Attentional Set-shifting Research Articles

Positive allosteric modulation of alpha 7 nicotinic acetylcholine receptors enhances recognition memory and cognitive flexibility in rats

A wide body of preclinical and clinical data suggests that alpha 7 nicotinic acetylcholine receptors (α7-nAChRs) may represent useful targets for cognitive improvement in schizophrenia and Alzheimer׳s disease. A promising recent approach is based on the use of positive allosteric modulators (PAMs) of α7-nAChRs due to their several advantages over the direct agonists. Nevertheless, the behavioural effects of this class of compounds, particularly with regard to higher-order cognitive functions, have not been broadly characterised. The aim of the present study was to evaluate the procognitive efficacies of type I and type II α7-nAChRs PAMs, N-(4-chlorophenyl)-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and N-(5-Chloro-2,4-dimethoxyphenyl)-N’-(5-methyl-3-isoxazolyl)urea (PNU-120596) in the novel object recognition task (NORT), attentional set-shifting task (ASST) and five-choice serial reaction time task (5-CSRTT) in rats. Additionally, the effects of galantamine, an acetylcholinesterase inhibitor that also allosterically modulates nAChRs, were assessed. We report that CCMI (0.3–3mg/kg), PNU-120596 (0.3–3mg/kg) and galantamine (1–3mg/kg) attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. Methyllycaconitine (3mg/kg) blocked the actions of CCMI, PNU-120596 and galantamine in the NORT and ASST, suggesting that the procognitive effects of these compounds are α7-nAChRs–dependent. However, none of the compounds tested affected the rats’ attentional performance in the 5-CSRTT. The present findings confirm and extend the observations indicating that the positive allosteric modulation of α7-nAChRs enhances recognition memory and cognitive flexibility in preclinical tasks. Therefore, the present study supports the utility of α7-nAChRs PAMs as a potential cognitive enhancing therapy.

Effects of acamprosate on attentional set-shifting and cellular function in the prefrontal cortex of chronic alcohol-exposed mice.

The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol (EtOH) exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons. We induced alcohol dependence in mice via chronic intermittent EtOH (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices. Chronic EtOH exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic EtOH exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-D-aspartate receptor function. Moreover, CIE treatment lowered input resistance, and decreased the threshold and the after hyperpolarization of action potentials, suggesting chronic EtOH exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these EtOH-induced changes cellular function. Acamprosate improved attentional control of EtOH exposed animals, but did not alter the concurrent changes in synaptic transmission or membrane excitability of mPFC neurons, indicating that these changes are not the pharmacological targets of acamprosate in the recovery of mPFC functions affected by chronic EtOH exposure.

Prenatal Protein Malnutrition in the Rat Reduces Extracellular Norepinephrine in the Ventral Medial Prefrontal Cortex and Impairs Performance in Attentional Set Shifting

Our research on the behavioral and neuroanatomical consequences of prenatal protein malnutrition (PPM) has focused on the prefrontal cortex (PFC) given clinical findings of deficits in executive function in a human population (Galler et al., 2012; Waber et al., 2014). Female rats were fed low protein (6% casein) or adequate protein (25% casein) diets for five weeks prior to mating and throughout gestation. At birth, litters were culled to eight pups and cross-fostered to well-nourished dams. At adulthood, males were tested in an attentional set shifting task (ASST, McGaughy et al., 2014). An additional group was tested in the ASST and then implanted with microdialysis probes bilaterally into the ventral medial PFC (vmPFC). Results from the ASST showed that malnourished rats took more trials on reversals than well-nourished rats. Microdialysis probes showed significantly lower levels of extracellular norepinephrine (NE) in the right vmPFC in malnourished rats, but no difference between groups in the left vmPFC. These data suggest that NE levels in right vmPFC normally contribute to ASST performance but that in the prenatally malnourished rats, reduction in NE may contribute to impaired ASST performance but individual differences within the malnourished group do not account for suggesting impairments in other systems as well. These data also suggest that prenatal protein malnutrition alters brain circuits in the two hemispheres in a different manner. Supported by NIH/MH 074811.

