Expert Review of Neurotherapeutics
ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
How can we exploit the brain’s ability to repair itself? Victoria Miller & Diego Gomez-Nicola To cite this article: Victoria Miller & Diego Gomez-Nicola (2014) How can we exploit the brain’s ability to repair itself?, Expert Review of Neurotherapeutics, 14:12, 1345-1348 To link to this article: http://dx.doi.org/10.1586/14737175.2014.985659
Published online: 26 Nov 2014.
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Article views: 258
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iern20 Download by: [125.71.212.31]
Date: 05 November 2015, At: 17:54
Editorial
How can we exploit the brain’s ability to repair itself? Expert Rev. Neurother. 14(12), 1345–1348 (2014)
Victoria Miller
Expert Review of Neurotherapeutics 2014.14:1345-1348.
Centre for Biological Sciences, University of Southampton, South Lab and Path Block, Mail Point 840, LD80C, Southampton General Hospital, Tremona Road, SO16 6YD, Southampton, UK
Diego GomezNicola Author for correspondence: Centre for Biological Sciences, University of Southampton, South Lab and Path Block, Mail Point 840, LD80C, Southampton General Hospital, Tremona Road, SO16 6YD, Southampton, UK [email protected]
The notion of our brain having a limited repertoire of cells to be used throughout our life has been refuted multiples times, showing systems by which new neurons are generated on demand, accounting for crucial aspects of brain function in a process known as neurogenesis. The potential of neurogenesis to replace lost neurons is enormous and has direct implications on how we understand the brain’s response to pathology. But replacing functional neurons is not trivial: an orchestrated sequence of steps is needed to ensure the timed generation of new cells, their migration to the sites of injury and their correct differentiation and integration into the pre-existing circuitry. However, there is evidence of this sequence being effective in replacing certain neuronal populations in brain disease. The perspective of understanding, manipulating and directing the brain’s self-repairing responses opens a vast avenue to explore novel therapeutic approaches to replace neuronal loss in neurodegenerative diseases.
The brain has an intrinsic ability to replace certain neuronal populations during adulthood, known as adult neurogenesis. Neural stem cells are located in the main neurogenic niches of the subventricular (SVZ) and subgranular (SGZ) zones. The SVZ gives rise to progenitors that migrate toward the olfactory bulb, further differentiating into neurons, while the SGZ niche replaces granule cells in the hippocampal dentate gyrus. However, the neurogenic capabilities of the brain may not be restricted to these two areas. Evidence for the activation of local neurogenic events has been provided at the macaque neocortex [1] and at the rat cortex [2,3]. In humans, while the production of new olfactory neurons from the SVZ is proposed to become inactivated early in life [4], the SVZ niche has been recently shown to generate striatal interneurons in the adult [5]. The neurogenic activity at the SGZ is remarkably high in humans, suggesting an active turnover of granule cells important for the preservation of memory processing [6]. But, can this huge potential be used to target new cells to damaged areas?
Can the brain orchestrate a self-repairing response to compensate neuronal loss? The answer is yes, although many considerations need to be taken into account to fully exploit the potential of self-repairing therapies. The intrinsic neurogenic activity can replace neurons at lesion sites, as for example shown in ischemic stroke, where progenitors proliferate and migrate to sites of damage [7]. This may also be true in the case of chronic neurodegenerative diseases, in which the progressive loss of neurons accounts for a significant part of the disease burden. We recently described an increased neurogenic response in the SGZ of animals with prion disease, a paradigm of chronic progressive neurodegeneration. We observed that the early and sustained death of granule neurons is balanced by an increased neurogenic response, preserving the integrity of the dentate gyrus [8]. Similarly, evidence supports that environmental enrichment and/or enhanced physical activity boosts hippocampal neurogenesis and prevents the cognitive decline observed in transgenic models of Alzheimer’s disease [9,10]. This enhanced hippocampal neurogenic
KEYWORDS: cell differentiation • cell migration • neural stem cells • neurodegeneration • neurogenesis • self-repair
informahealthcare.com
10.1586/14737175.2014.985659
Ó 2014 Informa UK Ltd
ISSN 1473-7175
1345
Expert Review of Neurotherapeutics 2014.14:1345-1348.
