Delayed Nonmatching-to-sample Research Articles

Neonatal aspiration lesions of the hippocampal formation impair visual recognition memory when assessed by paired-comparison task but not by delayed nonmatching-to-sample task.

Previous experiments showed that neonatal aspiration lesions of the hippocampal formation in monkeys yield no visual recognition loss at delays up to 10 min, when recognition memory was assessed by a trial-unique delayed nonmatching-to-sample (DNMS) task. The present study examined whether neonatal hippocampal lesions also have no effect on visual recognition when assessed by a visual paired-comparison (VPC) task. In the VPC task, animals are looking at visual stimuli and their preference for viewing new stimuli is measured. Normal adult monkeys showed strong preference for looking at the novel stimuli at all delays tested. By contrast, adult monkeys with neonatal hippocampal lesions, which included the dentate gyrus, cornus ammon (CA) fields, subicular complex, and portions of parahippocampal areas TH/TF, showed preference for novelty at short delays of 10 s but not at longer delays of 30 s to 24 h. This visual recognition loss contrasts with the normal performance of the same operated animals when tested in the DNMS task. The discrepancy between the results obtained in the two recognition tasks suggests that, to perform normally on the DNMS task, the operated monkeys may have used behavioral strategies that do not depend on the integrity of the hippocampal formation. In this respect, VPC appears to be a more sensitive task than DNMS to detect damage to the hippocampal region in primates.

Hippocampal formation lesions produce memory impairment in the rhesus monkey.

There is much debate over the role of temporal lobe structures in the ability to learn and retain new information. To further assess the contributions of the hippocampal formation (HF), five rhesus monkeys received stereotactically placed ibotenic acid lesions of this region without involvement of surrounding ventromedial temporal cortices. After surgery, the animals were trained on two recognition memory tasks: the Delayed Non-Match to Sample (DNMS) task, which tests the ability to remember specific trial unique stimuli, and the Delayed Recognition Span Task (DRST), which tests the ability to remember an increasing array of stimuli. Relative to normal control monkeys, those with HF lesions demonstrated significant impairments in both learning and memory stages of the DNMS task. Additionally, the HF group was significantly impaired on spatial, color, and object versions of the DRST. Contrary to suggestions that damage to the entorhinal and parahippocampal cortices is required to produce significant behavioral deficits in the monkey, these results demonstrate that selective damage to the HF is sufficient to produce impairments on tasks involving delayed recognition and memory load. This finding illustrates the importance of the HF in the acquisition and retention of new information.

Basal forebrain damage and object-recognition in rats

Damage to the basal forebrain (BF) produces permanent learning and memory impairments in humans. Most efforts to model these deficits in rats have focused on spatial memory dysfunction; this study was the first to assess the effects of BF damage in rats on the performance of a battery of object-memory tasks commonly employed to assess brain damage-produced amnesia in primates. The performance of rats with bilateral electrolytic lesions of the medial septum and diagonal band (MS/NDB) region of the BF was assessed on three object-memory tasks: nonrecurring items delayed nonmatching-to-sample (DNMS), simple object discrimination, and eight-pair concurrent object discrimination. Lesioned rats and sham-surgery controls were tested on the DNMS task at retention delays of 4, 15, 30, 60 and 120 s both before and after surgery. After surgery, the rats with MS/NDB lesions required significantly more trials than controls to relearn the nonmatching rule; and, once they relearned the rule, they were significantly and comparably impaired at all delays. This impairment did not diminish with either the passage of time or additional practice. In contrast, there were no significant differences between the MS/NDB-lesioned and control groups in the performance of either simple or concurrent object-discrimination tasks. The delay-independent nature of the DNMS deficit and the lack of deficits on the other two object-memory tasks suggest that the effect of the lesion is not the result of an impairment in retention.

Neonatal monoaminergic depletion in mice (Mus musculus) improves performance of a novel odor discrimination task.

