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      The Hippocampal Neuro-Glio-Vascular Network: Metabolic Vulnerability and Potential Neurogenic Regeneration in Disease

      review-article
      a , b , * , a , b , b
      Brain Plasticity
      IOS Press
      Neurovascular coupling, stroke, Alzheimer’s disease, neurogenesis, dentate gyrus

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          Abstract

          Brain metabolism is a fragile balance between nutrient/oxygen supply provided by the blood and neuronal/glial demand. Small perturbations in these parameters are necessary for proper homeostatic functioning and information processing, but can also cause significant damage and cell death if dysregulated. During embryonic and early post-natal development, massive neurogenesis occurs, a process that continues at a limited rate in adulthood in two neurogenic niches, one in the lateral ventricle and the other in the hippocampal dentate gyrus. When metabolic demand does not correspond with supply, which can occur dramatically in the case of hypoxia or ischemia, or more subtly in the case of neuropsychiatric or neurodegenerative disorders, both of these neurogenic niches can respond—either in a beneficial manner, to regenerate damaged or lost tissue, or in a detrimental fashion—creating aberrant synaptic connections. In this review, we focus on the complex relationship that exists between the cerebral vasculature and neurogenesis across development and in disease states including hypoxic-ischemic injury, hypertension, diabetes mellitus, and Alzheimer’s disease. Although there is still much to be elucidated, we are beginning to appreciate how neurogenesis may help or harm the metabolically-injured brain, in the hopes that these insights can be used to tailor novel therapeutics to regenerate damaged tissue after injury.

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          Most cited references129

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          Neuronal replacement from endogenous precursors in the adult brain after stroke.

          In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.
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            Neurons derived from radial glial cells establish radial units in neocortex.

            The neocortex of the adult brain consists of neurons and glia that are generated by precursor cells of the embryonic ventricular zone. In general, glia are generated after neurons during development, but radial glia are an exception to this rule. Radial glia are generated before neurogenesis and guide neuronal migration. Radial glia are mitotically active throughout neurogenesis, and disappear or become astrocytes when neuronal migration is complete. Although the lineage relationships of cortical neurons and glia have been explored, the clonal relationship of radial glia to other cortical cells remains unknown. It has been suggested that radial glia may be neuronal precursors, but this has not been demonstrated in vivo. We have used a retroviral vector encoding enhanced green fluorescent protein to label precursor cells in vivo and have examined clones 1-3 days later using morphological, immunohistochemical and electrophysiological techniques. Here we show that clones consist of mitotic radial glia and postmitotic neurons, and that neurons migrate along clonally related radial glia. Time-lapse images show that proliferative radial glia generate neurons. Our results support the concept that a lineage relationship between neurons and proliferative radial glia may underlie the radial organization of neocortex.
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              Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo.

              Vascular endothelial growth factor (VEGF) is an angiogenic protein with neurotrophic and neuroprotective effects. Because VEGF promotes the proliferation of vascular endothelial cells, we examined the possibility that it also stimulates the proliferation of neuronal precursors in murine cerebral cortical cultures and in adult rat brain in vivo. VEGF (>10 ng/ml) stimulated 5-bromo-2'-deoxyuridine (BrdUrd) incorporation into cells that expressed immature neuronal marker proteins and increased cell number in cultures by 20-30%. Cultured cells labeled by BrdUrd expressed VEGFR2/Flk-1, but not VEGFR1/Flt-1 receptors, and the effect of VEGF was blocked by the VEGFR2/Flk-1 receptor tyrosine kinase inhibitor SU1498. Intracerebroventricular administration of VEGF into rat brain increased BrdUrd labeling of cells in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), where VEGFR2/Flk-1 was colocalized with the immature neuronal marker, doublecortin (Dcx). The increase in BrdUrd labeling after the administration of VEGF was caused by an increase in cell proliferation, rather than a decrease in cell death, because VEGF did not reduce caspase-3 cleavage in SVZ or SGZ. Cells labeled with BrdUrd after VEGF treatment in vivo include immature and mature neurons, astroglia, and endothelial cells. These findings implicate the angiogenesis factor VEGF in neurogenesis as well.
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                Author and article information

                Journal
                Brain Plast
                Brain Plast
                BPL
                Brain Plasticity
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                2213-6304
                2213-6312
                25 March 2018
                10 August 2018
                2018
                : 3
                : 2 , The Role of Neurogenesis in Brain Disorders
                : 129-144
                Affiliations
                [a ]Medical Scientist Training Program (MSTP), Stony Brook Medicine, Stony Brook, NY, USA
                [b ]Department of Neurobiology and Behavior, Stony Brook University , Stony Brook, NY, USA
                Author notes
                [* ]Correspondence to: Gregory W. Kirschen, Ph.D., M.D. Candidate, Class of 2020, Medical Scientist Training Program (MSTP), Stony Brook University School of Medicine, Stony Brook, NY 11794, USA. E-mail: Gregory.kirschen@ 123456stonybrookmedicine.edu .
                Article
                BPL170055
                10.3233/BPL-170055
                6091038
                30151338
                c81f88b9-2d56-43d0-9bda-e89721f9f325
                © 2018 – IOS Press and the authors. All rights reserved

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Review

                neurovascular coupling,stroke,alzheimer’s disease,neurogenesis,dentate gyrus

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