Editorial
Miller & Nicola
response seems to be consistent with data obtained in postmortem samples of patients with Alzheimer’s disease [8,11]. Therefore, it appears logical to suggest that the use of proneurogenic therapies or approaches aimed at re-activating the proliferation of neural stem cells would provide a long-lasting repairing response in chronic neurodegenerative diseases. This idea has been recently validated in a model of Huntington’s disease, providing a therapeutic benefit by the induction of a pro-neurogenic response [12]. The strategy to stimulate the neurogenic potential in situ offers an alternative to therapies aimed at delivering exogenous neural progenitors, which have not yet been able to overcome significant challenges [13]. Facilitating the generation, migration, differentiation and integration of endogenous neural progenitors seems plausible at present. However, while the re-activation of protective neurogenic responses has been shown in disease conditions, manipulating the system to provide specific brain regions with custom input of a defined neuronal subtype seems challenging and will involve overcoming significant barriers. First, the neurogenic capability declines with age, complicating the manipulation of the neurogenic niches in late-onset pathological states (i.e., chronic neurodegenerative diseases). The number of hippocampal neurogenic events is inversely correlated with age, associated with the exhaustion of the neural stem cell population [14,15]. It has been suggested that neural stem cells can undergo a limited number of cell divisions, undergoing irreversible terminal differentiation into astrocytes [16]. However, this hypothesis has been challenged by the potential existence of a pool of dormant neural stem cells, which could be re-activated on demand [17]. Several studies indicate that acute or chronic neurodegeneration is accompanied by an increase in neurogenesis, with the potential to replace damaged neurons at the lesion sites [18]. These newly generated neurons are believed to serve a role in adaptive or regenerative mechanisms. But chronic neurodegenerative conditions are strongly correlated with age, therefore limiting the repertoire of regenerating abilities. Thus, it is important to understand what is the magnitude of the starting self-repairing potential, defining how the exhaustion of the neurogenic niche can be delayed or how can dormant progenitors be re-activated, in order to be able to meet the demands of the degenerating brain. In other words, without the existence of neural stem cells, self-repair would not be possible. In this direction, recent evidence supporting the key role of Ascl1 in determining the re-activation of Neural Stem Cells offers a promising approach to overcome cell dormancy [19]. The examination of the environmental cues and conditions promoting an increase in neurogenic activity will be fundamental to re-activate the latent neurogenic potential of the adult human brain therapeutically. Second, the newly generated cells would need to migrate to the target area(s), without losing their identity or modifying non-diseased regions. For example, while the capacity of neural progenitors from the SVZ to migrate to cortical, striatal, or white matter areas has been shown in several injury and disease models (for review, see [7]), the invasion of more caudal regions 1346
is very rare. Only one study in the literature has described the retrograde migration and the colonization of SVZ progenitors to the hippocampus, a particularly relevant region in several pathological conditions. Endogenous progenitors from the SVZ were observed to colonize the CA1 region of the hippocampus, spontaneously replacing pyramidal neurons previously lost in a model of ischemic stroke, the process further stimulated by the intraventricular infusion of growth factors [20]. Finding neural progenitors in a previously unexplored region not only confirms that microenvironmental cues ultimately determine a cell’s fate, but also suggests that if cells can be directed to any region of the brain, they may be able to mature into fully functional neurons, which is important for future treatment prospects. The exploration of these long-distance migrations of neural precursors, defining the specific molecular cocktail attracting cells to sites of injury will certainly provide useful tools to customize self-repairing therapies. Third, during and after migration, neural progenitors must undergo differentiation, whereby changes in the pattern of gene expression result in morphological and metabolic changes in the cell, essential to carrying out its functional role. Hippocampal precursors from the SGZ become immature neurons at the inner granule layer before differentiating into granule cells. Although the generation of granule cells is the preferential fate of hippocampal neural progenitors, the production of a minor proportion of interneurons (gamma-aminobutyric acid ergic basket cells) has been described, suggesting a more plastic repertoire of hippocampal neurogenesis [21]. Similarly, SVZ neural progenitors have been shown to travel from the SVZ anterogradely toward the olfactory bulb, where they differentiate into granule cells and periglomerular interneurons. As discussed above, SVZ progenitors show certain plasticity, being able to generate, for example, CA1 pyramidal hippocampal neurons [20]. This, together with the fact that gliogenesis is also more active at the SVZ than at the SGZ, presents the SVZ as an important reservoir of progenitors in the adult brain which could be exploited for neuroregenerative therapy. Although being apparently more limited, the invasion of extra-dentate areas by SGZ progenitors would provide a more targeted and restricted approach, worth exploring in future studies. Fourth, in order for functional brain circuits to be repaired, synapses and connections between neighboring neurons and those of more distant, distinct brain regions must be successfully formed. Factors such as size and shape of the cell, in addition to the physical location of synaptic contacts and the expression of the correct repertoire of synaptic receptors and channels, will influence the process of synaptic integration. This is illustrated by the distinct functional roles of adult-born granule neurons, versus granule neurons that are formed during development. The hippocampus serves roles in memory formation, and subsets of differently aged neurons form two discrete regions responsible for either recalling old memories or forming new ones [22]. The younger adult-born granule cells function in pattern separation whereas older neurons formed during development contribute to rapid pattern completion. As the younger Expert Rev. Neurother. 14(12), (2014)
Expert Review of Neurotherapeutics 2014.14:1345-1348.
How can we exploit the brain’s ability to repair itself?
neurons age, they will switch functions [22]. The integration of the subsets of neurons underpins the neural networks they serve. Therefore, a correct rewiring of the injury sites will define functional recovery, key for a complete self-repairing response. An alternative avenue to accomplish self-repair is the use of strategies not directed at the neurogenic niches, but at reprogramming somatic cells. Differentiation defines the morphological and physiological characteristics of a cell and, in the context of neurons, influences its downstream integration. It has been demonstrated that terminally differentiated brain cells can be reverted to a pluripotent state under the correct signals [23]. This is made possible not by modifying the genetic information of the cells, but by altering gene expression patterns. In vitro experiments have been able to induce the self-directed organization of complex tissues from pluripotent stem cells, which then form structures that resemble nervous tissue [24]. Key transcription factors controlling reprogramming, and additional master regulators enabling the generation of specific neurons from other types of cells, for example, human fibroblasts, have been identified [25–27]. Studying the in vivo ability of these reprogrammed neurons to integrate into the brain circuitry is essential References 1.
Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 2000;405(6789): 951-5
2.
Sirko S, Neitz A, Mittmann T, et al. Focal laser-lesions activate an endogenous population of neural stem/progenitor cells in the adult visual cortex. Brain 2009; 132(Pt 8):2252-64
3.
Ohira K, Furuta T, Hioki H, et al. Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells. Nat Neurosci 2010;13(2):173-9
4.
Sanai N, Nguyen T, Ihrie RA, et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 2011;478(7369):382-6
5.
Ernst A, Alkass K, Bernard S, et al. Neurogenesis in the striatum of the adult human brain. Cell 2014;156(5):1072-83
6.
Spalding KL, Bergmann O, Alkass K, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013;153(6):1219-27
7.
Cayre M, Canoll P, Goldman JE. Cell migration in the normal and pathological postnatal mammalian brain. Prog Neurobiol 2009;88(1):41-63
8.
Gomez-Nicola D, Suzzi S, Vargas-Caballero M, et al. Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration. Brain 137(Pt 8): 2312-28
informahealthcare.com
Editorial
to assess the true potential that reprogrammed neurons hold in self-repairing the degenerating brain, but this area focuses on a promising avenue to explore. In summary, we can conclude that the extensive and successful study of the neurogenic responses in the adult healthy and diseased brain has provided an optimal platform to evaluate the hypothesis of a customized self-repair response being a potential therapeutic avenue for acute or chronic neurodegeneration. However, there is still a long and exciting road to cover to overcome the intrinsic difficulties of the system and fully exploit the self-repairing ability of our brain. Financial & competing interests disclosure
The authors were funded by the European Union Seventh Framework Programme (IEF273243), by the MRC (MR/K022687/1), by Wessex Medical Research and by Alzheimer’ s Research UK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
9.