Conditional loss of GluN2B in cortex and hippocampus impairs attentional set formation.

The ability to attend to appropriate stimuli, to plan actions and then alter those actions when environmental conditions change, is essential for an organism to thrive. There is increasing evidence that these executive control processes are mediated in part by N-methyl-D-aspartate receptors (NMDAR). NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules and are differentially expressed during development. Recent findings have suggested that the GluN2B subunit may play a unique role in both the acquisition of adaptive choice and the behavioral flexibility required to shift between choices. Here we investigated the role of GluN2B containing NMDARs in the ability to learn, reverse and shift between stimulus dimensions. Mutant mice (floxed-GluN2B x CaMKII-Cre) lacking GluN2B in the dorsal CA1 of the hippocampus and throughout the cortex were tested on an attentional set-shifting task. To explore the role that alterations in motor behavior may have on these behaviors, gross and fine motor behaviors were analyzed in mutant and floxed-control mice. Results show that corticohippocampal loss of GluN2B selectively impaired an initial reversal in a stimulus specific manner and impaired the ability of mutant mice to form an attentional set. Further, GluN2B mice showed normal motor behavior in both overall movement and individual limb behaviors. Together, these results further support the role of NMDAR, and GluN2B in particular, in aspects of executive control including behavioral flexibility and attentional processes.

Combination of Sub‐effective Doses of NMDA and D1 Dopamine Receptor Antagonists Impairs Executive Function in Rats

Contemporary research in the pathophysiology of cognitive deficits in schizophrenia has provided a multifactorial view, in which the neurotransmitters dopamine, gamma aminobutyric acid (GABA) and glutamate are disturbed in the prefrontal cortex (PFC) of schizophrenic brains. This view is supported by the fact that current antipsychotic drugs, which are primarily dopamine receptor blockers, are not effective in treating the cognitive symptoms of schizophrenia. We hypothesized that abnormality in dopamine, GABA and glutamate neurotransmissions act synergistically to cause certain cognitive symptoms of schizophrenia. We tested the effect of blockade of all three neurotransmitter systems on executive function using an operant conditioning‐based attentional set‐shifting task to assess behavioral flexibility. In a series of dose‐response studies, we determined the effective doses of the specific antagonists for dopamine D1 receptors (SH‐23390), GABA‐A receptors (bicuculline methiodide) and NMDA receptors (MK‐801). Next, sub‐effective doses were administered subcutaneously 25 min before the set‐shifting task. Our results indicate that while the single antagonist treatments did not impair set‐shifting, combination of sub‐effective doses of SH‐23390 and MK‐801 severely affected performance. Present findings will help to elucidate mechanisms underlying cognitive deficits in schizophrenia.Acknowledgement: Supported by NSERC and the Dept. of Psychiatry, University of Western Ontario.

Increased palatable food intake and response to food cues in intrauterine growth-restricted rats are related to tyrosine hydroxylase content in the orbitofrontal cortex and nucleus accumbens

Intrauterine growth restriction (IUGR) is associated with altered food preferences, which may contribute to increased risk of obesity. We evaluated the effects of IUGR on attention to a palatable food cue, as well as tyrosine hydroxylase (TH) content in the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in response to sweet food intake. From day 10 of gestation and through lactation, Sprague–Dawley rats received either an ad libitum (Adlib) or a 50% food-restricted (FR) diet. At birth, pups were cross-fostered, generating four groups (gestation/lactation): Adlib/Adlib (control), FR/Adlib (intrauterine growth-restricted), Adlib/FR, and FR/FR. Adult attention to palatable food cues was measured using the Attentional Set-Shifting Task (ASST), which uses a sweet pellet as reward. TH content in the OFC and NAcc was measured at baseline and in response to palatable food intake. At 90 days of age, FR/Adlib males ate more sweet food than controls, without differences in females. However, when compared to Controls, FR/Adlib females needed fewer trials to reach criterion in the ASST (p=0.04) and exhibited increased TH content in the OFC in response to sweet food (p=0.03). In the NAcc, there was a differential response of TH content after sweet food intake in both FR/Adlib males and females (p<0.05). Fetal programming of adult food preferences involves the central response to palatable food cues and intake, affecting dopamine release in select structures of the brain reward system.

