog [175], leading to internal genetic expression of Nurr1 and Ptx3 transcription factors that further establish phenotype delineation. This is likely why those two secreted factors are used in protocols that guide the development of dopaminergic phenotypes from more pluripotent precursors *in vitro* (e.g., [189, 190]). When ventral mesencephalic-derived embryonic stem cells are left to develop freely in culture, many of them develop as dopaminergic, but there is also a mixture of phenotypes that might be expected from the ventral midbrain or hindbrain such as serotonergic and GABAergic neurons. Efforts to improve the yield of dopaminergic phenotypes have produced multiple proposed protocols involving different steps that replicate different aspects of developmental phenotype adoption. For example, one of these uses the Wnt signaling to influence developing neurons at the location of the developing nigra. Wnt signaling seems to be established to differential degrees in the developing nervous system, in large part by cell to cell contact information and signal gradients that get established during the course of progressive commitment in gene expression. Specifically, inducing the transcription factor known as Wnt5a via transfection, following sonic hedgehog and FGF-8 exposure, seems to generate greater dopaminergic phenotype yields than sonic hedgehog and FGF-8 alone [191]. In addition, bone marrow derived stem cells seem to require a neuronal-enhancing, region-specific environment characterized by low oxygen, retinoic acid, and continuous neurotrophin-3 stimulation, as these in combination with the aforementioned sonic hedgehog and FGF-8 stimulation seem to enhance dopaminergic phenotype expression further [192]. All this indicates that there are specific local environments that would induce phenotype commitment based on regionally-specific combinations of factors that are provided in the appropriate sequence during development, and these remain in a sort of residual form still capable of supporting, albeit at a more limited degree of commitment, in the adult structure. The capacity of dopaminergic neurons grafted into the nigra to acquire afferent control remains understudied, but this capacity would likely be higher than that of ectopic transplants into the striatum. If gap junction connections could also be established with the local endogenous dopamine neurons of the nigra, this could enhance temporal pattern production substantially. Of course, if there are ongoing deterioration-inducing challenges among the Parkinsonian endogenous dopamine neurons this could induce the closure of gap junction connections, due to sensed pH or calcium changes, as a protective response [193]. However, given the circumscribed positioning of the dopaminergic neurons within the nigra following the transplant, it would seem a far more straightforward incorporation process regarding afferent stimulation in general than what would otherwise be required within the striatum.

a glial toxin [181]. Among the putative interfering variables to this sort of existing cell regrowth are heparan sulfate proteoglycans, chondroitin sulfate proteoglycans, and keratan sulfate proteoglycans that are derived from activated astrocytes that surround lesions [182]. Developing dopaminergic neurons of the substantia nigra must sprout axons that grow anteriorly for substantial lengths to reach their target termination zones. Also, anatomists have recognized a substantial formation of synapses *en passant* among these and other monoaminergic neuron types, suggesting multiple way stations occur within target structures prior to establishing classic terminal boutons, each subject to various degrees of local control [183]. Their extensive growth trajectory requires growth-promoting and cell-death-diminishing signal molecules during axon extension, particularly when transplants are placed during adulthood when the road is longer. Thus, regrowth from such posterior-ventral origins likely depend on the presence of cellular *guideposts* along the way that might break up the full growth required of the nigrostriatal tract into growth stints that are supported by retrograde feedback signals, as well as the removal of potentially interfering substances derived from activated glia. The involvement of glia in the diminished propensity to grow extensive connections from posterior regions may also depend on the manner in which the original lesion is created. It may be that the neurotoxins used in animal models to induce dopamine-depleting lesions (e.g., 6-OHDA, MPTP) exacerbate glia, resulting in more activation of astrocytes and thereby interfering with regrowth (see [184, 185]). However in most idiopathic cases of Parkinson's disease, there is a distinct lack of reactive astrocytes during the course of deterioration or afterward [186, 187], indicating that the contributions of chondroitin sulfate and other growth-interfering responses might be lower in this condition, despite a clear insufficiency of dopaminergic regrowth. Nevertheless, the indication that reactive astrocytes may linger for up to 90 days following 6-OHDA administration [185] is intriguing when the rat 6-OHDA treated model system is considered because usually trans-

28 Neuroplasticity - Insights of Neural Reorganization

plantation is performed prior to that time in those animal models.

