Non-matching-to-sample Research Articles

Environmental enrichment protects against cognitive impairment following chemotherapy in an animal model.

Clinical studies indicate that up to 70% of cancer patients who receive chemotherapy experience cognitive impairment. The present study investigated environmental enrichment as a protective factor against the adverse effects of anticancer drugs on cognitive and biological processes in an animal model. Adult rats were housed in group cages with environmental stimulation or in standard cages for 3 months, before receiving 3 weekly injections of methotrexate + 5-fluorouracil, or equal volumes of saline. Rats were then administered tests of learning and memory that are sensitive to hippocampal or frontal lobe dysfunction. The relationship between cognitive performance and hippocampal neurogenesis was examined through sensitive time-dependent measures of neuronal maturation. Chemotherapy-treated rats in the standard environment were impaired on tests of spatial memory, nonmatching-to-sample (NMTS) rule learning, and delayed-NMTS. Chemotherapy-treated rats in the enriched environment performed at or near normal levels. The performance of the chemotherapy groups on the hippocampus-sensitive, spatial memory and delayed-NMTS tests correlated with neurogenesis levels. The results show that environmental enrichment can reduce the risk of chemotherapy-induced cognitive impairment, in part by promoting neuronal differentiation and growth during cell maturation. As well, they point to the importance of lifestyle factors in treating or preventing adverse effects of anticancer drugs on cognitive function. (PsycINFO Database Record

Temporal dynamics of task switching and abstract-concept learning in pigeons.

The current study examined whether pigeons could learn to use abstract concepts as the basis for conditionally switching behavior as a function of time. Using a mid-session reversal task, experienced pigeons were trained to switch from matching-to-sample (MTS) to non-matching-to-sample (NMTS) conditional discriminations within a session. One group had prior training with MTS, while the other had prior training with NMTS. Over training, stimulus set size was progressively doubled from 3 to 6 to 12 stimuli to promote abstract concept development. Prior experience had an effect on the initial learning at each of the set sizes but by the end of training there were no group differences, as both groups showed similar within-session linear matching functions. After acquiring the 12-item set, abstract-concept learning was tested by placing novel stimuli at the beginning and end of a test session. Prior matching and non-matching experience affected transfer behavior. The matching experienced group transferred to novel stimuli in both the matching and non-matching portion of the sessions using a matching rule. The non-matching experienced group transferred to novel stimuli in both portions of the session using a non-matching rule. The representations used as the basis for mid-session reversal of the conditional discrimination behaviors and subsequent transfer behavior appears to have different temporal sources. The implications for the flexibility and organization of complex behaviors are considered.

Physical exercise prevents suppression of hippocampal neurogenesis and reduces cognitive impairment in chemotherapy-treated rats

Chemotherapy, used for the treatment of cancer, often produces cognitive impairment that has been related to suppression of neurogenesis. Physical exercise, which promotes neurogenesis, is known to improve cognitive function in neurologically challenged animals and humans. It is unknown whether exercise similarly protects against chemotherapy-induced cognitive impairment and whether recovery of neurogenesis is a critical factor. The present study investigated the relationship between hippocampal neurogenesis and cognitive performance in chemotherapy-treated rats that engaged in different amounts of physical activity. Groups of rats, housed individually in standard cages or in specially designed cages that allowed unlimited access to a running wheel, received three injections of the chemotherapeutic drugs methotrexate and 5-fluorouracil, or equal volumes of saline. They were then administered the following cognitive tests in a water maze: (1) spatial memory (SM), (2) cued memory, (3) non-matching to sample (NMTS) rule learning; (4) delayed NMTS (DNMTS). Hippocampal neurogenesis was quantified by counting doublecortin-expressing cells in the dentate gyrus. Chemotherapy administered to rats in standard cages resulted in a significant reduction in hippocampal neurogenesis and impaired performance on the SM, NMTS, and DNMTS tasks. In rats receiving chemotherapy and housed in exercise cages, neurogenesis was not suppressed and cognitive performance was similar to controls. Physical exercise can reduce cognitive deficits that result from chemotherapy and this effect is mediated, at least in part, by preventing suppression of drug-induced hippocampal neurogenesis. The results suggest benefits of exercise in preventing or treating cognitive impairment associated with chemotherapy.