Effects of pubertal cannabinoid administration on attentional set-shifting and dopaminergic hyper-responsivity in a developmental disruption model of schizophrenia.

Background:Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing, or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia.Methods:This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2mg/kg) was extended over 25 days throughout puberty (postnatal days 40–65) in control and MAM rats. The rats received 20 injections, which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons.Results:MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration, and an increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats (Sal). Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states.Conclusions:Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted.

Ketamine administration during the second postnatal week induces enduring schizophrenia-like behavioral symptoms and reduces parvalbumin expression in the medial prefrontal cortex of adult mice

Dysfunctions in the GABAergic system are considered a core feature of schizophrenia. Pharmacological blockade of NMDA receptors (NMDAR), or their genetic ablation in parvalbumin (PV)-expressing GABAergic interneurons can induce schizophrenia-like behavior in animals. NMDAR-mediated currents shape the maturation of GABAergic interneurons during a critical period of development, making transient blockade of NMDARs during this period an attractive model for the developmental changes that occur in the course of schizophrenia's pathophysiology. Here, we examined whether developmental administration of the non-competitive NMDAR antagonist ketamine results in persistent deficits in PFC-dependent behaviors in adult animals. Mice received injections of ketamine (30mg/kg) on postnatal days (PND) 7, 9 and 11, and then tested on a battery of behavioral experiments aimed to mimic major symptoms of schizophrenia in adulthood (between PND 90 and 120). Ketamine treatment reduced the number of cells that expressed PV in the PFC by ∼60% as previously described. Ketamine affected performance in an attentional set-shifting task, impairing the ability of the animals to perform an extradimensional shift to acquire a new strategy. Ketamine-treated animals showed deficits in latent inhibition, novel-object recognition and social novelty detection compared to their SAL-treated littermates. These deficits were not a result of generalized anxiety, as both groups performed comparably on an elevated plus maze. Ketamine treatment did not cause changes in amphetamine-induced hyperlocomotion that are often taken as measures for the positive-like symptoms of the disorder. Thus, ketamine administration during development appears to be a useful model for inducing cognitive and negative symptoms of schizophrenia.

Attentional Set-Shifting Across Species.

Attentional set-shifting, as a measure of executive flexibility, has been a staple of investigations into human cognition for over six decades. Mediated by the frontal cortex in mammals, the cognitive processes involved in forming, maintaining and shifting an attentional set are vulnerable to dysfunction arising from a number of human neurodegenerative diseases (such as Alzheimer's, Parkinson's and Huntington's diseases) and other neurological disorders (such as schizophrenia, depression, and attention deficit/hyperactivity disorder). Our understanding of these diseases and disorders, and the cognitive impairments induced by them, continues to advance, in tandem with an increasing number of tools at our disposal. In this chapter, we review and compare commonly used attentional set-shifting tasks (the Wisconsin Card Sorting Task and Intradimensional/Extradimensional tasks) and their applicability across species. In addition to humans, attentional set-shifting has been observed in a number of other animals, with a substantial body of literature describing performance in monkeys and rodents. We consider the task designs used to investigate attentional set-shifting in these species and the methods used to model human diseases and disorders, and ultimately the comparisons and differences between species-specific tasks, and between performance across species.

Executive function.

