Injury-induced neurogenesis in the mammalian forebrain

Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 11/2010; 68(10):1645-56. DOI: 10.1007/s00018-010-0552-y
Source: PubMed


It has been accepted that new neurons are added to the olfactory bulb and the hippocampal dentate gyrus throughout life in the healthy adult mammalian brain. Recent studies have clarified that brain insult raises the proliferation of neural stem cells/neural progenitor cells existing in the subventricular zone and the subgranular zone, which become sources of new neurons for the olfactory bulb and the dentate gyrus, respectively. Interestingly, convincing data has shown that brain insult invokes neurogenesis in various brain regions, such as the hippocampal cornu ammonis region, striatum, and cortex. These reports suggest that neural stem cells/neural progenitor cells, which can be activated by brain injury, might be broadly located in the adult brain or that new neurons may migrate widely from the neurogenic regions. This review focuses on brain insult-induced neurogenesis in the mammalian forebrain, especially in the neocortex.

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Available from: Koji Ohira
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    • "A recent study demonstrated that the density of GABAergic interneurons increased in the white matter of the schizophrenic PFC [82], which suggests that new neurons might be generated or recruited in the white matter of patients with schizophrenia. However, neurogenesis is upregulated by less than 1% of the total neuron count in the adult cortex under pathological conditions, such as focal or global ischemia, cortical tissue aspiration, or a laser-induced lesion [83], suggesting that newly generated neurons can hardly account for the transcriptional immaturity of the schizophrenic PFC, even under pathological conditions. Although cortical adult neurogenesis cannot be excluded as a possible contributory factor, it might not be a major factor. "
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    ABSTRACT: Background Schizophrenia, a severe psychiatric disorder, has a lifetime prevalence of 1%. The exact mechanisms underlying this disorder remain unknown, though theories abound. Recent studies suggest that particular cell types and biological processes in the schizophrenic cortex have a pseudo-immature status in which the molecular properties partially resemble those in the normal immature brain. However, genome-wide gene expression patterns in the brains of patients with schizophrenia and those of normal infants have not been directly compared. Here, we show that the gene expression patterns in the schizophrenic prefrontal cortex (PFC) resemble those in the juvenile PFC. Results We conducted a gene expression meta-analysis in which, using microarray data derived from different studies, altered expression patterns in the dorsolateral PFC (DLFC) of patients with schizophrenia were compared with those in the DLFC of developing normal human brains, revealing a striking similarity. The results were replicated in a second DLFC data set and a medial PFC (MFC) data set. We also found that about half of the genes representing the transcriptomic immaturity of the schizophrenic PFC were developmentally regulated in fast-spiking interneurons, astrocytes, and oligodendrocytes. Furthermore, to test whether medications, which often confound the results of postmortem analyses, affect on the juvenile-like gene expressions in the schizophrenic PFC, we compared the gene expression patterns showing transcriptomic immaturity in the schizophrenic PFC with those in the PFC of rodents treated with antipsychotic drugs. The results showed no apparent similarities between the two conditions, suggesting that the juvenile-like gene expression patterns observed in the schizophrenic PFC could not be accounted for by medication effects. Moreover, the developing human PFC showed a gene expression pattern similar to that of the PFC of naive Schnurri-2 knockout mice, an animal model of schizophrenia with good face and construct validity. This result also supports the idea that the transcriptomic immaturity of the schizophrenic PFC is not due to medication effects. Conclusions Collectively, our results provide evidence that pseudo-immaturity of the PFC resembling juvenile PFC may be an endophenotype of schizophrenia.
    Full-text · Article · May 2014 · Molecular Brain
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    • "The fact that manipulation of morphogen signals skews NSC differentiation potential in vivo suggest that the local environment plays a role in regional specification of adult NSCs (Ihrie et al., 2011). Moreover, pathological conditions stimulate NSCs to produce progenies that are different from the ones generated during homeostasis and these can migrate toward non-canonical locations, suggesting that cell fate is not fixed (Kernie and Parent, 2010; Ohira, 2011). Defining the degree of lineage plasticity of adult NSCs and the signals that can override their intrinsic programming has important implications for developing cell replacement strategies based on the mobilization of endogenous cells. "
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    ABSTRACT: Adult neural stem cells (NSCs) are perceived as a homogeneous population of cells that divide infrequently and are capable of multi-lineage differentiation. However, recent data revealed that independent stem cell lineages act in parallel to maintain neurogenesis and provide a cellular source for tissue repair. In addition, even within the same lineage, the stem and progenitor cells are strikingly heterogeneous including NSCs that are dormant or mitotically active. We will discuss these different NSC populations and activity states with relation to their role in neurogenesis and regeneration but also how these different stem cells respond to aging. NSCs depend on Notch signaling for their maintenance. While Notch-dependence is a common feature among NSC populations, we will discuss how differences in Notch signaling might contribute to adult NSC heterogeneity. Understanding the fate of multiple NSC populations with distinct functions has implications for the mechanisms of aging and regeneration.
    Full-text · Article · Feb 2014 · Frontiers in Neuroscience
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    • "Upon completion of neocortical development, neurogenesis in the proliferative regions of the cerebral cortex largely ceases (31) while patterning of neuronal connectivity continues. Although injury to the brain can stimulate some degree of neurogenesis from NPCs present in the mature brain (32–35), this apparent attempt at circuit repair is insufficient for restoring damaged networks. "
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    ABSTRACT: Neurophysiological changes resulting from traumatic brain injury (TBI) can result in adverse changes in behavior including mood instability and cognitive dysfunction. Cell death following TBI likely contributes to these altered behaviors and remains an elusive but attractive target for therapies aiming at functional recovery. Previously we demonstrated that neural progenitor cells derived from embryonic rats can be transplanted into donor neonatal rat brain slices and, over the course of 2 weeks in culture, mature into neurons that express neuronal immunohistochemical markers and develop electrophysiological profiles consistent with excitatory and inhibitory interneurons. Here we examine the potential of generating electrophysiologically mature neurons with a layer-specific phenotype as a next step in developing a therapy designed to rebuild a damaged cortical column with the functionally appropriate neuronal subtypes. Preliminary results suggest that neurons derived from passaged neurospheres and grown in dissociated cell culture develop GABAergic and presumed glutamatergic phenotypes and that the percentage of GABAergic cells increases as a function of passage. After 2 weeks in culture, the neurons have a mix of immature and mature neuronal electrophysiological profiles and receive synaptic inputs from surrounding neurons. Subsets of cells expressing neuron specific markers also express layer-specific markers such as Cux1, ER81, and RORβ. Future studies will investigate the potential of transplanting layer-specific neurons generated and isolated in vitro into the neocortex of neonatal brain slices and their potential to maintain their phenotype and integrate into the host tissue.
    Full-text · Article · Jan 2014 · Frontiers in Neurology
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