The Effects of Chemotherapy on Cognitive Function in a Mouse Model: A Prospective Study

Clinical studies indicate that up to 70% of patients with cancer who receive chemotherapy experience cognitive impairment. The present study used a prospective longitudinal design to assess short- and long-term effects of commonly used anticancer drugs on cognitive performance in a mouse model. Normal mice received three weekly injections of a combination of methotrexate + 5-fluorouracil (CHEMO group) or an equal volume of saline (SAL group). Cognitive tests, measuring different aspects of learning and memory, were administered before treatment, immediately after treatment, and three months later. Structural MRI scanning was conducted at each stage of cognitive testing. The CHEMO group exhibited deficits on cognitive tasks acquired pretreatment [spatial memory, nonmatching-to-sample (NMTS) learning, and delayed NMTS], as well as impaired new learning on two tasks (conditional associative learning, discrimination learning) introduced posttreatment. Consistent with clinical evidence, cognitive deficits were pronounced on tests that are sensitive to hippocampal and frontal lobe dysfunction, but the CHEMO group's poor performance on the discrimination learning problem suggests that impairment is more widespread than previously thought. Cognitive deficits persisted for at least three months after treatment but some recovery was noted, particularly on tests thought to be under frontal lobe control. The MRI tests did not detect brain changes that could be attributed to treatment. Chemotherapeutic agents can have adverse effects on information acquired pretreatment as well as new learning and memory and, despite some recovery, impairment is long lasting.

Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model

Adjuvant cancer chemotherapy often causes cognitive impairment that can be long-lasting and adversely affect quality of life. The present study sought to determine if the cognitive enhancing drug, donepezil, can reduce cognitive impairment induced by a combination of methotrexate +5-fluorouracil, two drugs commonly used in cancer chemotherapy. Four groups of mice: (1) chemotherapy-only; (2) chemotherapy+donepezil; (3) saline-only; (4) saline+donepezil, were administered the following learning and memory tests: (1) standard spatial memory (SM); (2) non-spatial cued memory (CM); (3) non-matching-to-sample (NMTS) rule-learning; (4) delayed-NMTS (DNMTS). The chemotherapy-only group was impaired on the SM, NMTS, and DNMTS tasks. Chemotherapy-induced cognitive deficits were significantly reduced in the chemotherapy+donepezil group whose performance on some measures was very similar to that of the saline-only group. There was no evidence that donepezil improved the performance of saline-treated mice. The results confirm the adverse effects of chemotherapy on cognitive function and demonstrate that they can be ameliorated by donepezil, which is widely used to treat cognitive impairment in other clinical populations (e.g., Alzheimer’s disease).

Subtype-selective nicotinic agonists enhance olfactory working memory in normal rats: A novel use of the odour span task

Nicotinic agonists have been shown to enhance performance in cognitive tasks based on attention and memory. The aim of this study was to use a test of olfactory working memory; the odour span task (OST) in rodents, to investigate the effects of subtype-specific nicotinic agonists on working memory in normal rats. Rats were trained in a non-matching to sample (NMTS) rule and then the full OST, which involved identifying a novel odour from an increasing number of presented odours. Male hooded Lister rats were treated with nicotine, selective nicotinic agonists or vehicle (saline). In order to validate the task, muscarinic and nicotinic receptor antagonists were also examined. Nicotine at both 0.05 and 0.1mg/kg significantly increased mean span length in the OST. The selective alpha 4 beta 2 nicotinic receptor agonist metanicotine (0.1mg/kg s.c.) and the selective alpha 7 nicotinic receptor agonist (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide) (compound A, 10mg/kg i.p.) also improved performance. In contrast, mecamylamine and scopolamine significantly decreased mean span length. These findings suggest a role for the activation of both alpha 4 beta 2 and alpha 7 subtypes of neuronal nicotinic receptor in mediating enhancements of olfactory working memory capacity in normal, non-compromised rats. These nicotinic receptor subtypes may therefore prove to be useful targets for the development of novel treatments for neuropsychiatric disorders that involve cognitive dysfunction.

