Dissociating the effects of distraction and proactive interference on object memory through tests of novelty preference

Abstract

Encoding information into memory is sensitive to distraction while retrieving that memory may be compromised by proactive interference from pre-existing memories. These two debilitating effects are common in neuropsychiatric conditions, but modelling them preclinically to date is slow as it requires prolonged operant training. A step change would be the validation of functionally equivalent but fast, simple, high-throughput tasks based on spontaneous behaviour. Here, we show that spontaneous object preference testing meets these requirements in the subchronic phencyclidine rat model for cognitive impairments associated with schizophrenia. Subchronic phencyclidine rats show clear memory sensitivity to distraction in the standard novel object recognition task. However, due to this, standard novel object recognition task cannot assess proactive interference. Therefore, we compared subchronic phencyclidine performance in standard novel object recognition task to that using the continuous novel object recognition task, which offers minimal distraction, allowing disease-relevant memory deficits to be assessed directly. We first determined that subchronic phencyclidine treatment did not affect whisker movements during object exploration. Subchronic phencyclidine rats exhibited the expected distraction standard novel object recognition task effect but had intact performance on the first continuous novel object recognition task trial, effectively dissociating distraction using two novel object recognition task variants. In remaining continuous novel object recognition task trials, the cumulative discrimination index for subchronic phencyclidine rats was above chance throughout, but, importantly, their detection of object novelty was increasingly impaired relative to controls. We attribute this effect to the accumulation of proactive interference. This is the first demonstration that increased sensitivity to distraction and proactive interference, both key cognitive impairments in schizophrenia, can be dissociated in the subchronic phencyclidine rat using two variants of the same fast, simple, spontaneous object memory paradigm.

Keywords: Schizophrenia; novel object recognition; object memory; parvalbumin; phencyclidine; preclinical model; whisker movement.

Figure 1.

Experimental design. (a) Timeline for the study. (b) The stNOR arena. (c) The arena (left) and the trial design (right) for conNOR testing. Different pairs at test are displayed as A + A, A + B and so on.

Figure 2.

Whisker movement in scPCP and vehicle rats. (a) Top left panel: diagram of object exploration arena; top right panel: video frame taken from typical whisker contact with an object to show tracking of whiskers, tip of nose (blue) and body centroid (yellow); bottom panel: example of whisker tracking; object contact occurred at time x = 0; therefore, whisker measurements were extracted from after this time. (b) scPCP and vehicle groups were similar in terms of: general locomotion speed in the arena, asymmetry of whisker position; whisker protraction and retraction speed; mean angular whisker position; and whisker amplitude. N = 10 animals for both vehicle and scPCP groups, with data presented as individual values plotted over group mean.

Figure 3.

Standard NOR (stNOR) and PV deficits in scPCP rats. (a) Exploration times for novel and familiar objects during stNOR test; only vehicle rats show a preference for the novel object with scPCP rats exploring both novel and familiar objects similarly. (b) stNOR test performance plotted as discrimination index (DI); vehicle rats show significantly higher DI compared to scPCP. Only vehicle group performance was greater than chance. (c) Typical example of parvalbumin staining from rat mPFC. Image ×20. (d) The density of cells positively stained with anti-parvalbumin antibody (PV+) is lower in scPCP group. N = 10 for both vehicle and scPCP groups in all panels with their data presented as individual values plotted over group mean. *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 4.

Continuous NOR (conNOR) performance in vehicle and scPCP rats. (a) Vehicle and scPCP groups show intact performance throughout the conNOR session, but scPCP performance declines compared to vehicle group from trial 3, followed by a more consistent lower mean value from trial 7. (b) The stNOR deficit in scPCP rats and their intact performance on conNOR trial 1 support the specific effect of distraction in this group for object memory in stNOR but not conNOR. (c) Decrease in performance for scPCP rats over trials without distraction in conNOR is more substantial compared to vehicle. This supports an increased sensitivity of the scPCP group to proactive interference compared to the vehicle group in conNOR. N = 10 for both vehicle and scPCP groups in all panels with their data presented as individual values plotted over group mean. *p < 0.05; ***p < 0.001.