An Automated Home-Cage System to Assess Learning and Performance of a Skilled Motor Task in a Mouse Model of Huntington’s Disease

Apparatus for home-cage assessment of skilled motor learning. A, A small opening on one side of the home-cage allows 24-h access to a chamber containing a metal lever and water spout. Microchipped animals are identified by an RFID reader on entrance into the chamber, allowing for individual tracking and assessment of group-housed animals. B, The lever is restricted in its horizontal movement by two metal posts, and held in starting position by a small counterweight. In the first phase of testing, the mouse must pull the lever backwards 12° from its starting position to receive a water drop. C, A top-down view of the lever position range. In the second phase of testing, the mouse must first pull the lever back to the center (red line), and then hold it within a central goal position range (shaded area) to receive a water drop. The length of time the lever must be held for changes dynamically based on the individual animal’s success rate.

Acquisition and performance of lever-pull task in phase 1. A, Number of animals to reach the performance criteria of 200 trials performed in phase 1. An overall lower proportion of YAC128 animals acquired the task as assessed by this cutoff. B, Average weight over the course of testing as a percentage of baseline. Although six-month-old animals remained at their baseline weight, two-month-old WT and YAC128 animals and four-month-old YAC128 animals gained weight over 14 d in the lever-cage (asterisks indicate significant increase as compared to baseline weight). C, No significant differences between WT and YAC128 were seen in the number of trials performed per day; however, animals in both genotypes performed less daily trials with increasing age. D, Time spent in the chamber per day was also not significantly different between genotypes; however, both WT and YAC128 animals were much higher on this measure at two months old than at other ages. E, F, Sample lever traces from two four-month-old animals (WT and YAC128, respectively) in phase 1. Each line represents one trial. Numbers of animals (WT/YAC128) used for weight, trial frequency, and time in chamber analysis are n = 17/13 at two months old, n = 14/16 at four months old, and n = 18/12 at six months old. All data are presented as mean ± SEM. ns = not significant; *p < 0.5; **p < 0.01; ***p < 0.001; ****p < 0.0001.

Distribution of trials throughout the light/dark cycle. A, Raster plots show the distribution of trials through the day for representative four-month-old WT and YAC128 animals on the fifth day of testing (each line represents one trial). B, The average percentage of all trials performed during the dark phase of testing was significantly higher in WT than in YAC128 mice, suggesting a disruption of normal circadian rhythms in these animals. C-E, Trials were split into 1-h bins for each animal, and the percentage of trials occurring in each bin was calculated and graphed for two-, four-, and six-month-old age groups. A significant interaction between genotype and the hour of day was observed for four- and six-month-old, but not two-month-old, animals. Numbers of animals (WT/YAC128) used for analysis are n = 17/13 at two months old, n = 14/16 at four months old, and n = 18/12 at six months old. All data are presented as mean ± SEM. ns = not significant; *p < 0.5; **p < 0.01; ***p < 0.001; ****p < 0.0001.

Performance of the task during phase 2. A-C, Progression to the maximum required hold duration over the first 500 trials of phase 2 is plotted for two-, four-, and six-month-old age groups. At the end of each 25-trial bin, success rate was calculated over these trials to determine whether the animal met the threshold for their required hold duration to increase. Data are plotted as the required lever hold duration reached at the end of each 25-trial bin. YAC128 mice at two months old, but not other ages, had a significantly slower progression over the first 500 trials as compared to WT controls. D. The majority of animals reached the maximum hold duration within one week, and no significant differences were observed between genotypes. E, Success rate of animals over the first 500 trials of phase 2 is plotted for each age group. Two-month-old YAC128 animals had the lowest average success rate over this period, although no significant main or interaction effects were found. Numbers of animals (WT/YAC128) used for analysis are n = 15/12 at two months old, n = 11/14 at four months old, and n = 16/12 at six months old. All data are presented as mean ± SEM. ns = not significant; *p < 0.5; **p < 0.01; ***p < 0.001; ****p < 0.0001.