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

Abstract

Cognitive disturbances often predate characteristic motor dysfunction in individuals with Huntington’s disease (HD) and place an increasing burden on the HD patients and caregivers with the progression of the disorder. Therefore, application of maximally translational cognitive tests to animal models of HD is imperative for the development of treatments that could alleviate cognitive decline in human patients. Here, we examined the performance of the Q175 mouse knock-in model of HD in the touch screen version of the paired associates learning (PAL) task. We found that 10–11-month-old heterozygous Q175 mice had severely attenuated learning curve in the PAL task, which was conceptually similar to previously documented impaired performance of individuals with HD in the PAL task of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Besides high rate of errors in PAL task, Q175 mice exhibited considerably lower responding rate than age-matched wild-type (WT) animals. Our examination of effortful operant responding during fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in a separate cohort of similar age confirmed slower and unselective performance of mutant animals, as observed during PAL task, but suggested that motivation to work for nutritional reward in the touch screen setting was similar in Q175 and WT mice. We also demonstrated that pronounced sensorimotor disturbances in Q175 mice can be detected at early touch screen testing stages, (e.g., during “Punish Incorrect” phase of operant pretraining), so we propose that shorter test routines may be utilised for more expedient studies of treatments aimed at the rescue of HD-related phenotype.

Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

“…Cognitive deficits are a key clinical hallmark of HD, and impaired performance in tasks related to visual discrimination and cognitive flexibility are some of the earliest quantifiable changes observed in premanifest HD patients, occurring up to 20 years before predicted onset of manifest disease and in the absence of detectable motor phenotypes [119][120][121] . Impairments in learning and memory tasks have also been observed in zQ175 mice, but these assessments have been carried out only in older mice after development of striatal atrophy and other pathological hallmarks 17,[71][72][73][122][123][124][125] .…”

CK2 alpha prime and alpha-synuclein pathogenic functional interaction mediates synaptic dysregulation in Huntington’s disease

“…Cognitive dysfunction is often reported prior to overt motor symptoms in patients with HD (Stout et al 2012, Harrington et al 2012, Paulsen 2011), but it usually manifests after motor symptom onset in murine models of HD (Farrar et al 2014, Heikkinen et al 2012). Cognitive function in heterozygous zQ175 mice progressively decreases with age, beginning as early as 7 months with robust cognitive impairment at 10-12 months of age (Curtin et al 2015, Southwell et al 2016, Piiponniemi et al 2018). To assess whether cognitive behavior was altered as a function of CK2α’ in HD mice, we performed tests to evaluate associative learning (fear conditioning), spatial learning and memory (Barnes maze, BM), cognitive flexibility (BM reversal) and spatial working memory (Y radial arm maze) by comparing zQ175 and zQ175:CK2α’ (+/-) mice at 12 months of age.…”