Reversal Learning Performance Research Articles

D 1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D 1-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit ( P < 0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D 1-like receptor antagonist ( P < 0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase ( P < 0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 ( P < 0.05). These results suggest a role for D 1-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.

MAPPING ANTIPSYCHOTIC POTENTIAL USING MAGNETIC RESONANCE IMAGING (MRI) IN RATS TREATED WITH PHENCYCLIDINE (PCP)

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D1-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P < 0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D1-like receptor antagonist (P < 0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P < 0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P < 0.05). These results suggest a role for D1-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.

Dissociable Effects of Selective 5-HT2A and 5-HT2C Receptor Antagonists on Serial Spatial Reversal Learning in Rats

Serotonin (5-hydroxytryptamine, or 5-HT) is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. However, there is little information on the contribution of different 5-HT receptors in reversal learning. Thus, we investigated the effects of systemic administration of the 5-HT(2A) antagonist M100907 (0, 0.01, 0.03, and 0.1 mg/kg, i.p.) and the 5-HT(2C) antagonist SB 242084 (0, 0.1, 0.3, and 1.0 mg/kg, i.p.) on the performance of an instrumental two-lever spatial discrimination and serial spatial reversal learning task, where both levers were presented and only one was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of within-session reversals was presented. Neither M100907 nor SB 242084 altered performance during spatial discrimination and retention of the previously reinforced contingencies. M100907 significantly impaired reversal learning by increasing both trials to criterion (only at the highest dose) and incorrect responses to criterion in Reversal 1, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, SB 242084 improved reversal learning by decreasing trials and incorrect responses to criterion in Reversal 1, with significantly fewer perseverative responses. These data support the view that 5-HT(2A) and 5-HT(2C) receptors have distinct roles in cognitive flexibility and response inhibition. The improved performance in reversal learning observed following 5-HT(2C) receptor antagonism suggests these receptors may offer the potential for therapeutic advances in a number of neuropsychiatric disorders where cognitive deficits are a feature, including obsessive-compulsive disorder.

Dopamine D2/D3 Receptors Play a Specific Role in the Reversal of a Learned Visual Discrimination in Monkeys

Converging evidence supports a role for mesocorticolimbic dopaminergic systems in a subject's ability to shift behavior in response to changing stimulus-reward contingencies. To characterize the dopaminergic mechanisms involved in this function, we quantified the effects of subtype-specific dopamine (DA) receptor antagonists on acquisition, retention, and reversal of a visual discrimination task in non-human primates (Chlorocebus aethiops sabaeus). We used a modified Wisconsin General Test Apparatus that was equipped with three food boxes, each fitted with a lid bearing a unique visual cue; one of the cues concealed a food reward, whereas the other two concealed an empty box. The monkeys were trained first to acquire a novel discrimination (eg A(+), B(-), C(-)) in a single session, before experiencing either a reversal of the discrimination (eg A(-), B(+), C(-)) or the acquisition of a completely new discrimination (eg D(+), E(-), F(-)), on the following day. Systemic administration of the D(2)/D(3) receptor antagonist raclopride (0.001-0.03 mg/kg) failed to significantly affect the performance of reversal learning when reversal sessions were run without a retention session. But, raclopride (0.03 mg/kg) significantly impaired performance under the reversal condition when reversal sessions were run right after a retention session; however, it did not affect acquisition of a novel visual discrimination. Specifically, raclopride significantly increased the number of reversal errors made before reaching the performance criterion in the reversal, but not in new learning sessions. In contrast, the D(1)/D(5) receptor antagonist SCH 23390 did not significantly modulate acquisition of a novel discrimination or reversal learning at doses (0.001-0.03 mg/kg, i.m.) that did not suppress behavior generally. In addition, none of the drug treatments affected retention of a previously learned discrimination. The results strongly suggest that D(2)/D(3) receptors, but not D(1)/D(5) receptors, selectively mediate reversal learning, without affecting the capacity to learn a new stimulus-reward association. These data support the hypothesis that phasic DA release, acting through D(2)-like receptors, mediates behavioral flexibility.

