Abstract
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.
Highlights
Motor dysfunctions are core features of Huntington’s disease (HD) [1, 2], in the mid and later stages of the disease
During initial training in the nose poke response, at the first 6-month time point, no significant differences in performance were demonstrated between wild type and HdhQ111/+ animals (Fig 3: Genotype; F1,12 = 0.51, p = n.s.)
Longitudinal operant testing of HdhQ111/+ animals revealed cognitive and behavioural deficits in comparison to wild type animals in fixed ratio (FR), progressive ratio (PR), 5-choice serial reaction time task (5-CSRTT) and serial implicit learning task (SILT), these deficits were not demonstrated to be progressive over time
Summary
Motor dysfunctions are core features of Huntington’s disease (HD) [1, 2], in the mid and later stages of the disease. Cognitive and behavioural changes including; lack of motivation, apathy, anxiety and reduced ability to switch tasks, have been demonstrated in HD patients, often prior to the presentation of profound motor symptoms [3,4,5,6,7,8,9]. A range of knock-in mouse models of HD, have demonstrated cognitive and behavioural changes, these include specific deficits in; motivation, attention, extra dimensional set-shifting, working memory and reversal learning [13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Cognitive and behavioural changes are a core early symptom of HD, that are present in many of the HD mouse lines. In order to assess whether a mouse model of HD has good face and predictive validity in terms of recapitulating the symptoms of HD, a longitudinal characterisation of the development of any associated cognitive or behavioural changes is necessary
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