This experiment examined behavior and neurochemistry in adult mice (Mus musculus) after neonatal depletion of monoaminergic fibers projecting to the neocortex and hippocampus. Lesions were made on Postnatal Day 1; mice developed to adulthood and were assessed on simple odor discrimination (SOD) and odor delayed nonmatch-to-sample (DNMS) tasks, passive avoidance (PA), and locomotor activity. On SOD, lesioned mice performed faster than controls but with similar accuracy. On the DNMS task, the lesioned mice performed faster and more accurately than controls. On PA, the lesioned mice exhibited a retention deficit relative to controls. Locomotor activity was similar in the 2 groups. Postmortem analyses revealed that the lesions reduced significantly norepinephrine and serotonin levels in both the neocortex and hippocampus. The data suggest that cortically projecting monoaminergic fibers play an important role in normal cognitive development.

Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys

This study investigated the effects of different rearing conditions on neural and cognitive development of male rhesus monkeys ( Macaca mulatta). Infants raised individually in a nursery from 2 to 12 months of age (NURSERY, n=9) were compared to age-matched infants raised in a semi-naturalistic, social environment (CONTROL, n=11). Various brain regions were measured by MRI. Although overall brain volumes did not differ between NURSERY and CONTROL animals, corpus callosum (CC) size, measured in mid-sagittal sections, was significantly decreased in the NURSERY group. Group differences were most evident in the posterior aspects of the corpus callosum and appeared to result from changes in the number of cross-hemispheric projections rather than from a decrease in cortical gray matter volume. The decrease in corpus callosum size in the NURSERY animals persisted after 6 months of social housing in a peer-group. Rearing group differences were not found in other structures analyzed, including the hippocampus, cerebellum and anterior commissure. In cognitive testing, NURSERY animals had more difficulty acquiring the delayed non-matching to sample (DNMS) task, but showed no deficits in subsequent memory performance when a 2 or 10 min delay was imposed. The NURSERY infant monkeys were also impaired in object, but not in spatial, reversal learning, although there were no differences in a simple object discrimination task. The cognitive deficits exhibited by the NURSERY animals were significantly correlated with the alterations found in the CC. In summary, rearing environment was associated with sustained differences in cross-hemispheric projections, white matter volume and cognitive performance.

Facilitative Effects of the Ampakine CX516 on Short-Term Memory in Rats: Enhancement of Delayed-Nonmatch-to-Sample Performance

Ampakines are a family of drugs that selectively increase AMPA receptor-gated currents and improve performance on several behavioral tasks. This report describes evidence that ampakines cause a cumulative enhancement of performance in a spatial short-term memory task (Deadwyler et al., 1996). Two groups of rats were trained on a spatial variant of the delayed-nonmatch-to-sample (DNMS) paradigm. One group (n = 12) received the ampakine CX516 (Cortex Pharmaceuticals) alternated with vehicle for 17 consecutive days and then only vehicle for an additional 7 d. The second group (n = 6) received only vehicle injections over the same number of days. CX516 improved performance within sessions, particularly on trials with delays of 6-35 sec. In 9 of 12 rats, the positive effect of the drug was also present on nondrug days between CX516 administration and after cessation of CX516 injections. The animals that received only vehicle injections showed no improvement in DNMS performance over the entire 32 d of testing. Three of the 12 animals given CX516 did not exhibit "carryover" effects of the drug to the intervening (vehicle only) test sessions, but nonetheless exhibited superior performance during the first half of the session on days in which the ampakine was administered. Evaluation of errors suggests that the ampakine eliminated the necessity for a shift in response strategy that produced proactive interference on the following trial. Hippocampal involvement in these ampakine effects is discussed as a prelude to the second article in the series (Hampson et al., 1998).

Facilitative Effects of the Ampakine CX516 on Short-Term Memory in Rats: Correlations with Hippocampal Neuronal Activity

