Selective extra-dimensional set shifting deficit in a knock-in mouse model of Huntington's disease

People with early-stage Huntington's disease have been found to have a specific deficit in performing an extra-dimensional shift. To date no evidence of this deficit has been identified in transgenic or knock-in rodent models of the disease. The aim of the present paper then, was to test whether homozygous knock-in mice derived from the Hdh(CAG(150)) mouse line were impaired in any of five 2-choice discrimination tasks (simple, compound, compound reversal, intra-dimensional shift and extra-dimensional shift), and whether these mice were impaired at recalling these tasks on the following day. On the extra-dimensional shift task the Hdh(CAG(150)) homozygous mice required a greater number of trials to reach criteria than mice and the percentage of correct choices within the trials was also significantly reduced compared with the animals. For the recall tasks, a deficit for recalling the compound reversal test was found in the Hdh(CAG(150)) homozygous mice for both number of trials required to reach criteria and percentage of correct choices within the trials. Recall for the intra-dimensional shift task was also impaired in these animals when measured by the percentage of correct choices. Our results demonstrate a pronounced deficit in the Hdh(CAG(150)) mice not only on extra-dimensional shift performance in agreement with human studies, but also on recall tasks for both the compound reversal and the intra-dimensional shift tasks.     

Intra-dimensional/extra-dimensional set-shifting performance in schizophrenia: impact of distractors

BackgroundWe sought to determine if a representative group of young chronic patients with schizophrenia would demonstrate selective impairments in set shifting processes of the CANTAB Intra-dimensional/extra-dimensional (IDED) task. We predicted that patients would have prominent difficulties with Compound Discrimination (C_D) (stage of the task in which irrelevant stimuli are introduced) and Extra-Dimensional Shifting (EDS) (stage of the task in which a new stimulus dimension must be attended) on the basis of the results of cortical hypodopaminergic states in subhuman primates (for C_D) and effects of dorsolateral prefrontal cortical lesions on set shifting and prior results in schizophrenia (for EDS).MethodsWe administered the IDED to 36 patients and 26 healthy controls. Additionally, we administered the Wisconsin Card Sorting Test (WCST), another test of set shifting, and a Continuous Performance Test (CPT) type task of attention to patients with schizophrenia in order to investigate which cognitive components accounted for performance difficulties at different stages of the IDED task.ResultsPatients had selective difficulties on C_D and EDS stages of the task. In schizophrenic patients early stages of the task involving the introduction and establishment of attentional set were correlated to CPT performance, while later set shifting stages were correlated with WCST categories attained.ConclusionWe found evidence that patients with schizophrenia were susceptible to introduction of unreinforced irrelevant stimuli at the C_D stage, such that the previously rewarded target stimuli no longer held hegemony as a representation. This type of processing failure may reflect difficulties in stabilizing a representation and is consistent with effects of prefrontal hypodopaminergia in primates. Secondly, “survivors” of this stage experienced marked difficulties on EDS-stage, suggestive of classic prefrontal failures.     

Selective cognitive impairment in the YAC128 Huntington's disease mouse

People with HD have a demonstrated early extra-dimensional set-shifting deficit. In the present study, we use a novel water T-maze set-shifting procedure and demonstrate its validity as a set-shifting task in a mouse model of Huntington's disease. Three groups of YAC128 mice of different ages (27, 69 and 117 weeks) were run on the task, which incorporated six distinct stages in which the mice must learn a rule and then switch to a different rule. The six stages were: directional learning, directional learning reversal, light discrimination, light discrimination reversal, return to place learning and a maze rotation spatial learning test. Rule changes from place learning to light discrimination and back constitute extra-dimensional shifts. The results of the study demonstrate robust light/dark discrimination reversal learning deficits in transgenic mice from 27 weeks of age, and a directional learning to light discrimination extra-dimensional set-shifting deficit from 69 weeks of age. The extra-dimensional shift deficit was confirmed with control trials demonstrating the validity of the deficit and the task. The onset of reversal learning and extra-dimensional shift deficits corresponded with the development of mutant huntingtin N-terminal fragment aggregates in neurons of relevant forebrain regions.     