Reversal learning after prenatal or early postnatal alcohol exposure in juvenile and adult rats

Learning tasks that require the reversal of a previously learned contingency are disrupted in animals and humans exposed to alcohol during the perinatal period. The current experiments examined how varying the time of alcohol exposure and the age at which subjects were tested would affect the expression of reversal deficits in a T-maze task. Groups of rats were exposed to alcohol from gestational day (GD) 8 to GD20 or from postnatal day (PN) 4 to PN9, and then tested in a spatial reversal task at either PN28 or PN63. Results indicate that exposure to alcohol during the prenatal period did not lead to substantial dose-dependent reversal learning deficits in males or females at either age tested. However, exposure to alcohol during the early postnatal period, a period that corresponds to the third trimester in human neural development, selectively disrupted reversal learning performance in male rats at PN28 but not PN63. Statistically significant sex differences were seen when subjects were tested at PN63. These results demonstrate how the timing of alcohol exposure leads to variability in the age-dependent expression of learning deficits associated with fetal alcohol effects.

Sensitivity to a change in reward is heritable in the honeybee, Apis mellifera

Honeybees must track changing distributions of food resources in their environment. We evaluated the genetic basis for interindividual differences in this ability by selecting lines of honeybees that differed in their tendency to reverse a learned discrimination between two odours. We show that individual variation in reversal learning performance, which is an analogue of natural foraging problems such as risk sensitivity, has a heritable component. Selection on drones, which are haploid, was sufficient to obtain a significant selection response after a single generation. In addition, worker age and/or task specialization, in terms of performance of housekeeping versus outside duties, is a source of environmental control over expression of reversal performance. Finally, we identified a correlated response in latent inhibition, in which pre-exposure to a conditioned stimulus (CS) retards learning about that CS when it is subsequently paired with reinforcement. From an ecological standpoint, our results suggest that colonies that contain a variety of genetic lineages may be able to target foragers to learning tasks in which they are genetically predisposed to do well.

A comparison between the effects of medial septal lesions and entorhinal cortex lesions on performance of nonspatial working memory tasks and reversal learning

Rats with either electrolytic medial septal lesions or cytotoxic entorhinal lesions were compared to unoperated controls on a series of delayed matching-to-sample (DMS) tasks. A DMS trial consisted of two runs. In the first (information) run, the subject was familiarized with a sample discriminandum. In the second (choice) run, the subject was required to discriminate the sample discriminandum from a novel one. When a set of 20 discrete complex objects were used as discriminanda and each discriminandum was used once per day, neither lesions impaired choice accuracy. However, when a single pair of simple discriminanda was employed and re-used between trials within a day, rats with medial septal lesions were severely impaired whereas rats with entorhinal lesions performed at a level comparable to unoperated controls. Next, proactive interference was demonstrated by the introduction of an extra run prior to the information run. When this extra ( pre-information) run required the subjects to visit the (eventual) negative discriminandum such that correct choice had to be guided by relative familiarity judgement, choice performance was reduced. Neither lesion group was selectively affected by this manipulation. But when the relative reinforcement history of the pre-information run and the information run was manipulated, such that a correct response required the subject to approach a discriminandum that had recently been non-rewarded, rats with entorhinal lesions were selectively impaired. The effect of delay was demonstrated when a 20-s interval was imposed between information run and choice run. This reduced overall choice accuracy, and this effect appeared to be more pronounced in both lesion groups, although not significantly so. Finally, neither lesion affected the acquisition of a simple discrimination task, but reversal learning was selectively enhanced in the entorhinal lesion group.

A preliminary study of the relationship between discrimination reversal learning and performance tasks in yearling and 2-year-old horses

A study was conducted to determine the relationship between discrimination reversal learning and performance tasks in horses. Ten yearling and seven 2-year-old mares and geldings of Arabian ( n = 4), Quarter Horse ( n = 9), and Thoroughbred ( n = 4) breeding were given a two-choice discrimination task in which either a black or a white bucket contained a food reward for ten trials per day during 19 test days. The spatial position of the buckets was varied on a random schedule. The rewarded bucket color was reversed each time a subject met criterion of eight correct choices per day for 2 consecutive days. Discrimination reversal testing was followed by 6 days of performance tasks: three crossing a wooden bridge and three jumping an obstacle to reach food and conspecifics, within a maximum allotted time of 15 min day −1. Total reversals attained by the horses were low ( x = 1.5 ± 0.9). All subjects did attain at least one reversal, and six had two or more reversals. No differences ( P > .05) were detected between ages or sexes, nor among breeds in discrimination reversal learning or performance test measurements. However, there was a trend towards a breed difference ( P ≤ 0.09) in the mean number of correct responses to the first reversal criterion. Correlations between reversal learning results and performance task results were extremely low, indicating that the discrimination reversal learning test was not useful for predicting success at these performance tasks. Results from the two performance tasks also showed little correlation ( r = 0.04, P < 0.91), indicating that horses might not use the same approach when solving the problem of crossing these two obstacles. The overall poor performance of the horses on the discrimination reversal task suggests horses may have difficulty reversing previously learned tasks.

Prenatal cocaine exposure alters performance in reversal learning and delayed spatial alternation (DSA) tasks: Assessment of inhibitory control, proactive interference, and memory

Prenatal cocaine exposure alters performance in reversal learning and delayed spatial alternation (DSA) tasks: Assessment of inhibitory control, proactive interference, and memory

Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor.

The secreted form (sAPP) of the Alzheimer amyloid beta/A4 protein precursor (APP) has been shown to be involved in the in vitro regulation of fibroblast growth and neurite extension from neuronal cells. The active site of sAPP responsible for these functions is within a small domain just C-terminal to the Kunitz-type protease inhibitor (KPI) insertion site. We report here that a 17-mer peptide, containing this active domain of sAPP, can induce cellular and behavioral changes when infused into rat brains. After 2 weeks of APP 17-mer peptide infusion, the animals were tested for reversal learning and memory retention and were sacrificed for morphological examination of brains. We found that administration of the APP 17-mer peptide resulted in an 18% increase in the number of presynaptic terminals in the frontoparietal cortex. At the behavioral level, 17-mer-infused animals with nonimpaired learning capability showed an increased memory retention that seemed to interfere with reversal learning performance. This APP 17-mer effect on memory retention was not observed in animals with impaired initial learning capacity. These results suggest that APP is involved in memory retention through its effect on synaptic structure.

Comparison of the effects of acute and chronic ibotenic and quisqualic acid nucleus basalis lesioning

The present study examines the effects of acute (1 month recovery) and chronic (8 month recovery) bilateral quisqualic (quis) and ibotenic (ibo) acid nucleus basalis (NB) lesioning on the activity of cholinergic neurons and on passive avoidance (PA) and water-maze (WM) performance. Our data demonstrate that A: The activity of choline acetyltransferase (ChAT) in cortical tissue and the number of ChAT positive neurons in the NB were decreased 1 and 8 months after quis or ibo NB lesioning. B: Ibo NB lesioning produced a greater nonspecific subcortical cell loss than quis NB lesioning. C: PA retention was impaired by acute and chronic quis and ibo NB lesioning. D: Acute ibo NB lesioning impaired acquisition and reversal learning in WM performance whereas chronic ibo NB lesioning impaired only reversal WM learning. Acute and chronic quis NB lesioning impaired reversal WM learning. The present results suggest that NB cholinergic neurons do not recover spontaneously from excitotoxin-induced damage and that they may be importantly involved in inhibitory avoidance and spatial reversal learning performance.

Reversal learning in pigeons: Effects of selective lesions of the Wulst.

The effects of bilateral lesions of individual laminae of the Wulst on reversal-learning performance in pigeons were evaluated. After surgery, the birds were trained to perform a simultaneous color discrimination. Once successful discrimination was achieved, the positive and negative stimuli were reversed, and the birds were again trained to criterion. Twenty such reversals were carried out. A multiple regression analysis indicated that those components of the Wulst that were critical for increasing the numbers of errors on each reversal were the laminae that receive the thalamofugal visual projections, that is, the nucleus intercalatus of the hyperstriatum accessorium and the hyperstriatum dorsale. Lesions in the other laminae of the Wulst (the hyperstriatum accessorium and the hyperstriatum intercalatus superior) had no effect on errors. There was no evidence of an increase in either perseverative errors or position habits in the birds with lesions, which suggested that the reversal deficits were not likely to be due to perseveration, attentional impairment, or inappropriate processing of spatial information. The deficit may have been produced by excessive interference between learning in a given session and learning in previous sessions.

Reversal learning in pigeons: effects of selective lesions of the Wulst.

The effects of bilateral lesions of individual laminae of the Wulst on reversal-learning performance in pigeons were evaluated. After surgery, the birds were trained to perform a simultaneous color discrimination. Once successful discrimination was achieved, the positive and negative stimuli were reversed, and the birds were again trained to criterion. Twenty such reversals were carried out. A multiple regression analysis indicated that those components of the Wulst that were critical for increasing the numbers of errors on each reversal were the laminae that receive the thalamofugal visual projections, that is, the nucleus intercalatus of the hyperstriatum accessorium and the hyperstriatum dorsale. Lesions in the other laminae of the Wulst (the hyperstriatum accessorium and the hyperstriatum intercalatus superior) had no effect on errors. There was no evidence of an increase in either perseverative errors or position habits in the birds with lesions, which suggested that the reversal deficits were not likely to be due to perseveration, attentional impairment, or inappropriate processing of spatial information. The deficit may have been produced by excessive interference between learning in a given session and learning in previous sessions.

Beneficial effect of chronic treatment with Org 2766 and α-MSH on impaired reversal learning of rats with bilateral lesions of the parafascicular area

The effects of chronic treatment with the ACTH-(4–9) analogue Org 2766, α-MSH and γ 2-MSH were studied on T-maze reversal learning and on behavior assessed on the basis of open-field and other gross behavioral activities, grasping responses, inspection of various reflexes and electrical footshock sensitivity of rats with parafascicular lesions or sham-lesions. Repeated administration of Org 2766 and α-MSH to parafascicular area-lesioned rats resulted in functional recovery of impaired T-maze reversal learning. The structurally related neuropeptide γ 2-MSH was without any effect. The α-MSH effect did not depend on time after lesioning as treatments during the first or second post-operative week were equally effective. Chronic peptide treatments did not change disturbed motor functions of parafascicular-lesioned rats, as measured by open-field activity, other gross behavioral activities and grasping responses. Since acute peptide treatments did not affect the impaired reversal learning performance of lesioned rats, the beneficial effect of Org 2766 and α-MSH could not be explained as a short-term effect on attention and motivation. It was more likely to be an accelerated recovery of cognitive function as a result of long-term neurotropic influences.

Instrumental reversal learning and subsequent fixed ratio performance on simple and go/no-go schedules in neodecorticate rabbits

Neodecorticated rabbits (94%-97% of neocortex removed) were able to acquire and repeatedly reverse an instrumental two-treadle differentiation based on food reward. Completion of 15 reversals of the two-treadle differentiation by the neodecorticates was followed by successful training on fixed ratio (FR) schedules as high as FR 60. The neodecorticates’ rate of treadle pressing on FR was lower than normals’, but efficiency was high and food-tray-related behaviors did not intrude on the treadle-press response. The improvements in FR performance in these neodecorticates in comparison with those in previous studies was interpreted as a result of enhanced manipulandum identification produced by the prior reversal training. The neodecorticates were impaired, however, in their ability to form reversal learning sets and in the establishment of go/no-go performance on a FR baseline. Possible interpretations of the data in terms of Pavlovian and instrumental learning and the differential representation of these two processes in the brain were considered.

Neuroendocrine influences on visual discrimination and reversal learning in the albino and hooded rat

Pigmented and nonpigmented rats were treated with MSH and MRIH-I and tested on a brightness discrimination and reversal task. Pigmented rats acquired the original habit and performed the reversal task significantly faster than albino rats. MSH and MRIH-I administration significantly facilitated reversal learning performance. Simple effects tests indicated that the effects of MSH and MRIH-I were significant only for albino rats on the reversal task. The data were interpreted to suggest that MSH and MRIH-I affects attentional processes more profoundly in visually deficient animals.

The reversal index and ageing

The discrimination and reversal learning performance of rats was studied at four different ages, from 4 months to 18 months. The Reversal Index (RI) was found to reduce steadily as age increased. The age range studied in the rats approximately covers a range equivalent to childhood to maturity in humans. It does not extend into the period where significant effects due to old age are observed in humans.

Discrimination-reversal skills of primates: The reversal/acquisition ratio as a function of phyletic standing

The ratio of reversal performance to acquisition performance in discrimination reversal learning differentiated primate groups and varied with acquisition proficiency.