Effects of environmental and pharmacological manipulations on a novel delayed nonmatching-to-sample 'working memory' procedure in unrestrained rhesus monkeys

Abstract

Background: Working memory is a domain of 'executive function.' Delayed nonmatching-to-sample (DNMTS) procedures are commonly used to examine working memory in both human laboratory and preclinical studies.

New method: The aim was to develop an automated DNMTS procedure maintained by food pellets in rhesus monkeys using a touch-sensitive screen attached to the housing chamber. Specifically, the DNMTS procedure was a 2-stimulus, 2-choice recognition memory task employing unidimensional discriminative stimuli and randomized delay interval presentations.

Results: DNMTS maintained a delay-dependent decrease in discriminability that was independent of the retention interval distribution. Eliminating reinforcer availability during a single delay session or providing food pellets before the session did not systematically alter accuracy, but did reduce total choices. Increasing the intertrial interval enhanced accuracy at short delays. Acute Δ(9)-THC pretreatment produced delay interval-dependent changes in the forgetting function at doses that did not alter total choices. Acute methylphenidate pretreatment only decreased total choices.

Comparison with existing methods: All monkeys were trained to perform NMTS at the 1s training delay within 60 days of initiating operant touch training. Furthermore, forgetting functions were reliably delay interval-dependent and stable over the experimental period (∼6 months).

Conclusions: Consistent with previous studies, increasing the intertrial interval improved DNMTS performance, whereas Δ(9)-THC disrupted DNMTS performance independent of changes in total choices. Overall, the touchscreen-based DNMTS procedure described provides an efficient method for training and testing experimental manipulations on working memory in unrestrained rhesus monkeys.

Keywords: Delayed nonmatching to sample; Methylphenidate; Rhesus monkey; Touchscreen; Working memory; Δ(9)-Tetrahydrocannabinol.

Fig. 1

Schematic of the delayed nonmatching-to-sample (DNMTS) procedure. (A) Sequence of trial events. (B) The 2×2 matrix of events in a DNMTS procedure. C_i is the number of correct or nonmatching comparison choices, E_i is the number of error or matching comparison choices.

Fig. 2

Touch location training and the effects of increasing FR schedule requirements on active touch responses in rhesus monkeys (n=4). Ordinates: (A) Total responses per session. (B) Number of sessions required to achieve ≥ 0.85-proportion correct criterion. Abscissae: (A) Fixed-ratio schedule requirement (N). (B) delay to comparison presentation. Each symbol represents performance of a different monkey.

Fig. 3

Baseline forgetting functions and proportion trials completed in a DNMTS procedure with a long or short delay interval distribution in rhesus monkeys (n=4). Ordinates: (A Left) log d (A Right) proportion correct (B) proportion of trials completed. Abscissa: delay interval in seconds.

Fig. 4

Baseline within-session forgetting functions and total choices in a DNMTS procedure with a long or short delay interval distribution in rhesus monkeys (n=4). Ordinates: (A–B Left) log d (A–B Right) proportion correct and (C–D) number of choices. Abscissa: delay interval in seconds.

Fig. 5

Effects of environmental manipulations on DNMTS forgetting delay functions and total choices with either a long (A, C) or short (B, D) delay interval distribution in rhesus monkeys (n=4). Ordinates: A–B Left) log d (A–B Right) proportion correct and (C–D) number of choices completed per delay. Abscissa: delay in seconds. Filled points in C–D represent delay intervals at which total choices were statistically different from baseline (p<0.05).

Fig. 6

Effects of ITI duration on DNMTS performance in rhesus monkeys (n=4). Ordinates: (A Left) log d (A Right) proportion correct (B) proportion of trials completed. Abscissa: delay interval in seconds.

Fig. 7

Effects of Δ⁹-THC (A, C) and methylphenidate (B, D) on DNMTS performance in rhesus monkeys (n=4). Ordinates: (A–B Left) log d (A–B Right) proportion correct and (C–D) number of choices completed per delay. Abscissa: delay interval. Filled points in C–D represent delay intervals at which total choices were statistically different from vehicle rates (p<0.05).