Inflammation-Mediated Memory Dysfunction and Effects of a Ketogenic Diet in a Murine Model of Multiple Sclerosis
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{"title"=>"Inflammation-mediated memory dysfunction and effects of a ketogenic diet in a murine model of multiple sclerosis", "type"=>"journal", "authors"=>[{"first_name"=>"Do Young", "last_name"=>"Kim", "scopus_author_id"=>"56109746400"}, {"first_name"=>"Junwei", "last_name"=>"Hao", "scopus_author_id"=>"35364053600"}, {"first_name"=>"Ruolan", "last_name"=>"Liu", "scopus_author_id"=>"10040537300"}, {"first_name"=>"Gregory", "last_name"=>"Turner", "scopus_author_id"=>"8664633300"}, {"first_name"=>"Fu Dong", "last_name"=>"Shi", "scopus_author_id"=>"7202739770"}, {"first_name"=>"Jong M.", "last_name"=>"Rho", "scopus_author_id"=>"7102472905"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22567104", "doi"=>"10.1371/journal.pone.0035476", "sgr"=>"84860494814", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "scopus"=>"2-s2.0-84860494814", "issn"=>"19326203", "pui"=>"364721387"}, "id"=>"9bdfe214-d059-3342-bc16-eba646f90098", "abstract"=>"A prominent clinical symptom in multiple sclerosis (MS), a progressive disorder of the central nervous system (CNS) due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD) on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE), using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation) and spatial learning and memory (assessed with the Morris Water Maze). Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS), in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals.", "link"=>"http://www.mendeley.com/research/inflammationmediated-memory-dysfunction-effects-ketogenic-diet-murine-model-multiple-sclerosis-3", "reader_count"=>82, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>19, "Student > Doctoral Student"=>10, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>5, "Student > Master"=>13, "Other"=>10, "Student > Bachelor"=>9, "Lecturer"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>19, "Student > Doctoral Student"=>10, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>5, "Student > Master"=>13, "Other"=>10, "Student > Bachelor"=>9, "Lecturer"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>3, "Nursing and Health Professions"=>1, "Medicine and Dentistry"=>24, "Agricultural and Biological Sciences"=>26, "Neuroscience"=>11, "Psychology"=>7, "Chemistry"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>4}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>24}, "Neuroscience"=>{"Neuroscience"=>11}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>7}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>26}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"United States"=>1, "Germany"=>4}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/644039"], "description"=>"<p>(A) Assessment of spatial learning and memory using the Morris Water Maze (MWM) test. Naïve mice exhibited improved latencies to solve the maze during the consecutive 5-day trials, but EAE mice did not show any improvement in spatial learning and memory. (B) <i>In vivo</i> measurement of reactive oxygen species (ROS) after immunization. No change in ROS signal was found in naïve mice, but the progressive increases in superoxide production were seen 6–10 days post immunization. (C) No brain structural changes are seen in the early stage of immunization. All experiments were conducted in groups of mice (n = 4–8) between 6–10 days post immunization before gross motor deficits were observed.</p>", "links"=>[], "tags"=>["eae", "mice"], "article_id"=>314525, "categories"=>["Neuroscience", "Mental Health", "Immunology"], "users"=>["Do Young Kim", "Junwei Hao", "Ruolan Liu", "Gregory Turner", "Fu-Dong Shi", "Jong M. Rho"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0035476.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Changes_in_EAE_mice_prior_to_motor_disability_/314525", "title"=>"Changes in EAE mice prior to motor disability.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 05:40:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/644102"], "description"=>"<p>(A) Starting from day 17 post immunization (p.i.), KD-fed EAE mice (n = 11) showed significantly less motor disability than SD-fed EAE mice (**, <i>p<</i>0.01, Mann-Whitney <i>U</i> test). In KD- fed and SD- fed EAE mice, the mean clinical scores (1.9±0.20 vs 2.7±0.35 and 0.43±0.12 vs 1.0±0.15) were measured at 17 days and 25 days p.i., respectively. (B, C) Restoration of spatial learning and memory by the KD in EAE mice. MWM testing was conducted in groups of EAE mice either prior to the occurrence of motor deficits (before 10 days p.i., left panel, B) or from 30 days to 35 days p.i. (right panel, C). The graph illustrates average latencies to finding the submerged escape platform. Each group consisted of 5–8 mice. Values represent mean±SEM. One way ANOVA followed by Tukey test. (D) Change in the synaptic plasticity at 13–16 days p.i. with or without the KD. EAE mice exerted impairment in LTP after high-frequency stimulation (10 slices form 5 mice). Both the naïve and KD-fed EAE mice demonstrated intact LTP induction and maintenance (9 slices from 4 mice). (E) Change in synaptic plasticity at 25–35 days p.i. with or without the KD. Neither the naïve nor KD-fed EAE mice showed changes in LTP maintenance (10 slices from 5 mice). The dotted line indicates the baseline field potential amplitude. Synaptic plasticity seen during peak and mild stages of motor disability are depicted in the left and right panels, respectively.