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Important tools in the study of prefrontal cortical-dependent executive functions are cross-species behavioural tasks with translational validity. A widely used test of executive function and attention in humans is the continuous performance task (CPT). Optimal performance in variations of this task is associated with activity along the medial wall of the prefrontal cortex, including the anterior cingulate cortex (ACC), for its essential components such as response control, target detection and processing of false alarm errors. We assess the validity of a recently developed rodent touchscreen continuous performance task (rCPT) that is analogous to typical human CPT procedures. Here we evaluate the performance of mice with quinolinic acid-induced lesions centred on the ACC in the rCPT following a range of task parameter manipulations designed to challenge attention and impulse control. Lesioned mice showed a disinhibited response profile expressed as a decreased response criterion and increased false alarm rates. ACC lesions also resulted in a milder increase in inter-trial interval responses ('ITI touches') and hit rate. Lesions did not affect discriminative sensitivity d'. The disinhibited behaviour of ACC lesioned animals was stable and not affected by the manipulation of variable task parameter manipulations designed to increase task difficulty. The results are in general agreement with human studies implicating the ACC in the processing of inappropriate responses. We conclude that the rCPT may be useful for studying prefrontal cortex function in mice and has the capability of providing meaningful links between animal and human cognitive tasks.

An important link exists between intact metabolic processes and normal cognitive functioning; however, the underlying mechanisms remain unknown. There is accumulating evidence that the gut hormone ghrelin, an orexigenic peptide that is elevated during calorie restriction (CR) and known primarily for stimulating growth hormone release, has important extra-hypothalamic functions, such as enhancing synaptic plasticity and hippocampal neurogenesis. The present study was designed to evaluate the long-term effects of elevating acyl-ghrelin levels, albeit within the physiological range, on the number of new adult born neurons in the dentate gyrus (DG) and performance on the Spontaneous Location Recognition (SLR) task, previously shown to be DG-dependent and sensitive to manipulations of plasticity mechanisms and cell proliferation. The results revealed that peripheral treatment of rats with acyl-ghrelin enhanced both adult hippocampal neurogenesis and performance on SLR when measured 8-10 days after the end of acyl-ghrelin treatment. Our data show that systemic administration of physiological levels of acyl-ghrelin can produce long-lasting improvements in spatial memory that persist following the end of treatment. As ghrelin is potentially involved in regulating the relationship between metabolic and cognitive dysfunction in ageing and neurodegenerative disease, elucidating the underlying mechanisms holds promise for identifying novel therapeutic targets and modifiable lifestyle factors that may have beneficial effects on the brain. Fil: Kent, Brianne A.. University of Cambridge; Reino Unido Fil: Beynon, Amy L.. Swansea University; Reino Unido Fil: Hornsby, Amanda K. E.. Swansea University; Reino Unido Fil: Bekinschtein, Pedro Alejandro. University of Cambridge; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bussey, Timothy J.. University of Cambridge; Reino Unido Fil: Davies, Jeffrey S.. Swansea University; Reino Unido Fil: Saksida, Lisa M.. University of Cambridge; Reino Unido

The original version of the above article contained a mistake in the equation found in page 3953. Correct equation should be: c = -z(HR)+z(FAR)/2 Responsivityindex(RI) = HR+FAR-1/1-(HR-FAR)2.

Alzheimer's disease is increasing to epidemic levels with an estimated 36 million people affected worldwide (Wimo 2010). The aetiology of the disease is not known, which is hindering the progression of the treatment. This study is a longitudinal investigation into the performance of TgTauP301L mice as an animal model of Alzheimer's disease on the computer automated touchscreen 5-choice serial reaction time task (5-CSRTT). TgTauP301L mice have a single tau mutation in the P301L gene and develop the tau pathology that represents the observed tauopathy in patients with Alzheimer's disease. The aim of the investigation is to observe if tau pathology in the TgTauP301L mice causes a cognitive impairment in attention and executive function and at what stage this can be identified by the 5-CSRTT task. This will establish if the animals can be used as a therapeutic model for pre-clinical drug trials and help to identify an early indicator and intervention point in patients with Alzheimer's disease. The animals have previously been studied at 5-months and no differences between performances of the TgTauP301L mice and wild type mice were found (unpublished data). This study measured the performance of the animals at 7-months which is when the tauopathy begins to develop in TgTauP301L mice (Murakami 2005). The results of this study showed that there was no deficit in the performance of the TgTauP301L compared to the wild type mice and there had been no change in the animals' performance compared to at 5-months. The animals will be retested at 12-months once the pathology has extensively spread to see if the tauopathy causes a deficit in performance.

How the rich and diverse set of vertebrate higher cognitive functions and the susceptibility to human mental illness evolved is unknown. The vertebrate cognitive repertoire comprises multiple forms of learning, attention and executive functions, which are selectively disrupted in mental disorders, such as schizophrenia, autism and intellectual disability. Two whole genome duplications at the base of the vertebrate lineage generated gene paralogs that expanded and diversified the molecular complexity of simpler invertebrate synapse proteomes. Here we use computerized touchscreen tests for higher cognitive functions in mice and humans to examine the phenotype of mutations in one such set of paralogs, the Dlg family of synaptic scaffold proteins. Comparing mice carrying mutations in four Dlg paralogs shows simple associative learning required Dlg4 function while Dlg2 and Dlg3 diversified to play specific and opposing roles in complex learning and attentional processes. We compared the selective impairments of the mouse Dlg2 mutation with humans carrying Dlg2 mutations using homologous cognitive test apparatus and found a high degree of similarity in the selective disruption of the cognitive repertoire by Dlg2 mutations in both species. In humans, Dlg2 mutations are associated with schizophrenia and mutations in Dlg3 causes intellectual disability. Our data demonstrate that paralogous gene duplication and diversification initiated over 500 million years (My) ago diversified the regulation of vertebrate higher cognitive functions and that the constraint in structure and function of these genes within the last 100 My conserved the specific cognitive roles of genes underlying human mental illness. The demonstrated conservation in cognitive function using homologous psychological test apparatus also provides a new approach to translating the genetic studies of mental illness into therapeutic benefit.

Several mouse models of Alzheimer's disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.

The present experiment tested predictions of a 'perceptual-mnemonic/feature conjunction' (PMFC) model of perirhinal cortex function. The model predicts that lesions of perirhinal cortex should disrupt complex visual discriminations with a high degree of 'feature ambiguity', a property of visual discrimination problems that can emerge when features of an object are rewarded when they are part of one object, but not when part of another. As feature ambiguity is thought to be the critical factor, such effects should be independent of the number of objects to be discriminated. This was tested directly, by assessing performance of control monkeys and monkeys with aspiration lesions of perirhinal cortex on a series of concurrent discriminations in which the number of object pairs was held constant, but the degree of feature ambiguity was varied systematically. Monkeys were tested in three conditions: Maximum Feature Ambiguity, in which all features were explicitly ambiguous (AB+, CD+, BC-, AD-; the biconditional problem); Minimum Feature Ambiguity, in which no features were explicitly ambiguous (AB+, CD+, EF-, GH-); and Intermediate Feature Ambiguity, in which half the features were explicitly ambiguous (AB+, CD+, CE-, AF-). The pattern of results closely matched that predicted by simulations using a connectionist network: monkeys with perirhinal cortex lesions were unimpaired in the Minimum Feature Ambiguity condition, mildly impaired in the Intermediate Feature Ambiguity condition and severely impaired in the Maximum Feature Ambiguity condition. These results confirm the predictions of the PMFC model, and force a reconsideration of prevailing views regarding perirhinal cortex function.