The Alteration of Emotion Regulation Precedes the Deficits in Interval Timing in the BACHD Rat Model for Huntington Disease

Abstract

Huntington disease (HD) is an autosomal dominantly inherited, progressive neurodegenerative disorder which is accompanied by executive dysfunctions and emotional alteration. The aim of the present study was to assess the impact of emotion/stress on on-going highly demanding cognitive tasks, i.e., temporal processing, as a function of age in BACHD rats (a "full length" model of HD). Middle-aged (4-6 months) and old (10-12 months) rats were first trained on a 2 vs. 8-s temporal discrimination task, and then exposed to a series of bisection tests under normal and stressful (10 mild unpredictable foot-shocks) conditions. The animals were then trained on a peak interval task, in which reinforced fixed-interval (FI) 30-s trials were randomly intermixed with non-reinforced probe trials. After training, the effect of stress upon time perception was again assessed. Sensitivity to foot-shocks was also assessed independently. The results show effects of both age and genotype, with largely greater effects in old BACHD animals. The older BACHD animals had impaired learning in both tasks, but reached equivalent levels of performance as WT animals at the end of training in the temporal discrimination task, while remaining impaired in the peak interval task. Whereas sensitivity to foot-shock did not differ between BACHD and WT rats, delivery of foot-shocks during the test sessions had a disruptive impact on temporal behavior in WT animals, an effect which increased with age. In contrast, BACHD rats, independent of age, did not show any significant disruption under stress. In conclusion, BACHD rats showed a disruption in temporal learning in late symptomatic animals. Age-related modification in stress-induced impairment of temporal control of behavior was also observed, an effect which was greatly reduced in BACHD animals, thus confirming previous results suggesting reduced emotional reactivity in HD animals. The results suggest a staggered onset in cognitive and emotional alterations in HD, with emotional alteration being the earliest, possibly related to different time courses of degeneration in cortico-striatal and amygdala circuits.

Keywords: Huntington disease; interval timing; peak interval; stress; temporal bisection.

FIGURE 1

Temporal discrimination learning. Mean percentage (±SEM) of correct responses during sessions with 50% (top) and 100% (bottom) free-choice for middle-aged (left, filled symbols) and old (right, empty symbols) wild-type (blue) and BACHD (red) rats.

FIGURE 2

Response latencies (ms) for correct responses during temporal discrimination learning. Legends are identical to the ones in Figure 1.

FIGURE 3

Psychometric functions for the temporal bisection tests: Mean (±SEM) proportion of long responses as a function of the stimulus duration (s) in logarithmic scale in middle-aged and old wild-type (top) and in middle-aged and old BACHD rats (bottom) during the baseline bisection session (round symbols, colored curves), the bisection session with unpredictable foot-shocks (triangles, black curves) and 24 h post-shock session (squares, colored curves). Inserts represent individual curves for the session with electric foot-shocks.

FIGURE 4

Temporal parameters extracted from the fitted different bisection functions (baseline, session with shocks, 24 h post-shock) for the middle-aged and old wild-type (Blue) and the middle-aged and old BACHD (red) rats: PSE (A) and gamma (B). Error bars depict the SEM. Asterisks denote significant differences between sessions within a group (p < 0.05).

FIGURE 5

Group mean lever presses per second as a function of elapsed trial time on PI trials for wild-type (blue line) and BACHD (red line) rats. The top and bottom rows depict data from middle-aged and old rats, respectively, on each of the 7 two-session blocks (in columns). Response rates are plotted in 2-s bins. The trained FI criterion duration is denoted by a vertical gray dashed line at 30 s.

FIGURE 6

Temporal discrimination acquisition during the PI training phase. Group mean (±SEM) temporal discrimination index across session blocks for middle-aged (left) and old (right) rats for each genotype.

FIGURE 7

Group mean ratios of response rate in the second low-rate state (r₃) over response rate in the high-rate state (r₂) for middle-aged (left) and old (right) rats across session blocks for each genotype. Error bars depict the SEM.

FIGURE 8

Group mean start times (s) for middle-aged (left) and old (right) rats across session blocks for each genotype. Error bars depict the SEM.

FIGURE 9

Group mean interquartile ranges of stop time for middle-aged (left) and old (right) rats across session blocks for each genotype. Error bars depict the SEM.

FIGURE 10

Group mean proportion of PI trials with at least one lever press response during the shock test (Session 20) across ages and genotypes. Error bars depict the SEM. Asterisks denote significant differences between groups (p < 0.05).

FIGURE 11

Reactivity threshold to electric foot-shocks in middle-aged and old rats. Error bars depict the SEM. Asterisks denote significant differences between groups (p < 0.05).