Sparing of attentional relative to mnemonic function in a subgroup of patients with dementia of the Alzheimer type

Patients with dementia of the Alzheimer type (DAT) received two tests of visual selective attention, together with tests of spatial and visual recognition memory and visuospatial conditional learning previously used to show deficits early in the course of DAT. One set of attentional tests compared visual discrimination learning along intra- and extra-dimensional shifts, using a "total change" design. In the 12 DAT patients capable of attempting the extra-dimensional shift (subgroup 1), performance was equivalent to that of controls. This subgroup was also unimpaired at simple and compound discrimination learning and reversal and an intra-dimensional shift. They were as accurate as controls on a visual search task requiring matching of stimuli on two dimensions with variable numbers of alternatives, but were significantly impaired in the tests of recognition memory and learning. By contrast, the other 13 patients showed marked impairments in the attentional tasks. This subgroup was also significantly worse than subgroup 1 in performance on the visual recognition and conditional learning tasks, and showed greater severity on most of the clinical ratings of dementia. The sparing of attentional shifting in patients early in the course of DAT is contrasted with the impairments previously described in patients with Parkinson's disease with only mild or absent memory loss. The implications of this double dissociation of deficits for understanding the neural bases of the cognitive deficits in these two neurodegenerative diseases are discussed and their significance for the staging of DAT is considered.     

Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man.

Attentional "set" shifting was assessed in a group of 20 neurosurgical patients with localized excisions of the frontal lobes, a group of 20 patients with unilateral temporal lobe lesions and a group of 11 patients who had undergone amygdalo-hippocampus removal. These three patient groups were compared with groups of both young (age-matched) and elderly normal control volunteers on a computerized test of visual discrimination learning involving both an intra- and an extra-dimensional shift. The frontal lobe group were selectively impaired in their ability to shift response set to a previously irrelevant dimension but not to shift attention to new exemplars of a previously relevant dimension. A similar pattern was observed in the elderly group of normal control volunteers. By comparison, both the temporal lobe patients and the amygdalo-hippocampectomy patients were unimpaired in their ability to perform either shift, although both groups had significantly prolonged selection latencies at the extra-dimensional shift stage of the task. These data are compared to previous findings from patients with idiopathic Parkinson's disease and are discussed in terms of a specific attentional set shifting deficit following frontal lobe damage.     

Discrimination, reversal, and shift learning in Huntington's disease: mechanisms of impaired response selection

In a series of three experiments, we investigated different aspects of response selection in early-stage clinically symptomatic Huntington's disease (HD) patients in the context of discrimination learning. A series of structurally related response selection tasks involving discrimination, reversal, and shift learning were employed. In Experiment 1, the mechanisms of our previously reported [37] finding of impaired extra-dimensional shift learning were explored. The results suggested that impaired shift learning in HD is a result of perseverative responding. In Experiment 2, performance on a concurrent-pair (CP) discrimination and reversal task was examined. HD patients showed no deficits in CP discrimination learning or reversal. In Experiment 3, the performance of HD patients on a probabilistic discrimination and reversal task was examined. HD patients were impaired in the learning of a probabilistic discrimination, and also its reversal. This reversal deficit was again the result of perseverative responding. In addition, there was a strong correlation between HD patients' activities of daily living scores and reversal errors. The result are consistent with current theories of the role of the basal ganglia in cognition, and suggest specific impairments in response selection mechanisms in HD, in particular, in overcoming selection biases based on prior reinforcement.     