In the companion article (Hampson et al., 1998), the ampakine CX516 (Cortex Pharmaceuticals) was shown to produce a marked facilitation of performance of a spatial delayed-nonmatch-to-sample (DNMS) task in rats. Injections of the drug before each daily session produced a marked and progressive improvement in performance at longer delays (>5 sec) that persisted for 7 d after drug treatment was terminated. In most animals (n = 9) the increase in performance carried over to the intervening vehicle for days, whereas in others (n = 3) the effects dissipated within the session according to the pharmacological half-life of CX516. In this article we report firing correlates of simultaneously recorded cells in the CA1 and CA3 fields of the hippocampus over the period in which DNMS performance was facilitated by CX516. Sample and Delay period firing was enhanced by 100-350% under CX516 and increased progressively over days as did DNMS performance. The firing increases were restricted to correct trials only and were largest on trials with long delays. Firing in the intertrial interval was also altered, but in a manner consistent with a previously demonstrated reduction in between-trial proactive interference by CX516. Finally, in animals in which the effects of CX516 were restricted to when the drug was actually present (i.e., no carryover effects), increased cell firing also paralleled the time course of the performance increase. Results are discussed with respect to the actions of ampakines on hippocampal cellular and synaptic processes that underlie DNMS performance.

Learning/Memory Impairments in Rat Offspring Prenatally Exposed to Phenytoin

Phenytoin (PHT) was orally administered in dosages of 50 and 100 mg/kg/day to pregnant rats on days 7-18 of gestation. Offspring were tested on the negative geotaxis test, a figure-eight maze (F8), the Biel water maze (BM), the Morris maze (MM), and the radial maze (RM). In addition, a delayed nonmatching-to-sample (DNMTS) test was employed. The levels of neuropeptides in brain and brain weights were determined. The maturation of negative geotaxis was delayed in both PHT groups. PHT groups showed no differences in F8, BM, and MM. In the RM, the total number of choices was high, whereas the number of correct choices was low. In the DNMTS, PHT groups showed low for correct choices with a long interval. The concentrations of neuropeptides were changed in the mesolimbic cortex, hippocampus, and amygdala. Brain weights were lower at 6 weeks of age in the 100 mg/kg/day PHT group, but were comparable at 16 weeks of age. This study suggests that the RM is a detectable task for the learning/memory impairments induced by PHT. In addition, it is surmised that the learning deficit is due to a working memory impairment arising from abnormal changes in neuropeptides and an injury in the fetal hippocampus.

Lesions of the frontal cortex, hippocampus, and intralaminar thalamic nuclei have distinct effects on remembering in rats.

Lesions of the intralaminar thalamic nuclei (ILn), the medial wall (MW) area of prefrontal cortex, and the hippocampus were compared and found to have distinct effects on delayed matching-to-sample (DMS) and delayed non-matching-to-sample (DNMS) tasks based on different types of stimulus cues. Hippocampal lesions impaired DNMS trained in a radial arm maze but had little effect on DMS trained with retractable levers or olfactory DNMS. MW lesions affected the DMS task but had limited effects on olfactory DNMS and radial arm maze DNMS. ILn lesions resulted in a more generalized pattern of impairment for radial maze tasks and (in previous studies) for the DMS and olfactory DNMS tasks. Only the hippocampal lesion was associated with a delay-dependent impairment. It is argued that ILn lesions disrupt remembering through their effects on the recurrent, feedback pathways that link functionally related areas of the basal ganglia and cortex.

Effects of thalamic and olfactory cortical lesions on continuous olfactory delayed nonmatching-to-sample and olfactory discrimination in rats (Rattus norvegicus).

We conducted 2 studies to determine the importance of several brain systems for remembering odorants in a go/no-go delayed nonmatching-to-sample (DNMTS) task. In Experiment 1, impairments were observed for lesions of pyriform cortex or (to a lesser extent) the lateral internal medullary lamina of thalamus. Lesions of the entorhinal cortex or the mediodorsal (MDn) or the paracentral and centrolateral (PC-CL) thalamic nuclei did not affect DNMTS. In Experiment 2, an impairment comparable to the pyriform lesion was observed for a lesion of the intralaminar nuclei (PC-CL plus the central medial nucleus) but not for a larger lesion of MDn. None of the lesions in either study affected the ability to learn a 2-choice odor discrimination using go/no-go procedures comparable with the DNMTS task.

