Object Reversal Learning Research Articles

(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

Long-term environmental impact on object recognition, spatial memory and reversal learning capabilities in Cacna1c-haploinsufficient rats.

Genetic and environmental influences are thought to interact in their contribution to the etiology of major neuropsychiatric disorders. One of the best replicated findings obtained in genome-wide association studies are genetic variants in the CACNA1C gene. Here, we used our constitutive heterozygous Cacna1c rat model in combination with a 4-week exposure to either post-weaning social isolation, standard housing or social and physical environmental enrichment during the critical juvenile developmental period to observe their long-term interactive effects with Cacna1c haploinsufficiency. Our study provides evidence for a gene × environment interaction, i.e. an interplay between Cacna1c haploinsufficiency and environment during juvenile development, on object recognition, spatial memory and reversal learning capabilities. Social and physical enrichment had a positive influence on Cacna1c+/- rats and Cacna1c+/+ littermate controls on spatial and reversal learning, while post-weaning social isolation negatively affected novel object recognition in both genotypes. Despite intact spatial learning and re-learning abilities in all groups, slight but consistent deficits were evident in Cacna1c+/- rats previously housed under standard conditions particularly during reversal learning but not Cacna1c+/- rats previously exposed to social and physical enrichment. Together, this supports the notion that Cacna1c interacts with the environment to shape disease vulnerability and associated alterations in cognitive functioning.

TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABAA receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia

GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABAA α2,3 subtype-selective GABAA partial agonist and α1/5 antagonist, and the neurosteroid, pregnenolone sulfate, a GABAA antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABAA agonists may be of benefit to treat CIAS.

Attentional updating and monitoring and affective shifting are impacted independently by aging in macaque monkeys

One hallmark of the normal cognitive aging process involves alterations in executive function. Executive function can be divided into at least three separable components, including set shifting, attentional updating and monitoring, and inhibition of prepotent responses. The ability to study the neural basis of cognitive aging has been enriched by the use of animal models such as the macaque monkey. In aged macaques, changes in attentional updating and monitoring systems are poorly understood compared to changes in shifting and inhibition. A partial explanation for this is the fact that the tasks designed to study executive function in aged monkeys, to date, primarily have probed shifting and inhibition processes. Here we examine how aging impacts attentional updating and monitoring processes in monkeys using an interference task designed after a paradigm used to examine multi-tasking in older humans. Young and aged macaque monkeys were tested on this interference task as well as on an object reversal learning task to study these processes in the same animals. Relative to the young monkeys, aged animals were impaired on both tasks. Proactive and retroactive interference did not differ between age groups on an array of 40 object pairs presented each day in the object reversal learning task. The levels of performance on the interference task were not correlated with levels of performance in the object reversal task. These results suggest that attentional updating and monitoring and affective shifting are separable functions in the macaque, and that normal aging affects these mental operations independently.

Prefrontal mechanisms of behavioral flexibility, emotion regulation and value updating

Two ideas have dominated the neuropsychology of the orbitofrontal cortex (OFC). One holds that OFC regulates emotion and enhances behavioral flexibility through inhibitory control. The other ascribes to OFC a role in updating valuations based on current motivational states. Neuroimaging, neurophysiological and clinical observations are consistent with either or both hypotheses. Although these hypotheses are compatible in principle, the present results support the latter view of OFC function and argue against the former. We show that excitotoxic, fibersparing lesions confined to OFC in monkeys do not alter either behavioral flexibility, as measured by object reversal learning, or emotion regulation, as assessed by snake fear. A follow-up experiment indicates that previous reports of a loss of inhibitory control resulted from damage to nearby fiber tracts and not from OFC dysfunction. Thus, OFC plays a more specialized role in reward-guided behavior and emotion than currently thought, a function that includes value updating.

Neural correlates of feedback processing in obsessive–compulsive disorder.