Attentional set-shifting in mice: modification of a rat paradigm, and evidence for strain-dependent variation

Increasingly precise molecular genetic tools are available to study in mice the cellular mechanisms underlying complex brain functions, but the behavioural paradigms to assess these functions often lack the required specificity. In this study, an attentional set-shifting paradigm to assess medial frontal cortex functions in rats was modified for use in mice and variation between two relevant mouse strains assessed. Male 129/SvEv and C57BL/6J mice and their F1 intercross (n=8 per genotype) were trained to dig in bowls for a food reward. On four consecutive days, mice performed a series of discriminations to criterion (six consecutive correct choices) between pairs of food bowls that differed along two dimensions (odour, digging medium), including a reversal, an intra-dimensional shift, and an extra-dimensional shift. Mice from the 129 strain performed significantly better than C57 mice in the initial acquisition of a simple discrimination and in the final extra-dimensional shift test, with no difference in the reversal and intra-dimensional shift. Performance of the F1 mice was intermediate or similar to that of the 129 mice. These results indicate a selective difference between these two strains in attentional selection processes that have been shown in humans, monkeys and rats to be mediated by prefrontal cortex.     

Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat

Rats with medial prefrontal cortex (mPFC) lesions are impaired in attentional set-shifting, when it is required to shift to a previously irrelevant perceptual dimension. The main source of noradrenergic input to the mPFC is from the locus coeruleus via the dorsal noradrenergic ascending bundle (DNAB). This study examined the effects of selective cortical noradrenaline depletion following 6-hydroxydopamine-induced lesions of the DNAB on attentional set-shifting and other aspects of discrimination learning and performance. Rats learned to dig in baited bowls, and then acquired discriminations based on one of two aspects of a bowl--odour or digging medium. The task tested acquisition of novel discriminations (both intra- and extra-dimensional) and reversal learning when contingencies were reversed with the same stimuli. At the conclusion of testing, the DNAB-lesioned rats were shown to have a selective depletion of noradrenaline of approximately 70% within the mPFC (cingulate and prelimbic cortex subregions), with no other significant changes in dopamine or 5-hydroxytryptamine. Rats required more trials to learn new discriminations when attentional shifting was required [extra-dimensional (ED)-shift]. Rats with dorsal noradrenergic ascending bundle (DNAB) lesions were impaired in novel acquisitions when an ED-shift was required, but were unimpaired in reversal learning and other aspects of discrimination learning, relative to controls. These data are consistent with other evidence implicating noradrenaline (NA) in attentional set-shifting, and contrast with effects of manipulations of 5-hydroxytryptamine (5-HT) and acetylcholine within the medial prefrontal cortex (mPFC). The findings are also relevant to recent theorizing about the functions of the coeruleo-cortical noradrenergic system.     

Atomoxetine facilitates attentional set shifting in adolescent rats

Adolescent rats show immaturities in executive function and are less able than adult rats to learn reinforcement reversals and shift attentional set. These two forms of executive function rely on the functional integrity of the orbitofrontal and prelimbic cortices respectively. Drugs used to treat attention deficit disorder, such as atomoxetine, that increase cortical catecholamine levels improve executive functions in humans, non-human primates and adult rats with prefrontal lesions. Cortical noradrenergic systems are some of the last to mature in primates and rats. Moreover, norepinephrine transporters (NET) are higher in juvenile rats than adults. The underdeveloped cortical noradrenergic system and higher number of NET are hypothesized to underlie the immaturities in executive function found in adolescents. We assessed executive function in male Long-Evans rats using an intra-dimensional/extra-dimensional set shifting task. We administered the NET blocker, atomoxetine (0.0, 0.1, 0.9 mg/kg/ml; i.p.), prior to the test of attentional set shift and a reinforcement reversal. The lowest dose of drug facilitated attentional set shifting but had no effect on reversal learning. These data demonstrate that NET blockade allows adolescent rats to more easily perform attentional set shifting.     

