Effects of ketamine on context-processing performance in monkeys: a new animal model of cognitive deficits in schizophrenia

Abstract

Cognitive deficits are at the crux of why many schizophrenia patients have poor functional outcomes. One of the cognitive symptoms experienced by schizophrenia patients is a deficit in context processing, the ability to use contextual information stored in working memory to adaptively respond to subsequent stimuli. As such, context processing can be thought of as the intersection between working memory and executive control. Although deficits in context processing have been extensively characterized by neuropsychological testing in schizophrenia patients, they have never been effectively translated to an animal model of the disease. To bridge that gap, we trained monkeys to perform the same dot pattern expectancy (DPX) task, which has been used to measure context-processing deficits in human patients with schizophrenia. In the DPX task, the first stimulus in each trial provides the contextual information that subjects must remember in order to appropriately respond to the second stimulus in the trial. We found that administration of ketamine, an N-methyl-D-aspartate receptor antagonist, in monkeys caused a dose-dependent failure in context processing, replicating in monkeys the same specific pattern of errors committed by patients with schizophrenia when performing the same task. Therefore, our results provide the first evidence that context-processing dysfunction can be modeled in animals. Replicating a schizophrenia-like behavioral performance pattern in monkeys performing the same task used in humans provides a strong bridge to better understand the biological basis for this psychiatric disease and its cognitive manifestations using animal models.

Figure 1

Schematic of the dot pattern expectancy (DPX) task. The dot patterns used as stimuli in the task are also depicted, grouped by their respective category designation. The monkeys performed the task while fixating at the cross at the center of the screen. ‘Target' cue-probe sequences (‘AX' trials) required a leftward motor response; ‘non-target' cue-probe sequences (all other trial types) required a rightward motor response. ISI, inter-stimulus interval; ITI, intertrial interval.

Figure 2

Effect of ketamine dose on performance accuracy (a–d). Replications for monkey 1: two replications per drug dose and two replications of the saline condition. Replications for monkey 2: two replications per drug dose and six replications of the saline condition. (a, b) Overall performance accuracy by dose. Dashed line represents the logistic function fit line to the data for baseline performance. Solid line represents the logistic function fit to the data for post-injection performance. (c, d) Effect of ketamine dose on performance accuracy for each trial type. Error bars are 1 SEM. (e) Data illustrating schizophrenia patient (n=47) vs control (n=48) performance on the DPX task were adapted from a prior human study (Jones et al, 2010). Copyright © 2010 by the American Psychological Association. The use of APA information does not imply endorsement by APA.

Figure 3

Effect of ketamine dose on reaction time. Replications for monkey 1: two replications per drug dose and two replications of the saline condition. Replications for monkey 2: two replications per drug dose and six replications of the saline condition. (a, b) Overall reaction time by dose. Dashed line represents baseline performance. Solid line represents post-injection performance. (c, d) Effect of ketamine dose on reaction time for each trial type. Error bars=SEM.

Figure 4

Effect of ketamine dosage on context (a, b) and probe processing (c). Dashed (monkey 1) and solid (monkey 2) lines represent linear fits obtained by regressing performance data onto ketamine dose. Replications for monkey 1: two replications per drug dose and two replications of the saline condition. Replications for monkey 2: two replications per drug dose and six replications of the saline condition. (a) D'_context (Z(proportion of correct ‘AX' trials)−Z(proportion of ‘BX' errors)) values for each replication of each dose in the experiment. (b) Difference in proportion of ‘BX' and ‘AY' errors for each replication of each dose in the experiment. (c) D'_probe (Z(proportion of correct ‘AX' trials)−Z(proportion of ‘AY' errors)) values for each day of the experiment.

Figure 5

Proportion of perseverative ‘BX' errors after ketamine administration (a–d). Replications for monkey 1: two replications per drug dose and two replications of the saline condition. Replications for monkey 2: two replications per drug dose and six replications of the saline condition. (a, b) Performance accuracy on trials that followed ‘BX' trials during the experiment, as a function of trial type and previous ‘BX' trial performance (data collapsed across dose). (c, d) Effect of ketamine dose on ‘BX' perseverative errors. Analysis restricted to consecutive pairs of ‘BX' trials during the experiment. Bars plot the proportion of erroneous trials on the second ‘BX' trial as a function of whether the monkey performed correctly (open bars) or incorrectly (filled bars) on the previous ‘BX' trial. (e) Effect of ketamine dose on nonperseverative ‘BX' errors. Proportion of ‘BX' errors on ‘BX' trials that followed a correctly performed trial as a function of ketamine dose. Error bars =SEM.