Obsessive-compulsive disorder (OCD) patients show hyperactive performance monitoring when monitoring their own actions. Hyperactive performance monitoring is related to OCD symptomatology, like the unflexibility of compulsive behaviors, and was suggested as a potential endophenotype for the disorder. However, thus far the functioning of the performance monitoring system in OCD remains unclear in processes where performance is not monitored in one's own actions internally, but through external feedback during learning. The present study investigated whether electrocortical indicators of feedback processing are hyperactive, and whether feedback-guided learning is compromised in OCD. A modified deterministic four-choice object reversal learning task was used that required recurrent feedback-based behavioral adjustment in response to changing reward contingencies. Electrophysiological correlates of feedback processing (i.e. feedback-related negativity [FRN] and P300) were measured in 25 OCD patients and 25 matched healthy comparison subjects. Deficits in behavioral adjustment were found in terms of higher error rates of OCD patients in response to negative feedback. Whereas the FRN was unchanged for reversal negative feedback, it was reduced for negative feedback that indicated that a newly selected stimulus was still incorrect. The observed FRN reduction suggests attenuated monitoring of feedback during the learning process in OCD potentially contributing to a deficit in adaptive behavior reflected in obsessive thoughts and actions. The reduction of FRN amplitudes contrasts with overactive performance monitoring of self-generated errors. Nevertheless, the findings contribute to the theoretical framework of performance monitoring, suggesting a dissociation of processing systems for actions and feedback with specific alterations of these two systems in OCD.

The Role of the Anterior Cingulate Cortex in Choices based on Reward Value and Reward Contingency

Although several studies have emphasized the role of the anterior cingulate cortex (ACC) in associating actions with reward value, its role in guiding choices on the basis of changes in reward value has not been assessed. Accordingly, we compared rhesus monkeys with ACC lesions and controls on object- and action-based reinforcer devaluation tasks. Monkeys were required to associate an object or an action with one of two reward outcomes, and we assessed the monkey's shift in choices of objects or actions after changes in the value of 1 outcome. No group differences emerged on either task. For comparison, we tested the same monkeys on their ability to make choices guided by reward contingency in object- and action-based reversal learning tasks. Monkeys with ACC lesions were impaired in using rewarded trials to sustain the selection of the correct object during object reversal learning. They were also impaired in using errors to guide choices in action reversal learning. These data indicate that the role of the ACC is not restricted to linking specific actions with reward outcomes, as previously reported. Instead, the data suggest a more general role for the ACC in using information about reward and nonreward to sustain effective choice behavior.

Dissociable Effects of Subtotal Lesions within the Macaque Orbital Prefrontal Cortex on Reward-Guided Behavior

The macaque orbital prefrontal cortex (PFo) has been implicated in a wide range of reward-guided behaviors essential for efficient foraging. The PFo, however, is not a homogeneous structure. Two major subregions, distinct by their cytoarchitecture and connections to other brain structures, compose the PFo. One subregion encompasses Walker's areas 11 and 13 and the other centers on Walker's area 14. Although it has been suggested that these subregions play dissociable roles in reward-guided behavior, direct neuropsychological evidence for this hypothesis is limited. To explore the independent contributions of PFo subregions to behavior, we studied rhesus monkeys (Macaca mulatta) with restricted excitotoxic lesions targeting either Walker's areas 11/13 or area 14. The performance of these two groups was compared to that of a group of unoperated controls on a series of reward-based tasks that has been shown to be sensitive to lesions of the PFo as a whole (Walker's areas 11, 13, and 14). Lesions of areas 11/13, but not area 14, disrupted the rapid updating of object value during selective satiation. In contrast, lesions targeting area 14, but not areas 11/13, impaired the ability of monkeys to learn to stop responding to a previously rewarded object. Somewhat surprisingly, neither lesion disrupted performance on a serial object reversal learning task, although aspiration lesions of the entire PFo produce severe deficits on this task. Our data indicate that anatomically defined subregions within macaque PFo make dissociable contributions to reward-guided behavior.

