New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

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New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration

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Ismael Fernandez-Hernandez 1 , Christa Rhiner ∗ Institute of Cell Biology, IZB, Baltzerstrasse 4, 3012 Bern, Switzerland

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Article history: Received 9 March 2015 Received in revised form 22 June 2015 Accepted 23 June 2015 Available online xxx

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Keywords: Adult neurogenesis Adult neural stem cells Regenerative neurogenesis Activation of quiescent stem cells Traumatic brain injury models

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Neuronal circuits in the adult brain have long been viewed as static and stable. However, research in the past 20 years has shown that specialized regions of the adult brain, which harbor adult neural stem cells, continue to produce new neurons in a wide range of species. Brain plasticity is also observed after injury. Depending on the extent and permissive environment of neurogenic regions, different organisms show great variability in their capacity to replace lost neurons by endogenous neurogenesis. In Zebrafish and Drosophila, the formation of new neurons from progenitor cells in the adult brain was only discovered recently. Here, we compare properties of adult neural stem cells, their niches and regenerative responses from mammals to flies. Current models of brain injury have revealed that specific injury-induced genetic programs and comparison of neuronal fitness are implicated in brain repair. We highlight the potential of these recently implemented models of brain regeneration to identify novel regulators of stem cell activation and regenerative neurogenesis. © 2015 Published by Elsevier Ltd.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Adult neurogenesis in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Signals orchestrating proliferation as well as cell fate decisions in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. External regulators of NSC proliferation in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.3. Internal regulators of NSC proliferation in mammals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Adult neurogenesis in Zebrafish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Factors regulating the proliferation of Zebrafish adult NSCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Low level adult neurogenesis in Drosophila . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Regenerative neurogenesis and brain repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. Sparks of neurogenesis after mammalian brain injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2. Extensive brain regeneration in Zebrafish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.3. Drosophila, a new model for regenerative neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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∗ Corresponding author. Tel.: +41 788123056. E-mail address: [email protected] (C. Rhiner). 1 Present address: Institute for Research in Biomedicine, IRB, Baldiri Reixac 10, 08028 Barcelona, Spain. http://dx.doi.org/10.1016/j.neubiorev.2015.06.021 0149-7634/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Fernandez-Hernandez, I., Rhiner, C., New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.06.021

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1. Introduction For a long time, it was assumed that little or no neurogenesis occurred in the adult vertebrate brain. Nowadays, it is well recognized that adult neural stem cells (NSCs) exist in the mature brain of all mammalian organisms (Gould, 2007; Grandel and Brand, 2013; Kempermann, 2012) including humans (Eriksson et al., 1998; Kukekov et al., 1999; Spalding et al., 2013). Such adult NSCs selfrenew and continuously give rise to new neurons throughout adulthood. Moreover, adult neurogenesis is not restricted to mammals, but equally occurs in other species such as birds (Goldman and Nottebohm, 1983), lizards (Garcia-Verdugo et al., 1989), fish (Easter and Hitchcock, 2000; Zupanc et al., 2005) and, as discovered only recently, in fruit flies (Fernandez-Hernandez et al., 2013). Adult neurogenesis is a complex process, which involves genesis, migration, differentiation, selection and maintenance of new neurons in the adult brain. In mammals, NSCs self-renew and can differentiate both into neural or glial lineages (Gage, 2000). A subset of newly generated neurons will incorporate into preexisting neuronal circuits, thereby contributing to structural and functional plasticity of the adult brain. The significance and functional implications of adult neurogenesis in mammals is still a matter of ongoing debate and research. Newborn neurons have been proposed to play a role in learning, pattern separation (reviewed in Deng et al., 2010; Ming and Song, 2011), the formation of new memories (Aimone et al., 2011; Clelland et al., 2009; Zhang et al., 2008) and the regulation of anxiety behavior (Saxe et al., 2006; Snyder et al., 2011). However, these suggested functions are still controversial. New genetic techniques have been introduced, which allow more specific and inducible inhibition of adult neurogenesis compared to earlier methods using irradiation or anti-mitotic drugs, but conflicting results persist. For example, neurogenesis has been found to be important for spatial navigation in the water maze, a hippocampus-dependent task, by some studies (e.g. Zhang et al., 2008), but not others (Groves et al., 2013; Saxe et al., 2006). Possible reasons for the inconsistent results are heterogeneities in behavioral protocols, age of experimental animals, distinct genetic backgrounds or treatments, which can influence behavior on its own (Lazic et al., 2014), apart from changing rates of neurogenesis. Therefore, the function of adult neurogenesis in mammals still remains unsettled. Current efforts in the field to standardize procedures, employ computational models and refine the tools to specifically and locally interfere with neurogenesis seem to be the key to understand the role of new neurons in the mammalian hippocampus. The extent of adult neurogenesis has also been studied in relation to brain pathology. Adult-born neurons have been shown to benefit the remission of effects in the major psychiatric disorders of depression, schizophrenia and drug addiction (Jun et al., 2012). Seizures enhance the proliferation in neurogenic regions and cause migration defects of newly generated neurons (Jessberger and Parent, 2007). Moreover, altered neurogenesis in the adult hippocampus can represent an early event in the course of Alzheimer’s disease (reviewed in Mu and Gage, 2011; Lazarov and Marr, 2010) or in the appearance of intellectual disability disorders (Pons-Espinal et al., 2013). Because adult neurogenesis is conserved in the animal kingdom, it has also been addressed from an evolutionary perspective (Kempermann, 2012; Tanaka and Ferretti, 2009). Nevertheless, in this review we will focus mainly on studies performed in rodents, Zebrafish, and Drosophila, where research is facilitated by an extensive genetic toolbox. We compare relevant features such as the location and types of adult neural progenitors and – if known – the regulatory mechanisms. Finally, we comment on the

regenerative potential of these different systems and strategies to identify new factors involved in physiologic and damage-induced neurogenesis. Adult neurogenesis has been extensively studied in rats and mice. In Zebrafish and Drosophila, the knowledge is still limited and started to emerge only recently, since research initially concentrated on regulation of neurogenesis during development. Because fish and flies show robust neurogenesis upon injury, current efforts are directed to understand neurogenesis in the context of brain regeneration. However, both systems are likely to contribute to our understanding of normal adult neurogenesis in the future, especially if tools become available to specifically target the adult neural stem cell pool.

