"Blocking-like" effects in attentional set-shifting: Redundant cues facilitate shifting in male rats with medial prefrontal cortex inactivation.

Without a functioning prefrontal cortex, humans and other animals are impaired in measures of cognitive control and behavioral flexibility, including attentional set-shifting. However, the reason for this is unclear with evidence suggesting both impaired and enhanced attentional shifting. We inhibited the medial prefrontal cortex (mPFC) of rats while they performed a modified version of an attentional set-shifting task to explore the nature of this apparent contradiction.

Exacerbation of the credit assignment problem in rats with lesions of the medial prefrontal cortex is revealed by Bayesian analysis of behavior in the pre-solution period of learning.

Our internal models of the world help us to process information rapidly: in general model-based learning is more rapid than model-free learning. However, the cognitive flexibility required to overcome cognitive predispositions can let us down: it is not fully developed until adulthood; predispositions can be unconscious biases; and cognitive flexibility is impaired in many psychiatric and neurological conditions. To understand these limits to flexibility, we need to know how the brain generates predispositions and deploys flexibility.

More rapid reversal learning following overtraining in the rat is evidence that behavioural and cognitive flexibility are dissociable.

Cognitive flexibility is a term used to describe the brain processes underlying the phenomenon of adaptive change in behaviour in response to changed contingencies in the internal or external environment. Cognitive flexibility is often assessed in complex tasks measuring perceptual attentional shifting or response or task switching, but, arguably, reversal learning is a simple assay of cognitive flexibility. Reversal learning requires the detection of a changed outcome, the cessation of a previously-rewarded response and the selection of an alternative, previously-unrewarded, response.

Food or friends? What motivates zebrafish (Danio rerio) performing a visual discrimination.

As a model organism, zebrafish have much to offer neuroscientific research and they are increasingly being used in behavioral neuroscience, for example to study the genetics of learning and memory. As fish are often considered "less clever" than mammals, it is important to understand how they learn and to establish optimal testing conditions. In this study, we compared the efficacy of food reinforcement and social stimuli in supporting Pavlovian conditioning, Pavlovian-to-instrumental transfer, and acquisition of a two-alternative forced choice visual discrimination.

Oral dosing of rodents using a palatable tablet.

Rationale: Delivering orally bioavailable drugs to rodents is an important component to investigating that route of administration in novel treatments for humans. However, the traditional method of oral gavage requires training, is stressful, and can induce oesophageal damage in rodents.

Objectives: To demonstrate a novel administrative technique-palatable gelatine tablets-as a stress-free route of oral delivery.

Assessment of intradimensional/extradimensional attentional set-shifting in rats.

The rat intradimensional/extradimensional (ID/ED) task, first described by Birrell and Brown 18 years ago, has become the predominant means by which attentional set-shifting is investigated in rodents: the use of rats in the task has been described in over 135 publications by researchers from nearly 90 universities and pharmaceutical companies. There is variation in the protocols used by different groups, including differences in apparatus, stimuli (both stimulus dimensions and exemplars within), and also the methodology. Nevertheless, most of these variations seem to be of little consequence: there is remarkable similarity in the profile of published data, with consistency of learning rates and in the size and reliability of the set-shifting and reversal 'costs'.

Effects of lesions of the subthalamic nucleus/zona incerta area and dorsomedial striatum on attentional set-shifting in the rat.

Patients with Parkinson's disease (PD) show cognitive impairments, including difficulty in shifting attention between perceptual dimensions of complex stimuli. Inactivation of the subthalamic nucleus (STN) has been shown to be effective in ameliorating the motor abnormalities associated with striatal dopamine (DA) depletion, but it is possible that STN inactivation might result in additional, perhaps attentional, deficits. This study examined the effects of: DA depletion from the dorsomedial striatum (DMS); lesions of the STN area; and the effects of the two lesions together, on the ability to shift attentional set in the rat.

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.

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.

Stratified medicine for mental disorders.

There is recognition that biomedical research into the causes of mental disorders and their treatment needs to adopt new approaches to research. Novel biomedical techniques have advanced our understanding of how the brain develops and is shaped by behaviour and environment. This has led to the advent of stratified medicine, which translates advances in basic research by targeting aetiological mechanisms underlying mental disorder.

Tacrine improves reversal learning in older rats.

Age-related decline has been reported in most cognitive domains, including executive function: in particular, attentional set-shifting and reversal learning, as measures of executive control, are impaired in aged populations of both humans and rats. Despite the importance of the cholinergic system in age-related cognitive decline, no data are available on the effects of cholinergic enhancement on age-related performance deficits in tests of attentional set-shifting. We investigated the effects of the cholinesterase inhibitor tetrahydroacridin-9-amine (tacrine) on reversal learning and attentional set-shifting in older rats (aged 16-21 months) using the rodent version of the intradimensional/extradimensional attentional set-shifting task in a repeated-measures design.

Lesions of the dorsomedial striatum impair formation of attentional set in rats.

