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      Running rescues a fear-based contextual discrimination deficit in aged mice

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          Abstract

          Normal aging and exercise exert extensive, often opposing, effects on the dentate gyrus (DG) of the hippocampus altering volume, synaptic function, and behaviors. The DG is especially important for behaviors requiring pattern separation—a cognitive process that enables animals to differentiate between highly similar contextual experiences. To determine how age and exercise modulate pattern separation in an aversive setting, young, aged, and aged mice provided with a running wheel were assayed on a fear-based contextual discrimination task. Aged mice showed a profound impairment in contextual discrimination compared to young animals. Voluntary exercise rescued this deficit to such an extent that behavioral pattern separation of aged-run mice was now similar to young animals. Running also resulted in a significant increase in the number of immature neurons with tertiary dendrites in aged mice. Despite this, neurogenesis levels in aged-run mice were still considerably lower than in young animals. Thus, mechanisms other than DG neurogenesis likely play significant roles in improving behavioral pattern separation elicited by exercise in aged animals.

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          Most cited references30

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          Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation.

          Recently, investigation of new neurons in memory formation has focused on a specific function-pattern separation. However, it has been difficult to reconcile the form of separation tested in behavioral tasks with how it is conceptualized according to computational and electrophysiology perspectives. Here, we propose a memory resolution hypothesis that considers the unique information contributions of broadly tuned young neurons and highly specific mature neurons and describe how the fidelity of memories can relate to spatial and contextual discrimination. See the related Perspective from Sahay, Wilson, and Hen, "Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb," in this issue of Neuron. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Running enhances spatial pattern separation in mice.

            Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.
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              Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders.

              Although an influence of adult neurogenesis in mediating some of the effects of antidepressants has received considerable attention in recent years, much less is known about how alterations in this form of plasticity may contribute to psychiatric disorders such as anxiety and depression. One way to begin to address this question is to link the functions of adult-born hippocampal neurons with specific endophenotypes of these disorders. Recent studies have implicated adult-born hippocampal neurons in pattern separation, a process by which similar experiences or events are transformed into discrete, non-overlapping representations. Here we propose that impaired pattern separation underlies the overgeneralization often seen in anxiety disorders, specifically post-traumatic stress disorder and panic disorder, and therefore represents an endophenotype for these disorders. The development of new, pro-neurogenic compounds may therefore have therapeutic potential for patients who display pattern separation deficits.
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                Author and article information

                Contributors
                Journal
                Front Syst Neurosci
                Front Syst Neurosci
                Front. Syst. Neurosci.
                Frontiers in Systems Neuroscience
                Frontiers Media S.A.
                1662-5137
                11 August 2015
                2015
                : 9
                : 114
                Affiliations
                [1] 1Department of Psychiatry, Columbia University New York, NY, USA
                [2] 2Division of Integrative Neuroscience, New York State Psychiatric Institute New York, NY, USA
                [3] 3Departments of Neuroscience and Pharmacology, Columbia University New York, NY, USA
                Author notes

                Edited by: Michael A. Yassa, University of California, Irvine, USA

                Reviewed by: José M. Delgado-García, University Pablo de Olavide, Spain; Raúl G. Paredes, Universidad Nacional Autónoma de México, Mexico

                *Correspondence: René Hen, New York State Psychiatric Institute and Columbia University, 1051 Riverside Dr., Unit 87, Kolb Annex, Rm. 767, New York, NY 10032, USA rh95@ 123456columbia.edu

                †Present Address: Melody V. Wu, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

                Article
                10.3389/fnsys.2015.00114
                4531235
                26321926
                c85f7666-9b01-4985-a4cf-f8e34a1bc9c5
                Copyright © 2015 Wu, Luna and Hen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 April 2015
                : 28 July 2015
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 45, Pages: 10, Words: 6775
                Categories
                Neuroscience
                Original Research

                Neurosciences
                aging,exercise,pattern separation,dentate gyrus,neurogenesis
                Neurosciences
                aging, exercise, pattern separation, dentate gyrus, neurogenesis

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