Use of a force-sensing automated open field apparatus in a longitudinal study of multiple behavioral deficits in CAG140 Huntington's disease model mice

Abstract

Behavioral testing of mouse models of Huntington's disease (HD) is a key component of preclinical assessment for potential pharmacological intervention. An open field with a force plate floor was used to quantify numerous spontaneous behaviors in a slowly progressing model of HD. CAG140 (+/+, +/-, -/-) male and female mice were compared in a longitudinal study from 6 to 65 weeks of age. Distance traveled, wall rears, wall rear duration, number of low mobility bouts, in-place movements, number of high velocity runs, and gait parameters (stride rate, stride length, and velocity) were extracted from the ground reaction forces recorded in 20-min actometer sessions. Beginning at 11 weeks, HD mice (both +/- and +/+) were consistently hypoactive throughout testing. Robust hypoactivity at 39 weeks of age was not accompanied by gait disturbances. By 52 and 65 weeks of age the duration of wall rears increased and in-place tremor-like movements emerged at 65 weeks of age in the +/+, but not in the +/- HD mice. Taken together, these results suggest that hypoactivity preceding frank motor dysfunction is a characteristic of CAG140 mice that may correspond to low motivation to move seen clinically in the premanifest/prediagnostic stage in human HD. The results also show that the force plate method provides a means for tracking the progression of behavioral dysfunction in HD mice beyond the stage when locomotion is lost while enabling quantification of tremor-like and similar in-place behaviors without a change in instrumentation. Use of force plate actometry also minimizes testing-induced enrichment effects when batteries of different tests are carried out longitudinally.

Keywords: CAG140 knock-in mouse; Distance traveled; Force plate; Gait; Huntington’s disease; Power spectra.

Figure 1

Data for one representative mouse illustrating the kind of information that was used to extract selected gait parameters from continuously recorded ground reaction forces. This specific individual was a −/− female aged 39 weeks at the time of data collection. Fig. 1A1, Fig. 1A2, and Fig.1A3 are for a 7.00-s data segment that depicts ground reaction force, x coordinate, and y coordinate, respectively. Fig.1B1, Fig.1B2, and Fig.1B3 correspond to A1, A2, and A3, respectively but, with an expanded time scale that encompasses one run that lasted 1.38 s and comprised 9 half strides or 4.5 full strides. Fig.1C is the movement trajectory plot for the 1.38-s run. The run began at x-y coordinates 150,-171 and ended at x-y coordinates −156,−170 (i.e., the mouse moved from right to left and stayed near the front wall). During a run, diagonally opposite feet strike the load plate together (stance phase) while the other two feet are in the air (swing phase), and so on.

Figure 2

Body weight for female (A) and male (B) CAG140 mice as a function of age and HD-related genotype. ♀,+/+: n=9; ♀,+/−: n=19; ♀,−/−: n=8; ♂,+/+: n=9; ♂,+/−: n=17; ♂,−/−: n=11. Error bars are SEMs.

Figure 3

Distance traveled (A) and vertical force variability (B) for the six sessions across the 65 weeks of force plate actometer measurements shown in 4-min time blocks of the 20-min recording sessions. +/+: n=18; +/−: n=36; −/−: n=19. Error bars are SEMs. Asterisks indicate significant differences in the first time block between −/− and +/+ or between −/− and +/− mice (*p<0.05; **p<0.01). In B, # indicates a significant difference between +/+ and −/− mice across the five time blocks.

Figure 4

Group average power spectra of ground reaction forces of low mobility bouts (periods of non-locomotion) for +/+ (n=18) and −/− (n=19) mice calculated for the recording session run when the mice were 65 week old. On the average −/− mice had 92.8 low mobility bouts in the 20-min session, while the +/+ mice averaged 111.3 bouts.

Figure 5

Group mean number of wall rears (A) and group means of the median rear durations (B) as a function of age and genotype. Error bars are SEMs. Asterisks denote significant differences between +/+ or +/− from −/− mice based on post hoc univariate F tests (*p<0.05). Numbers of mice per group are the same as those shown in the caption for Fig. 3.

Figure 6

Low mobility bouts as a function of age and genotype. The asterisks indicate significant (*p<0.05) post hoc contrasts between the −/− group and groups +/− and +/+ combined. Error bars are SEMs.

Figure 7

Mean number of long, straight, fast runs as a function of genotype and age. Asterisks identify significant (p<.05) differences between wild type and mutant mice. Error bars are SEMs.

Figure 8

Group average data for velocity (A), stride length (B), and stride rate (C) quantified for force plate data when the mice were 39 weeks old. Error bars are SEMs. ANOVA did not detect any significant effects of genetic status.