Valero J, Espana J, Parra-Damas A, et al. Short-term environmental enrichment rescues adult neurogenesis and memory deficits in APP (Sw,Ind) transgenic mice. PLoS One 2011;6(2):e16832
16.
Encinas JM, Michurina TV, Peunova N, et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 2011;8(5):566-79
10.
Marlatt MW, Potter MC, Bayer TA, et al. Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer’s disease. Current Top Behav Neurosci 2013;15: 313-40
17.
Bonaguidi MA, Song J, Ming GL, et al. A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus. Curr Opin Neurobiol 2012; 22(5):754-61
18.
Winner B, Kohl Z, Gage FH. Neurodegenerative disease and adult neurogenesis. Eur J Neurosci 2011;33(6): 1139-51
19.
Andersen J, Urban N, Achimastou A, et al. A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron 2014; 83(5):1085-97
20.
Nakatomi H, Kuriu T, Okabe S, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002;110(4):429-41
11.
12.
Jin K, Peel AL, Mao XO, et al. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA 2004; 101(1):343-7 Benraiss A, Toner MJ, Xu Q, et al. Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington’s disease. Cell Stem Cell 2013;12(6):787-99
13.
Chen WW, Blurton-Jones M. Concise review: can stem cells be used to treat or model Alzheimer’s disease? Stem Cells 2012; 30(12):2612-18
21.
14.
Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965;124(3):319-35
Liu S, Wang J, Zhu D, et al. Generation of functional inhibitory neurons in the adult rat hippocampus. J Neurosci 2003;23(3): 732-6
22.
15.
Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature 1997;386(6624):493-5
Nakashiba T, Cushman JD, Pelkey KA, et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 2012; 149(1):188-201
1347
Editorial
Miller & Nicola
Hochedlinger K, Jaenisch R. Nuclear reprogramming and pluripotency. Nature 2006;441(7097):1061-7
24.
Eiraku M, Takata N, Ishibashi H, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 2011; 472(7341):51-6
25.
26.
Karow M, Sanchez R, Schichor C, et al. Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell 2012;11(4): 471-6 Niu W, Zang T, Zou Y, et al. In vivo reprogramming of astrocytes to neuroblasts
in the adult brain. Nat Cell Biol 2013; 15(10):1164-75 27.
Vierbuchen T, Ostermeier A, Pang ZP, et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 2010;463(7284):1035-41
Expert Review of Neurotherapeutics 2014.14:1345-1348.
23.
1348
Expert Rev. Neurother. 14(12), (2014)
ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
How can we exploit the brain’s ability to repair itself? Victoria Miller & Diego Gomez-Nicola To cite this article: Victoria Miller & Diego Gomez-Nicola (2014) How can we exploit the brain’s ability to repair itself?, Expert Review of Neurotherapeutics, 14:12, 1345-1348 To link to this article: http://dx.doi.org/10.1586/14737175.2014.985659
Published online: 26 Nov 2014.
Submit your article to this journal
Article views: 258
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iern20 Download by: [125.71.212.31]
Date: 05 November 2015, At: 17:54
Editorial
How can we exploit the brain’s ability to repair itself? Expert Rev. Neurother. 14(12), 1345–1348 (2014)
Victoria Miller
Expert Review of Neurotherapeutics 2014.14:1345-1348.
Centre for Biological Sciences, University of Southampton, South Lab and Path Block, Mail Point 840, LD80C, Southampton General Hospital, Tremona Road, SO16 6YD, Southampton, UK
Diego GomezNicola Author for correspondence: Centre for Biological Sciences, University of Southampton, South Lab and Path Block, Mail Point 840, LD80C, Southampton General Hospital, Tremona Road, SO16 6YD, Southampton, UK [email protected]
The notion of our brain having a limited repertoire of cells to be used throughout our life has been refuted multiples times, showing systems by which new neurons are generated on demand, accounting for crucial aspects of brain function in a process known as neurogenesis. The potential of neurogenesis to replace lost neurons is enormous and has direct implications on how we understand the brain’s response to pathology. But replacing functional neurons is not trivial: an orchestrated sequence of steps is needed to ensure the timed generation of new cells, their migration to the sites of injury and their correct differentiation and integration into the pre-existing circuitry. However, there is evidence of this sequence being effective in replacing certain neuronal populations in brain disease. The perspective of understanding, manipulating and directing the brain’s self-repairing responses opens a vast avenue to explore novel therapeutic approaches to replace neuronal loss in neurodegenerative diseases.
