**Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington's or Parkinson's Disease of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington's or Parkinson's Disease**

**Plastic Adaptation: A Neuronal Imperative Capable** 

DOI: 10.5772/intechopen.71790

Michael I. Sandstrom, Kevin A. Anderson, Naveen Jayaprakash, Parnit K. Bhupal and Gary L. Dunbar Naveen Jayaprakash, Parnit K. Bhupal and Gary L. Dunbar Additional information is available at the end of the chapter

Michael I. Sandstrom, Kevin A. Anderson,

Additional information is available at the end of the chapter

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

#### **Abstract**

**References**

6 Neuroplasticity - Insights of Neural Reorganization

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[9] Li J, McDonald J, Rapkin A, Micevych P, Chaban V. Inflammation in the uterus induces pERK and substance P activation in DRG neurons innervating both uterus and colon in

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[12] Chaban V. Estrogen modulation of visceral nociception. In: Ritzner, Weizman, editors. Neuroactive Steroids in Brain Function, and Mental Health: New Perspectives for

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Although stem cell transplant therapy offers considerable promise for deteriorative diseases, the efficacy of its application may be mitigated by endogenous compensatory mechanisms in the host brain. Plastic compensation follows neurodegeneration, beginning at its very onset and minimizing early symptom expression. As researchers attempt to correlate symptom remission with the ability of transplanted cells to adopt specific cell phenotypes, they need to be vigilant of the possibility that competing, local compensatory effects may be altering the outcome. Clearly plastic compensatory mechanisms could confound desired transplant-derived improvements by supplanting the beneficial contributions of the transplants. As circuit-level adaptations occur, more explicit explorations of their relevance to neuronal transplantation success are needed. Conceptual models of undirected transplanted cells adopting preconceived appropriate roles require revision. The notion that newly transplanted neuronal precursors will incorporate themselves into host circuitry with mutual cooperation across both parties (i.e., transplant and host) without some symbiosis-promoting mechanism is naïve. Undirected local circuits could react to newly transplanted additions as intruders. We advocate that appropriate signaling from transplanted cells to the host environment is required to optimize the therapeutic relevance of transplantation. This review surveys critical signaling mechanisms that might promote symbiotic interdependence between the host and new transplants.

**Keywords:** stem cells, transplantation, Parkinson's disease, Huntington's disease, adaptive plasticity, development

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1. Introduction**

For several years now, efforts have been underway to examine and refine technology associated with promoting the incorporation of pluripotent stem cells from various origins following transplantation into the brains of patients suffering from various deteriorative diseases [1–3], or to test the viability of such treatments using experimental animal models [4–6]. The typical pattern of findings associated with clinical efforts is initial moderate symptom improvement, followed by either resumption of symptoms over time or highly variable therapeutic outcomes [7–9]. Common arguments raised for the mechanism underlying inconsistent effectiveness are that either the transplanted cells are not merging sufficiently with the host brain due to a timely competition-related synaptogenesis process, that transplanted cells are not surviving in the harsh environment of the host due to immune-system/inflammatory host responses, or both [8–11] (also see the extensive review by cell type [12]). While evidence for these arguments certainly exists, it remains unclear whether those arguments cover all the relevant possibilities that threaten the longevity of the transplanted stem cells' utility. One potential threat to the long-term efficacy of this treatment, or to stem cell transplant therapies in general, which is frequently overlooked, would be *plastic adaptation*. Briefly, plastic adaptation represents a multitude of cellular responses that occur with the apparent role of maintaining cellular homeostasis, yet within the nervous system also supports 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. Plastic adaptation also occurs within the physiologically healthy brain in order to adjust for novel needs, supporting changes such as long-term memory, habit formation, and other sorts of behavioral adaptation of organisms to new surroundings and demands (for examples see [13, 14]). A surge of inquiry into what are now known as epigenetic mechanisms supports the notion of a clear capacity of cells to respond to environmental stimuli by generating enduring changes in their genetic expression [15–18]. This, combined with numerous demonstrations of more transient receptor plasticity [19–22], defines neuronal cells as versatile in both shortand long-term periods in adjusting to their neurochemical and electrophysiological circumstances at their membranes and within their nuclei, respectively. Following transplantation, it is likely that plastic adaptation responses could occur in both populations of neuronal cells of concern, either the transplanted cells or the surrounding host cells that likely interact with the transplanted cells.