2. Adult neurogenesis in mammals Adult neurogenesis is a conserved trait in the animal kingdom and occurs in all mammalian species studied so far (Kempermann, 2012). In mammals, adult neurogenesis is restricted mainly to two neurogenic regions: the subgranular zone (SGZ) of the dentate gyrus in the hippocampus, and the subventricular zone (SVZ) lining the lateral ventricles (Fig. 1A and B) (reviewed in Zhao et al., 2008). The SGZ resides between the granule cell layer and the hilus of the hippocampal dentate gyrus (Fig. 1A and B). In the adult human brain, it represents the most relevant neurogenic zone (Spalding et al., 2013) (Fig. 1A). However, our knowledge about the SGZ mainly derives from studies with rats and mice (Fig. 1B). There, radial glia-like stem cells (type I cells) proliferate to yield intermediate progenitor cells (also named transient amplifying cells), which migrate towards the granule cell layer (reviewed in Zhao et al., 2008). Here, they undergo several rounds of division and differentiation to produce a population of post-mitotic immature granule cells that differentiate into one neuronal subtype, the excitatory glutamatergic granule neurons and establish nascent network connections. However, only a small fraction of newly generated neurons in the SGZ survives and finally integrates into hippocampal circuits; the bulk of them die by apoptosis (Biebl et al., 2000). The percentage of surviving neurons, but also their connectivity can be increased by experience such as spatial learning or exposure to an “enriched environment” (Bergami et al., 2015; Kee et al., 2007; Ramirez-Amaya et al., 2006). It has been shown that newborn neurons (4–6 weeks old) in the mouse hippocampus do preferentially respond to activity-dependent stimulation (Tashiro et al., 2006) during learning because they display hyperexcitability and enhanced synaptic plasticity compared to mature dentate granule cells (Ge et al., 2007; Schmidt-Hieber et al., 2004). The selective activation and recruitment of newborn neurons in the course of learning tasks (Dupret et al., 2007) indicates that they may play a role for hippocampus-directed storage of new information in the brain. In the other major neurogenic zone, the rodent subventircular zone (SVZ) (Fig. 1B), astrocyte-like cells with stem cell characteristics divide asymmetrically to produce transient amplifying cells, which in turn form neuroblasts (reviewed in Zhao et al., 2008). Chains of neuroblasts migrate then to the olfactory bulb through a tube formed by astrocytes in the so-called rostral migratory stream (RMS) (Doetsch and Alvarez-Buylla, 1996; Lois et al., 1996) (Fig. 1B). Once in the olfactory bulb, neuroblasts spread out in a radial fashion and differentiate into several types of interneurons, integrating with the granule cells and periglomerular layers. This process of neurogenesis in the olfactory bulb of mice is very robust and persists throughout life. In contrast, the SVZ of primates becomes

Please cite this article in press as: Fernandez-Hernandez, I., Rhiner, C., New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.06.021

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Fig. 1. Neurogenic regions in different model organisms. (A) In the human brain, neurogenic regions include the subventricular zone (SVZ) of the lateral ventricles (LV) and the subgranular zone in the dentate gyrus (DG) of the hippocampus. In addition, neurogenic turnover has been detected in the striatum. Oligodendrocyte progenitor cells (OPCs) are spread throughout the brain and mainly give rise to myelinating oligodendrocytes.(A) adapted from (Ernst and Frisen, 2015) (B) In the mouse SVZ, astrocyte-like stem cells (type B cells) self-renew and give rise to transient amplifying progenitors (type C cells). Type C precursors generate a hetergenous population of neuroblasts (type A cells), which migrate through the rostral migratory stream (RMS) towards the olfactory bulb (OB), where they differentiate into neurons. The subgranular zone of the DG in the hippocampus represents another prominent neurogenic region. Here, quiescent radial glia-like cells (type 1) generate actively self-renewing non-radial progenitors (type 2 cells), which produce neuroblasts, which will differentiate into granule cells (C) The adult brain of Zebrafish contains several neurogenic regions along the anterior-posterior axis. In the telencephalon, radial glia-like quiescent cells (type I) produce slow-cycling (type II) cells. These, in turn generate neuroblasts (type III cells), which proliferate and differentiate into neurons. (D) Optic lobes (OLs) in the adult Drosophila brain harbor a dispersed population of undifferentiated progenitor cells expressing the larval neuroblast marker Deadpan (Dpn+). They are proposed to be quiescent and resume proliferation rather sporadically by still unknown signals to generate adult neurons. AL: antennal lobes.