Quality of Care for Chronic Diseases in a British Cohort of Long-Term Cancer Survivors

Previous research has shown that long-term cancer survivors with other chronic diseases may receive poorer care for those diseases compared with the general population. We sought to establish the quality of care for chronic diseases among cancer survivors in the United Kingdom. From the UK General Practice Research Database, we identified 21,366 adult patients who had survived 5 or more years after a diagnosis of breast, colorectal, or prostate cancer with a diagnosis of hypertension, coronary artery disease, diabetes, or cerebrovascular disease. For each patient, an age-sex matched noncancer control patient was selected from the same general practice and with the same chronic disease. We compared the chronic disease care in cancer survivors and their matched controls. The proportion of patients meeting quality standards for chronic disease care was high in both cancer survivors and control patients. Although cancer survivors were slightly less likely to receive blood pressure monitoring and cholesterol tests, this difference was no longer apparent if patients who died during the study period were excluded. For instance, 93% of breast cancer survivors received blood pressure monitoring compared with 94% of matched control patients. Similarly, control of disease was comparable among all patients, with the exception of diabetic prostate cancer survivors, who had fewer cholesterol readings under the control limit (17% reduction, 95% CI, 7%-26%) and diabetic colorectal survivors, who had fewer calendar quarters of glycated hemoglobin control (12% reduction, 95% CI, 2%-23%). Care of comorbidities is not neglected in the United Kingdom because people have had a previous diagnosis of cancer. One explanation is that in the United Kingdom, such care is provided through a robust primary care system.

Amygdala and Orbitofrontal Cortex Lesions Differentially Influence Choices during Object Reversal Learning

In nonhuman primates, interaction between the orbitofrontal cortex (OFC) and the amygdala (AMG) has been seen as critical for learning and subsequently changing associations between stimuli and reinforcement. However, it is still unclear what the precise role of the OFC is in altering these stimulus-reward associations, and recent research has questioned whether the AMG makes an essential contribution at all. To gain a better understanding of the role of these two structures in flexibly associating stimuli with reinforcement, we reanalyzed a set of previously published data from groups of monkeys with either OFC or AMG lesions that had been tested on an object reversal learning task. Based on trial-by-trial analyses of rewarded and unrewarded choices, we report two new findings. First, monkeys with OFC lesions were, compared with both control and AMG groups, unable to use correctly performed trials to optimally guide subsequent choices. Second, monkeys with AMG lesions showed the opposite pattern of behavior. This group benefited more than controls from correctly performed trials that followed an error. Finally, as has been reported by others, after a change in reward contingencies, monkeys with OFC lesions also showed a slightly greater tendency to choose the previously rewarded object. These findings demonstrate that the OFC and AMG make different contributions to object reversal learning not highlighted previously.

Prefrontal–Inferotemporal Interaction Is Not Always Necessary for Reversal Learning

Prefrontal cortex (PFC) is thought to have a wide-ranging role in cognition, often described as executive function or behavioral inhibition. A specific example of such a role is the inhibition of representations in more posterior regions of cortex in a "top-down" manner, a function thought to be tested by reversal learning tasks. The direct action of PFC on posterior regions can be directly tested by disconnecting PFC from the region in question. We tested whether PFC directly inhibits visual object representations in inferotemporal cortex (IT) during reversal learning by studying the effect, in macaque monkeys, of disconnecting PFC from IT by crossed unilateral ablations. We tested two visual object reversal learning tasks, namely serial and concurrent reversal learning. We found that the disconnection severely impairs serial reversal learning but leaves concurrent reversal learning completely intact. Thus, PFC cannot be said to always have direct inhibitory control over visual object representations in reversal learning. Furthermore, our results cannot be explained by generalized theories of PFC function such as executive function and behavioral inhibition, because those theories do not make predictions that differentiate different forms of reversal learning. The results do, however, support our proposal, based on other experimental evidence from macaque monkeys, that PFC has a highly specific role in the representation of temporally complex events.

Rhesus Monkeys with Orbital Prefrontal Cortex Lesions Can Learn to Inhibit Prepotent Responses in the Reversed Reward Contingency Task

Monkeys with lesions of the orbital prefrontal cortex (PFo) are impaired on behavioral tasks that require the ability to respond flexibly to changes in reward contingency (e.g., object reversal learning and extinction). These and related findings in rodents and humans have led to the suggestion that PFo is critical for the inhibitory control needed to overcome prepotent responses. To test this idea, we trained rhesus monkeys with PFo lesions and unoperated controls on acquisition of the reversed reward contingency task. In this task, selecting the smaller of 2 food quantities (1 half peanut [1P]) leads to receipt of the larger quantity (4 half peanuts [4P]) and vice versa. Choice of a larger quantity of food is a reliable prepotent response, and, accordingly, all monkeys initially selected 4P rather than one. With experience, however, all monkeys learned to select 1P in order to receive 4. Surprisingly, monkeys with PFo lesions learned as quickly as unoperated controls. Thus, PFo lesions do not yield a deficit in all tests that require the inhibition of a prepotent response.

