Cognitive Deficits in Transgenic and Knock-in HTT Mice Parallel those in Huntington's Disease

Abstract

Background: Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline. Objective: The BACHD and zQ175 mouse models present a more slowly progressing disease phenotype in both motor and cognitive domains, and might therefore offer a better opportunity to measure cognitive decline over a longer timeframe; such models could be useful in screening therapeutic compounds. In order to better define the cognitive impairments evident in BACHD and zQ175 HD mice, both were tested in an instrumental touchscreen visual discrimination assay designed to assess discrimination learning and cognitive flexibility. Methods: BACHD and zQ175 mice, as well as their WT controls were tested for their ability to discriminate two complex visual stimuli. Following this discrimination phase, the reinforcement contingencies were reversed and the previously incorrect stimulus became the correct stimulus. In a final, third phase of testing, two novel stimuli were introduced and mice were required to undergo a second round of discrimination testing with these stimuli. Results: Our results show that learning during the discrimination phase was similar between the WT and BACHD mice. In contrast, the zQ175 at 26 weeks of age showed decreased accuracy over the last 10 days of discrimination, compared to WT controls. During subsequent reversal and novel stimuli phases, both BACHD and zQ175 mice exhibited significant deficits compared to WT controls. Conclusions: Our results suggest that the BACHD, and for the first time, zQ175 HD models exhibit cognitive inflexibility and psychomotor slowing, a phenotype that is consistent with cognitive symptoms described in HD patients.

Dysfunctional striatal dopamine signaling in Huntington's disease

“…Interestingly, increased neural noise in the striatum due to dysfunctional dopamine and glutamate signaling has been suggested to contribute to behavioral inflexibility, a deficit in the ability to switch strategies during learning (Hong & Rebec, ). This behavior is impaired in many mouse models of HD and in HD patients (Abada, Nguyen, Ellenbroek, & Schreiber, ; Brooks, Higgs, Jones, & Dunnett, ; Farrar et al, ; Glynn, Reim, Brose, & Morton, ; Josiassen, Curry, & Mancall, ; Van Raamsdonk et al, ). Motor and cognitive function are impaired by diminished signal‐to‐noise ratios in forebrain neurons (Kiyatkin & Rebec, ).…”

Impaired Performance of the Q175 Mouse Model of Huntington’s Disease in the Touch Screen Paired Associates Learning Task

“…This deficit may be explained by impaired proactive selective stopping, a process that involves activation of striatal, pallidal and frontal areas in humans, which is disturbed in HD patients (Majid et al, 2013 ). Similar deficit has not been reported during instrumental pretraining of zQ175 and R6/2 HD mice for the pairwise discrimination touch screen task, likely because the “Punish incorrect” step was not used (Morton et al, 2006 ; Farrar et al, 2014 ; Curtin et al, 2015 ). Acquisition of the simple nose poke response (akin to “Must Touch” pretraining stage used here) was impaired slightly in 53-week and 74-week old heterozygous zQ175 mice and nearly completely abrogated in homozygous mutants (Oakeshott et al, 2011 ).…”

“…On the one hand, protracted execution of FR task (Figures 8A,B ) and longer inter-touch intervals during both FR and PR schedules (Figures 8C , 9D ) were in line with decelerated performance of similar mutants in the PAL task (Figure 6 ). Psychomotor slowing in zQ175 mice was also noted in touch screen visual discrimination task (Farrar et al, 2014 ), so these data collectively demonstrate that Q175 mouse lines can be used for modelling HD-related bradykinesia (Thompson et al, 1988 ; Sánchez-Pernaute et al, 2000 ). On the other hand, indices related to the motivation, such as breakpoint, the rate of empty food magazine visits, or reward collection latency, were similar between genotypes (Figures 8I , 9A ), despite an earlier study of zQ175 mice, which utilised a lever-equipped apparatus, revealed lower breakpoints in 30-week old mutants (Covey et al, 2016 ).…”

“…Impaired ability to discriminate between two visual images in touch screen chambers had been noted in 26-week old but, surprisingly, not in 48-week old zQ175 mice (Farrar et al, 2014 ; Curtin et al, 2015 ). In R6/2 mice, age- and CAG repeat number-dependent impairments in pairwise visual discrimination have been shown (Morton et al, 2006 ; Glynn et al, 2016 ).…”

“…Touch screen-based approach has a high translational value as unlike some more forceful techniques to assess cognitive functions in rodents, it is based on interactions with a touch-sensitive screen prompted by visual stimuli and nutritional rewards for correct responses (Bussey et al, 2012 ; Hvoslef-Eide et al, 2016 ). Q175 mice, as well as other HD mouse models, such as R6/2 and BACHD, were recently tested in touch screen chambers and found to exhibit age-dependent deficits in the acquisition of pairwise visual discrimination skills and in the reversal of visual discrimination learning (Morton et al, 2006 ; Farrar et al, 2014 ; Skillings et al, 2014 ; Curtin et al, 2015 ; Glynn et al, 2016 ). From the instrumental point of view, the touch screen-based setting is analogous to the one used for clinical assessment of cognitive impairment in humans, e.g., by the Cambridge Neuropsychological Test Automated Battery (CANTAB; Nithianantharajah and Grant, 2013 ).…”