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Coexistence of perseveration and apathy in the TDP-43 Q331K knock-in mouse model of ALS-FTD.

التفاصيل البيبلوغرافية
العنوان: Coexistence of perseveration and apathy in the TDP-43 Q331K knock-in mouse model of ALS-FTD.
المؤلفون: Kim E; Department of Psychiatry, Institute of Behavioral Science in Medicine, Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.; Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK., White MA; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Phillips BU; Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK., Lopez-Cruz L; Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.; School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, UK., Kim H; Department of Psychiatry, Institute of Behavioral Science in Medicine, Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.; Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.; Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea., Heath CJ; School of Life, Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, UK., Lee JE; Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea., Saksida LM; Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.; Molecular Medicine Research Laboratories, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.; The Brain and Mind Institute, Western University, London, ON, Canada., Sreedharan J; Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. jemeen.sreedharan@kcl.ac.uk., Bussey TJ; Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. tbussey@uwo.ca.; Molecular Medicine Research Laboratories, Robarts Research Institute & Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada. tbussey@uwo.ca.; The Brain and Mind Institute, Western University, London, ON, Canada. tbussey@uwo.ca.
المصدر: Translational psychiatry [Transl Psychiatry] 2020 Nov 04; Vol. 10 (1), pp. 377. Date of Electronic Publication: 2020 Nov 04.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: United States NLM ID: 101562664 Publication Model: Electronic Cited Medium: Internet ISSN: 2158-3188 (Electronic) Linking ISSN: 21583188 NLM ISO Abbreviation: Transl Psychiatry Subsets: MEDLINE
أسماء مطبوعة: Original Publication: New York, NY : Nature Pub. Group
مواضيع طبية MeSH: Amyotrophic Lateral Sclerosis*/genetics , Apathy* , Frontotemporal Dementia*/genetics, Aged ; Animals ; DNA-Binding Proteins/genetics ; Humans ; Male ; Mice ; Mutation
مستخلص: Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43 Q331K mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43 Q331K ) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43 Q331K mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43 Q331K mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43 Q331K mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43 Q331K mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43 Q331K knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD.
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معلومات مُعتمدة: SREEDHARAN/JAN13/943-795 United Kingdom MNDA_ Motor Neurone Disease Association; SREEDHARAN/APR16/849-791 United Kingdom MNDA_ Motor Neurone Disease Association; NC/N001451/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; HI14C2173 International Ministry of Health and Welfare (Ministry of Health, Welfare and Family Affairs); MR/K010611/1 United Kingdom MRC_ Medical Research Council
المشرفين على المادة: 0 (DNA-Binding Proteins)
0 (TARDBP protein, human)
0 (TDP-43 protein, mouse)
SCR Disease Name: Amyotrophic Lateral Sclerosis 2, Juvenile
تواريخ الأحداث: Date Created: 20201105 Date Completed: 20210518 Latest Revision: 20230322
رمز التحديث: 20230322
مُعرف محوري في PubMed: PMC7643138
DOI: 10.1038/s41398-020-01078-9
PMID: 33149110
قاعدة البيانات: MEDLINE
الوصف
تدمد:2158-3188
DOI:10.1038/s41398-020-01078-9