Behavioural flexibility refers to the ability to rapidly adapt to novel situations and it has been suggested that the frontal lobe and basal ganglia are implicated in various components of adjusting to changes in environmental contingencies. Behavioural flexibility can be assessed using attentional set-shifting tasks, in which performance is impaired after damage to the prefrontal cortex. The present study explores the downstream contribution of the prefrontal projection zone in the dorsomedial striatum (DMS) to attentional set shifting.

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.

Discrimination reversal and attentional sets in zebrafish (Danio rerio).

The potential of zebrafish as a comparative model in behavioural neuroscience is currently hampered only by the lack of reliable and validated behavioural assays available to researchers. In the present experiment, we describe the performance of zebrafish in a test of attentional set formation. The fish were initially trained on a two-choice colour discrimination.

Measuring the construct of executive control in schizophrenia: defining and validating translational animal paradigms for discovery research.

Executive control is an aspect of cognitive function known to be impaired in schizophrenia. Previous meetings of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) group have more precisely defined executive control in terms of two constructs: "rule generation and selection", and "dynamic adjustments of control". Next, human cognitive tasks that may effectively measure performance with regard to these constructs were identified to be developed into practical and reliable measures for use in treatment development.

The effects of DISC1 risk variants on brain activation in controls, patients with bipolar disorder and patients with schizophrenia.

Three risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-Schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n=33), patients with schizophrenia (n=20) and patients with bipolar disorder (n=36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus.

Refinement of the use of food and fluid control as motivational tools for macaques used in behavioural neuroscience research: report of a Working Group of the NC3Rs.

This report provides practical guidance on refinement of the use of food and fluid control as motivational tools for macaques used in behavioural neuroscience research. The guidance is based on consideration of the scientific literature and, where data are lacking, expert opinion and professional experience, including that of the members of a Working Group convened by the United Kingdom National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). The report should be useful to researchers, veterinarians and animal care staff responsible for the welfare of macaques used in food and fluid control protocols, as well as those involved with designing, performing and analysing studies that use these protocols.

Attention to visual, but not tactile, properties of a stimulus results in activation of FOS protein in the visual thalamic reticular nucleus of rats.

Previous reports have suggested that the modality-specific sectors of the thalamic reticular nucleus (TRN) may become selectively activated as a result of attention being drawn to their respective sensory modalities. Here we used a task that required the discrimination of digging bowls on the basis of their visual (the colour of the bowl) or tactile (the external texture of the bowl) characteristics. We trained rats to perform both modality discriminations, ensuring the equity of exposure to both visual and tactile aspects of the stimuli.

Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors.

The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP) is a GABA(A) receptor (GABA(A)R) agonist that preferentially activates delta-subunit-containing GABA(A)Rs (delta-GABA(A)Rs). To clarify the role of delta-GABA(A)Rs in mediating the sedative actions of THIP, we utilized mice lacking the alpha(1)- or delta-subunit in a combined electrophysiological and behavioural analysis. Whole-cell patch-clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of -60 mV.

Asenapine restores cognitive flexibility in rats with medial prefrontal cortex lesions.

Rationale: Cognitive inflexibility in schizophrenia is treatment-resistant and predictive of poor outcome. This study examined the effect of asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, on cognitive dysfunction in the rat.

Objectives: The objective of this paper was to establish whether asenapine has a beneficial effect on the performance of rats with ibotenic acid-induced lesion of the medial prefrontal cortex (mPFC) in an intradimensional/extradimensional (ID/ED) test of cognitive flexibility.

Lesions of the basal forebrain impair reversal learning but not shifting of attentional set in rats.

The cholinergic neurons of the basal forebrain, which project to cortex, the thalamic reticular nucleus and the amygdala, are implicated in many aspects of attentional function, while the intrinsic neurons of the basal forebrain are implicated in learning and memory. This study compared the effects of lesions of the basal forebrain made with either the immunotoxin 192-IgG-saporin (which selectively destroys cholinergic neurons), or the non-selective excitotoxin, ibotenic acid (which destroys both cholinergic and non-cholinergic neurons) on a task which measure the acquisition and shifting of attentional set as well as the ability to learn reversals of specific stimulus-reward pairings. Rats learned to obtain food reward by digging in small bowls containing distinctive digging media that were differentially scented with distinct odours.

Difficulty overcoming learned non-reward during reversal learning in rats with ibotenic acid lesions of orbital prefrontal cortex.

Behavioral flexibility is a concept often invoked when describing the function of the prefrontal cortex. However, the psychological substrate of behavioral flexibility is complex. Its key components are allocation of attention, goal-directedness, planning, working memory, and response selection.

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.

Amphetamine and the adenosine A(2A) antagonist KW-6002 enhance the effects of conditional temporal probability of a stimulus in rats.

As the length of foreperiod preceding an imperative signal increases, reaction time decreases and anticipatory (prior to the signal) responding increases. The authors designed a task to dissociate the effect of elapsing time in the foreperiod and conditional temporal probability of the imperative stimulus. The effects of 2 drugs--amphetamine and KW-6002--known to enhance the effect of foreperiod were compared.