The effects of frontal cortical lesions on remembering depend on the procedural demands of tasks performed in the radial arm maze

We trained 24 rats to perform an eight-arm radial maze task and then assigned them with a matching procedure to one of three treatments: sham surgery or lesions of the projection areas of the mediodorsal thalamic nucleus (MDn) in the medial wall (MW) or in both the MW and rhinal sulcal (RS) areas of frontal cortex. After recovery we trained the rats to perform six tasks, beginning with the standard eight-arm task, followed by two versions of a four forced choice procedure, and then three versions of a two-choice delayed-nonmatching-to-sample (DNMTS) task. The two lesion groups performed comparably on all tasks, showing that impairments were not exacerbated by extension of the MW lesion to include all cortical areas innervated by MDn. As in previous studies, frontal animals performed the radial maze task poorly immediately after surgery but improved with subsequent training. Controlling the order of the arm entries by opening the first four gates in a random sequence had little effect on performance, although frontal animals were impaired when lengthy delays (5 or 15 min) were imposed after the last of the four forced entries. Frontal animals were not impaired on two-choice DNMTS when the arms used for training were selected at random from the eight alternatives on a trial by trial basis, even when visual cues were eliminated by darkening the room and covering the maze. Frontal animals were significantly impaired when the selection of sample and choice arms was limited to the same two alternatives on every trial. This finding may explain the reported sensitivity of DNMTS to the effects of frontal lesions when training is carried out in operant chambers.

Disruption of spatial but not object-recognition memory by neurotoxic lesions of the dorsal hippocampus in rats.

Ischemia-induced cell loss in the CA1 region of the dorsal hippocampus results in severe deficits on delayed non-matching-to-sample (DNMS), whereas hippocampectomy produces little or no impairment, suggesting that partial hippocampal damage is more detrimental to DNMS performance than total ablation. To test this hypothesis, rats with or without preoperative DNMS training were given partial cytotoxic lesions of the dorsal hippocampus. When tested, neither group displayed any DNMS deficits despite widespread cell loss in the CA1 and other regions of the dorsal hippocampus. In the final experiments, rats tested previously on DNMS were found to be impaired on the Morris water maze. The finding that partial hippocampal lesions disrupt spatial memory while leaving object-recognition memory intact indicates a specialized role for the hippocampus in mnemonic processes.

Object-recognition and spatial learning and memory in rats prenatally exposed to ethanol.

Prenatal ethanol exposure can produce cognitive and behavioral impairments. In the present study, rats from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) treatment conditions were tested on the object-recognition delayed-nonmatching-to-sample (DNMS) task with nonrecurring items and on the spatial-navigation Morris water maze task. In Experiment 1, there were no significant differences among groups in object-recognition learning and memory, distractibility, or response perseveration on the DNMS task. In Experiment 2, the same rats were tested in the water maze; E rats took significantly longer to learn the task than did the PF or C rats. These data suggest that the mechanisms underlying spatial cognitive abilities are more vulnerable to the teratogenic effects of prenatal ethanol exposure than those underlying object-recognition abilities.

The effects of electrolytic lesion to the shell subterritory of the nucleus accumbens on delayed non-matching-to-sample and four-arm baited eight-arm radial-maze tasks.

The effects of bilateral electrolytic lesions of the "shell" subterritory of the nucleus accumbens in the rat were examined on 2 tasks known to be sensitive to hippocampal damage. Experiment 1 tested the effects of shell lesion on delayed non-matching-to-sample (DNMS) task in a T-maze. The maze was rotated 180 degrees after the end of acquisition. Experiment 2 used a 4-arm baited, 4-arm unbaited, 8-arm radial-maze task and its reversal. Shell lesion led to impaired acquisition of DNMS in a T-maze and of 4-arm baited, 4-arm unbaited, 8-arm radial maze tasks, suggestive of mnemonic deficits. Following analysis of animals' choice pattern in both tasks, the deficit was interpreted as being largely due to an extensive use of response strategy. The results suggest that the inappropriate use of response strategy by shell animals was a result of their inability to switch from initial response strategy to a later, more appropriate, memory-dependent strategy.

The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N -methyl- d -aspartate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (±)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1–10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficit following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2–32 μg/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 μg/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 μg/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.

The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N-methyl- d-aspartate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (±)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1–10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficit following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2–32 μg/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 μg/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 μg/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.