Impaired extra-dimensional shift performance in medicated and unmedicated Parkinson''s disease: Evidence for a specific attentional dysfunction

Groups of patients with Parkinson's disease, either medicated, or unmedicated and early in the course, together with age- and IQ-matched control subjects were tested in two paradigms measuring different aspects of selective attention. The first set of tests compared visual discrimination learning following intra- and extra-dimensional shifts, using a "total change" design in which each shift was made in the presence of novel exemplars of the compound stimuli used as discriminanda. The second test consisted of a visual search task in which the number of alternatives was varied. The results of the first experiment showed a selective deficit in both groups of Parkinsonian subjects in their ability to perform an extra-dimensional shift. In the visual search task, the patients were less accurate, but responded with equivalent choice reaction times to those of controls. The results are discussed in terms of the nature of the attentional dysfunction that occurs in Parkinson's disease.     

Stimulus specific deficit on visual reversal learning after lesions of medial prefrontal cortex in the mouse

Tests of executive abilities, such as discrimination reversal and attentional set shifting, are sensitive to prefrontal cortex (PFC) damage in primates. The purpose of the present study was to use a primate reversal task to determine if PFC in the mouse is involved in similar cognitive functions. Mice with lesions of medial PFC and Sham operated control animals were trained on a series of visual problems in a computer-automated touchscreen apparatus using stimuli that varied in either pattern (lines) or luminance (black-white). PFC-lesioned mice learned to discriminate both sets of stimuli as readily as controls, but displayed a stimulus specific (pattern only) deficit on the reversal task. Analysis of error patterns on the line reversal suggests the deficit exhibited by PFC-lesioned mice was related to stimulus specific aspects of visual attention, rather than perseveration. These results demonstrate that medial PFC may play a role in control of directed attention and provide further evidence that the touchscreen procedure can be a useful tool for examining functional similarities in brain regions of very diverse species.     

Lesions of the orbital prefrontal cortex impair the formation of attentional set in rats

In rats, reversal learning impairments are commonly reported after lesions of the orbital prefrontal cortex (OFC), in contrast to the effect of lesions of the medial prefrontal cortex, which impair attentional set-shifting. Comparable dissociations have also been reported in humans, monkeys and mice. However, these two manifestations of behavioural flexibility may share common cognitive processes. The present study tested the hypothesis that lesions of the OFC (an area that integrates expected and actual outcomes to signal which cues in the environment predict reward) would impair the formation of attentional set as well as impairing reversal learning. We compared the performance of lesioned and control rats on two set-shifting tasks. The first task we used, 'the 4ID task', had no reversal stages, but multiple intradimensional acquisitions before the extradimensional shift stage, to assess set-formation as well as set-shifting. The second task was the standard intradimensional/extradimensional '7-stage task', which includes reversal learning stages after each compound acquisition. Compared with controls, lesioned rats were slower to form attentional set on the 4ID task. When they did form a set, they required more trials to complete the extradimensional shift stage. On the 7-stage task, we replicated our previous finding of impaired reversal learning and reduced shift-costs. We interpret these findings as reflecting a single deficit in identifying relevant cues after unexpected outcomes, which supports recent models of OFC function. Our findings challenge the assumption that the contribution of the OFC to behavioural flexibility is limited to reversal learning.     

An investigation of the relationship between response latency across several cognitive tasks in the beagle dog

Response latencies (RLs) extracted from simple motor tasks are a commonly used index of human intelligence. To date few human or animal studies have investigated the relationship between an individuals RL scores across a number of diverse cognitive tasks: Does RL remain consistent between individuals across several cognitive domains? Thus, the current study examined how RL measures gathered from beagle dogs (n=13) tested on three different cognitive tasks were related. RL scores were collected following both discrimination and reversal learning and a test of visuospatial memory, the 3 component delayed non-matching to position (3-DNMP) task. RL scores were recorded from the time the choice stimulus was presented until the animal selected a response. Results indicated that strong correlations emerged between 3-DNMP RLs and both the discrimination and reversal RLs, indicating that animals that responded fast on the 3-DNMP task also responded fast on the discrimination and reversal tasks. Interestingly, 3-DNMP RLs were more strongly correlated with reversal learning RLs. Finally, when mean RL performance across the three tasks was examined, strong RL differences emerged indicating that animals displayed significantly slower RLs on the 3-DNMP task than on the discrimination task, while reversal RLs remained indistinguishable from both. In conclusion, RLs show high between task correlations, indicating individual differences, and also vary between tasks, probably because of differences in task difficulty. These results further validate the use of RLs as an index of cognition, and also highlight the importance of further studies using animal models.     

