title: Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington's Disease.
abstract: A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington's disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the "clinical horizon" of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments.
authors.affiliation: King's College London, Institute of Psychiatry, Department of Neuroscience, London, United Kingdom.|King's College London School of Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, United Kingdom.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rattray
authors.affiliation: King's College London, Institute of Psychiatry, Department of Neuroscience, London, United Kingdom.|King's College London School of Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, United Kingdom.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Smith
authors.affiliation: King's College London, Department of Neuroimaging, Institute of Psychiatry London, United Kingdom.
authors.forename: William R
authors.initials: WR
authors.lastname: Crum
authors.affiliation: King's College London School of Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, United Kingdom.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Walker
authors.affiliation: King's College London School of Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Gale
authors.affiliation: King's College London School of Medicine, Department of Medical and Molecular Genetics, Guy's Hospital, London, United Kingdom.
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.affiliation: King's College London, Institute of Psychiatry, Department of Neuroscience, London, United Kingdom.|University of Pittsburgh, Department of Radiology, McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States of America.
authors.forename: Michel
authors.identifier: http://orcid.org/0000-0003-4436-735X
authors.initials: M
authors.lastname: Modo
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology*; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000473:pathology*; D000071058:Huntingtin Protein / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D045442:Rotarod Performance Test; D015430:Weight Gain / Q000235:genetics
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein