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ItemRegulation of endogenous neural stem/progenitor cells for neural repair-factors that promote neurogenesis and gliogenesis in the normal and damaged brainChristie, KJ ; Turnley, AM (FRONTIERS MEDIA SA, 2013-01-18)Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation.
ItemADULT HIPPOCAMPAL NEUROGENESIS, RHO KINASE INHIBITION AND ENHANCEMENT OF NEURONAL SURVIVALChristie, KJ ; Turbic, A ; Turnley, AM (PERGAMON-ELSEVIER SCIENCE LTD, 2013-09-05)Adult neurogenesis occurs throughout life; however the majority of new neurons do not survive. Enhancing the survival of these new neurons will increase the likelihood that these neurons could return function following injury. Inhibition of Rho kinase is known to increase neurite outgrowth and regeneration. Previous work in our lab has demonstrated a role for Rho kinase inhibition and survival of new born neurons from the sub-ventricular zone. In this study we examined the role of Rho kinase inhibition on hippocampal neurogenesis. Two concentrations of Rho kinase inhibitor Y27632 (20 and 100 μM) and the proliferative marker EdU were infused in the lateral ventricle for 7 days. Quantification of doublecortin+/EdU+ cells on the 7th day showed that cell numbers were not significantly different, suggesting no effect on neuroblast generation. Following infusion of 100μM Y27632, the number of newborn NeuN+/EdU+ neurons at 35 days in the granular cell layer of the dentate gyrus of the ipsilateral side of the infusion did not display a significant difference; however there was an increase on the contralateral side, suggesting a dose effect. Infusion of a lower dose (20 μM) of Y27632 resulted in an increase in NeuN+/EdU+ cells in the granular cell layer of the ipsilateral side at 35 days. These mice also demonstrated enhanced spatial memory as tested by the Y maze with no significant changes in anxiety or novel object recognition. Rho kinase inhibition enhanced the survival of new born neurons in the dentate gyrus with a specific dosage effect. These results suggest that inhibition of Rho kinase following injury could be beneficial for increasing the survival of new neurons that may aid recovery.