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      Donepezil Rescues Spatial Learning and Memory Deficits following Traumatic Brain Injury Independent of Its Effects on Neurogenesis

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          Abstract

          Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury-induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis.

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          Most cited references17

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          Hippocampal neurogenesis regulates forgetting during adulthood and infancy.

          Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.
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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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              A controlled cortical impact model of traumatic brain injury in the rat.

              Controlled cortical impact models produce brain injury by using a pneumatic impactor to impact exposed brain. This study systematically examined the effects of varying magnitudes of controlled cortical impact to the rat brain on neurological, cardiovascular, and histopathological variables. As the magnitude of injury increased, the duration of suppression of somatomotor reflexes and the duration of chronic vestibular motor deficits increased. The blood pressure response was observed to depend on injury levels; a moderate injury level produced a hypotensive response while a high injury level produced an immediate brief hypertensive response followed by hypotension. Low injury levels produced no significant macroscopic or microscopic change, but higher injury levels produced cortical contusion and intraparenchymal hemorrhage which, with increasing survival time, evolved into necrotic changes and cavitation underlying the injury site. Also with high levels of injury, axonal injury was found throughout the brain-stem with the greatest concentration of injured axons occurring in the cerebellar peduncles and pontomedullary junction. These data demonstrate that controlled cortical impact in the rat reproduces many of the features observed in other experimental animal models. This model allows independent control of many mechanical loading parameters associated with traumatic brain injury. The controlled cortical impact rat model should be an effective experimental tool to investigators of traumatic brain injury.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                25 February 2015
                2015
                : 10
                : 2
                : e0118793
                Affiliations
                [001]Departments of Pediatrics and Pathology & Cell Biology, Columbia University College of Physicians and Surgeons, 3959 Broadway, CHN 10-24, New York, NY 10032, United States of America
                Univ. Kentucky, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SK TY. Performed the experiments: TY AK. Analyzed the data: SK TY. Wrote the paper: SK TY.

                Article
                PONE-D-14-41676
                10.1371/journal.pone.0118793
                4340948
                25714524
                b061cd76-8c1f-4aa3-862a-c660295ef3a9
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 16 September 2014
                : 6 January 2015
                Page count
                Figures: 4, Tables: 0, Pages: 13
                Funding
                National Institutes of Health R21 NS083077, SK, TY, AK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper.

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