Children's Performance on “Animal Tests” of Oddity: Implications for Cognitive Processes Required for Tests of Oddity and Delayed Nonmatch to Sample

To investigate the ontogenesis of oddity learning, children (16 to 102 months of age) and adults were tested on two versions of the oddity task using non-verbal procedures originally developed for monkeys. On the standard, “one-part” or “simultaneous” oddity task (Experiment 1), young children (16 to 74 months of age) performed more poorly than older children (81–102 months of age) who were as proficient as adults. The delayed mastery of one-part oddity contrasts to mastery, at much younger ages (3 to 4 years of age) of a similar, but two-part task, delayed non-match to sample (DNMS) (Overman, 1990). In Experiment 2, those children from the first experiment who had difficulty in learning the one-part oddity task were tested on a two-part oddity task, and a subset of the subjects was retested on the one-part oddity task, and, finally, given verbal instructions for the one-part oddity task. The two-part oddity task was mastered significantly more rapidly than the previous one-part task; however, children's performance dropped significantly when retested on the one-part oddity task, and finally, children rapidly mastered the one-part oddity task when given verbal instructions. The data suggested that (a) children used different strategies to solve the different versions of the oddity task, (b) the solution for the two-part-task appeared earlier in life than the solution for the one-part task and did not involve the use of the concept of “oddity relations”, and (c) in tasks in which stimuli are shown twice, behavior may come under control of the absolute properties of the exemplar stimulus via a simple “win-shift” pattern of behavior. In contrast, in tasks in which all stimuli are presented simultaneously, behavior may be controlled by stimulus relations, the analysis of which has a protracted ontogenetic development.

A comparison of the effects of frontal cortical and thalamic lesions on measures of spatial learning and memory in the rat

Two experiments were conducted to compare the effects of radiofrequency lesions of thalamus and frontal cortex on three measures of spatial learning and memory: delayed non-matching to sample (DNMTS), radial arm maze with imposed delays, and serial reversal learning. Thalamic lesions were aimed at the lateral internal medullary lamina (L-IML) and cortical lesions at the projection areas of the mediodorsal nucleus along the medial wall (MW) and dorsal to the rhinal sulcus (RS) in frontal cortex. In Experiment 1 rats were trained on DNMTS prior to surgery. After recovery, rats with MW lesions showed persistent deficits on DNMTS that were significantly greater than for RS lesions. The deficits observed in MW lesioned animals were comparable to the effects of L-IML lesions on this task that have been described in previous studies. In Experiment 2 animals were trained to perform the radial arm maze task prior to treatment. After recovery, animals with L-IML lesions were impaired on the radial arm maze and on subsequent acquisition of the serial reversal task. Rats with RS and MW lesions showed transient impairments on the radial arm maze task, but otherwise performed as well as controls on both these tasks.

Ischemia-induced object-recognition deficits in rats are attenuated by hippocampal ablation before or soon after ischemia.

The literature on the role of the hippocampus in object-recognition contains a paradox: Transient forebrain ischemia (ISC) produces hippocampal damage and severe deficits on the delayed nonmatching-to-sample (DNMS) task, yet hippocampal ablation (ABL) produces milder deficits. Experiment 1 confirmed that pretrained rats display severe DNMS deficits following ISC, but not ABL. Ischemia produced loss of CA1 neurons, but no obvious extrahippocampal damage. In Experiments 2 and 3, ISC rats from Experiment 1 received ABL, and ABL rats received ISC; neither treatment affected DNMS performance. In Experiment 4, rats that received ISC followed 1 hr later by ABL displayed only mild deficits. It is hypothesized that ISC-induced DNMS deficits are due to extrahippocampal damage produced by pathogenic processes that involve the hippocampus.

Cholinergic-glutamatergic interactions in visual recognition memory of rhesus monkeys.

Administration of either a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (dizocilpine), or a muscarinic antagonist, scopolamine, produces dose-related impairments in performance of a visual recognition memory task, delayed non-matching to sample (DNMS) with lists of 20 symbols, in rhesus monkeys. In the present study, low doses of these two drugs, which were ineffective when given alone, significantly impaired performance when given in combination. Moreover, the effect was greater than additive, indicating a synergistic interaction. These results suggest that interactions between cholinergic and glutamatergic systems play an important role in regulation of visual recognition memory.