Impaired dimensional selection but intact use of reward feedback during visual discrimination learning in Parkinson's disease

It has been suggested that Parkinson's disease (PD) impairs the ability to learn on the basis of reward or reinforcing feedback i.e., by trial-and-error. In many learning tasks, particular 'dimensions' of stimulus information are relevant whilst others are irrelevant; therefore, efficient performance depends on identifying the dimensions of these 'compound' stimuli and selecting the relevant dimension for further processing. We investigated the ability of patients with PD, as well as patients with Huntington's disease and patients with frontal or temporal lobe lesions, to learn visual discriminations which required either a number of associations to be learned concurrently (the 'eight-pair' task) or the selection of information from compound stimuli (the 'five-dimension' task), both tasks being learned by trial-and-error. None of the basal ganglia disorder patient groups was impaired on the eight-pair task, militating against a crucial role for these brain structures in trial-and-error learning per se. Patients with mild, medicated PD, but not unmedicated PD patients, were impaired at identifying all five feature dimensions in the five-dimension task, implying dopaminergic 'overdosing' of the ability to analyse compound stimuli in terms of their component dimensions. Temporal lobe lesion patients performed similarly, suggesting that the temporal lobe may be the site of the medication overdose effect. Patients with severe, medicated PD were impaired at compound discrimination learning on the five-dimension task in the absence of an underlying impairment in identifying component stimulus dimensions; this pattern resembled that seen in Huntington's disease and frontal lobe lesion patients, implying that fronto-striatal circuitry is involved in the formation of rules based upon selected stimulus dimensions.     

Performance norms for a rhesus monkey neuropsychological testing battery: acquisition and long-term performance.

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.     

Behavioural rigidity and rule-learning deficits following isolation-rearing in the rat: neurochemical correlates.

Isolation-reared rats were compared to those reared in social groups on the acquisition of a conditional visual discrimination (Expt. I), a simultaneous (simple) light/dark discrimination and serial reversal learning (Expt. II). In Expt. I, rats reared in social isolation made more errors during the acquisition of the conditional discrimination but did reach a level of accurate performance which was comparable with that of socially-reared rats. Discrimination performance in isolates was less disruptable by manipulations of the task requirements. Reducing the number of stimulus lights or the introduction of a distracting stimulus increased the number of errors committed by socially-reared rats but did not significantly affect accuracy in isolates. Performance in isolated rats was also remarkably resistant to changes in motivational variables. Isolates responded more frequently during conditions of extinction and were virtually unaffected by pre-feeding prior to testing. In Expt. II, isolation-reared rats were not impaired in the acquisition of a simultaneous discrimination but unlike socially-reared rats isolates failed to show improvement with successive reversals of this discrimination. Isolates exhibited stronger position habits than socially-reared rats following reversal of the contingencies. These results of these two experiments combined have demonstrated a specific impairment in rule learning in isolates. Isolated rats were not impaired on a simultaneous discrimination in which accurate performance can be achieved simply by approaching the stimulus associated with reinforcement, but performed worse than controls on both the conditional discrimination and on serial reversal learning, another form of conditional task. In both of these latter tasks each stimulus becomes equally associated with reward and therefore performance can be improved by learning a rule. Post-mortem neurochemical measurements made at the completion of Expt. II revealed selective alterations in dopaminergic, serotoninergic and cholinergic markers in isolated rats. Correlational analyses indicated specific relationships between neurochemical and behavioural measurements.     