Bilateral orbital prefrontal cortex lesions in rhesus monkeys disrupt choices guided by both reward value and reward contingency.

The orbital prefrontal cortex (PFo) operates as part of a network involved in reward-based learning and goal-directed behavior. To test whether the PFo is necessary for guiding behavior based on the value of expected reward outcomes, we compared four rhesus monkeys with two-stage bilateral PFo removals and six unoperated controls for their responses to reinforcer devaluation, a task that assesses the monkeys' abilities to alter choices of objects when the value of the underlying food has changed. For comparison, the same monkeys were tested on a standard test of flexible stimulus-reward learning, namely object reversal learning. Relative to controls, monkeys with bilateral PFo removals showed a significant attenuation of reinforcer devaluation effects on each of two separate assessments, one performed shortly after surgery and the other approximately 19 months after surgery; the operated monkeys were also impaired on object reversal learning. The same monkeys, however, were unimpaired in acquisition of object discrimination learning problems and responded like controls when allowed to choose foods alone, either on a food preference test among six different foods or after selective satiation. Thus, satiety mechanisms and the ability to assign value to familiar foods appear to be intact in monkeys with PFo lesions. The pattern of results suggests that the PFo is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals (reinforcer devaluation) or by visual signals conveying reward contingency (object reversal learning).

Combined unilateral lesions of the amygdala and orbital prefrontal cortex impair affective processing in rhesus monkeys.

The amygdala and orbital prefrontal cortex (PFo) interact as part of a system for affective processing. To assess whether there is a hemispheric functional specialization for the processing of emotion or reward or both in nonhuman primates, rhesus monkeys (Macaca mulatta) with combined lesions of the amygdala and PFo in one hemisphere, either left or right, were compared with unoperated controls on a battery of tasks that tax affective processing, including two tasks that tax reward processing and two that assess emotional reactions. Although the two operated groups did not differ from each other, monkeys with unilateral lesions, left and right, showed altered reward-processing abilities as evidenced by attenuated reinforcer devaluation effects and an impairment in object reversal learning relative to controls. In addition, both operated groups showed blunted emotional reactions to a rubber snake. By contrast, monkeys with unilateral lesions did not differ from controls in their responses to an unfamiliar human (human "intruder"). Although the results provide no support for a hemispheric specialization of function, they yield the novel finding that unilateral lesions of the amygdala-orbitofrontal cortical circuit in monkeys are sufficient to significantly disrupt affective processing.

Monkeys with rhinal cortex damage or neurotoxic hippocampal lesions are impaired on spatial scene learning and object reversals.

Rhesus monkeys (Macaca mulatta) with lesions of the rhinal cortex or parahippocampal gyrus (made by aspiration) or hippocampus (made with ibotenic acid) and unoperated controls were tested on object discrimination and reversal, place discrimination and reversal, and spatial scene learning to determine the contribution of these temporal lobe structures to these forms of learning and memory. Rhinal cortex lesions produced a severe deficit in object reversal learning; hippocampal lesions produced a milder deficit. Monkeys with rhinal cortex removals and those with hippocampal lesions were equally impaired on spatial scene learning. None of the lesions impaired place discrimination or reversal. These results argue against the idea that the mnemonic contributions of the rhinal cortex and hippocampus are limited to object and spatial domains, respectively.

