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Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington's Disease

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Title: Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington's Disease
Authors: Rattray, I
Smith, EJ
Crum, WR
Walker, TA
Gale, R
Bates, GP
Modo, M
Item Type: Journal Article
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.
Issue Date: 18-Jan-2017
Date of Acceptance: 3-Dec-2016
URI: http://hdl.handle.net/10044/1/48137
DOI: https://dx.doi.org/10.1371/journal.pone.0168556
ISSN: 1932-6203
Publisher: Public Library of Science
Journal / Book Title: PLOS ONE
Volume: 12
Issue: 1
Copyright Statement: © 2017 Rattray et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
KNOCK-IN MOUSE
TRANSGENIC MICE
ALZHEIMERS-DISEASE
FLUID REGISTRATION
MUTANT HUNTINGTIN
GENE-EXPRESSION
CAG REPEAT
PREMANIFEST
ABNORMALITIES
BIOMARKERS
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Open Access location: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168556
Article Number: ARTN e0168556
Appears in Collections:Division of Surgery
Division of Cancer



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