might contribute to the developing circuit [35, 36]. As needs are met, postsynaptic neurons decrease their encouragement of subsequent equivalent connections by adapting their signaling [37–40]. How new afferents drive or control action potentials contributes significantly to circuit behavior, depending on factors as subtle as the proximity of synapses to a target neuron's trigger zone, while on the postsynaptic side the development of the trigger zone may modify when and how action potentials arise [41–46]. Incorporation into circuits relates to both identity and survival as neurons develop. As the neuronal phenotype is established, developing cells become increasingly dependent upon both afferent and efferent connections to other neurons. Neuronal fate seems to result from aspects of stimulation in the context of neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Excitatory postsynaptic potentials known to increase intracellular calcium seem to participate in driving developmental determinations. This was shown by a series of experiments performed on precursor cells *in vitro* where calcium chelation blocked the establishment of neuronal phenotypes normally induced by either electrical or NMDA-glutamate stimulation in conjunction with BDNF [47–49]. Thus, precursors that receive insufficient controlling input to engage their activity likely adopt non-neuronal, glial, or support cell status, modifying or diminishing their contribution to circuits. When growing neurons establish connections to other neuronal populations, this provides them with target-derived trophic support that staves off programmed cell death that is likely to occur in its absence [50–53]. Surviving long enough to establish contributions is of course also important for transplanted populations, but evidence indicates that this is easier in the more forgiving context of development. A very useful series of explorations documenting how transplantation faces diminished success as the host ages was thoroughly documented in a mini-review by Sally Temple [54]. In addition, often the younger and less "experienced" or "committed" precursor cells are shown to more easily adapt into their transplanted roles than similar, yet older, populations [55–57]. In other contexts, such as the ability to properly generate blood cells following bone marrow transplants, younger donors seem to yield more successful results than older donors, indicating this age-dependency is not limited to neuronal populations [58, 59]. The similar goals of establishing appropriate cell populations to fill various niches following transplantation suggest if the environment were less competitive or more accommodating, and cells were guided by the more overt signals available during development, the process of incorporation would be more straightforward. In the adult brain, the mechanisms of plasticity engage to maintain the continuity of established function with mechanisms to prevent deviation from working systems; otherwise all nervous systems would constantly deteriorate into chaos. Thus, while similar concerns are present with transplantation, (i.e., coaxing the new cells to make useful and appropriate contributions to established circuitry), we cannot expect that new additions will naturally get swept into correct and working interactions the way they do

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

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

9

To tease out the contributions of plastic adaptation to the success or longevity of stem cell transplantation therapy, it seems there is a need to expand inquiry further than whether transplanted cells develop into neurons, survive, or form mutually integrative connections with endogenous neurons. It appears equally important to determine how the cell populations influence each other and how each population adapts to this influence over time. There may be important clues

during development.

During nervous system development, the mechanisms that guide the distributions of cells and their connectivity offer a far more forgiving flexibility when compared to the harsher, more demanding adult environment we face when attempting to correct deterioration with transplants [23–26]. Growth distances for neurites are shorter given the smaller neuropil, and more overt chemical gradients support pathfinding [27–29]. A developmental neurogenesis surge supports self-repair in the event of cell destruction because phenotype commitment is guided by a progressive fulfillment of niches and feedback signals once niches are filled [30–34]. Differential neuronal responsibilities within developing circuits are coaxed into existence in the context of an enhanced adaptive plasticity on either side of synaptic clefts, where each contributes to phenotype adoption of the other while it is determined what they might contribute to the developing circuit [35, 36]. As needs are met, postsynaptic neurons decrease their encouragement of subsequent equivalent connections by adapting their signaling [37–40]. How new afferents drive or control action potentials contributes significantly to circuit behavior, depending on factors as subtle as the proximity of synapses to a target neuron's trigger zone, while on the postsynaptic side the development of the trigger zone may modify when and how action potentials arise [41–46]. Incorporation into circuits relates to both identity and survival as neurons develop. As the neuronal phenotype is established, developing cells become increasingly dependent upon both afferent and efferent connections to other neurons. Neuronal fate seems to result from aspects of stimulation in the context of neurotrophic factors such as brain-derived neurotrophic factor (BDNF). Excitatory postsynaptic potentials known to increase intracellular calcium seem to participate in driving developmental determinations. This was shown by a series of experiments performed on precursor cells *in vitro* where calcium chelation blocked the establishment of neuronal phenotypes normally induced by either electrical or NMDA-glutamate stimulation in conjunction with BDNF [47–49]. Thus, precursors that receive insufficient controlling input to engage their activity likely adopt non-neuronal, glial, or support cell status, modifying or diminishing their contribution to circuits. When growing neurons establish connections to other neuronal populations, this provides them with target-derived trophic support that staves off programmed cell death that is likely to occur in its absence [50–53]. Surviving long enough to establish contributions is of course also important for transplanted populations, but evidence indicates that this is easier in the more forgiving context of development. A very useful series of explorations documenting how transplantation faces diminished success as the host ages was thoroughly documented in a mini-review by Sally Temple [54]. In addition, often the younger and less "experienced" or "committed" precursor cells are shown to more easily adapt into their transplanted roles than similar, yet older, populations [55–57]. In other contexts, such as the ability to properly generate blood cells following bone marrow transplants, younger donors seem to yield more successful results than older donors, indicating this age-dependency is not limited to neuronal populations [58, 59]. The similar goals of establishing appropriate cell populations to fill various niches following transplantation suggest if the environment were less competitive or more accommodating, and cells were guided by the more overt signals available during development, the process of incorporation would be more straightforward. In the adult brain, the mechanisms of plasticity engage to maintain the continuity of established function with mechanisms to prevent deviation from working systems; otherwise all nervous systems would constantly deteriorate into chaos. Thus, while similar concerns are present with transplantation, (i.e., coaxing the new cells to make useful and appropriate contributions to established circuitry), we cannot expect that new additions will naturally get swept into correct and working interactions the way they do during development.

**1. Introduction**

8 Neuroplasticity - Insights of Neural Reorganization

the transplanted cells.

For several years now, efforts have been underway to examine and refine technology associated with promoting the incorporation of pluripotent stem cells from various origins following transplantation into the brains of patients suffering from various deteriorative diseases [1–3], or to test the viability of such treatments using experimental animal models [4–6]. The typical pattern of findings associated with clinical efforts is initial moderate symptom improvement, followed by either resumption of symptoms over time or highly variable therapeutic outcomes [7–9]. Common arguments raised for the mechanism underlying inconsistent effectiveness are that either the transplanted cells are not merging sufficiently with the host brain due to a timely competition-related synaptogenesis process, that transplanted cells are not surviving in the harsh environment of the host due to immune-system/inflammatory host responses, or both [8–11] (also see the extensive review by cell type [12]). While evidence for these arguments certainly exists, it remains unclear whether those arguments cover all the relevant possibilities that threaten the longevity of the transplanted stem cells' utility. One potential threat to the long-term efficacy of this treatment, or to stem cell transplant therapies in general, which is frequently overlooked, would be *plastic adaptation*. Briefly, plastic adaptation represents a multitude of cellular responses that occur with the apparent role of maintaining cellular homeostasis, yet within the nervous system also supports 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. Plastic adaptation also occurs within the physiologically healthy brain in order to adjust for novel needs, supporting changes such as long-term memory, habit formation, and other sorts of behavioral adaptation of organisms to new surroundings and demands (for examples see [13, 14]). A surge of inquiry into what are now known as epigenetic mechanisms supports the notion of a clear capacity of cells to respond to environmental stimuli by generating enduring changes in their genetic expression [15–18]. This, combined with numerous demonstrations of more transient receptor plasticity [19–22], defines neuronal cells as versatile in both shortand long-term periods in adjusting to their neurochemical and electrophysiological circumstances at their membranes and within their nuclei, respectively. Following transplantation, it is likely that plastic adaptation responses could occur in both populations of neuronal cells of concern, either the transplanted cells or the surrounding host cells that likely interact with

During nervous system development, the mechanisms that guide the distributions of cells and their connectivity offer a far more forgiving flexibility when compared to the harsher, more demanding adult environment we face when attempting to correct deterioration with transplants [23–26]. Growth distances for neurites are shorter given the smaller neuropil, and more overt chemical gradients support pathfinding [27–29]. A developmental neurogenesis surge supports self-repair in the event of cell destruction because phenotype commitment is guided by a progressive fulfillment of niches and feedback signals once niches are filled [30–34]. Differential neuronal responsibilities within developing circuits are coaxed into existence in the context of an enhanced adaptive plasticity on either side of synaptic clefts, where each contributes to phenotype adoption of the other while it is determined what they

To tease out the contributions of plastic adaptation to the success or longevity of stem cell transplantation therapy, it seems there is a need to expand inquiry further than whether transplanted cells develop into neurons, survive, or form mutually integrative connections with endogenous neurons. It appears equally important to determine how the cell populations influence each other and how each population adapts to this influence over time. There may be important clues to the mysteries surrounding the impermanence of replacement therapy in how these populations adjust to the presence of the *other*. This chapter was written to consider current knowledge about plastic adaptation as it pertains to the act of incorporating transplanted neuronal cells or precursors into a damaged host brain. In addition, this review represents a general call for more direct inquiry into this subject in future efforts to explore and hone such a promising therapeutic technology. If plastic changes compromise the capacity to maintain symptom-suppressing benefits of these transplants, solutions to this will likely require more than tracking the quality and longevity of behavioral benefit or the anatomical persistence of the transplants over extended periods. Success may be enhanced by recognizing the ongoing patterns of plasticity with which transplanted neuronal cells must cooperate to earn the opportunity to contribute. Given that the age of both the cells transplanted and the host into which they have been transplanted are relevant to their incorporation and therapeutic efficacy, it appears that the capacity to adapt into the new environment depends on factors or signals from both elements that need to be understood to support moving forward intelligently with this therapeutic endeavor. The remainder of this review will address concerns regarding the host adaptive responses to the transplant as well as the transplant's adaptive response to the host that ought to be considered in this regard, focusing largely on efforts with Huntington's and Parkinson's disease.

this does not happen, we appear surprised that transplantation efforts impede healthy behavior restoration over time, or show diminished effectiveness over time—but we should not be. While beyond the scope of this chapter, we nonetheless feel it is important to also acknowledge the prominence of neuronal circuit dependence on both use and the ongoing local actions of the immune system. It is likely that a repetitive drive on the circuit due to the person or animal engaging in systemic practice to recapture the skill they once had also supports circuit-level adaptation. This is likely why Parkinson's patients who regularly move and push themselves to actively engage compromised limbs rather than remaining sedentary reap clinical benefits from those actions [62, 63]. It is intriguing to consider these effects in the context of their ultimate therapeutic mechanisms which promote restoration or strengthening of key circuits with positive contributions to adaptation efforts, as well as the fact that once a part of a circuit, transplant-derived neurons may require practice to become proficient in their established roles. Of course, immune rejection and the broader context of inflammation also enter into this equation, given the common desire to utilize transplants in the context of deteriorative diseases or trauma-related damage. While it is arguable that convincing the immune system not to overreact has been extensively studied as a factor in this context (e.g., [64]), the inflammatory response certainly has the capacity to tailor the very adaptation mechanisms we will discuss (e.g., [65]). For extensive reviews of the reciprocal interactions between neural systems and inflammatory systems relevant to plasticity see Di Filipo and colleagues [66], or

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

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

11

Do the new additions engage with the existing circuits in positive adaptation-enhancing ways? Along the way it appears that there are adaptations on both sides that might enhance or diminish this relationship. If the adaptations diminish this circuit-supporting relationship, then the ability of the new transplanted cells to continue their presence and effectively support positive behavioral improvements will likely be lost and the clinical efforts of transplantation will likely be considered insufficient or transient. Alternatively, if the adaptations that occur enhance the circuit-supporting relationship while avoiding interfering with ongoing adaptive efforts, the success may extend further than the initial witnessed improvements into continuous ongoing improvements, rather than plateauing at some yet incomplete recovery. In this chapter we will divide our appreciation of transplantationrelated plasticity as new cells establish roles contributing to existing yet compromised circuits first into whether the endogenous circuit adopts the newcomers as team players, and second whether the transplanted cells adopt the roles required of them to contribute to the

**3. Adaptation of endogenous host tissue to neural transplantation**

Although adult neurogenesis was overlooked in the past and neuroscientists were convinced that new neurons were not produced beyond the early stages of development, it has now been demonstrated conclusively that there are select regions in the brain that regularly accept new neurons into established circuits that are derived from precursor neuroblasts that retain mitotic capacity throughout our lives, and divide asymmetrically to produce new neurons as

Xanthos and Sandkuhler [67].

circuit or not.

#### **2. Achievements of "successful" transplantations**

Therapeutic support derived from neural transplantation likely necessitates circuit-level reconstruction so that certain missing neurobehavioral actions are restored. However, it is important to acknowledge that circuits can be supported by either the addition of new neuronal contributions that might restore disconnected components or by bolstering the inherent capacity of compromised circuits to adjust or compensate. The brain's inherent capacity to compensate for damage/disruption or "repair itself" is considerable and likely the reason why physical or occupational therapies support function restoration. Trophic support and other general support of persisting residual circuit components, receptor sensitivity adjustments, sprouting, and several other inherent mechanisms contribute to reparation (for an extensive review of these mechanisms see [60]). These trophic or supportive contributions can be accomplished by nonneural cells or glia that likely contribute mostly indirectly to neuronal circuit actions. In fact, Blurton-Jones and colleagues [61] demonstrated that transplant-derived BDNF was eventually responsible for supporting cognitive improvements in a rodent Alzheimer's model by promoting enhanced synaptic density in the hippocampus between preexisting neurons. Thus, it appears that either the transplanted cells become active contributors to the circuit or they support the existing circuit that itself seems to engage compensatory mechanisms supporting at least partial function. Therefore, it appears beneficial to respect that plastic adaptation persists as an ongoing process, regularly promoting positive improvements in functional circuits, and that a *successful* contribution of transplanted stem cells to existing neural circuitry necessitates a recognizable supportive contribution to this endeavor. It is our overarching concern that transplant efforts do not typically respect this context, usually holding a more direct circuit reconstruction as paramount with the presumption that the host brain will somehow also recognize our clinical perspective and modify ongoing adaptive mechanisms accordingly. When this does not happen, we appear surprised that transplantation efforts impede healthy behavior restoration over time, or show diminished effectiveness over time—but we should not be.

to the mysteries surrounding the impermanence of replacement therapy in how these populations adjust to the presence of the *other*. This chapter was written to consider current knowledge about plastic adaptation as it pertains to the act of incorporating transplanted neuronal cells or precursors into a damaged host brain. In addition, this review represents a general call for more direct inquiry into this subject in future efforts to explore and hone such a promising therapeutic technology. If plastic changes compromise the capacity to maintain symptom-suppressing benefits of these transplants, solutions to this will likely require more than tracking the quality and longevity of behavioral benefit or the anatomical persistence of the transplants over extended periods. Success may be enhanced by recognizing the ongoing patterns of plasticity with which transplanted neuronal cells must cooperate to earn the opportunity to contribute. Given that the age of both the cells transplanted and the host into which they have been transplanted are relevant to their incorporation and therapeutic efficacy, it appears that the capacity to adapt into the new environment depends on factors or signals from both elements that need to be understood to support moving forward intelligently with this therapeutic endeavor. The remainder of this review will address concerns regarding the host adaptive responses to the transplant as well as the transplant's adaptive response to the host that ought to be considered

in this regard, focusing largely on efforts with Huntington's and Parkinson's disease.