Components of human executive function, like rule generation and selection in response to stimuli (attention set-shifting) or overcoming a habit (reversal learning), can be reliably modelled in rodents. The rodent paradigms are based upon tasks that assess cognitive flexibility in clinical populations and have been effective in distinguishing the neurobiological substrates and the underlying neurotransmitter systems relevant to executive function. A review of the literature on the attentional set-shifting task highlights a prominent role for the medial region of the prefrontal cortex in the ability to adapt to a new rule (extradimensional shift) while the orbitofrontal cortex has been associated with the reversal learning component of the task. In other paradigms specifically developed to examine reversal learning in rodents, the orbitofrontal cortex also plays a prominent role. Modulation of dopamine, serotonin, and glutamatergic receptors can disrupt executive function, a feature commonly exploited to develop concepts underlying psychiatric disorders. While these paradigms do have excellent translational construct validity, they have been less effective as predictive preclinical models for cognitive enhancers, especially for cognition in health subjects. Accordingly, a more diverse battery of tasks may be necessary to model normal human executive function in the rodent for drug development.

Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review.

Cognitive dysfunction and negative symptoms of schizophrenia remain an unmet clinical need. Therefore, it is essential that new treatments and approaches are developed to recover the cognitive and social impairments that are seen in patients with schizophrenia. These may only be discovered through the use of carefully validated, aetiologically relevant and translational animal models. With recent renewed interest in the neurodevelopmental hypothesis of schizophrenia, postnatal administration of N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) has been proposed as a model that can mimic aspects of schizophrenia pathophysiology. The purpose of the current review is to examine the validity of this model and compare it with the adult subchronic PCP model. We review the ability of postnatal PCP administration to produce behaviours (specifically cognitive deficits) and neuropathology of relevance to schizophrenia and their subsequent reversal by pharmacological treatments. We review studies investigating effects of postnatal PCP on cognitive domains in schizophrenia in rats. Morris water maze and delayed spontaneous alternation tasks have been used for working memory, attentional set-shifting for executive function, social novelty discrimination for selective attention and prepulse inhibition of acoustic startle for sensorimotor gating. In addition, we review studies on locomotor activity and neuropathology. We also include two studies using dual hit models incorporating postnatal PCP and two studies on social behaviour deficits following postnatal PCP. Overall, the evidence we provide supports the use of postnatal PCP to model cognitive and neuropathological disturbances of relevance to schizophrenia. To date, there is a lack of evidence to support a significant advantage of postnatal PCP over the adult subchronic PCP model and full advantage has not been taken of its neurodevelopmental component. When thoroughly characterised, it is likely that it will provide a useful neurodevelopmental model to complement other models such as maternal immune activation, particularly when combined with other manipulations to produce dual or triple hit models. However, the developmental trajectory of behavioural and neuropathological changes induced by postnatal PCP and their relevance to schizophrenia must be carefully mapped out. Overall, we support further development of dual (or triple) hit models incorporating genetic, neurodevelopmental and appropriate environmental elements in the search for more aetiologically valid animal models of schizophrenia and neurodevelopmental disorders (NDDs).

D4 dopamine receptor-specific antagonist improves reversal learning impairment in amphetamine-treated male rats.

The Attentional Set-Shifting Task (ASST) is a rodent analog of the Wisconsin Card Sorting Task, which measures executive functioning. The ASST tests for reversal of stimulus-response learning and the formation and maintenance of attentional sets. Depletion of dopamine has been shown to improve performance on attentional shifts. The study presented here questioned whether a D₄-specific antagonist, L-745,870, could have a similar effect on animals, even after being treated with repeated doses of amphetamine. Three groups of male rats were given either 10 saline injections (n = 12), 10 amphetamine injections (2 mg/kg; n = 8), or 10 amphetamine injections plus 1 pretreatment injection of L-745,870 (0.1 mg/kg; n = 8) 20 min prior to testing. One-way ANOVA results showed that amphetamine-only rats were impaired on all 3 reversals (Ms = 19, 16.4, and 17.1) compared with L-745,870-treated rats (Ms = 9.8, 10.9, and 9.6) and controls (Ms = 8.6, 9.6, 9.3; all ps < .01). L-745,870-treated rats also displayed reduced latencies to respond compared with both saline controls and amphetamine rats. It is thought that D₄ receptors play a role in cue salience, and that by blocking these receptors, animals display less attachment to previously rewarded cues. The results presented support this idea and imply that blocking of D₄ receptors can reverse the impairment in reversals caused by amphetamine.

Attention shifting in Parkinson's disease: an analysis of behavioral and cortical responses.

The study was designed to examine persistent (input selection) versus transient (input shifting) mechanisms of attention control in Parkinson's disease (PD). The study identifies behavioral and neural markers of selective control and shifting control using a novel combination of a flanker task with an attentional set-shifting task, and it compares patients with PD with matched controls. Event-related brain potentials (ERPs) were recorded, and analyses focused on frontally distributed N2 waves, parietally distributed P3 waves, and error-related negativities (Ne/ERN). Controls showed robust shifting costs (prolonged response times), but patients with PD did not show evidence for comparable shifting costs. Patients with PD made more errors than controls when required to shift between attentional sets, but also when they had to initially maintain an attentional set. At the neural level it was found that contrary to controls, patients with PD did not display any N2 and P3 augmentations on shift trials. Patients with PD further did not display any error-related activity or posterror N2 augmentation. Our results reveal that intact selective control and disrupted shifting control are dissociable in patients with PD, but additional work is required to dissect the proportionate effects of disease and treatment on shifting control in PD. Our ERP-based approach opens a new window onto an understanding of motor and cognitive flexibility that seems to be associated with the dopaminergic innervation of cortico-striatal loops.

Prenatal Malnutrition Leads to Deficits in Attentional Set Shifting and Decreases Metabolic Activity in Prefrontal Subregions that Control Executive Function

Globally, over 25% of all children under the age of 5 years experience malnutrition leading to cognitive and emotional impairments that can persist into adulthood and beyond. We use a rodent model to determine the impact of prenatal protein malnutrition on executive functions in an attentional set-shifting task and metabolic activity in prefrontal cortex (PFC) subregions critical to these behaviors. Long-Evans dams were provided with a low (6% casein) or adequate (25% casein) protein diet 5 weeks before mating and during pregnancy. At birth, the litters were culled to 8 pups and fostered to control dams on the 25% casein diet. At postnatal day 90, prenatally malnourished rats were less able to shift attentional set and reverse reward contingencies than controls, demonstrating cognitive rigidity. Naive same-sexed littermates were assessed for regional brain activity using the metabolic marker ¹⁴C-2-deoxyglucose (2DG). The prenatally malnourished rats had lower metabolic activity than controls in prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices, but had comparable activity in the nearby piriform cortex and superior colliculus. This study demonstrates that prenatal protein malnutrition in a well-described animal model produces cognitive deficits in tests of attentional set shifting and reversal learning, similar to findings of cognitive inflexibility reported in humans exposed to early childhood malnutrition.

Attentional Set-Shifting in Parkinson’s Disease Patients with Freezing of Gait-Acquisition and Discrimination Set Learning Deficits at the Background?

Cognitive loading aggravates the freezing of gait (FoG), which is observed in approximately 50% of patients with Parkinson's disease (PD) in the advanced stages. To investigate whether a specific pattern of executive deficits, that is, attentional set-shifting and/or inhibitory control, are associated with FoG in PD, 30 PD patients with FoG (PD-FoG+) and 36 PD patients without FoG (PD-FoG-) and 22 control healthy subjects were examined with a comprehensive neuropsychological battery. Intra-Extra Dimensional Set shifting Test (IED) and Stop Signal Task (SST), selected from the Cambridge Automated Neuropsychological Battery (CANTAB battery), were administered to analyze set-shifting and motor inhibition, respectively. The IED task was significantly sensitive for differentiating between PD-FoG+ and PD-FoG- groups (p<.01), as well Adenbrook's clock drawing task (p=.033). By contrast, no differences emerged on any aspect of the SST task and other cognitive tasks. The attrition rate during the IED task showed that the problem in the PD-FoG+ group appeared at the pre-ID level, on the discrimination-learning set; the 32% PD-FoG+ subjects did not achieve the ID level of the task in comparison to negligible 4% of the PD-FoG- patients (p=.011). The logistic regression analysis, indicated the higher the IED stage successfully completed, the less likely presence of FoG in PD subjects. These results demonstrate that the complex cognitive-motor interplay might be responsible for FoG in PD and have had real life implication for the patients.

