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      The aging systemic milieu negatively regulates neurogenesis and cognitive function

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          Summary

          In the central nervous system (CNS), aging results in a precipitous decline in adult neural stem/progenitor cells (NPCs) and neurogenesis, with concomitant impairments in cognitive functions 1 . Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise 1 . Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age dependent fashion in mice. Accordingly, exposing a young animal to an old systemic environment, or to plasma from old mice, decreased synaptic plasticity and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines - including CCL11/Eotaxin – whose plasma levels correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and whose levels are increased in plasma and cerebral spinal fluid of healthy aging humans. Finally, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis, and cognitive impairments, observed during aging can be in part attributed to changes in blood-borne factors.

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          Mechanisms and functional implications of adult neurogenesis.

          The generation of new neurons is sustained throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. In this review, we discuss the factors that regulate proliferation and fate determination of adult neural stem cells and describe recent studies concerning the integration of newborn neurons into the existing neural circuitry. We further address the potential significance of adult neurogenesis in memory, depression, and neurodegenerative disorders such as Alzheimer's and Parkinson's disease.
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            Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

            Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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              Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus.

              Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                1 August 2011
                31 August 2011
                01 March 2012
                : 477
                : 7362
                : 90-94
                Affiliations
                [1 ]Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA
                [2 ]Neuroscience IDP Program, Stanford University School of Medicine, Stanford, California 94305, USA
                [3 ]AfaSci Research Laboratory, Redwood City, California, 94063, USA
                [4 ]School of Life Sciences, Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland
                [5 ]Immunology IDP Program, Stanford University School of Medicine, Stanford, California 94305, USA
                [6 ]Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Strubergasse 21, A-5020 Salzburg, Austria
                [7 ]Dept. of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98108-1597, USA
                [8 ]Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle, WA 98108-1597, USA
                [9 ]Layton Aging & Alzheimer’s Disease Center, Oregon Health and Science University, CR131, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA and Portland VA Medical Center, Portland, OR 97207
                [10 ]Department of Neurosciences, University of California San Diego, 9500 Gilman Drive #0948, La Jolla, CA 92093-0948, USA
                [11 ]Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
                [12 ]The Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94305, USA
                Author notes
                [* ]Corresponding Author: twc@ 123456stanford.edu
                [#]

                Current address: CNS Discovery, pRED, F. Hoffmann-La Roche Ltd., Basel, Switzerland

                Article
                nihpa313001
                10.1038/nature10357
                3170097
                21886162
                9b6c629c-6016-4edb-94f5-d3844aab27f0

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG027505-05 || AG
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG027505-04 || AG
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG027505-03 || AG
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG027505-02 || AG
                Funded by: National Institute on Aging : NIA
                Award ID: R01 AG027505-01A1 || AG
                Funded by: National Institute on Aging : NIA
                Award ID: F31 AG034045-03 || AG
                Funded by: National Institute on Aging : NIA
                Award ID: F31 AG034045-02 || AG
                Funded by: National Institute on Aging : NIA
                Award ID: F31 AG034045-01 || AG
                Funded by: Office of the Director : NIH
                Award ID: DP1 OD000392-05 || OD
                Funded by: Office of the Director : NIH
                Award ID: DP1 OD000392-04 || OD
                Funded by: Office of the Director : NIH
                Award ID: DP1 OD000392-03 || OD
                Funded by: Office of the Director : NIH
                Award ID: DP1 OD000392-02 || OD
                Funded by: Office of the Director : NIH
                Award ID: DP1 OD000392-01 || OD
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