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.

Antidepressant Effects of Probucol on Early-Symptomatic YAC128 Transgenic Mice for Huntington’s Disease

“…Indeed, we have also observed a decrease in the volume of the total hippocampus as well as of its DG subregion in 6-month-old YAC128 mice. Our results are in accordance with studies in diverse HD transgenic mouse models that have documented reduced cortical, globus pallidus, and hippocampal volumes [ 80 , 86 – 89 ]. Moreover, in humans, Rosas et al observed atrophy in several brain regions, including the hippocampus [ 85 ].…”

Alzheimer’s associated amyloid and tau deposition co-localizes with a homeostatic myelin repair pathway in two mouse models of post-stroke mixed dementia

“…Enlargement of the lateral ventricles and cortical shrinkage appear in both human [ 5 , 58 ] and animal models [ 1 , 34 , 73 , 112 ] of dementia. Atrophy of the brain likely results from progressive degeneration of neurons, and the loss of these neurons is a likely contributor to the manifestation of dementia.…”

Overview of Huntington's Disease Models: Neuropathological, Molecular, and Behavioral Differences

“…For example, in homozygous Q140 mice, stereological techniques revealed no significant atrophy of cortex and only mild volumetric changes in striatum at 12 months of age (Deng, Wong, Wan, & Reiner, ; Lerner, Trejo Martinez Ldel, Zhu, Chesselet, & Hickey, ). In Q150 mice, a recent analysis using structural MRI techniques demonstrated that progressive cortical and striatal volumetric decline can be detected from 3.5 months of age (Rattray et al., ). Accordingly, in Q175 mice the most prominent changes revealed by stereological techniques were detected at 12 months of age (Smith et al., ), but with MRI, the alterations in cortex and striatum were found at much earlier ages (4 months of age), and although sustained up to 12 months, interestingly did not worsen (Heikkinen et al., ; Peng et al., ).…”

“…Similar to full‐length mouse models, KI models display a late‐onset motor phenotype directly related to the number of CAG repeats. For example, whereas the Q111 mouse shows few, if any, motor alterations (Menalled et al., ), homozygous Q140 mice display mild motor abnormalities in parameters such as distance in running wheel assessment at 3.5 months of age, but no changes are observed in latency to fall in rotarod or stride length (Stefanko et al., ), whereas Q150 mice show reduced latency to fall in rotarod at 10 months of age and reduced locomotor activity at 17, but reduced grip strength was found much earlier at 3 months (Rattray et al., ). Motor phenotype onset is more evident in Q175 mice: altered coordination in rotarod occurs at 6 to 7 months in both heterozygous and homozygous animals (Menalled et al., ; Smith et al., ; Peng et al., 2014).…”

“…In homozygous Q150s, several alterations were found in spatial learning in the MWM test. For example, KI mice swam slower and traversed longer distances to reach the platform, and during the training phase, the improvement in latency and distance traveled was significantly lower in KI mice (Brooks, Higgs, Jones, & Dunnett, ); however, no deficits in reversal learning were found (Rattray et al., ). For Q175 mice, Menalled and colleagues (, 2012) reported that in general, homozygous mice display a more severe cognitive phenotype than heterozygous mice, but heterozygotes also have learning deficits.…”