The brain has an intrinsic ability to replace certain neuronal populations during adulthood, known as adult neurogenesis. Neural stem cells are located in the main neurogenic niches of the subventricular (SVZ) and subgranular (SGZ) zones. The SVZ gives rise to progenitors that migrate toward the olfactory bulb, further differentiating into neurons, while the SGZ niche replaces granule cells in the hippocampal dentate gyrus. However, the neurogenic capabilities of the brain may not be restricted to these two areas. Evidence for the activation of local neurogenic events has been provided at the macaque neocortex [1] and at the rat cortex [2,3]. In humans, while the production of new olfactory neurons from the SVZ is proposed to become inactivated early in life [4], the SVZ niche has been recently shown to generate striatal interneurons in the adult [5]. The neurogenic activity at the SGZ is remarkably high in humans, suggesting an active turnover of granule cells important for the preservation of memory processing [6]. But, can this huge potential be used to target new cells to damaged areas?
Can the brain orchestrate a self-repairing response to compensate neuronal loss? The answer is yes, although many considerations need to be taken into account to fully exploit the potential of self-repairing therapies. The intrinsic neurogenic activity can replace neurons at lesion sites, as for example shown in ischemic stroke, where progenitors proliferate and migrate to sites of damage [7]. This may also be true in the case of chronic neurodegenerative diseases, in which the progressive loss of neurons accounts for a significant part of the disease burden. We recently described an increased neurogenic response in the SGZ of animals with prion disease, a paradigm of chronic progressive neurodegeneration. We observed that the early and sustained death of granule neurons is balanced by an increased neurogenic response, preserving the integrity of the dentate gyrus [8]. Similarly, evidence supports that environmental enrichment and/or enhanced physical activity boosts hippocampal neurogenesis and prevents the cognitive decline observed in transgenic models of Alzheimer’s disease [9,10]. This enhanced hippocampal neurogenic
KEYWORDS: cell differentiation • cell migration • neural stem cells • neurodegeneration • neurogenesis • self-repair
informahealthcare.com
10.1586/14737175.2014.985659
Ó 2014 Informa UK Ltd
ISSN 1473-7175
1345
Expert Review of Neurotherapeutics 2014.14:1345-1348.
Editorial
Miller & Nicola
response seems to be consistent with data obtained in postmortem samples of patients with Alzheimer’s disease [8,11]. Therefore, it appears logical to suggest that the use of proneurogenic therapies or approaches aimed at re-activating the proliferation of neural stem cells would provide a long-lasting repairing response in chronic neurodegenerative diseases. This idea has been recently validated in a model of Huntington’s disease, providing a therapeutic benefit by the induction of a pro-neurogenic response [12]. The strategy to stimulate the neurogenic potential in situ offers an alternative to therapies aimed at delivering exogenous neural progenitors, which have not yet been able to overcome significant challenges [13]. Facilitating the generation, migration, differentiation and integration of endogenous neural progenitors seems plausible at present. However, while the re-activation of protective neurogenic responses has been shown in disease conditions, manipulating the system to provide specific brain regions with custom input of a defined neuronal subtype seems challenging and will involve overcoming significant barriers. First, the neurogenic capability declines with age, complicating the manipulation of the neurogenic niches in late-onset pathological states (i.e., chronic neurodegenerative diseases). The number of hippocampal neurogenic events is inversely correlated with age, associated with the exhaustion of the neural stem cell population [14,15]. It has been suggested that neural stem cells can undergo a limited number of cell divisions, undergoing irreversible terminal differentiation into astrocytes [16]. However, this hypothesis has been challenged by the potential existence of a pool of dormant neural stem cells, which could be re-activated on demand [17]. Several studies indicate that acute or chronic neurodegeneration is accompanied by an increase in neurogenesis, with the potential to replace damaged neurons at the lesion sites [18]. These newly generated neurons are believed to serve a role in adaptive or regenerative mechanisms. But chronic neurodegenerative conditions are strongly correlated