Therapeutic support derived from neural transplantation likely necessitates circuit-level reconstruction so that certain missing neurobehavioral actions are restored. However, it is important to acknowledge that circuits can be supported by either the addition of new neuronal contributions that might restore disconnected components or by bolstering the inherent capacity of compromised circuits to adjust or compensate. The brain's inherent capacity to compensate for damage/disruption or "repair itself" is considerable and likely the reason why physical or occupational therapies support function restoration. Trophic support and other general support of persisting residual circuit components, receptor sensitivity adjustments, sprouting, and several other inherent mechanisms contribute to reparation (for an extensive review of these mechanisms see [60]). These trophic or supportive contributions can be accomplished by nonneural cells or glia that likely contribute mostly indirectly to neuronal circuit actions. In fact, Blurton-Jones and colleagues [61] demonstrated that transplant-derived BDNF was eventually responsible for supporting cognitive improvements in a rodent Alzheimer's model by promoting enhanced synaptic density in the hippocampus between preexisting neurons. Thus, it appears that either the transplanted cells become active contributors to the circuit or they support the existing circuit that itself seems to engage compensatory mechanisms supporting at least partial function. Therefore, it appears beneficial to respect that plastic adaptation persists as an ongoing process, regularly promoting positive improvements in functional circuits, and that a *successful* contribution of transplanted stem cells to existing neural circuitry necessitates a recognizable supportive contribution to this endeavor. It is our overarching concern that transplant efforts do not typically respect this context, usually holding a more direct circuit reconstruction as paramount with the presumption that the host brain will somehow also recognize our clinical perspective and modify ongoing adaptive mechanisms accordingly. When

**2. Achievements of "successful" transplantations**

10 Neuroplasticity - Insights of Neural Reorganization

While beyond the scope of this chapter, we nonetheless feel it is important to also acknowledge the prominence of neuronal circuit dependence on both use and the ongoing local actions of the immune system. It is likely that a repetitive drive on the circuit due to the person or animal engaging in systemic practice to recapture the skill they once had also supports circuit-level adaptation. This is likely why Parkinson's patients who regularly move and push themselves to actively engage compromised limbs rather than remaining sedentary reap clinical benefits from those actions [62, 63]. It is intriguing to consider these effects in the context of their ultimate therapeutic mechanisms which promote restoration or strengthening of key circuits with positive contributions to adaptation efforts, as well as the fact that once a part of a circuit, transplant-derived neurons may require practice to become proficient in their established roles. Of course, immune rejection and the broader context of inflammation also enter into this equation, given the common desire to utilize transplants in the context of deteriorative diseases or trauma-related damage. While it is arguable that convincing the immune system not to overreact has been extensively studied as a factor in this context (e.g., [64]), the inflammatory response certainly has the capacity to tailor the very adaptation mechanisms we will discuss (e.g., [65]). For extensive reviews of the reciprocal interactions between neural systems and inflammatory systems relevant to plasticity see Di Filipo and colleagues [66], or Xanthos and Sandkuhler [67].

Do the new additions engage with the existing circuits in positive adaptation-enhancing ways? Along the way it appears that there are adaptations on both sides that might enhance or diminish this relationship. If the adaptations diminish this circuit-supporting relationship, then the ability of the new transplanted cells to continue their presence and effectively support positive behavioral improvements will likely be lost and the clinical efforts of transplantation will likely be considered insufficient or transient. Alternatively, if the adaptations that occur enhance the circuit-supporting relationship while avoiding interfering with ongoing adaptive efforts, the success may extend further than the initial witnessed improvements into continuous ongoing improvements, rather than plateauing at some yet incomplete recovery. In this chapter we will divide our appreciation of transplantationrelated plasticity as new cells establish roles contributing to existing yet compromised circuits first into whether the endogenous circuit adopts the newcomers as team players, and second whether the transplanted cells adopt the roles required of them to contribute to the circuit or not.
