Social approach and repetitive behavior in eleven inbred mouse strains

Abstract

Core symptoms of autism include deficits in social interaction, impaired communication, and restricted, repetitive behaviors. The repetitive behavior domain encompasses abnormal motoric stereotypy, an inflexible insistence on sameness, and resistance to change. In recent years, many genetic mouse models of autism and related disorders have been developed, based on candidate genes for disease susceptibility. The present studies are part of an ongoing initiative to develop appropriate behavioral tasks for the evaluation of mouse models relevant to autism. We have previously reported profiles for sociability, preference for social novelty, and resistance to changes in a learned pattern of behavior, as well as other functional domains, for 10 inbred mouse strains of divergent genetic backgrounds. The present studies extend this multi-component behavioral characterization to several additional strains: C58/J, NOD/LtJ, NZB/B1NJ, PL/J, SJL/J, SWR/J, and the wild-derived PERA/EiJ. C58/J, NOD/LtJ, NZB/B1NJ, SJL/J, and PERA/EiJ demonstrated low sociability, measured by time spent in proximity to an unfamiliar conspecific, with 30-60% of mice from these strains showing social avoidance. In the Morris water maze, NZB/B1NJ had a persistent bias for the quadrant where the hidden platform was located during acquisition, even after 9 days of reversal training. A particularly interesting profile was found for C58/J, which had low social preference, poor performance in the T-maze, and overt motoric stereotypy. Overall, this set of tasks and observational methods provides a strategy for evaluating novel mouse models in behavioral domains relevant to the autism phenotype.

Figure 1. Exploration in a novel open field in 11 inbred mouse strains

Activity was assessed by a 5-min trial in an open field chamber. Low time in the center (E), as observed in DBA/2J (DBA) and NZB/B1NJ (NZB), may reflect anxiety-like behavior in these strains. Data shown are mean percent + SEM. AKR/J (AKR), C57BL/6J (C57BL), C58/J (C58), FVB/NJ (FVB), NOD/LtJ (NOD), PERA/EiJ (PERA), PL/J (PL), SJL/J (SJL), SWR/J (SWR).

Figure 2. Elevated plus maze performance in 10 inbred mouse strains

Mice from the AKR and NZB strains had very low percent time in the open arms (A), an index of anxiety-like behavior. Data shown are mean percent + SEM for each strain during one 5-min test.

Figure 3. Time spent in each side during the tests for (A) sociability and (B) preference for social novelty

Data shown are mean + SEM for each strain. 2 separate sets of DBA/2J mice (DBA and DBA (2)) were tested. No preference for the social stimuli (stranger 1 side) was observed in 6 of the 11 strains, including wild-derived PERA/EiJ (A). 1 mouse from the PERA/EiJ strain died, leaving 10 mice in the group. * p<0.05, within-strain comparison, stranger 1 side different from empty cage side (A) or stranger 2 side (B).

Figure 4. Time spent sniffing each wire cage during the tests for (A) sociability and (B) preference for social novelty

All strains demonstrated a significant preference for the wire cage containing an unfamiliar mouse (stranger 1) versus an empty cage (A). Data shown are mean + SEM for each strain. * p<0.05, within-strain comparison, stranger 1 side different from empty cage side (A) or stranger 2 side (B).

Figure 5. Entries into each side during the tests for (A) sociability and (B) preference for social novelty

Data shown are mean + SEM for each strain. * p<0.05, within-strain comparison, stranger 1 side different from empty cage side (A) or stranger 2 side (B).

Figure 6. Time spent in each side during the test for sociability in mice with (A) positive difference scores or (B) negative difference scores

Data were taken from the 6 strains which did not have significant social approach, as shown in Figure 3A. Difference scores were calculated as time spent in side containing stranger 1 minus time spent in the empty cage side. Data shown are mean + SEM. N values indicate number of mice from each group, followed by percent of each group, having either positive or negative difference scores. For all of these strains, only 1 or 2 subjects had difference scores falling between 30 and -30 sec (indicating a 30 sec or less difference between time spent in either side). The exception was the first set of DBA/2J mice, which included 6 subjects with difference scores between 30 and -30 sec (inclusive). * p<0.05, within-strain comparison, stranger 1 side different from empty cage side.

Figure 7. Acquisition and reversal in the Morris water maze task for 3 inbred strains

Mice were given up to 9 days to reach criterion for learning, set at a group average latency of 15 sec or less to find the hidden platform. The location of the hidden platform was changed to a new quadrant for the reversal task. Only NOD/LtJ (A) met the learning criterion during acquisition, while both NOD/LtJ and PERA/EiJ (C) met criterion during reversal. Data shown are mean (± SEM) of 4 trials per day. 1 mouse from the NOD/LtJ strain died during the reversal phase, leaving a total of 16 subjects in this group.

Figure 8. Selective quadrant search on the Morris water maze

Each mouse was given a 1-min probe trial with the escape platform removed. Target (black bars) indicates the quadrant where the platform had been located during training trials. NZB/B1NJ was the only strain to demonstrate a persistent bias for quadrant 1 following reversal (B). * p<0.05, within-strain repeated measures ANOVA, significant main effect of quadrant.

Figure 9. T-maze learning in 4 inbred strains

Data are mean (± SEM) number of correct trials out of 10 trials per day. 5 correct trials out of 10 would be expected by chance. C58/J (A) showed poor acquisition, with only 5 mice reaching criterion for learning. These 5 mice received further testing for reversal learning. PL/J (B) and SWR/J (D) also showed poor acquisition, precluding further testing.