Homotypic transplant placement may also be promoted in the context of dopaminergic cells, given that their qualities may be guided more substantially by local cues, as well as gaining from local afferent control. During development, the local ventral midbrain environment seems to contribute considerable epigenetic guidance to newly generated neurons in the form of morphogens. One of these morphogens that has been classically associated with ventral development beginning at the neural tube stage is sonic hedgehog (for review see [188]). The two prominent locally secreted factors that drive dopaminergic phenotype development are fibroblast growth factor 8 (FGF-8) and sonic hedgehog [175], leading to internal genetic expression of Nurr1 and Ptx3 transcription factors that further establish phenotype delineation. This is likely why those two secreted factors are used in protocols that guide the development of dopaminergic phenotypes from more pluripotent precursors *in vitro* (e.g., [189, 190]). When ventral mesencephalic-derived embryonic stem cells are left to develop freely in culture, many of them develop as dopaminergic, but there is also a mixture of phenotypes that might be expected from the ventral midbrain or hindbrain such as serotonergic and GABAergic neurons. Efforts to improve the yield of dopaminergic phenotypes have produced multiple proposed protocols involving different steps that replicate different aspects of developmental phenotype adoption. For example, one of these uses the Wnt signaling to influence developing neurons at the location of the developing nigra. Wnt signaling seems to be established to differential degrees in the developing nervous system, in large part by Multiple placement transplants have been performed using animal models that have shown more substantial support for behavior. Experiments performed by Mukhida and colleagues showed considerable improvement in behavioral control with dopaminergic-destined fetal ventral mesencephalic transplants into the striatum, substantia nigra, and subthalamic nucleus that seemed to improve behavioral recovery better than the typical single transplant alone [194]. Clearly there may be a benefit to such extended transplantation but there are two major issues drawing the practicality of such strategies into question. First, transplantation of cells into one area in human patients is already a significant procedure, fraught with considerable risk and expense. The idea of multiple sites of transplantation would need to be justified by not only significant movement restoration but also in long-term viability beyond the 5-week, post-transplantation assessments commonly used. Second, given the concerns raised in this review, each ectopic transplant performed is likely to both provide some distortion in the temporal dynamics of delivery and also would perhaps block the more successful growth and penetration of the homotypic aspect. How well would new nigrostriatal terminals grow into the striatum if there are already local striatal dopaminergic terminals competing for CNS real estate in the same region? Given the clinical limitations and the likely extended growth time that would be required for nigrostriatal restoration, it may be prudent to consider formulating temporary neurons that could be progressively eliminated as fibers reach the striatum that could maintain a "substitute" dopamine presence. The concern with dual transplants (both in the nigra and the striatum) is that striatal transplants would likely diminish the growth or synaptogenesis drive among incoming nigrostriatal growth cones in a manner similar to what seems to occur among striatal neurons transplanted into the intact striatum (establishing limited interactions with the host as a result). At this point, developing transgenic transplantable cells with pharmacologically inducible properties may be able to accomplish this temporary substitute goal. Initial inefficient support might be maintained during the growth process and this might be progressively and selectively removed as dopaminergic growth from homotypic regions reaches the area.

of deep brain stimulation, as derived from earlier therapies for Parkinson's disease, was to render excessive and aberrant activity quiescent (see [196, 197]). It is important that our clinical efforts consider the adaptive nature of the host tissue, into which we desire our transplants to be incorporated as this strategy will meet with greater long-term success and fewer potentially disruptive side-effects that generate additional, unwanted measures into the equation if

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell…

Support for this work was provided by the Central Michigan Neuroscience Program, the Central Michigan University Office of Research and Sponsored Programs, the John G. Kulhavi

1 Neuroscience and Experimental Psychology Programs, Central Michigan University,

[1] Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, Testa L, Stecco A, Tarletti R, Miglioretti M, Fava E, Nasuelli N, Cisari C, Massara M, Vercelli R.Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A phase I clinical trial. Experi-

[2] Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature. 2006;

