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      Corticohippocampal Dysfunction In The OBiden Mouse Model Of Primary Oligodendrogliopathy

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          Abstract

          Despite concerted efforts over decades, the etiology of multiple sclerosis (MS) remains unclear. Autoimmunity, environmental-challenges, molecular mimicry and viral hypotheses have proven equivocal because early-stage disease is typically presymptomatic. Indeed, most animal models of MS also lack defined etiologies. We have developed a novel adult-onset oligodendrogliopathy using a delineated metabolic stress etiology in myelinating cells, and our central question is, “how much of the pathobiology of MS can be recapitulated in this model?” The analyses described herein demonstrate that innate immune activation, glial scarring, cortical and hippocampal damage with accompanying electrophysiological, behavioral and memory deficits naturally emerge from disease progression. Molecular analyses reveal neurofilament changes in normal-appearing gray matter that parallel those in cortical samples from MS patients with progressive disease. Finally, axon initial segments of deep layer pyramidal neurons are perturbed in entorhinal/frontal cortex and hippocampus from OBiden mice, and computational modeling provides insight into vulnerabilities of action potential generation during demyelination and early remyelination. We integrate these findings into a working model of corticohippocampal circuit dysfunction to predict how myelin damage might eventually lead to cognitive decline.

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          Most cited references75

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          Object recognition test in mice.

          The object recognition test is now among the most commonly used behavioral tests for mice. A mouse is presented with two similar objects during the first session, and then one of the two objects is replaced by a new object during a second session. The amount of time taken to explore the new object provides an index of recognition memory. As more groups have used the protocol, the variability of the procedures used in the object recognition test has increased steadily. This protocol provides a necessary standardization of the procedure. This protocol reduces inter-individual variability with the use of a selection criterion based on a minimal time of exploration for both objects during each session. In this protocol, we describe the three most commonly used variants, containing long (3 d), short (1 d) or no habituation phases. Thus, with a short intersession interval (e.g., 6 h), this procedure can be performed in 4, 2 or 1 d, respectively, according to the duration of the habituation phase. This protocol should allow for the comparison of results from different studies, while permitting adaption of the protocol to the constraints of the experimenter.
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            Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.

            Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.
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              Axonal damage in acute multiple sclerosis lesions.

              One of the histological hallmarks of early multiple sclerosis lesions is primary demyelination, with myelin destruction and relative sparing of axons. On the other hand, it is widely accepted that axonal loss occurs in, and is responsible for, the permanent disability characterizing the later chronic progressive stage of the disease. In this study, we have used an antibody against amyloid precursor protein, known to be a sensitive marker of axonal damage in a number of other contexts, in immunocytochemical experiments on paraffin embedded multiple sclerosis lesions of varying ages in order to see at which stage of the disease axonal damage, in addition to demyelination, occurs and may thus contribute to the development of disability in patients. The results show the expression of amyloid precursor protein in damaged axons within acute multiple sclerosis lesions, and in the active borders of less acute lesions. This observation may have implications for the design and timing of therapeutic intervention, one of the most important aims of which must be the reduction of permanent disability.
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                Author and article information

                Contributors
                agow@med.wayne.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                31 October 2018
                31 October 2018
                2018
                : 8
                : 16116
                Affiliations
                [1 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Center for Molecular Medicine and Genetics, School of Medicine, , Wayne State University, ; Detroit, MI 48201 USA
                [2 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Institute of Gerontology, Wayne State University, ; Detroit, MI 48202 USA
                [3 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Department of Psychiatry and Behavioral Neurosciences, School of Medicine, , Wayne State University, ; Detroit, MI 48201 USA
                [4 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Carman and Ann Adams Department of Pediatrics, School of Medicine, , Wayne State University, ; Detroit, MI 48201 USA
                [5 ]ISNI 0000 0001 1456 7807, GRID grid.254444.7, Department of Neurology, School of Medicine, , Wayne State University, ; Detroit, MI 48201 USA
                [6 ]ISNI 0000 0001 2181 7878, GRID grid.47840.3f, Helen Wills Neuroscience Institute, , University of California, ; Berkeley, CA 94720 USA
                [7 ]ISNI 0000 0001 2167 3675, GRID grid.14003.36, Present Address: Department of Comparative Biosciences, , University of Wisconsin-Madison School of Veterinary Medicine, ; Madison, WI 53706 USA
                Author information
                http://orcid.org/0000-0001-5297-5019
                http://orcid.org/0000-0001-7446-8990
                Article
                34414
                10.1038/s41598-018-34414-7
                6208344
                a95532e9-6b1c-4374-8f89-944e551dfd3a
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 April 2018
                : 25 September 2018
                Funding
                Funded by: Rumble Fellowship Wayne State University
                Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);
                Award ID: MH107512
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000065, U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS);
                Award ID: NS021135
                Award ID: NS043783
                Award ID: NS067157
                Award Recipient :
                Funded by: Center for Molecular Medicine and Genetics SURP fellowship
                Funded by: FundRef https://doi.org/10.13039/100000890, National Multiple Sclerosis Society (National MS Society);
                Award ID: RG2891
                Award ID: RG4078
                Award ID: RG4639
                Award ID: RG4906
                Award Recipient :
                Funded by: Detroit Medical Center Foundation
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