The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice

There is evidence that standard-dose chemotherapy may impact cognitive function in cancer patients. The present study evaluated the effects of a combination of two anti-cancer drugs, methotrexate (37.5 mg/kg) and 5-fluorouracil (5FU, 75 mg/kg) on cognitive function in a mouse model. Drug-induced deficits were observed in adult BALB/C mice on tests of spatial memory, non-matching-to-sample (NMTS) learning and in a delayed-NMTS test of non-spatial memory. There were no group differences on tests of cued memory or discrimination learning. Performance-related variables were ruled out as possible explanations of the observed impairments. The impaired performance of the drug group, which was consistent with cognitive deficits observed in human cancer patients treated with similar types of chemotherapy, was attributed to functional changes in specific brain regions, including the frontal lobes and hippocampus.

Inhibition of neurogenesis interferes with hippocampus‐dependent memory function

Rats treated with low dose irradiation, to inhibit adult hippocampal neurogenesis, and control rats were administered a non-matching-to-sample (NMTS) task, which measured conditional rule learning and memory for specific events, and a test of fear conditioning in which a discrete CS was paired with an aversive US in a complex environment. Irradiated rats were impaired on the NMTS task when the intervals between sample and test trials were relatively long, and in associating the shock-induced fear with contextual cues in the fear conditioning task. Irradiated rats were not impaired in learning the basic NMTS rule or in performing that task when the intervals between the sample and test trials were short. Nor were there group differences in conditioning the fear response to the CS in the fear conditioning task. The results, which extend the range of hippocampus-dependent tasks that can be said to be vulnerable to the effects of neurogenesis suppression, support the hypothesis that new hippocampal cells generated in adulthood participate in a broad range of hippocampal functions.

Prenatal stress, moderate fetal alcohol, and dopamine system function in rhesus monkeys

This study examined the striatal dopamine system integrity and associated behavior in 5- to 7-year-old rhesus monkeys born from mothers that experienced stress and/or consumed moderate levels of alcohol during pregnancy. Thirty-one young adult rhesus monkeys were derived from females randomly assigned to one of four groups: (1) control group that consumed isocaloric sucrose solution throughout gestation; (2) stress group that experienced prenatal stress (10-min removal from home cage and exposure to three random loud noise bursts, gestational days 90 through 145); (3) alcohol group that consumed alcohol (0.6 g/kg/day) throughout gestation; or (4) combined alcohol plus stress group that received both treatments. The subjects were assessed for striatal dopamine system function using positron emission tomography (PET), in which the dopamine (DA)-rich striatum was evaluated in separate scans for the trapping of [ 18F]-Fallypride (FAL) and 6-[ 18F]fluoro- m-tyrosine (FMT) to assess dopamine D2 receptor binding potential (BP) and DA synthesis via dopa decarboxylase activity, respectively. Subjects were previously assessed for non-matching-to-sample (NMS) task acquisition, with ratings of behavioral inhibition, stereotypies, and activity made after each NMS testing session. Subjects from prenatal stress conditions (Groups 2 and 4) showed an increase in the ratio of striatal dopamine D2 receptor BP and DA synthesis compared to controls (Group 1). An increase in the radiotracer distribution volume ratios (DVRs), which is used to evaluate the balance between striatal DA synthesis and receptor availability, respectively, was significantly correlated with less behavioral inhibition. The latter supports a hypothesis linking striatal function to behavioral inhibitory control.

Age and time-of-day effects on learning and memory in a non-matching-to-sample test

This study provides further evidence that the time-of-day (TOD) when testing is conducted affects cognitive performance in old rats and, for the first time in an animal model, in young adult rats as well. Groups of young and old rats were entrained to a 12-h light–dark schedule and administered tests of learning and memory in a non-matching-to-sample (NMTS) task in a water maze. Testing was conducted at the beginning of the rats’ activity cycle (AM) or at the end of the cycle (PM). In addition to age differences in performing the task, there were major findings with respect to time of testing: (1) young rats tested in the PM were better than young rats tested in the AM at learning the NMTS rule and in the delayed-NMTS (DNMTS) task; (2) old rats tested in the AM were better than PM-tested old rats on the DNMTS task, with the former attaining performance levels that approximated those of young rats; (3) the TOD effect in old rats extended to a DNMTS reversal (DNMTS-R) condition in which rats, originally tested in the AM, subsequently were administered the test in the PM, and vice versa; (4) the TOD effects in young and old rats in the DNMTS and DNMTS-R tests were strongest at relatively long delays, suggesting that hippocampal function may be particularly vulnerable to such effects; (5) there was evidence in the old rats of a relationship between diurnal drinking patterns and performance at the longest delay in the DNMTS test. These results, which parallel similar findings with human subjects, emphasize a linkage between circadian rhythmicity and cognitive performance throughout adulthood, and indicate the importance of circadian disruption in old age as a contributing factor to age differences in learning and memory performance.

A comparison of old and young rats’ performance on a test of nonmatching-to-sample: An analysis of age-related encoding and memory deficits

Using a multiple probe testing procedure (Roitblat, 1980), young and old rats were tested on a nonmatching-to-sample (NMTS) task in a three-arm maze. Subjects were forced to visit two different arms successively and, after variable delays, were required to choose the nonmatching arm. Incorrect responses on an initial probe run were followed by a second probe run. On no-delay trials, old rats performed poorly on first probe runs but they improved significantly on second probe runs. At longer delays, old rats exhibited faster rates of decline than did young rats. The results indicated that old rats suffered a decline in their ability to encode new information and rapid memory loss, and that the two deficits combined to adversely affect overall performance. Results were related to neuropsychological evidence that implicated prefrontal and hippocampal dysfunction in the types of age-related deficits observed in the present study.

Nicotinic and muscarinic receptors in the rat prefrontal cortex: Differential roles in working memory, response selection and effortful processing

The aim of the present study was to evaluate the effects of cholinergic receptor blockade in the rat prefrontal cortex on cognitive processes. The nicotinic antagonists neuronal bungarotoxin and dihydro-beta-erythroidine and the muscarinic antagonist scopolamine were injected into the prelimbic area of the prefrontal cortex. Their behavioural effects were assessed in a T-maze to test reference memory (visual discrimination task) and working memory in delayed matching (MTS) and non-matching to sample (NMTS) tasks. Neuronal bungarotoxin produced a significant decrease in working memory performance in the MTS task but not in the NMTS task. In contrast, scopolamine impaired working memory in both MTS and NMTS tasks. Reference memory was not altered by any of the cholinergic antagonists. These results demonstrate a differential role of nicotinic and muscarinic receptors in the rat prefrontal cortex. Nicotinic transmission appears to be important in delayed response tasks requiring effortful processing for response selection, while the muscarinic system is involved in general working memory processes.

Relational learning in pigeons: The role of perceptual processes in between-key recognition of complex stimuli

In Experiment 1, we used six procedures in a series of unsuccessful attempts to obtain relational learning using trial-unique pictorial stimuli in pigeons. The Experiment began by testing conventional (three-key) matching-to-sample (MTS) and nonmatching-to-sample (NMTS); in subsequent stages of the experiment we progressively incorporated features of techniques that do obtain relational learning in a single-key apparatus. In Experiment 2, we found that acquisition of NMTS using pictorial stimuli proceeded no more rapidly than acquisition of a conditional discrimination. Experiment 3 showed that acquisition of NMTS was more rapid than acquisition of MTS when plain colored stimuli were used, but not when pictorial stimuli were used. These three experiments suggest that pigeons do not recognize pictorial stimuli shown on different keys. In Experiment 4, between-key recognition was obtained with familiar but not with novel pictorial stimuli. It is argued that perceptual learning facilitates the detection of the between-key identity of complex stimuli, and that perceptual processes may underlie the difficulty in demonstrating relational learning in pigeons.

Response latency and accuracy on a pretrained nonmatching-to-sample task in rats recovered from pyrithiamine-induced thiamine deficiency.

Rats were trained for 1,345 spatial nonmatching-to-sample (NMTS) trials, matched, assigned to pyrithiamine-induced thiamine deficiency (PTD) or control treatments, recovered, and re-tested for 400 trials of NMTS. The PTD model produced two bilaterally symmetrical lesions: one of medial thalamus that was centered on the internal medullary lamina (IML) and another involving the mammillary bodies. PTD rats with complete IML lesions showed a sharp drop in performance that persisted throughout posttreatment training. PTD rats with IML sparing were impaired immediately after treatment but improved to a level comparable to that of controls. For all animals, NMTS accuracy decreased for longer latency responses. PTD animals differed from controls primarily in the low frequency and inaccuracy of their short-latency (0-2.9 s) responses. The improvement of the PTD rats with IML sparing was marked by an increase in both the number and accuracy of short-latency responses.

Analysis of aversively conditioned learning and memory in rats recovered from pyrithiamine-induced thiamine deficiency.

Rats that had recovered from pyrithiamine-induced thiamine deficiency (PTD) were trained on tasks motivated by escape from mild footshock. On postmortem examination, the PTD model showed two consistent lesions: a bilaterally symmetrical lesion of the medial thalamus, which was centered on the internal medullary lamina (IML), and a lesion centered on the medial mammillary nuclei. PTD rats with IML lesions were impaired in learning a spatial nonmatching-to-sample (NMTS) task that was mastered without error by controls and PTD animals without IML lesions. These same animals were able to perform as well as controls on discrimination tasks based on either place or visual (light-dark) cues, although they made more errors than controls in reaching criterion in the initial place discrimination problem. These findings are consistent with findings from appetitively motivated tasks that PTD rats with IML lesions have an impaired capacity for working memory but not for reference memory.

The long-term retention of events in monkey memory

Nine monkeys ( Macaca fascicularis) demonstrated long-term memory for objects in a recognition task based on the non-matching-to-sample (NMTS) paradigm. In this task, the subjects were required to choose a novel object when it was paired with an alternative that had become familiar in previous NMTS training. When the familiar objects had been experienced an average of 3.4 times 4–9 months previously, 5 monkeys made 79% correct choices of the novel object. Three other monkeys exposed to the objects a mean of 12.8 times were 65% accurate at retention intervals of 20 months. A ninth subject achieved an accuracy of 68% after a retention interval of 34 months based on an exposure frequency of 10.6. These levels of performance indicate that in monkey event memory the mnemonic representation of an object is quite durable and a proportion of visual information may last for at least 3 years.

Medial versus lateral hyperstriatal lesions in pigeons: effects on autoshaping, non-matching-to-sample and spatial discrimination learning at short and long intertrial intervals

Three experiments contrasted the effects of medial and lateral hyperstriatal lesions in pigeons. Expt. 1 found that both types of lesion obtained slower acquisition of autoshaping, compared to unoperated controls. No group differences in maintained rate of autoshaped responding were found. Expt. 2 found that lateral but not medial lesions disrupted choice performance in a non-matching-to-sample (NMTS) task, in which initial preference was for the correct stimulus; birds with lateral lesions responded more slowly to the sample stimulus than did birds with medial lesions. Expt. 3 found that medial but not lateral lesions disrupted both acquisition and reversal of a spatial discrimination at a long, but not at a short intertrial interval (ITI). Medial lesions damage primarily the hyperstriatum accessorium and lateral lesions, the hyperstriatum ventrale; but no significant correlations between the extent of damage to either of these structures and severity of behavioural disruption were obtained. Implications of these findings for theoretical accounts of hyperstriatal involvement in learning processes are discussed.