[3] Mezey E, Key S, Vogelsang G, Szalayova I, Lange D, Crain B. Transplanted bone marrow generates new neurons in human brains. Proceedings of the National Academy of Sciences of the United States of America. 2003;**100**(3):1364-1369. DOI: 10.1073/pnas.0336479100 [4] Rossignol J, Fink K, Davis K, Clerc S, Crane A, Matchynski J, Lowrance S, Bombard M, Derkorver N, Lescaudron L, Dunbar GL. Transplants of adult mesenchymal and neural stem cells provide neuroprotection and behavioral sparing in a transgenic rat model of

mental Neurology. 2010;**223**(1):229-237. DOI: 10.1016/j.expneurol.2009.08.007

Huntington's disease. Stem Cells. 2014;**32**(2):500-509. DOI: 10.1002/stem.1508

, Naveen Jayaprakash<sup>2</sup>

, Parnit K. Bhupal<sup>1</sup>

http://dx.doi.org/10.5772/intechopen.71790

and

31

these concerns are not accounted for from the outset.

Professorship, and the Field Neurosciences Institute.

\*Address all correspondence to: sands1m@cmich.edu

3 Field Neurosciences Institute, Saginaw, MI, USA

**441**:1094-1096. DOI: 10.1038/nature04960

\*, Kevin A. Anderson<sup>1</sup>

2 Biomedical Science, Marquette University, Milwaukee, WI, USA

**Acknowledgements**

**Author details**

Gary L. Dunbar1,3

**References**

Michael I. Sandstrom<sup>1</sup>

Mount Pleasant, MI, USA

### **5. Concluding remarks**

Plastic adaptation was described above as representing a multitude of cellular responses that occur with the apparent role of maintaining cellular homeostasis, yet within the nervous system also support the maintenance of a sort of dynamic status quo in which compensatory changes adjust the actions or response capacities of local healthy neurons in support of a superseding circuit-associated need. We understand that various CNS circuits establish the capacity to process a wide range of information with various degrees of versatility that presumably evolved to provide stability in some areas of common reliance and flexibility in areas where learning functions occur regularly and synaptic adjustments are correspondingly at higher demand. Neurons appear to undergo adaptations as they attempt to enter a circuit, and the environmental guidance for the control contributed by new additions extends to various degrees backward into the history of the newly added cells in question as it signals what it can provide and encourages host connections while it negotiates for acceptance into the host circuit and the privilege of contributing. As neurons do this during development, their relative pluripotency diminishes toward the eventual niche they enter into and it is highly likely that new neuronal contributions transplanted into these circumstances go through similar steps as they adapt to the roles they play. The long-term viability of additions requires that a utility anticipated by the circuit is fulfilled or the host circuit may adapt the addition out of relevance like an efficient social system isolates and eventually eliminates an influence perceived as disruptive. As an example, a long-term neurotransmitter lingering without dynamic change could come from leaky or malfunctioning neurons, so it would benefit a circuit to recognize this and diminish postsynaptic responses until the signal once again exceeds noise. Synaptic negotiation during development of the mammalian neuromuscular system, which has been more accessible and easier to manipulate with experiments, shows a series of back and forth messages that eventually culminate in the muscle fiber accepting one motoneuron terminal and rejecting other applications for the job (see [195] for detailed discussion of this process). It is likely that whether neurons incorporate into CNS circuits depends upon their capacity to apply themselves and on whether the corresponding job has already been taken, as indicated by the diminished success of transplants into adult intact CNS structures achieving synaptic incorporation. While it is possible for neuronal precursors to be conditioned in a manner that promotes certain wanted phenotypes, the ability to properly incorporate into a workable circuit is challenged when they are placed into an ectopic environment as described above. To draw an analogy to human socialization, it's as if the cells in question either have, or are given, an agenda that may or may not merge with the agenda of the local host circuit. The mechanisms in place that promote apoptosis, in this context, are a useful and positive contribution to the overall circuit despite the fact that the death of cells seems unfortunate. Neurons in various deteriorative diseases adopt abnormal activities. In fact, the whole basis of deep brain stimulation, as derived from earlier therapies for Parkinson's disease, was to render excessive and aberrant activity quiescent (see [196, 197]). It is important that our clinical efforts consider the adaptive nature of the host tissue, into which we desire our transplants to be incorporated as this strategy will meet with greater long-term success and fewer potentially disruptive side-effects that generate additional, unwanted measures into the equation if these concerns are not accounted for from the outset.