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thinner and the proliferative capacity of the SVZ and RMS drop during ageing (Azim et al., 2013; Pencea et al., 2001). In humans, the extent of neurogenesis in the SVZ may be negligible beyond infancy, but the topic remains a matter of controversy (Fig. 1A) (Bergmann et al., 2012; Curtis et al., 2007; Sanai et al., 2011). Nevertheless, the formation of new neurons in the adult human hippocampus occurs to a much greater extent than previously estimated and through at least the fifth decade of life, showing a much less dramatic decline with aging compared to mice. It has been estimated that one third of hippocampal neurons are subjected to exchange, with about 700 new neurons added daily in each hippocampus of the adult human DG (Spalding et al., 2013). Recently, using 14 C retrospective birth-dating techniques, the generation of new interneurons was detected in the striatum of the human brain (Fig. 1A) (Ernst et al., 2014). Evidence for striatal neurogenesis has also been found previously in the brain of rats or guinea pigs under homeostatic conditions (Dayer et al., 2005; Luzzati et al., 2014; Nacher et al., 2001) or in the rat brain after stroke induction (Arvidsson et al., 2002; Parent et al., 2002). Interestingly, adult generated neurons in the striatum were absent in brains of advanced-stage Huntington’s disease patients, a pathology affecting striatal neurons (Ernst et al., 2014). These results await further characterization, but underlines that neuronal turnover in

the adult human brain is not restricted to the hippocampus or olfactory bulb. In addition, adult-born neurons have also been described in the mouse hypothalamus (Kokoeva et al., 2005; Lee et al., 2012). Whether neurogenesis occurs and may as well occur in neocortical areas remains controversial (Bhardwaj et al., 2006; Gould et al., 1999; Zhao et al., 2008). Finally, a third population of progenitor cells, known as Oligodendrocyte Progenitor Cells (OPCs, also known as NG2 glia), has been found diffusely distributed in the brain grey and white matter and spinal cord of rats (Ffrench-Constant and Raff, 1986; Horner et al., 2000) and humans (Nunes et al., 2003; Scolding et al., 1998) (Fig. 1A). In rodents, they constitute ∼5% of the glial cell population in the CNS. Although the vast majority of adult OPCs are mitotically quiescent, they are multipotent, giving rise mainly to myelinating oligodendrocytes, but also to Schwann cells, astrocytes and possibly neurons (reviewed in van Wijngaarden and Franklin, 2013). During remyelination, OPCs proliferate and migrate to the site of injury, where they differentiate into myelinating oligendrocytes, thereby preventing axonal degeneration (Franklin and FfrenchConstant, 2008). In addition, OPCs have also been shown to generate action potentials and to communicate with neurons via synapses (Karadottir et al., 2008), blurring the boundaries between neuronal and glial cell types.

Please cite this article in press as: Fernandez-Hernandez, I., Rhiner, C., New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.06.021

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2.1. Signals orchestrating proliferation as well as cell fate decisions in mammals Numerous and diverse signaling pathways are known to regulate the proliferation of adult neural stem cells in rodents, underlining their capability to respond to slight changes in their environment (reviewed in Fuentealba et al., 2012; Mu et al., 2010). The NSCs of the SGZ and the SVZ differ based on their morphology, proliferative behavior and marker expression (Fuentealba et al., 2012). The rodent SGZ harbors type 1 cells (radial cells), which are quiescent NSCs, characterized by glial fibrillary acidic protein (GFAP), Sox2, and Nestin expression (Fig. 1B). When activated, they can generate self-renewing non-radial progenitors (type 2 cells), expressing Sox2 and Nestin but not GFAP. Type 2 cells in turn give rise to DCX+ neuroblasts, which predominantly differentiate into local glutamatergic dentate granule cells (reviewed in Zhao et al., 2008). How efficient are radial glia-like stem cells to sustain neurogenesis throughout life? In mice, contrasting models have been proposed: One study provides evidence for life-long self-renew of stem cell pools due to asymmetric and symmetric division modes of radial glia-like stem cells (Bonaguidi et al., 2011), whereas another group describes time-dependent decline of radial glia-like stem cells due to limited self-renewal and progressing terminal differentiation into astrocytes during ageing (Encinas et al., 2011). The SVZ contains type B cells, which are slow-dividing, astrocyte-like progenitors (reviewed in Zhao et al., 2008). They express markers such as GFAP and CD133 (Fig. 1B). Type B progenitors generate fast dividing, transit amplifying precursors (type C cells) that stain positive for Dlx2, Mash1, and EGFR. Most type B cells give rise to neuroblasts (type A cells) expressing DCX or PSANCAM. Depending on their position along the SVZ, different types of neuroblasts with distinct neurogenic potential migrate in chains to the olfactory bulb through the RMS and differentiate into diverse types of GABA- and dopaminergic interneurons (Merkle et al., 2007, 2014). Interestingly, if progenitor cells are explanted to nonneurogenic regions, they show altered or no differentiation, clearly suggesting that the microenvironment or neurogenic niche controls major aspects of neurogenesis (Seidenfaden et al., 2006; Shihabuddin et al., 2000). However, not all, but only a subset of marker-expressing cells in the germinal zones of the adult brain, are able to proliferate and engage in the neurogenic process. This demonstrates that both internal and external signals regulate neurogenesis, acting in a coordinated way. Understanding the control and integration of such signals is challenging, considering that new adult neurons are generated throughout life and therefore during many different maturation stages and conditions. 2.2. External regulators of NSC proliferation in mammals Neurogenesis is strongly regulated by numerous nichedependent signals including cellular interactions with niche cells and blood vessels and direct electric input from different neuronal groups (Paez-Gonzalez et al., 2014; Tong et al., 2014). A series of niche-derived growth factors and morphogens are known to regulate adult neurogenesis in mice and rats (reviewed in Mu et al., 2010; Zhao et al., 2008). Members of the TGF-superfamily of growth factors are required to control the quiescent state of adult NSCs (Schwarz et al., 2012). In contrast, Wingless ligands (Wnts) secreted by astrocytes or the proper NSCs (autocrine control) support the proliferation and the multipotent state of NSCs (Lie et al., 2005; Song et al., 2002). Wnt signaling also leads to expression of LINE-1, a retrotransposon important for NSC survival. Besides Wnt, also autocrine secretion of VEGF by NSCs is functionally relevant to maintain the neurogenic niche (Kirby et al., 2015). Sonic

