Other – Circadian function
Neurodegenerative diseases are marked by psychiatric and motor problems are often accompanied by deficits in sleep and circadian function. As expected, deficits in sleep-wake patterns have profound consequences in many physiological functions. In Huntington’s Disease patients (HD), for examples, abnormal sleep patterns correlate with symptom severity, specifically in depression and cognitive dysfunction, and in caudate atrophy [4,5,6]. We studied the behavior of the BAC HD model [7,8] using an 24/7 automated home-cage system and custom-built computer vision assessment of behavior, PhenoCube™. Using this system we could, in just 6 days, measure a significant lengthening of the circadian period in the mutants. The results reinforce previous findings in the R6/2 mouse and in a transgenic rat model of HD [2,3], indicating that circadian dysfunction is a fundamental feature of HD. These results also provide the validation of PhenoCube™ as a system for the fast assessment of circadian function.
Mutant mice carried the full-length human mutant huntingtin, with 97 glutamine repeats under the control of endogenous htt regulatory machinery on a bacterial artificial chromosome (BAC). All mice tested here (32 BAC female mice and 32 female WT controls) were generated on an FVB/n x C57Bl6 F1, created by crossing BAC hemizygous FVB/n male animals with WT C57Bl6 female animals. The congenic line used for these breedings, originally sourced from the laboratory of X. William Yang at the UCLA David Geffen School of Medicine, Los Angeles, is maintained by crossing hemizygous male BAC mice with FVB/n female animals. Mice were implanted with RFID electronic chips (DataMars, OH) for identification. The animals housed in OptiRAT® cages (Animal Care Systems, CO – groups of 8 animals of the same genotype) for several months prior to the experiment, with free access to water in 4 gated corners and to standard 5001 lab chow except as described. Experiments were conducted using eight modified IntelliCage units (IC, New Behavior AG), each with a camera mounted on top of the cage for computer vision analysis. The cages were maintained with constant dim red light (7 lux using a photographic bandpass filter (LDP LLC, NJ) that eliminates long wavelength light frequencies not visible to mice). Visits to the corners are monitored through the RFID chips.
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Figure 2. Periodogram and power analysis of visit frequency shown in figure 1. (A) The bar above the actograms shows the continuous red light regimen for a 24h cycle. Actograms depict daily activity of representative WT and BAC mice. (B) Spectral analyses of Chi-square periodogram indicating the period and amplitude for each actogram in A. (C) Bar graphs showing the average period and amplitude (±SEM) for WT and BAC mice under constant red light; **p<0.01.
BAC HD mice, showed a highly significant reduction in overall activity in the BAC TG mice, t(61) = 11.3, p < 0.001, while also indicating a pronounced shift in the daily activity peaks (Figure 1). This shift in phase was confirmed by chi-square periodogram for the number of corner entries, revealing that BAC mice had both a longer period and smaller rhythm amplitude than did WT mice, smaller t(60)= 2.82, ps < 0.01, with an average difference in period of 1 h 18 min (see Figure 2).