</p>", "links"=>[], "tags"=>["ketogenic", "eae"], "article_id"=>314597, "categories"=>["Neuroscience", "Mental Health", "Immunology"], "users"=>["Do Young Kim", "Junwei Hao", "Ruolan Liu", "Gregory Turner", "Fu-Dong Shi", "Jong M. Rho"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0035476.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_the_ketogenic_diet_on_motor_disability_and_memory_deficit_in_EAE_mice_/314597", "title"=>"Effects of the ketogenic diet on motor disability and memory deficit in EAE mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 05:40:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/644208"], "description"=>"<p>(A) T2-weighted images were obtained with a 7T MR scanner during the peak stage of motor disability. EAE mice showed abnormal signal intensities adjacent to the lateral ventricles. Arrows indicate focal lesions on T2-weighted imaging. In contrast, lesion volumes were significantly reduced in KD-fed EAE mice (N = 4–8). (B) In contrast to the observed hippocampal volume loss in EAE mice at 30 days post immunization, neither naïve mice nor KD-fed EAE mice showed changes in hippocampal volume.</p>", "links"=>[], "tags"=>["changes", "eae", "mice", "kd"], "article_id"=>314699, "categories"=>["Neuroscience", "Mental Health", "Immunology"], "users"=>["Do Young Kim", "Junwei Hao", "Ruolan Liu", "Gregory Turner", "Fu-Dong Shi", "Jong M. Rho"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0035476.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_brain_changes_in_EAE_mice_with_and_without_KD_treatment_/314699", "title"=>"Structural brain changes in EAE mice with and without KD treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 05:41:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/644309"], "description"=>"<p>Comparison of the frequencies of (A) CD4<sup>+</sup>/CD8<sup>+</sup> T cells, (B) CD11b<sup>+</sup>/CD45<sup>+</sup> cells on gated lymphocyte populations in EAE with and without KD treatment. (C) Frequencies of CD4<sup>+</sup>CD25<sup>+</sup> Foxp3<sup>+</sup> regulatory T cells. The KD suppressed CNS cellular infiltration and myelin-reactive T cell responses in EAE. Groups of mice (receiving standard diet [SD] and KD diet) were immunized with MOG/CFA/PT, and sacrificed between day 16–19 p.i. Lymph node, spleen and CNS cells were isolated. (D) Lymphoid (LN) or CNS cells were re-stimulated with MOG<sub>35–55</sub> peptide overnight and IFN-γ- and IL-17-expressing CD4<sup>+</sup> T cells were measured by intracellular staining. The number seen in the box indicated the average percentage of individual markers on the cells. (E) Summary data of the percentage of individual marker in the cells (LN <i>vs.</i> CNS) in SD-treated EAE mice or KD-treated EAE mice. Data are representative of two independent experiments (n = 4–8/group). P values, Student’s <i>t</i>-test; *, <i>p</i><0.05. (E) Visualization and quantification of brain inflammation by <i>in vivo</i> bioluminescence imaging. This is achieved by imaging reactive oxygen species (ROS) levels in the brain. Bioluminescent images in live mice were captured during a 1 min acquisition time using the Xenogen IVIS system at several time points after injection of 27 mg/kg dihydroethidium. Representative images of ROS seen in the left panel were captured in naïve mice and EAE mice with and without KD treatment. All experiments were conducted on groups of mice (n = 4–8) between days 14–19 p.i. Data are representative of two independent experiments (mean and SEM). P values, one way ANOVA; **, <i>p</i><0.01; ***, <i>p</i><0.001.</p>", "links"=>[], "tags"=>["kd", "ameliorates", "eae-mediated", "cns-inflammation", "oxidative"], "article_id"=>314795, "categories"=>["Neuroscience", "Mental Health", "Immunology"], "users"=>["Do Young Kim", "Junwei Hao", "Ruolan Liu", "Gregory Turner", "Fu-Dong Shi", "Jong M. Rho"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0035476.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_KD_ameliorates_EAE_mediated_CNS_inflammation_and_oxidative_stress_/314795", "title"=>"The KD ameliorates EAE-mediated CNS-inflammation and oxidative stress.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 05:41:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/644417"], "description"=>"<p>Lymph node and CNS homogenates were prepared from mice in the indicated groups at day 15 p.i. Cytokine concentrations were measured by a Multi-Analyte ELISArray Kit (SA Biosciences, MD). Unit: pg/ml; n = 4/group. P values, student’s <i>t</i>-test or Wilcoxon test;</p>**<p>, <i>p</i><0.01;</p>*<p>, <i>p</i><0.05.</p>", "links"=>[], "tags"=>["mediators", "assayed", "eae"], "article_id"=>314908, "categories"=>["Neuroscience", "Mental Health", "Immunology"], "users"=>["Do Young Kim", "Junwei Hao", "Ruolan Liu", "Gregory Turner", "Fu-Dong Shi", "Jong M. Rho"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0035476.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inflammatory_mediators_assayed_in_EAE_mice_/314908", "title"=>"Inflammatory mediators assayed in EAE mice.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-20 05:42:35"}

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Relative Metric

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