P.1.b.006 Role of striatal cholinergic interneurons in attention during learning in the rat

Aim of this study: Attentional set-shifting is a kind of flexible behaviour in which attention shifts from one stimulus dimension to another stimulus dimension. Many pieces of evidence suggest that the striatum plays a role in the set-shifting [1,2]. We investigated the hypothesis that cholinergic interneurons (CINs) play a role in such flexible behavior, using a set-shifting paradigm and immunotoxin-induced lesions of the CINs. Materials and Methods: We used Long-Evans rats (n = 42) weighing 250–300 g on arrival. All procedures were approved by OIST Animal Care and Use Committee. Control and lesion groups were prepared for each of three behavioural conditions (n = 7 in each group). Immunotoxin (anti-cholineacetyl transferase saporin) was bilaterally injected into the dorsomedial striatum (DMS), causing a specific lesion of the CINs while leaving other types of cells intact [3]. After recovery, instrumental conditioning was commenced in operant chambers. Throughout the experiments, each daily session consisted of 80 trials. In the initial 4 sessions, both left and right levers were inserted and animals learnt to press either the left or right lever to obtain a sucrose pellet, during which the light stimulus was differently presented as follows: condition 1, no light given; condition 2, a light presented always above the correct lever; condition 3, a light presented randomly on either side. In the subsequent 10 sessions, the light stimulus was randomly presented on either the left or right lever and animals learnt to choose a correct lever cued by the light (visual-cue learning). These procedures enabled us to examine different types of attentional shift to the light during visual-cue learning based on attention to: a novel stimulus; a previously relevant stimulus; or a previously irrelevant stimulus. Percentages of correct responses in each session were analyzed. After completion of the behavioural experiments, we analyzed the lesion histologically. Results: Comparing the percentages of correct responses in visual-cue learning between control groups showed that learning was faster in the condition when the light cue was previously relevant than when there was no light cue or the light was previously irrelevant. Lesions of the CINs impaired switching during visual-cue learning in the condition when the light cue was previously irrelevant, which required the animals to attend to a previously ignored stimulus. On the other hand, the lesion did not have a prominent effect on visual-cue learning under previously no-cue or relevant-cue conditions. Lesioned rats finally acquired visual-cue learning at 10th session in all conditions. Conclusions: The present results suggest that the CINs in DMS play an important role in attending to a previously irrelevant stimulus during set-shifting. However, these neurons do not strongly contribute to attentional processes when attending to a previously relevant or a novel stimulus for shifting attentional set during learning.

The Attentional Set-Shifting Test Paradigm in Rats for the Screening of Novel Pro-Cognitive Compounds with Relevance for Cognitive Deficits in Schizophrenia

Cognition deficits in schizophrenia remain an untreated area, and one in which R&D investment by pharmaceutical companies is high. However, whilst many preclinical assays demonstrate pro-cognitive activity with new drugs, in the main, they have not yet been translated successfully to the clinic. In an attempt to address this and reduce the high attrition rate for drugs in the clinic, selected preclinical researchers are re-focusing their efforts on the development and validation of more translational assays. The attentional setshifting task is an example of such an assay, which has been back-translated from the clinic to a preclinical setting. Here we review its application in schizophrenia research across humans and animals, specifically with regards to the neural basis underlying cognitive performance, the various disease-like or symptom models employed in rodents to mimic cognitive dysfunction in schizophrenia, and the resulting impact of drug treatment on executive function. Using the attentional set-shifting task, we highlight the potential promise a more translational approach can bring, whilst demonstrating the need for closer alignment in the validation and integration of this task to fully realize this promise.