hedgehog (Shh) acts as mitogen for NSCs by increasing their proliferation (Ahn and Joyner, 2005; Han et al., 2008; Lai et al., 2003). Moreover, Insulin-like growth factor-1 (IGF-1) is important for the division and differentiation of neural progenitors and controls the migration of neuroblasts from the SVZ to the olfactory bulb (Hurtado-Chong et al., 2009; Otaegi et al., 2006). Finally, also Notch is implicated in NSC proliferation since ablation of Notch1-receptor from type 1 stem cells reduces NSC proliferation and neurogenesis (Ables et al., 2010). On top of these classic developmental pathways, also other growth factors like brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), fibroblast growth factor 2 (FGF2), cytokines (interleukin 6) and neurotransmitters (GABA) are known to modulate NSC activity and neuronal differentiation (reviewed in Zhao et al., 2008). Hormones provide a further level of regulatory input. Elevated levels of stress hormones have, for example, been correlated with reduced neurogenesis (Mirescu and Gould, 2006). Moreover, growth hormones can impact on metabolic pathways of NSCs and modulate proliferation by promoting lipogenesis via the thyroid hormone responsive protein Thrsp/Spot14 (Knobloch et al., 2013). Taken together, this shows that NSC are exposed and respond to a mix of growth factors, morphogens and activity-dependent input from neighboring neurons. 2.3. Internal regulators of NSC proliferation in mammals Besides signals from the environment, there are intrinsic regulators, which control differentiation and maturation steps during neurogenesis. For example, the orphan nuclear receptor Tlx plays an essential role in the maintenance and self-renewal of adult NSCs, presumably by complexing with histone deacetylases (HDACs) to repress cell cycle genes p21 and PTEN (Liu et al., 2008; Zhang et al., 2008). Overexpression of Tlx counteracts age-dependent depletion of NSCs by increasing their numbers, but eventually leads to glioma formation (Liu et al., 2010). Sox genes, which encode for transcription factors, also regulate NSC maintenance or proliferation, possibly by repressing GFAP transcription (Cavallaro et al., 2008). Other sox genes regulate neurogenesis through their interaction with microRNAs (miRNAs). Repressor element 1-silencing transcription factor (REST) is a further transcriptional repressor that has been linked to maintenance of type 1 stem cells (Gao et al., 2011). Neuronal differentiation of progenitors is controlled by a series of bHLH (basic helix-loop-helix) transcription factors. Ascl1 (Mash1), Neurog2 and Tbr2 are expressed in the SVZ progenitors and regulate the formation of GABAergic and glutamatergic neurons (Brill et al., 2009; Kim et al., 2007). The maturation and proper functional integration of newborn neurons is regulated by numerous additional factors such as NeuroD1, DISC1, Klf-9, the small Rho GTPases, Cdk5, IGF2 and the receptors for TrkB and NMDA (reviewed in Braun and Jessberger, 2014; Mu et al., 2010). Finally, also epigenetic mechanisms such as DNA methylation, chromatin remodeling, histone modification and non-coding RNA expression have been found to modulate multiple aspects of adult neurogenesis (reviewed in Mu et al., 2010). These findings demonstrate that the adult brain is integrating and responding to a plethora of signals and external cues to control the extent of adult neurogenesis. 3. Adult neurogenesis in Zebrafish In fish, life-long neurogenesis has been known for decades (Müller, 1952). Before the extensive use of Zebrafish, work in goldfish provided important insights into persistent neurogenesis and

Please cite this article in press as: Fernandez-Hernandez, I., Rhiner, C., New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.06.021

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stem cell-based retinal regeneration (Easter and Hitchcock, 2000). In Zebrafish, adult neurogenesis is also well-documented. Early works report the generation of adult neurons in the visual system (Cameron, 2000; Marcus et al., 1999), olfactory bulb (Byrd and Brunjes, 2001), telencephalon (Adolf et al., 2006) and many other regions along the anterior to posterior axis (Zupanc et al., 2005) (Fig. 1C). Especially well described is the proliferation and migration of new cells in the telencephalon: there, newborn cells in the ventral telencephalon migrate tangentially, but only with a minor RMS to the olfactory bulb. In contrast, the lateral telencephalic area, a domain considered homologous to the mammalian dentate gyrus, shows production and migration of interneurons, as it happens in mammals (Grandel et al., 2006). Proliferating adult stem cells in adult zebrafish show a glial identity and are able to self-renew and generate new neurons (Rothenaigner et al., 2011). Based on the expression of proliferation markers, such as PCNA, or by detecting incorporation of the thymidine analog BrdU, two classes of radial glial cells can be identified: Type I cells, which are in a quiescent state, and slow cycling type II cells. Nevertheless, the majority of radial glial cells are in a resting state. Both types of glial cells possess long processes, which have been proposed to serve as a scaffold for newborn neurons to migrate out of the ventricular zone (reviewed in Schmidt et al., 2013). Type II stem cells can divide symmetrically to self-renew or asymmetrically to generate type III cells (Rothenaigner et al., 2011). These type III correspond to actual neuroblasts, which continue proliferating, turn on neural marker genes such as PSA-NCAM and the pro-neural gene ascl1, and eventually enter the RMS or leave the periventricular zone to move deeper into the parenchyma (reviewed in Schmidt et al., 2013). 3.1. Factors regulating the proliferation of Zebrafish adult NSCs In contrast to mammals, activation of Notch signaling in the Zebrafish adult brain drives stem cells into quiescence rather than proliferation, thus balancing the proportion of type I and type II cells (Chapouton et al., 2010). Furthermore, FGF is required for proliferation of progenitors in the periventricular domain, but not in dorsal proliferative domains (Ganz et al., 2010). Although the telencephalon is the neurogenic region most intensively investigated, other neurogenic zones are present in the adult Zebrafish brain (Kizil et al., 2012b). Those include the cerebellum (Grandel et al., 2006), the boundary between the midbrain and the hindbrain (Chapouton et al., 2006) and the optic tectum (Ito et al., 2010). Molecular markers and regulators of progenitor cells in those regions include Nestin, Sox2, Meis homeobox 2 (Meis), Musashi homolog (Msi1), GFAP, BLBP, her5 and PCNA. In addition, these progenitors also express neuroepithelial markers, like ZO-1, ␥-tubulin, ␤-catenin and aPKC (reviewed in Schmidt et al., 2013). 4. Low level adult neurogenesis in Drosophila In Drosophila, adult stem cells have been well characterized in the germline (reviewed in Fuller and Spradling, 2007), the posterior midgut (Micchelli and Perrimon, 2006; Ohlstein and Spradling, 2006), the hindgut (Fox and Spradling, 2009; Takashima et al., 2008) and the malpighian tubules (Singh et al., 2007), but not in the adult brain. However, neurogenesis was intensively studied in Drosophila larvae and pupae, providing insight into mechanisms controlling neuroblast proliferation and lineage specification during nervous system development (Cabernard et al., 2010; Egger et al., 2010; Homem and Knoblich, 2012; Kang and Reichert, 2014; Maurange

