Neuronal regeneration in a zebrafish model of adult brain injury

Department of Developmental and Regenerative Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Disease Models and Mechanisms (Impact Factor: 4.97). 03/2012; 5(2):200-9. DOI: 10.1242/dmm.007336
Source: PubMed


Neural stem cells in the subventricular zone (SVZ) of the adult mammalian forebrain are a potential source of neurons for neural tissue repair after brain insults such as ischemic stroke and traumatic brain injury (TBI). Recent studies show that neurogenesis in the ventricular zone (VZ) of the adult zebrafish telencephalon has features in common with neurogenesis in the adult mammalian SVZ. Here, we established a zebrafish model to study injury-induced neurogenesis in the adult brain. We show that the adult zebrafish brain possesses a remarkable capacity for neuronal regeneration. Telencephalon injury prompted the proliferation of neuronal precursor cells (NPCs) in the VZ of the injured hemisphere, compared with in the contralateral hemisphere. The distribution of NPCs, viewed by BrdU labeling and ngn1-promoter-driven GFP, suggested that they migrated laterally and reached the injury site via the subpallium and pallium. The number of NPCs reaching the injury site significantly decreased when the fish were treated with an inhibitor of γ-secretase, a component of the Notch signaling pathway, suggesting that injury-induced neurogenesis mechanisms are at least partly conserved between fish and mammals. The injury-induced NPCs differentiated into mature neurons in the regions surrounding the injury site within a week after the injury. Most of these cells expressed T-box brain protein (Tbr1), suggesting they had adopted the normal neuronal fate in this region. These results suggest that the telencephalic VZ contributes to neural tissue recovery following telencephalic injury in the adult zebrafish, and that the adult zebrafish is a useful model for regenerative medicine.

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    • " markers ( Ganz et al . , 2010 ) . A large subset of these cells expresses the Notch target gene her4 as shown by our data and by others ( Cha - pouton et al . , 2011 ; Kroehne et al . , 2011 ) . Activation of Notch signaling is required for injury - induced proliferation of forebrain progenitors in zebrafish and rodents ( Givogri et al . , 2006 ; Kishimoto et al . , 2012 ; Wang et al . , 2009 ) . We show that new neurons are derived from her4 - expressing progeni - tors following QA - induced injury , but the degree of radial glial activation and subsequent neurogenesis determined by transgenic lineage mapping is greater in our QA lesion model than that reported in previous studies . Although this in pa"
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    ABSTRACT: Zebrafish maintain a greater capacity than mammals for central nervous system repair after injury. Understanding differences in regenerative responses between different vertebrate species may shed light on mechanisms to improve repair in humans. Quinolinic acid is an excitotoxin that has been used to induce brain injury in rodents for modeling Huntington's disease and stroke. When injected into the adult rodent striatum, this toxin stimulates subventricular zone neurogenesis and neuroblast migration to injury. However, most new neurons fail to survive and lesion repair is minimal. We used quinolinic acid to lesion the adult zebrafish telencephalon to study reparative processes. We also used conditional transgenic lineage mapping of adult radial glial stem cells to explore survival and integration of neurons generated after injury. Telencephalic lesioning with quinolinic acid, and to a lesser extent vehicle injection, produced cell death, microglial infiltration, increased cell proliferation, and enhanced neurogenesis in the injured hemisphere. Lesion repair was more complete with quinolinic acid injection than after vehicle injection. Fate mapping of her4-expressing radial glia showed injury-induced expansion of radial glial stem cells that gave rise to neurons which migrated to injury, survived at least 8 weeks and formed long-distance projections that crossed the anterior commissure and synapsed in the contralateral hemisphere. These findings suggest that quinolinic acid lesioning of the zebrafish brain stimulates adult neural stem cells to produce robust regeneration with long-distance integration of new neurons. This model should prove useful for elucidating reparative mechanisms that can be applied to restorative therapies for mammalian brain injury. GLIA 2014
    Glia 12/2014; 62(12). DOI:10.1002/glia.22726 · 6.03 Impact Factor
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    • "It harbors 16 proliferative zones distributed in many brain regions (Zupanc et al., 2005; Lindsey and Tropepe, 2006; Adolf et al., 2006; Grandel et al., 2006; Kaslin et al., 2008; Grandel and Brand, 2013). Moreover, injury increases this baseline of constitutive neurogenesis even further, leading to effective production of neurons and repair of the injured tissue (Zupanc, 2006; Ayari et al., 2010; Kroehne et al., 2011; M€ arz et al., 2011; Baumgart et al., 2012; Kishimoto et al., 2012; Kizil et al., 2012a,c; Diotel et al., 2013; Edelmann et al., 2013; Kyritsis et al., 2013). The proliferative activity observed in the adult zebrafish brain is due to the persistence of neurogenic progenitors, such as radial glial cells (RGCs) and neuroblasts (Adolf et al., 2006; Pellegrini et al., 2007; Lam et al., 2009; M€ arz et al., 2010a; Lindsey et al., 2012). "
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    ABSTRACT: The zebrafish has become a model to study adult vertebrate neurogenesis. In particular, the adult telencephalon has been an intensely studied structure in the zebrafish brain. Differential expression of transcriptional regulators (TRs) is a key feature of development and tissue homeostasis. Here we report an expression map of 1,202 TR genes in the telencephalon of adult zebrafish. Our results are summarized in a database with search and clustering functions to identify genes expressed in particular regions of the telencephalon. We classified 562 genes into 13 distinct patterns, including genes expressed in the proliferative zone. The remaining 640 genes displayed unique and complex patterns of expression and could thus not be grouped into distinct classes. The neurogenic ventricular regions express overlapping but distinct sets of TR genes, suggesting regional differences in the neurogenic niches in the telencephalon. In summary, the small telencephalon of the zebrafish shows a remarkable complexity in TR gene expression. This article is protected by copyright. All rights reserved.
    The Journal of Comparative Neurology 12/2014; 523(8). DOI:10.1002/cne.23733 · 3.23 Impact Factor
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    ABSTRACT: Central nervous system (CNS) injuries affect all levels of society indiscriminately, resulting in functional and behavioral deficits with devastating impacts on life expectancies, physical and emotional wellbeing. Considerable literature exists describing the pathophysiology of CNS injuries as well as the cellular and molecular factors that inhibit regrowth and regeneration of damaged connections. Based on these data, numerous therapeutic strategies targeting the various factors of repair inhibition have been proposed and on-going assessment has demonstrated some promising results in the laboratory environ. However, several of these treatment strategies have subsequently been taken into clinical trials but demonstrated little to no improvement in patient outcomes. As a result, options for clinical interventions following CNS injuries remain limited and effective restorative treatment strategies do not as yet exist. This review discusses some of the current animal models, with focus on nonhuman primates, which are currently being modeled in the laboratory for the study of CNS injuries. Last, we review the current understanding of the mechanisms underlying repair/regrowth inhibition and the current trends in experimental treatment strategies that are being assessed for potential translation to clinical applications.
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