Delayed matching-to-position performance in C57BL/6N mice
Introduction
Delayed matching-to-sample (DMTS) tasks using operant-conditioning chambers have been a powerful means by which to study animal working memory (Blough, 1959, D’Amato, 1973, D’Amato and Worsham, 1974, White, 1985), but surprisingly, few studies in laboratory mice have been carried out in operant-conditioning chambers. Instead, numerous versions of maze tasks have been developed to examine genetic and physiological factors involved in spatial reference and working memory in various strains of mice, and many studies in mice have been carried out with maze procedures (Brown and Wong, 2007, Deacon and Rawlins, 2006, Hodges, 1996, Yoshida et al., 2001).
When examining spatial working memory in mice, T-maze alternation (Deacon and Rawlins, 2006) and delayed matching (nonmatching)-to-place (Morris and Frey, 1997, Steele and Morris, 1999, Wietrzych et al., 2005) have often been used. In the former procedure, entering one of two arms is reinforced on alternating trials. The number of entries ascribed to correct and incorrect arms are behavioral measures. In the latter procedure, the animal is first released into a T-maze in which one of the two arms is blocked. This is the acquisition phase. After a short delay following the animal's arrival at the reinforcer placed at the end of the open arm, the animal is placed back at the start position and is then released into the maze with both arms opened. A choice is reinforced and considered correct if the animal enters the arm visited (matching) or not visited (nonmatching) during the acquisition phase. Although delayed responding paradigms using maze procedures allowed us to examine working memory in animals, the use of a relatively novel paradigm such as those in operant-conditioning chambers extend the generality of the findings in maze paradigms with the precise control of retention and intertrial intervals (ITIs) as well as incorporating new measurements of behaviors such as lever pressings.
Dunnett and colleagues (Dunnett, 1985, Dunnett and Martel, 1990, Dunnett et al., 1988, Dunnett et al., 1990) developed a lever-pressing delayed matching-to-position (DMTP) protocol for examining spatial working memory in rats by modifying the delayed conditional discrimination task (Herremans et al., 1994, Wallace et al., 1980). At the beginning of the trial, one of the front retractable levers, left or right, was extended into the chamber. When rats responded by pressing the lever, the lever retracted, and the delay interval clock was started. During the delay, rats made either nose poke responses at the panel (e.g., Dunnett, 1985) or performed rear-lever pressings (e.g., Bailey and Mair, 2005, Burk and Mair, 1998, Burk and Mair, 2001). The first such response after the end of the programmed delay caused both levers to be extended. The choice of the same lever as the sample was reinforced, whereas the choice of the other was not. Memory of the lever location decayed over lengthening delay intervals, but it did not drop to chance even with delays of around 30 s in rats.
Although the lever-pressing DMTP and other versions of delayed lever-pressing paradigms (e.g., Heise, 1984, Heise et al., 1976, Pontecorvo, 1983) are fundamentally similar to maze paradigms as a means of testing spatial working memory, lever-pressing procedures have numerous analytic advantages over maze procedures in terms of more precise control of timing and behaviors.
Two notable examples are the manipulations of ITI duration (Dunnett and Martel, 1990) and the fixed-ratio requirement for sample responding (Burk and Mair, 1998). Dunnett and Martel (1990) revealed that matching accuracy was higher in the trials in which the sample lever was same as that used in the previous trial whereas matching accuracy decreased in the trials in which the sample lever was different from that used in the previous trial. These results suggest that proactive interference is one of the potential processes influencing the successful retrieval of sample memory. The authors further revealed that such interference diminishes as the ITI increases (Dunnett and Martel, 1990). Burk and Mair (1998) showed that matching accuracy was higher when the response count requirement for the sample lever was larger, independent of delay interval duration, suggesting that the sample response requirement affects the discriminability of the sample location, but not the forgetting rate.
Thus, the purposes of the present study were to validate the DMTP task (adopted from the procedure used by Mair and colleagues, i.e., Bailey and Mair, 2005, Burk and Mair, 1998, Burk and Mair, 2001) as a measure of the construct of working memory and to demonstrate the analytical power of this method by characterizing the effects of a number of parametric manipulations on working memory in laboratory mice. Lever-pressing DMTP tasks have already been used to examine the effects of genetic or pharmacological manipulations on laboratory mice (Bernardo et al., 2007, Escher and Mittleman, 2004, Estape and Steckler, 2001, Krueger et al., 2006, Martin et al., 2004, Nordquist et al., 2008, Woolley and Ballard, 2005). However, previous authors were less interested in examining how the effects parametric manipulations influence the discriminability and forgetting rate on DMTP performance in mice. The present study, then, examined the effects of changing both the fixed-ratio (FR) requirement for sample responding and the duration of the ITI. In addition, proactive interference was examined, since it is one of the most pervasive parameters in the paradigm.
Section snippets
Subjects
Subjects were five male C57BL/6N Crj mice obtained from CLEA Japan, Inc. (Tokyo, Japan) and were 12 weeks old when the experiment began. Although naïve to lever-pressing tasks, all mice had experienced a paw preference test and an open-field maze task prior to the present experiment. The mice were housed in groups of three and two in cages (29 cm long × 19 cm wide × 13 cm high) and were kept on a 12-h light/dark schedule. Training was carried out during the dark phase. Mice were kept at or above 85%
Acquisition of the delayed spatial matching-to-position task
Performance was first assessed by calculating the means of the proportion correct scores, where proportion correct is calculated as the number of correct responses divided by the total number of responses in a session, excluding correction trials. Fig. 1a shows mean proportion correct values for five mice in the first 30 sessions. Mice performed at chance in the first 10 sessions but gradually improved their performance as training proceeded. In accordance with the improvement in response
Discussion
The results of the present study illustrate the validity of the lever-pressing delayed matching-to-position task as a means of quantifying working memory and characterize the effects of a number of parametric manipulations in testing laboratory mice. Validation of the technique was demonstrated first by verifying a delay-dependent decrement of response accuracy, and second by demonstrating the effects of FR requirement to the sample on DMTP performance. Third, it was shown that intertrial
Acknowledgements
The work was funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, Grant-in-Aid for Scientific Research under Grant No. 18/5950 to KG and the Global COE Program (D029) to Keio University. We thank Dr. Takayuki Tanno for his advice on data analysis using R.
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