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et al., 2008). It has been long assumed that no new neurons were formed in the adult fly brain due to either apoptosis or terminal differentiation of neural progenitor cells during the final stages of development. The generation of new neurons in the adult brain was only observed when the elimination of larval neuroblasts was blocked by genetic manipulation and they continued to proliferate during adult stages (Siegrist et al., 2010). BrdU incorporation and traditional lineage-tracing MARCM techniques (Wu and Luo, 2006) revealed newly generated cells in the young adult brain (Kato et al., 2009; von Trotha et al., 2009), but they were glial cells. Recently, a more sensitive lineage tracing method revealed that low level of adult neurogenesis occurs constitutively in the optic lobes of the adult fly brain (Fernandez-Hernandez et al., 2013) (Fig. 1D). The source of these new neurons is not well characterized yet, but a scattered population of undifferentiated cells, expressing the larval neuroblast marker Deadpan (Dpn) (Karandikar et al., 2005) was identified in small clusters of dividing cells, which also contained newly formed neurons (Fernandez-Hernandez et al., 2013). If Dpn+ progenitors fulfill all criteria of true adult neural stem cells remains to be shown. Under physiologic conditions, most neural precursor cells show cytoplasmic localization of the HES family basic-helix-loop-helix transcription factor Dpn, suggesting that they are in a quiescent state and resume proliferation rather sporadically. The level of normal adult neurogenesis has been estimated as low as 4–6 division events per optic lobe in a week (Fernandez-Hernandez et al., 2013). Drosophila myc (dMyc), the homolog of the human c-myc oncogene, is upregulated in activated Dpn+ progenitor cells upon brain damage (Fernandez-Hernandez et al., 2013). Moreover, transient overexpression of dMyc in the optic lobe is sufficient to induce division of neural progenitor cells. After a short pulse of dMyc overexpression, neuronal progenitors stop proliferating, but adjacent cells keep dividing up to 5 days, indicating that they may represent transient amplifying cells (Fernandez-Hernandez et al., 2013). However, more markers need to be identified to characterize the putative NSCs in Drosophila and possible intermediate amplifying cells.

5. Regenerative neurogenesis and brain repair Besides physiological levels of adult neurogenesis, injured brains can initiate specific regeneration programs to recover internal homeostasis. In particular acute brain injury can stimulate proliferation of adult NSCs in a wide range of organisms, although their capabilities to form new neurons varies greatly (Arvidsson et al., 2002; Fernandez-Hernandez et al., 2013; Kyritsis et al., 2012; Ohira, 2011). Brain injuries including traumatic brain injury and stroke are frequent and have long-lasting disabling consequences for cognition, sensorimotor function and even personality (Blennow et al., 2012; Xiong et al., 2013). Providing the brain with new neurons to repair the damage would therefore be a promising strategy both to treat acute brain insults as well as neurodegenerative diseases. For these reasons, understanding the molecular nature of regenerative neurogenesis is of outstanding interest and may be instrumental for devising therapeutic applications in humans. In general, successful tissue regeneration is based on one or a combination of the following strategies: I. Recruitment and/or activation of adult stem cells II. de-differentiation to a progenitorlike state III. trans-differentiation of cells close to the injury site (reviewed in Poss, 2010; Sanchez Alvarado and Tsonis, 2006). For successful regeneration it is often critical that a sufficient amount of progenitors can be activated in proximity to the damage. Both damage-sensing and actual proliferative programs need to be

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activated in adult NSCs to ensure a robust regenerative response. Lastly, differentiation towards neural lineage, proper maturation and correct integration need to be controlled to allow functional tissue replacement.