with age, therefore limiting the repertoire of regenerating abilities. Thus, it is important to understand what is the magnitude of the starting self-repairing potential, defining how the exhaustion of the neurogenic niche can be delayed or how can dormant progenitors be re-activated, in order to be able to meet the demands of the degenerating brain. In other words, without the existence of neural stem cells, self-repair would not be possible. In this direction, recent evidence supporting the key role of Ascl1 in determining the re-activation of Neural Stem Cells offers a promising approach to overcome cell dormancy [19]. The examination of the environmental cues and conditions promoting an increase in neurogenic activity will be fundamental to re-activate the latent neurogenic potential of the adult human brain therapeutically. Second, the newly generated cells would need to migrate to the target area(s), without losing their identity or modifying non-diseased regions. For example, while the capacity of neural progenitors from the SVZ to migrate to cortical, striatal, or white matter areas has been shown in several injury and disease models (for review, see [7]), the invasion of more caudal regions 1346
is very rare. Only one study in the literature has described the retrograde migration and the colonization of SVZ progenitors to the hippocampus, a particularly relevant region in several pathological conditions. Endogenous progenitors from the SVZ were observed to colonize the CA1 region of the hippocampus, spontaneously replacing pyramidal neurons previously lost in a model of ischemic stroke, the process further stimulated by the intraventricular infusion of growth factors [20]. Finding neural progenitors in a previously unexplored region not only confirms that microenvironmental cues ultimately determine a cell’s fate, but also suggests that if cells can be directed to any region of the brain, they may be able to mature into fully functional neurons, which is important for future treatment prospects. The exploration of these long-distance migrations of neural precursors, defining the specific molecular cocktail attracting cells to sites of injury will certainly provide useful tools to customize self-repairing therapies. Third, during and after migration, neural progenitors must undergo differentiation, whereby changes in the pattern of gene expression result in morphological and metabolic changes in the cell, essential to carrying out its functional role. Hippocampal precursors from the SGZ become immature neurons at the inner granule layer before differentiating into granule cells. Although the generation of granule cells is the preferential fate of hippocampal neural progenitors, the production of a minor proportion of interneurons (gamma-aminobutyric acid ergic basket cells) has been described, suggesting a more plastic repertoire of hippocampal neurogenesis [21]. Similarly, SVZ neural progenitors have been shown to travel from the SVZ anterogradely toward the olfactory bulb, where they differentiate into granule cells and periglomerular interneurons. As discussed above, SVZ progenitors show certain plasticity, being able to generate, for example, CA1 pyramidal hippocampal neurons [20]. This, together with the fact that gliogenesis is also more active at the SVZ than at the SGZ, presents the SVZ as an important reservoir of progenitors in the adult brain which could be exploited for neuroregenerative therapy. Although being apparently more limited, the invasion of extra-dentate areas by SGZ progenitors would provide a more targeted and restricted approach, worth exploring in future studies. Fourth, in order for functional brain circuits to be repaired, synapses and connections between neighboring neurons and those of more distant, distinct brain regions must be successfully formed. Factors such as size and shape of the cell, in addition to the physical location of synaptic contacts and the expression of the correct repertoire of synaptic receptors and channels, will influence the process of synaptic integration. This is illustrated by the distinct functional roles of adult-born granule neurons, versus granule neurons that are formed during development. The hippocampus serves roles in memory formation, and subsets of differently aged neurons form two discrete regions responsible for either recalling old memories or forming new ones [22]. The younger adult-born granule cells function in pattern separation whereas older neurons formed during development contribute to rapid pattern completion. As the younger Expert Rev. Neurother. 14(12), (2014)
Expert Review of Neurotherapeutics 2014.14:1345-1348.
