Huntington’s disease (HD) is characterised by motor symptoms which are often preceded by cognitive and behavioural changes, that can significantly contribute to disease burden for people living with HD. Numerous knock-in mouse models of HD are currently available for scientific research. However, before their use, they must be behaviourally characterised to determine their suitability in recapitulating the symptoms of the human condition. Thus, we sought to longitudinally characterise the nature, severity and time course of cognitive and behavioural changes observed in HdhQ111 heterozygous knock-in mice.To determine changes in cognition and behaviour an extensive battery of operant tests including: fixed ratio, progressive ratio, the five choice serial reaction time task and the serial implicit learning task, were applied longitudinally to HdhQ111 and wild type mice. The operant test battery was conducted at 6, 12 and 18 months of age. Significant deficits were observed in HdhQ111 animals in comparison to wild type animals in all operant tests indicating altered cognition (attentional and executive function) and motivation. However, the cognitive and behavioural deficits observed were not shown to be progressive over time in the longitudinal testing paradigm that was utilised. The results therefore demonstrate that the HdhQ111 mouse model of HD reflects some features of the cognitive and behavioural changes shown in the human condition of HD. Although, the cognitive and behavioural deficits demonstrated were not shown to be progressive over time.

Huntington’s disease (HD) is a genetically-determined neurodegenerative disease. Characterising neuropathology in mouse models of HD is commonly restricted to cross-sectional ex vivo analyses, beset by tissue fixation issues. In vivo longitudinal magnetic resonance imaging (MRI) allows for disease progression to be probed non-invasively. In the HdhQ150 mouse model of HD, in vivo MRI was employed at two time points, before and after the onset of motor signs, to assess brain macrostructure and white matter microstructure. Ex vivo MRI, immunohistochemistry, transmission electron microscopy and behavioural testing were also conducted. Global brain atrophy was found in HdhQ150 mice at both time points, with no neuropathological progression across time and a selective sparing of the cerebellum. In contrast, no white matter abnormalities were detected from the MRI images or electron microscopy images alike. The relationship between motor function and MR-based structural measurements was different for the HdhQ150 and wild-type mice, although there was no relationship between motor deficits and histopathology. Widespread neuropathology prior to symptom onset is consistent with patient studies, whereas the absence of white matter abnormalities conflicts with patient data. The myriad reasons for this inconsistency require further attention to improve the translatability from mouse models of disease.

HighlightsWe compared delayed matching and non-matching to position (DMTP and DNMTP) tasks in two different operant apparatus, the 9-hole operant apparatus configuration and the Skinner-like operant apparatus configuration.We determined that the DMTP and DNMTP operant tasks produce more efficient, robust and reliable results in the Skinner-like operant apparatus configuration.We therefore used the Skinner-like operant apparatus configuration to test DMTP and DNMTP tasks in the HdhQ111 mouse model of HD.We tested the DMTP and DNMTP tasks in the HdhQ111 knock-in mouse model of HD which revealed significant deficits in task acquisition and reversal learning in comparison to wildtype animals.

Huntington's disease (HD) is an incurable neurodegenerative disorder which causes a triad of motor, cognitive and psychiatric disturbances. Cognitive disruptions are a core feature of the disease, which significantly affect daily activities and quality of life, therefore cognitive training interventions present an exciting therapeutic intervention possibility for HD. We aimed to determine if specific cognitive training, in an operant task of attention, modifies the subsequent behavioural and neuropathological phenotype of the HdhQ111 mouse model of HD.Three testing groups comprising both HdhQ111 mice and wildtype controls were used. The first group received cognitive training in an operant task of attention at 4 months of age. The second group received cognitive training in a comparable non-attentional operant task at 4 months of age, and the third group were control animals that did not receive cognitive training. All groups were then tested in an operant task of attention at 12 months of age. Relative to naïve untrained mice, both wildtype and HdhQ111 mice that received cognitive training in the operant task of attention demonstrated an increased number of trials initiated, greater accuracy, and fewer ‘time out’ errors. A specific improvement in response time performance was observed in HdhQ111 mice, relative to naïve untrained HdhQ111 mice. Relative to the group that received comparable training in a non-attentional task, both wildtype and HdhQ111 mice that received attentional training demonstrated superior accuracy in the task and made fewer ‘time out’ errors. Despite significant behavioural change, in both wildtype and HdhQ111 mice that had received cognitive training, no significant changes in neuropathology were observed between any of the testing groups. These results demonstrate that attentional cognitive training implemented at a young age significantly improves attentional performance, at an older age, in both wildtype and HdhQ111 mice. Attentional cognitive training also improved motor performance in HdhQ111 mice, thus leading to the conclusion that cognitive training can improve disease symptoms in a mouse model of HD.

Background: Huntington’s disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms.Objective: Manifest HD is currently diagnosed upon the onset of motor symptoms, thus we sought to longitudinally characterise the progression and severity of motor signs in the HdhQ111 knock-in mouse model of HD, in heterozygous mice.Methods: An extensive battery of motor tests including: rotarod, inverted lid test, balance beam, spontaneous locomotor activity and gait analysis were applied longitudinally to a cohort of HdhQ111 heterozygous mice in order to progressively assess motor function.Results: A progressive failure to gain body weight was demonstrated from 11 months of age and motor problems in all measures of balance beam performance were shown in HdhQ111 heterozygous animals in comparison to wild type control animals from 9 months of age. A decreased latency to fall from the rotarod was demonstrated in HdhQ111 heterozygous animals in comparison to wild type animals, although this was not progressive with time. No genotype specific differences were demonstrated in any of the other motor tests included in the test battery.Conclusions: The HdhQ111 heterozygous mouse demonstrates a subtle and progressive motor phenotype that begins at 9 months of age. This mouse model represents an early disease stage and would be ideal for testing therapeutic strategies that require elongated lead-in times, such as viral gene therapies or striatal transplantation.