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Unfortunately, the capacity of the mammalian brain to regenerate after brain injury is rather low. Although neurogenesis is induced upon damage, adult NSCs form neurons only poorly and thus regenerative neurogenesis is usually strongly limited (Arvidsson et al., 2002; Robel et al., 2011; Rolls et al., 2009; Yiu and He, 2006). This hampered regeneration in mammals is attributed largely to I. damage-induced inflammatory responses leading to the formation of glial scar tissue that impairs neurogenesis and II. the generally non-favorable environment for adult neurogenesis in the central nervous system (CNS) outside the neurogenic niches (the SVZ and SGZ). Especially chondroitin sulfate proteoglycans and myelin components of the CNS have been identified as inhibitors of neurogenesis (reviewed in Yiu and He, 2006). Current efforts to replenish the brain after neuronal loss concentrate around boosting endogenous NSC proliferation with administered growth factors (Schanzer et al., 2004), redirecting the fate of progenitor cells (Jessberger et al., 2008) or inducing trans-differentiation of fibroblasts into functional neurons in vitro (Vierbuchen et al., 2010) and in vivo (Torper et al., 2013). Along this line, recent reports have described conversion of injury-induced reactive glial cells into functional neurons upon NeuroD1 (Guo et al., 2014) or SOX2 expression (Heinrich et al., 2014; Niu et al., 2015). In addition, transplantation of exogenous NSCs, which can provide trophic and immune-modulatory support, is explored as a tool to strengthen the endogenous restorative response of host NSCs (Mine et al., 2013). An alternative innovative approach concentrates on harnessing the potential of glial cells, which in contrast to adult NSCs are present in high numbers in all brain regions. Severe brain trauma, hypoxia or stroke leads to activation of local differentiated glia (ependymal cells or astrocytes) through a process termed “astrogliosis”. Research of the past ten years has revealed that reactive glia share several hallmarks with adult NSCs (reviewed in Robel et al., 2011) and can re-acquire multi-lineage potential to form neurons, at least in vitro, but only give rise to glial cells in the non-permissive environment of the adult brain. Also non-reactive astrocytes are related to adult neural stem cells based on marker expression underlining that they are related cell types. This proliferative capacity of glial cells would represent a widespread endogenous source of cells with NSC potential if it could be harnessed for local repair strategies (Robel et al., 2011). Local neurogenesis after injury could also be increased by improving conditions for migration and differentiation of neuroblasts. Studies have shown that SVZ neurogenesis is stimulated after middle cerebral artery occlusion, which produces ischemic damage in the striatum and cerebral cortex. Remarkably, numerous neuroblasts are induced to migrate along injury-induced blood vessels to reach the infarcted region, but only a small fraction survives and differentiates into mature neurons in the striatum (Fig. 2A) (Arvidsson et al., 2002; Parent et al., 2002; Sawada and Sawamoto, 2013). Newly formed blood vessels upon injury are not only important as scaffold for migration neuroblasts, but can also produce prostacyclin, which activates axonal sprouting and promotes recovery of function (Muramatsu et al., 2012). After targeted ablation of corticothalamic projection neurons, newly generated neurons from the SVZ were even observed to replace lost neurons in the cortex and grow long-distance connections (Magavi et al., 2000). These encouraging findings

show that neuroblasts can migrate from NSC niches to sites of brain damage and differentiate, but their survival is still a large issue. Recent results also describe injury-induced neurogenesis based on adult NSCs that reside in certain regions of the rat cortex (Ohira et al., 2010). Exploring the nature of these local NSCs may open new avenues to support a more efficient regenerative response in the mammalian brain. 5.2. Extensive brain regeneration in Zebrafish Zebrafish show a remarkable capacity to regrow different organs such as amputated fins, the lesioned brain, retina, spinal cord, heart and other tissues (reviewed in (Gemberling et al., 2013). Also gold fish show a strong neurogenic response after spinal cord hemisection with many new neurons generated around the lesion site, which seem to participate in the regeneration of damaged axon tracts (Takeda et al., 2008). Zebrafish regenerate large parts of the adult brain after traumatic brain injury owing to the neurogenic capacity of stem cells with radial glial identity (Kroehne et al., 2011) (Fig. 2B). The mechanisms of neurogenesis are mainly studied after stab-lesion of the telencephalon of 6 months old fish (Kroehne et al., 2011). In contrast to mammals, brain injury in adult Zebrafish does not lead to permanent glial scarring. Although, oligodendrocyte progenitor cells and microglia accumulate around the wound, they do so only transiently. Upon brain damage, the radial glia progenitor cells proliferate and generate neuroblasts, which then migrate to the lesion site and produce mature neurons. Such neurons establish synaptic contacts and survive until several months after the injury. Substantial progress has already been made to understand which molecular pathways are implicated in regrowth (reviewed in Kizil et al., 2012b). Here, we only focus on recently discovered key aspects. The newest studies have revealed that inflammation associated with brain injury is a mayor driving force for NSC activation in Zebrafish (Kyritsis et al., 2012). Michael Brand and coworkers showed that NSC proliferation and neurogenesis could be fully induced with immunogenic particles even in the absence of mechanical wounding. In particular, cysteinyl leukotriene signaling was implicated in triggering the neurogenic response (Kyritsis et al., 2012). By comparing the transcriptome of injured versus non-injured Zebrafish brains, the transcription factor Gata3 was identified as highly regulated factor upon damage (Kizil et al., 2012c). Gata 3 is required upon injury to activate regenerative programs including the proliferation of progenitor cells and the formation and migration of new neurons. Gata3 upregulation is regulated by FGF signaling after brain damage, but needs to act in the context of additional injury-induced pathways since its sole overexpression in the uninjured adult brain is not sufficient to induce neurogenesis (Kizil et al., 2012c). In a different model of telencephalic injury in Zebrafish, new insight was gained on the migration behavior of neural precursor cells (NPCs) by combining traditional BrdU labeling and reporter constructs for immature NPCs (Kishimoto et al., 2012): tracking of the immature progenitors revealed that they migrate from the telencephalic ventricular zone to the damaged region, where they differentiate into glutamatergic cortical neurons expressing the transcription factor Tbr-1. The regenerative response was controlled, at least in part, by Notch signaling as inhibition of ␥secretase (a component of the Notch pathway) reduced the number of NPCs reaching the injury site (Kishimoto et al., 2012). In mammals, activated neuroblasts are known to be recruited to the injury site by chemokine signaling (reviewed in Hermann et al., 2014). In Zebrafish, the chemokine receptor Cxcr5 has been