Modulation of Behavior by Expected Reward Magnitude Depends on Dopamine in the Dorsomedial Striatum

Reward-predictive cues are important to guide behavioral responding. In a series of experiments, we sought to characterize the role of dopamine in the dorsomedial striatum in modulation of reward-directed responding by visual cues. Different groups of rats subjected to infusion of 6-hydroxydopamine or vehicle into the posterior part of the dorsomedial striatum (pDMS) were tested in three experiments. In experiment 1, rats were examined in an operant task demanding a lever release response. In intact rats, reaction times of responding were reliably shorter on cued large reward trials than on cued small reward trials. Results showed that pDMS dopamine depletion impaired reward-dependent modulation of reaction times, if visual cues predict large versus small reward, but not if visual cues predict reward versus no reward. These observations suggest that dopamine signaling in the pDMS contributes to a process through which reward-directed responses become guided by cues associated with distinct reward magnitudes. Experiment 2 revealed that pDMS dopamine depletion did not compromise the acquisition of a conditional visual discrimination task in an operant box that required learning a rule of the type “if the cue light is bright press left lever for reward, if dim press right lever”. Furthermore, experiment 3 showed that pDMS dopamine depletion did not impair the acquisition of a cross maze task that required learning a visual cue discrimination strategy to obtain food reward. Together results of experiments 2 and 3 indicate that dopamine signaling in the pDMS does not subserve stimulus discrimination per se and stimulus-response learning.     

Prefrontal cortex lesions and scopolamine impair attention performance of C57BL/6 mice in a novel 2-choice visual discrimination task

Sustained attention is defined as the ability or capacity to remain focused on the occurrence of rare events over long periods of time. We describe here the development of a novel, operant-based attention task that can be learned by mice in 8–10 days. Mice were trained on a 2-choice visual discrimination task in an operant chamber, wherein the correct response on any given trial was a lever-press cued by a stimulus light. Upon reaching a criterion of greater than 80% correct responses, all subjects were tested in a mixed-trial attention paradigm combining four different stimulus durations within a single session (0.5, 1, 2, or 10 s). During attention testing, the percentage of correct responses decreased as a function of stimulus duration, indicating a performance decrement which parallels increasing attentional demand within the task. Pretreatment with the muscarinic-receptor antagonist scopolamine yielded a reliable, dose-dependent performance deficit whereas nicotine treatment improved the percentage of correct responses during trials with the greatest attentional demand. Moreover, medial prefrontal cortex lesions impaired attention performance without affecting acquisition or retention of the discrimination rule. These results underscore the utility of this task as a novel means of assessing attentional processes in mice in a relatively high-throughput manner.     

Effects of preference, prompt, and task agreement on the discrimination learning of mentally retarded adults

Twenty-seven mentally retarded employees of a sheltered workshop were trained on five discrimination tasks (wires, hardware, moldings, capacitors, and fasteners) using five combination of preference, prompt, and task agreement: all agree, preference different, prompt different, tasks different, and all different. The data revealed that when the learners were prompted in the dimension of the target discrimination (a) fewer errors were made, (b) training time was reduced, and (c) fewer training trials were required to reach criterion. Preference for a particular dimension (color, shape, or size, as measured by a screening test) did not significantly affect performance on the discrimination tasks. Findings were discussed in terms of the functions of prompts as feedback, reinforcement, and symbolic parts of a compound stimulus.     

Position reversal learning in aged Japanese macaques.

We examined aged and young monkeys using a multiple position reversal task to investigate declines in cognitive functions with aging. The task consisted of an original learning task (simple position discrimination task) and a reversal learning task. While the performance of the aged monkeys was not different from that of the young monkeys in the original learning task, the aged monkeys showed a poorer performance than the young monkeys in the reversal learning task. According to our response analysis, the poor performance of aged monkeys in the reversal learning was not caused mainly by repetition of error responses, but rather by the impairment of understanding of the association between stimulus and reward. These results suggest that the prefrontal cortex, particularly the medial orbital cortex, is impaired with aging.