How can we exploit the brain’s ability to repair itself?
neurons age, they will switch functions [22]. The integration of the subsets of neurons underpins the neural networks they serve. Therefore, a correct rewiring of the injury sites will define functional recovery, key for a complete self-repairing response. An alternative avenue to accomplish self-repair is the use of strategies not directed at the neurogenic niches, but at reprogramming somatic cells. Differentiation defines the morphological and physiological characteristics of a cell and, in the context of neurons, influences its downstream integration. It has been demonstrated that terminally differentiated brain cells can be reverted to a pluripotent state under the correct signals [23]. This is made possible not by modifying the genetic information of the cells, but by altering gene expression patterns. In vitro experiments have been able to induce the self-directed organization of complex tissues from pluripotent stem cells, which then form structures that resemble nervous tissue [24]. Key transcription factors controlling reprogramming, and additional master regulators enabling the generation of specific neurons from other types of cells, for example, human fibroblasts, have been identified [25–27]. Studying the in vivo ability of these reprogrammed neurons to integrate into the brain circuitry is essential References 1.
Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 2000;405(6789): 951-5
2.
Sirko S, Neitz A, Mittmann T, et al. Focal laser-lesions activate an endogenous population of neural stem/progenitor cells in the adult visual cortex. Brain 2009; 132(Pt 8):2252-64
3.
Ohira K, Furuta T, Hioki H, et al. Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells. Nat Neurosci 2010;13(2):173-9
4.
Sanai N, Nguyen T, Ihrie RA, et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 2011;478(7369):382-6
5.
Ernst A, Alkass K, Bernard S, et al. Neurogenesis in the striatum of the adult human brain. Cell 2014;156(5):1072-83
6.
Spalding KL, Bergmann O, Alkass K, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013;153(6):1219-27
7.
Cayre M, Canoll P, Goldman JE. Cell migration in the normal and pathological postnatal mammalian brain. Prog Neurobiol 2009;88(1):41-63
8.
Gomez-Nicola D, Suzzi S, Vargas-Caballero M, et al. Temporal dynamics of hippocampal neurogenesis in chronic neurodegeneration. Brain 137(Pt 8): 2312-28
informahealthcare.com
Editorial
to assess the true potential that reprogrammed neurons hold in self-repairing the degenerating brain, but this area focuses on a promising avenue to explore. In summary, we can conclude that the extensive and successful study of the neurogenic responses in the adult healthy and diseased brain has provided an optimal platform to evaluate the hypothesis of a customized self-repair response being a potential therapeutic avenue for acute or chronic neurodegeneration. However, there is still a long and exciting road to cover to overcome the intrinsic difficulties of the system and fully exploit the self-repairing ability of our brain. Financial & competing interests disclosure
The authors were funded by the European Union Seventh Framework Programme (IEF273243), by the MRC (MR/K022687/1), by Wessex Medical Research and by Alzheimer’ s Research UK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
9.
Valero J, Espana J, Parra-Damas A, et al. Short-term environmental enrichment rescues adult neurogenesis and memory deficits in APP (Sw,Ind) transgenic mice. PLoS One 2011;6(2):e16832
16.
Encinas JM, Michurina TV, Peunova N, et al. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 2011;8(5):566-79
10.
Marlatt MW, Potter MC, Bayer TA, et al. Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer’s disease. Current Top Behav Neurosci 2013;15: 313-40
17.
Bonaguidi MA, Song J, Ming GL, et al. A unifying hypothesis on mammalian neural stem cell properties in the adult hippocampus. Curr Opin Neurobiol 2012; 22(5):754-61
18.
Winner B, Kohl Z, Gage FH. Neurodegenerative disease and adult neurogenesis. Eur J Neurosci 2011;33(6): 1139-51
19.
Andersen J, Urban N, Achimastou A, et al. A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron 2014; 83(5):1085-97
20.
Nakatomi H, Kuriu T, Okabe S, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002;110(4):429-41
11.
12.
Jin K, Peel AL, Mao XO, et al. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci USA 2004; 101(1):343-7 Benraiss A, Toner MJ, Xu Q, et al. Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington’s disease. Cell Stem Cell 2013;12(6):787-99
13.
Chen WW, Blurton-Jones M. Concise review: can stem cells be used to treat or model Alzheimer’s disease? Stem Cells 2012; 30(12):2612-18
21.
14.
Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965;124(3):319-35
Liu S, Wang J, Zhu D, et al. Generation of functional inhibitory neurons in the adult rat hippocampus. J Neurosci 2003;23(3): 732-6
22.
15.
Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature 1997;386(6624):493-5
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