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Fig. 2. Models of injury-induced adult neurogenesis. (A) Scheme depicting the migration of neuroblasts (green) from the subventricular zone (SVZ) to the lesioned area (L, red) in the cortex after stroke induction by middle cerebral artery occlusion (MCAO) in rats. OB, olfactory bulb; SGZ, subgranular zone. Middle panel shows newly generated Dcx+/BrdU+ cells outside the SVZ in the ischemic lesion two weeks after MCAO. Lowest panel (Inset of area labeled f above) shows newly generated neurons with migratory or mature phenotype, which are double positive for Dcx and BrdU (arrows) (Images reproduced with permission of O Lindvall, from Arvidsson et al., 2002). (B) Picture illustrating the inflammatory response in Zebrafish after traumatic brain injury (stab lesion) (Image, courtesy of Michael Brand). Leukocytes (green) accumulate around the lesion site (arrow) in the damaged hemisphere. Activated radial glia cells are shown in red (Kyritsis et al., 2012). (C) Newly generated neurons visualized by mitotic lineage tracing (green/red) 9 days after traumatic brain injury in Drosophila. The arrow marks the lesion site in the right optic lobe of the adult fly brain. (D) Brain injury in Drosophila triggers upregulation of dMyc in neuronal progenitor cells, which start to divide symmetrically and produce neurons either directly or indirectly over transit amplifying cells. Adult-born neurons express the panneuronal marker Elav+. Activation of the stress JNK pathway is induced shortly after damage, but its connection to regenerative neurogenesis is still unclear. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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identified recently as important component of the regenerative response (Kizil et al., 2012a), with functions that go beyond chemoattractive behavior. The authors suggest that Cxcr5 provides the radial glial cells with a proliferative permissiveness and is required for their differentiation to neurons. It is often assumed that regeneration functions by recapitulating previous developmental programs. Although there is substantial evidence for this hypothesis, recent results in Zebrafish have revealed that there may also be dedicated “injury-induced molecular programs” (Kyritsis et al., 2012), which are able to propel regeneration in adult brain tissue. If those programs are also present in mammals, understanding their function and connection may provide new approaches to enhance brain regeneration in injured brains. Taken together, these results demonstrates that processes such as injury-induced proliferation of NSCs, recruitment to the injury

site and neuronal differentiation and integration can be modeled in Zebrafish and exploited to gain mechanistic insight. 5.3. Drosophila, a new model for regenerative neurogenesis In Drosophila, regeneration of axonal damage has been modeled extensively, uncovering a marked conservation in the molecular mechanisms underlying neuronal responses to injury in flies and mammals (reviewed in Fang and Bonini, 2012; Leyssen and Hassan, 2007). Models for acute brain injury were underexplored, which recently changed with the introduction of two different models of traumatic brain injury (Katzenberger et al., 2013; FernandezHernandez et al., 2013). David Wasserman and colleagues established a system of closed head trauma, where adult flies kept in a small tube are subjected to strong acceleration and

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de-acceleration, which – depending on the strength or repetition of the impact – produced large vacuoles in the brain, ataxia or death (Katzenberger et al., 2013). Their initial results revealed that ageing and tissue health, regulated by longevity pathways, does modulate the mortality rate after high impact trauma. An alternative model is based on penetrating traumatic brain injury, where the optic lobe of the fly brain is lesioned unilaterally with a thin metal filament (Fernandez-Hernandez et al., 2013) (Fig. 2C). In this model, mechanical damage leads to activation of normally quiescent neural progenitor cells. Progenitor cells in proximity to the needle insertion site, upregulate dMyc and show nuclear translocation of the zinc finger transcription factor Dpn, known to mediate asymmetric division of neuroblasts during development (Fig. 2D). The injury-induced proliferation of neural progenitors finally leads to the formation and insertion of new neurons around the lesion site in the optic lobe (Fig. 2C) (FernandezHernandez et al., 2013). Such newborn neurons persist up to 11 days after injury (Moreno et al., 2015) and seem to differentiate properly since they develop long axonal projections to their cognate target areas. Moreover, JNK stress signaling was identified as an early induced pathway upon brain damage (Moreno et al., 2015), but its link to stem cell activation is still unclear. Behavioral assays and measurements of synaptic activity in this model of regenerative neurogenesis could provide important answers in the future such as if newly formed neurons lead to recovery of brain function. Since stab lesions in Drosophila lead to interaction of compromised and newly generated neurons upon injury, this system allows to model replacement of brain tissue and the fate of damaged or displaced neurons. A new study revealed that partially impaired neurons after injury are detected and eventually replaced by new ones based on conserved cell surface proteins, which allow neurons to compare their “fitness” state (Moreno et al., 2015). Interestingly, neurons with lower fitness undergo apoptosis in close proximity to regenerated tissue containing fresh neurons. The apparent abundance of apoptosis and lack of scar formation in flies and Zebrafish represent a major difference to mammals, where necrotic cell death is predominant (Liou et al., 2003) and induces inflammation and scar formation. The proportion of necrotic versus apoptotic cell death may therefore be a crucial determinant for the recovery of neural tissue after injury. Altogether, these recent advances establish Drosophila as new model to study adult neurogenesis and analyze the genetic underpinnings of brain regeneration and tissue repair. The plethora of genetic tools available in flies may help to uncover conserved mechanisms of adult stem cell activation and neurogenesis, which could be instrumental for the design of therapies in brain regeneration. Both fish and flies have often provided mechanistic insight into biologic processes and serve as a tool to explore new therapeutics (Gonzalez, 2013; Stewart et al., 2014).

