Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism

Abstract

The BTBR T+tf/J inbred mouse strain displays a variety of persistent phenotypic alterations similar to those exhibited in autism spectrum disorders (ASDs). The unique genetic background of the BTBR strain is thought to underlie its lack of reciprocal social interactions, elevated repetitive self-directed grooming, and restricted exploratory behaviors. In order to clarify the existence, range, and mechanisms of abnormal repetitive behaviors within BTBR mice, we performed detailed analyses of the microstructure of self-grooming patterns and noted increased overall grooming, higher percentages of interruptions in grooming bouts and a concomitant decrease in the proportion of incorrect sequence transitions compared to C57BL/6J inbred mice. Analyses of active phase home-cage behavior also revealed an increase in stereotypic bar-biting behavior in the BTBR strain relative to B6 mice. Finally, in a novel object investigation task, the BTBR mice exhibited greater baseline preference for specific unfamiliar objects as well as more patterned sequences of sequential investigations of those items. These results suggest that the repetitive, stereotyped behavior patterns of BTBR mice are relatively pervasive and reflect both motor and cognitive mechanisms. Furthermore, other pre-clinical mouse models of ASDs may benefit from these more detailed analyses of stereotypic behavior.

Figure 1

Analysis chamber for high quality video tape collection and scoring of self-grooming microstructure.

Figure 2

BTBR mouse in a standard mouse cage with four novel objects for the repetitive novel object contact task. The micro isolator lid has been removed for the photograph.

Figure 3

In the self-grooming analysis, BTBR mice displayed increased frequencies of all grooming subtypes (Fig. 3a upper panel) and increased duration of head wash, body groom, leg licking, and tail/genital grooming relative to B6 mice (Fig. 3a lower panel). B6 and BTBR mice showed comparable grooming bouts, and showed no significant difference in the number of interrupted bouts (Fig. 3b left panel). BTBR mice showed increased correct and incorrect transitions in grooming sub-types (Fig. 3b right panel). BTBR mice showed an increased proportion if bouts that were interrupted, and a decrease in the proportion of transitions that were incorrect (Fig. 3c) N=12/ group, * p<0.05, ** p<0.01, *** p<0.001.

Figure 4

Significantly increased prevalence of stereotypic bar-biting in BTBR mice across the first four hours of the dark phase (Fig. 4a). BTBR mice also showed a higher average prevalence of bar-biting during all 24, 10 minute scans during this period (Fig. 4b). N=12/group, * p<0.05.

Figure 5

BTBR and B6 mice showed comparable total numbers of visits to the novel objects (Fig. 5a). BTBR and B6 mice showed significantly different proportions of visits to each of the four novel objects (Fig. 5b). When toy preferences were ranked and ordered for each subject, then averaged across the strain and compared, it was revealed that BTBR mice show a more inequitable preference for certain objects compared to C57BL/6J mice (Fig. 5c). BTBR mice showed increased numbers of identical visits to the same order of three objects and four objects in sequence (Fig. 5d). N=10/group, * p<0.05, ** p<0.01. *** p<0.001.