Attentional Set-Shifting in Rodents: A Review of Behavioural Methods and Pharmacological Results

Attentional set-shifting tasks have been used as a measure of human fronto-executive function for over 60 years. The major contribution these tasks have made has been the quantification of cognitive deficits associated with human pathologies such as schizophrenia, attention deficit/hyperactivity disorder and dementias related to Parkinson's, Huntington's and Alzheimer's diseases. Thirteen years ago an intradimensional/extradimensional attentional set-shifting task was developed for rats. Since then, there have been over 70 publications detailing the effects of various manipulations on task performance in rats, and 17 publications describing adaptations of the task for mice. Much of this literature has focused on animal models of neuropathology and cognitive deficits associated with schizophrenia and other human conditions. Altogether, these results have elucidated the roles of multiple neurotransmitters in the manifestation of cognitive deficits, and their subsequent amelioration, including dopamine, serotonin, acetylcholine and noradrenaline. However, the fundamental promise of the attentional set-shifting task, to measure cognitive flexibility in humans and rodents in a formally analogous way, has often been under investigated and over simplified. This review explores the research that led to the development of the rat attentional set-shifting task, and how subsequent use of the task has expanded our understanding of the psychological and neurological underpinnings of discrimination and reversal learning, as well as the formation, maintenance and shifting of attentional set.

Loss of GluN2A-containing NMDA receptors impairs extra-dimensional set-shifting.

Glutamate neurotransmission via the N-methyl-D-aspartate receptor (NMDAR) is thought to mediate the synaptic plasticity underlying learning and memory formation. There is increasing evidence that deficits in NMDAR function are involved in the pathophysiology of cognitive dysfunction seen in neuropsychiatric disorders and addiction. NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules, and are differentially expressed during development. Despite these known differences, the relative contribution of individual subunit composition to synaptic plasticity and learning is not fully elucidated. We have previously shown that constitutive deletion of GluN2A subunit in the mouse impairs discrimination and re-learning phase of reversal when exemplars are complex picture stimuli, but spares acquisition and extinction of non-discriminative visually cued instrumental response. To investigate the role of GluN2A containing NMDARs in executive control, we tested GluN2A knockout (GluN2A(KO) ), heterozygous (GluN2A(HET) ) and wild-type (WT) littermates on an attentional set-shifting task using species-specific stimulus dimensions. To further explore the nature of deficits in this model, mice were tested on a visual discrimination reversal paradigm using simplified rotational stimuli. GluN2A(KO) were not impaired on discrimination or reversal problems when tactile or olfactory stimuli were used, or when visual stimuli were sufficiently easy to discriminate. GluN2A(KO) showed a specific and significant impairment in ventromedial prefrontal cortex-mediated set-shifting. Together these results support a role for GluN2A containing NMDAR in modulating executive control that can be masked by overlapping deficits in attentional processes during high task demands.

Impaired fear recognition and attentional set-shifting is associated with brain structural changes in alcoholic patients.

Alcoholic patients with multiple detoxifications/relapses show cognitive and emotional deficits. We performed structural magnetic resonance imaging and examined performance on a cognitive flexibility task (intra-extradimensional set shift and reversal; IED). We also presented subjects with fearful, disgust and anger facial emotional expressions. Participants were abstaining, multiply detoxified (MDTx; n = 12) or singly detoxified patients (SDTx; n = 17) and social drinker controls (n = 31). Alcoholic patients were less able than controls to change their behavior in accordance with the changing of the rules in the IED and they were less accurate in recognizing fearful expressions in particular. They also showed lower gray matter volume compared with controls in frontal brain areas, including inferior frontal cortex (IFC) and insula that mediate emotional processing, inferior parietal lobule and medial frontal cortex that mediate attentional and motor planning processes, respectively. Impairments in performance and some of the regional decreases in gray matter were greater in MDTx. Gray matter volume in IFC in patients was negatively correlated with the number of detoxifications, whereas inferior parietal lobule was negatively correlated with the control over drinking score (impaired control over drinking questionnaire). Performance in IED was also negatively correlated with gray matter volume in IFC/BA47, whereas recognition of fearful faces was positively correlated with the IFC gray matter. Repeated episodes of detoxification from alcohol, related to severity of dependency, are coupled with altered brain structure in areas of emotional regulation, attention and motor planning. Such changes may confer increased inability to switch behavior according to environmental demands and social incompetence, contributing to relapse.