Patterns of cognitive decline in aged rhesus monkeys

Although cognitive decline has been well established as a consequence of aging in non-human primate models, the prevalence or frequency of impairment for specific age ranges has not been described. The first aim of this study was to estimate prevalence of cognitive impairment on each of the six tests of cognitive performance by comparing the performance of early-aged (19–23 years old), advanced-aged (24–28 yeras old), and oldest-aged (29+ years old) monkeys to that of young adults (<15 years old). The second aim was to derive a single overall measure of cognitive performance to help classify behavioral function in our aged monkeys. Accordingly, we obtained performance measures for these age groups on six behavioral measures: (1) acquisition of the delayed non-matching-to-sample task (DNMS); (2) performance of the DNMS with a delay of 120 sec; (3) the spatial condition of the delayed recognition span test (DRST); (4) the color condition of the DRST; (5) spatial reversal learning; and (6) object reversal learning. Early-aged monkeys displayed prevalence rates of impairment significantly greater than zero on all tasks except the DRST-color. The highest prevalence of impairment was observed in this age group in a task measuring spatial memory (DRST). Significant trends toward progressively higher impairment rates in advanced-aged and oldest-aged monkeys were observed for DNMS-acquisition, DRST-color and spatial reversal learning tasks. A linear transformation of standardized scores on the six cognitive tests was derived by means of principal components analysis (PCA). The first PCA (PCA1) included data from 30 monkeys with available data on all six measures, and yielded a composite measure which declined linearly with increasing age ( r=−0.74). A second PCA (PCA2) was performed on data from 53 monkeys for which three test scores (DNMS-acquisition, DNMS-120s delay, and DRST-spatial condition) were available. The composite score derived from this analysis was highly correlated ( r=0.93) with the composite score from PCA1, suggesting that a score based on only three tests may provide an adequate classification of global cognitive ability.

Effects of orbital frontal and anterior cingulate lesions on object and spatial memory in rhesus monkeys

Object memory processes, evaluated in rhesus monkeys by delayed nonmatching-to-sample with trial-unique stimuli and object reversal learning, were more severely impaired by orbital frontal than by anterior cingulate lesions. Spatial memory processes, assessed by spatial delayed response and spatial reversal learning, showed a weak trend in the opposite direction, though on these tasks neither lesion produced a serious loss. Comparison of the present results with those of earlier studies on the effects of various limbic system lesions suggests that object memory processes, including object recognition and object-reward association, are served by a circuit consisting mainly of the rhinal cortex, orbitofrontal cortex, and the magnocellular division of the medial dorsal thalamic nucleus. Although both the rhinal and orbitofrontal components of this circuit appear to participate in both functions, evidence from the present and earlier studies suggests that the orbitofrontal component is the more important one for associative memory, i.e. the formation across trials of associations between particular objects or classes of objects and reward, whereas the rhinal component is the more critical one for recognition memory, i.e. the storage and retrieval within trials of the representations of particular objects.

Executive system dysfunction in the aged monkey: Spatial and object reversal learning

As part of an effort to characterize age-related cognitive changes in executive system function in a nonhuman primate model of human aging, the performance of seven rhesus monkeys, 20 to 28 years of age, was compared to that of five young adult monkeys, 6 to 11 years of age, on spatial and object reversal tasks. No differences in performance were found between the two groups in the initial learning of either task. On spatial reversals, aged monkeys were impaired relative to young adults, but there was no difference in overall performance between the groups on object reversals. Central to this article, a perseverative tendency was noted in the aged group on both spatial and object reversal tasks. Changes in executive system dysfunction may represent an important aspect of age-related cognitive decline.

Learning about rules but not about reward is impaired following lesions of the cholinergic projection to the hippocampus

Common marmosets with bilateral ibotenic acid-induced destruction of the neurones of the vertical limb of the diagonal band of Broca, which provide the major cholinergic input to the hippocampal formation, were impaired on the acquisition but not on the retention of a repeated-trial visuospatial discrimination learning task. They were also impaired on serial spatial reversal learning (but not on serial object reversal learning), on acquisition of a trial-independent successive concurrent discrimination using novel objects (but not on acquisition of a comparable discrimination in which two familiar objects had predictable reward value) and were unable to acquire a difficult conditional object discrimination. It is argued that the role of the hippocampus is in the acquisition but not the retention of ruled-based behaviour (which includes spatial responding) in contrast to the acquistion of discriminations based on stimulus-reward association formation.

An analysis of visual object reversal learning in the marmoset after amphetamine and haloperidol

The effect of amphetamine and haloperidol pretreatment on visual object reversal learning was assessed in the marmoset. Amphetamine induced perseverative responding demonstrated by high learning scores and worse than chance performance in the early stages of reversal. This perseverative responding was prevented by pretreatment with haloperidol. Haloperidol, either alone or in conjunction with amphetamine caused a mild, non-perseverative impairment on reversal learning only.