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Comparison of neurogenesis in the adult fly, Zebrafish or rodent brain reveals that the formation of new neurons relies in all cases on the activation of adult neural progenitor cells. The identification of adult neurogenesis and adult NSCs in the human brain has raised expectations to treat neurodegenerative diseases and enhance brain regeneration after damage. A wealth of knowledge has been gained in the last years about the characteristics of adult neural stem cells in mammals, their microenvironment and potential to provide new neurons to repair the brain. Nevertheless, it has proven difficult to stimulate neurorestorative processes sufficiently in the mammalian brain. Several promising neuroprotective drugs have been identified in rodent models of traumatic brain injury, however they have not proven effective in clinical trials (Xiong et al., 2013).

The analysis of regenerative neurogenesis in recently developed models of acute brain injury in Zebrafish or Drosophila may provide an opportunity to search for new factors regulating stem cell activation or regenerative neurogenesis based on comparative transcriptome analysis or large scale RNAi-based screens. Drosophila, where adult neurogenesis has long been assumed to be absent, has unexpectedly emerged as a new model system to track processes linked to brain regeneration. Understanding how neurogenesis can be boosted in genetic model organisms may ultimately allow to develop efficient treatments to harness endogenous neurogenesis for brain repair. Acknowledgement This work has been supported by the University of Bern (C. Q4 Q5 Rhiner). References Ables, J.L., Decarolis, N.A., Johnson, M.A., Rivera, P.D., Gao, Z., Cooper, D.C., Radtke, F., Hsieh, J., Eisch, A.J., 2010. Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells. J. Neurosci. 30, 10484–10492 (the official journal of the Society for Neuroscience). Adolf, B., Chapouton, P., Lam, C.S., Topp, S., Tannhauser, B., Strahle, U., Gotz, M., Bally-Cuif, L., 2006. Conserved and acquired features of adult neurogenesis in the zebrafish telencephalon. Dev. Biol. 295, 278–293. Ahn, S., Joyner, A.L., 2005. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437, 894–897. Aimone, J.B., Deng, W., Gage, F.H., 2011. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589–596. Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z., Lindvall, O., 2002. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8, 963–970. Azim, K., Zweifel, S., Klaus, F., Yoshikawa, K., Amrein, I., Raineteau, O., 2013. Early decline in progenitor diversity in the marmoset lateral ventricle. Cereb Cortex 23, 922–931. Bergami, M., Masserdotti, G., Temprana, S.G., Motori, E., Eriksson, T.M., Gobel, J., Yang, S.M., Conzelmann, K.K., Schinder, A.F., Gotz, M., et al., 2015. A critical period for experience-dependent remodeling of adult-born neuron connectivity. Neuron 85, 710–717. Bergmann, O., Liebl, J., Bernard, S., Alkass, K., Yeung, M.S., Steier, P., Kutschera, W., Johnson, L., Landen, M., Druid, H., et al., 2012. The age of olfactory bulb neurons in humans. Neuron 74, 634–639. Bhardwaj, R.D., Curtis, M.A., Spalding, K.L., Buchholz, B.A., Fink, D., Bjork-Eriksson, T., Nordborg, C., Gage, F.H., Druid, H., Eriksson, P.S., et al., 2006. Neocortical neurogenesis in humans is restricted to development. Proc. Natl. Acad. Sci. U.S.A. 103, 12564–12568. Biebl, M., Cooper, C.M., Winkler, J., Kuhn, H.G., 2000. Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci. Lett. 291, 17–20. Blennow, K., Hardy, J., Zetterberg, H., 2012. The neuropathology and neurobiology of traumatic brain injury. Neuron 76, 886–899. Bonaguidi, M.A., Wheeler, M.A., Shapiro, J.S., Stadel, R.P., Sun, G.J., Ming, G.L., Song, H., 2011. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145, 1142–1155. Braun, S.M., Jessberger, S., 2014. Adult neurogenesis: mechanisms and functional significance. Development 141, 1983–1986. Brill, M.S., Ninkovic, J., Winpenny, E., Hodge, R.D., Ozen, I., Yang, R., Lepier, A., Gascon, S., Erdelyi, F., Szabo, G., et al., 2009. Adult generation of glutamatergic olfactory bulb interneurons. Nat. Neurosci. 12, 1524–1533. Byrd, C.A., Brunjes, P.C., 2001. Neurogenesis in the olfactory bulb of adult zebrafish. Neuroscience 105, 793–801. Cabernard, C., Prehoda, K.E., Doe, C.Q., 2010. A spindle-independent cleavage furrow positioning pathway. Nature 467, 91–94. Cameron, D.A., 2000. Cellular proliferation and neurogenesis in the injured retina of adult zebrafish. Visual Neurosci. 17, 789–797. Cavallaro, M., Mariani, J., Lancini, C., Latorre, E., Caccia, R., Gullo, F., Valotta, M., DeBiasi, S., Spinardi, L., Ronchi, A., et al., 2008. Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants. Development 135, 541–557. Clelland, C.D., Choi, M., Romberg, C., Clemenson Jr., G.D., Fragniere, A., Tyers, P., Jessberger, S., Saksida, L.M., Barker, R.A., Gage, F.H., et al., 2009. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213. Curtis, M.A., Kam, M., Nannmark, U., Anderson, M.F., Axell, M.Z., Wikkelso, C., Holtas, S., van Roon-Mom, W.M., Bjork-Eriksson, T., Nordborg, C., et al., 2007. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315, 1243–1249.

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Please cite this article in press as: Fernandez-Hernandez, I., Rhiner, C., New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration. Neurosci. Biobehav. Rev. (2015), http://dx.doi.org/10.1016/j.neubiorev.2015.06.021

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