Working memory and pattern separation in founder strains of the BXD recombinant inbred mouse panel

Abstract

Working memory and pattern separation are fundamental cognitive abilities which, when impaired, significantly diminish quality of life. Discovering genetic mechanisms underlying innate and disease-induced variation in these cognitive abilities is a critical step towards treatments for common and devastating neurodegenerative conditions such as Alzheimer's disease. In this regard, the trial-unique nonmatching-to-location assay (TUNL) is a touchscreen operant conditioning procedure allowing simultaneous quantification of working memory and pattern separation in mice and rats. In the present study, we used the TUNL assay to quantify these cognitive abilities in C57BL/6J and DBA/2J mice. These strains are the founders of the BXD recombinant inbred mouse panel which enables discovery of genetic mechanisms underlying phenotypic variation. TUNL testing revealed that pattern separation was significantly influenced by mouse strain, whereas working memory was not. Moreover, horizontal distance and vertical distance between choice-phase stimuli had dissociable effects on TUNL performance. These findings provide novel data on mouse strain differences in pattern separation and support previous findings of equivalent working memory performance in C57BL/6J and DBA/2J mice. Although working memory of the BXD founder strains was equivalent in this study, working memory of BXD strains may be divergent because of transgressive segregation. Collectively, data presented here indicate that pattern separation is heritable in the mouse and that the BXD panel can be used to identify mechanisms underlying variation in pattern separation.

Figure 1

The TUNL assay for quantification of working memory and pattern separation in C57BL/6J and DBA/2J mice. The flowchart illustrates the different phases of the TUNL assay. The inset illustrates the stimuli that were displayed on the touchscreen during the sample phase and the choice phase. Dark gray stimuli shown in the inset illustrate the matrix of possible locations for the sample and novel stimuli; in the TUNL experiment, only the white sample stimulus and white novel stimulus were shown on the touchscreen. During correction trials, both the sample stimulus and novel stimulus were displayed at the same locations as they were displayed in the preceding trial. During non-correction trials, the sample stimulus and novel stimulus were displayed at random locations.

Figure 2

TUNL performance was significantly influenced by strain, delay, horizontal distance, and vertical distance in C57BL/6J and DBA/2J mice. (a) TUNL performance of C57BL/6J mice was significantly better than performance of DBA/2J mice. (b) Increasing the delay between the sample phase and choice phase significantly impaired TUNL performance. (c,d) Increasing the horizontal distance between choice-phase stimuli significantly facilitated TUNL performance. (e,f) In contrast, increasing the vertical distance between choice-phase stimuli significantly impaired TUNL performance. Error bars represent SEM.

Figure 3

Mouse strain significantly influenced the effect of delay and horizontal distance, but not vertical distance, on TUNL performance in C57BL/6J and DBA/2J mice (a) Percentage correct on the 0, 5, and 10 s delay was significantly higher in C57BL/6J mice than in DBA/2J mice. Performance of C57BL/6J mice and DBA/2J mice did not differ significantly on the 15 s delay. The largest difference between C57BL/6J and DBA/2J mice was observed on the 0 s delay during which working memory would be expected to have a negligible impact on performance. (b) Performance of C57BL/6J mice and DBA/2J mice did not differ on the easiest discrimination during which the two choice-phase stimuli were displayed at the widest distance. In contrast, performance of DBA/2J mice was significantly impaired relative to C57BL/6J mice on more difficult discriminations during which stimuli were displayed at narrower distances. The two-way interactions illustrated here are fully decomposed in Fig. 4. Error bars represent SEM. * p < .05.

Figure 4

Pattern separation, but not working memory, is significantly impaired in DBA/2J mice relative to C57BL/6J mice¹. (a,d) TUNL performance of C57BL/6J mice and DBA/2J mice was equivalent at all delays when choice-phase stimuli were presented at the widest horizontal distance. (b,c,e,f) In contrast, when choice-phase stimuli were presented at an intermediate horizontal distance and narrow horizontal distance, performance of DBA/2J mice was significantly impaired relative to C57BL/6J mice. This performance impairment was observed at multiple delays, most consistently at the 0 s delay when pattern separation but not working memory would be expected to account for performance variation. This horizontal separation deficit was observed irrespective of vertical distance between choice-phase stimuli (compare top row panels vs bottom row panels). Error bars represent SEM. * p < .05. ¹Stimuli in the top left of each panel represent one example of a choice-phase stimuli configuration within the horizontal and vertical distance category combination. There were multiple possible stimuli configurations within each category combination, and all configurations were used in the TUNL experiment.