An Operant Intra-/Extra-dimensional Set-shift Task for Mice

Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set-shifting in human subjects are the Wisconsin Card Sorting Test (WCST) and the CANTAB Intra-/Extra-dimensional set shift task (ID/ED). These tasks have proven clinical relevance and have been modified and successfully adapted for research in animal models. However, currently available tasks for rodents present several limitations, mainly due to their manual-based testing procedures, which are hampering translational advances in psychiatric medicine. To overcome these limitations and to better mimic the original version in primates, we present the development of a novel operant-based two-chamber ID/ED "Operon" task for rodents. We demonstrated the effectiveness of this novel task to measure different facets of cognitive flexibility in mice including attentional set formation and shifting, and reversal learning. Moreover, we show the high flexibility of this task in which three different perceptual dimensions can be manipulated with a high number of stimuli cues for each dimension. This novel ID/ED Operon task can be an effective preclinical tool for drug testing and/or large genetic screening relevant to the study of executive dysfunction and cognitive symptoms found in psychiatric disorders.     

Determination of Sheep Learning Responses to a Directional Audio Cue

There are scientific opinions that a nonhuman animal cannot feel emotions, and, hence, positive experiences, without being cognitive. Therefore, determining an animal's cognitive capacity can be useful in supporting the existence of emotions. Research shows that sheep can perform tasks based on olfactory and visual stimuli; however, little research exists on determining the ability of sheep to perform such tasks based on auditory cues. This study demonstrates that sheep can perform a discriminant, operant task based on a visual cue (p < .001); however, sheep could not exhibit the desired response to a directional audio cue in 2 subsequent studies (p = .346; p = .031). Nonetheless, the study provides further evidence on the complex cognitive abilities of sheep and indicates the potential for sheep to use audio cues in their learning.     

Reproductive experience does not persistently alter prefrontal cortical-dependent learning but does alter strategy use dependent on estrous phase

Reproductive experiences in females comprise substantial hormonal and experiential changes and can exert long lasting changes in cognitive function, stress physiology, and brain plasticity. The goal of this research was to determine whether prior reproductive experience could alter a prefrontal–cortical dependent form of learning (strategy set shifting) in an operant box. In this study, female Sprague–Dawley rats were mated and mothered once or twice to produce either primiparous or biparous dams, respectively. Age-matched nulliparous controls (reproductively-naïve females with no exposure to pup cues) were also used. Maternal behaviors were also assessed to determine whether these factors would predict cognitive flexibility. For strategy set shifting, rats were trained in a visual-cue discrimination task on the first day and on the following day, were required to switch to a response strategy to obtain a reward. We also investigated a simpler form of behavioral flexibility (reversal learning) in which rats were trained to press a lever on one side of the box the first day, and on the following day, were required to press the opposite lever to obtain a reward. Estrous phase was determined daily after testing. Neither parity nor estrous phase altered total errors or trials to reach criterion in either the set-shifting or reversal-learning tasks, suggesting that PFC-dependent cognitive performance remains largely stable after 1 or 2 reproductive experiences. However, parity and estrous phase interacted to alter the frequency of particular error types, with biparous rats in estrus committing more perseverative but fewer regressive errors during the set-shifting task. This suggests that parity and estrous phase interfere with the ability to disengage from a previously used, but no longer relevant strategy. These data also suggest that parity alters the behavioral sensitivity to ovarian hormones without changing overall performance.     

鸟类学习记忆研究进展

在学习记忆研究中,需根据不同的实验目的选用不同的实验动物和模型。鸟类在生物进化上具有独特的地位,由此决定了其在认知科学研究中的价值。现已建立了呜禽呜唱学习、鸟类空间学习及视觉分辨学习等重要实验模型,并开展了一系列的学习记忆机制研究。文章对近年来鸟类学习记忆研究的进展,从鸟类鸣唱行为、海马功能以及神经递质作用等方面做了回顾。     

Individuality in nest building: do southern masked weaver (Ploceus velatus) males vary in their nest-building behaviour?

This study investigated how infant pigtailed macaque monkeys performed on two separate learning assessments, two-object discrimination/reversal and Hamilton search learning. Although the learning tasks have been tested on several species, including non-human primates, there have been no normative results reported for young macaque monkeys. The present study provides normative results for these learning tasks in very young captive pigtailed macaques and investigates the degree to which performances on these assessments are related. In addition, an error analysis was conducted to understand the choice patterns of the animals on each task. It was found that males took longer to reach criterion than females on the two-object reversal task. Performance and latency on the discrimination task predicted performance and latency on the reversal task. Performance on Hamilton Search Set-Breaking negatively predicted performance on the later Hamilton Search Forced Set-Breaking task. Finally, latency on reversal significantly predicted the latency on the Hamilton search task. These data provide strong evidence of a relationship between performance on discrimination and reversal. This study shows that, otherwise, each task assesses a different cognitive function.     

An economic evaluation of preclinical testing strategies compared to the compulsory scrapie flock scheme in the control of classical scrapie

Cost-benefit is rarely combined with nonlinear dynamic models when evaluating control options for infectious diseases. The current strategy for scrapie in Great Britain requires that all genetically susceptible livestock in affected flocks be culled (Compulsory Scrapie Flock Scheme or CSFS). However, this results in the removal of many healthy sheep, and a recently developed pre-clinical test for scrapie now offers a strategy based on disease detection. We explore the flock level cost-effectiveness of scrapie control using a deterministic transmission model and industry estimates of costs associated with genotype testing, pre-clinical tests and the value of a sheep culled. Benefit was measured in terms of the reduction in the number of infected sheep sold on, compared to a baseline strategy of doing nothing, using Incremental Cost Effectiveness analysis to compare across strategies. As market data was not available for pre-clinical testing, a threshold analysis was used to set a unit-cost giving equal costs for CSFS and multiple pre-clinical testing (MT, one test each year for three consecutive years). Assuming a 40% within-flock proportion of susceptible genotypes and a test sensitivity of 90%, a single test (ST) was cheaper but less effective than either the CSFS or MT strategies (30 infected-sales-averted over the lifetime of the average epidemic). The MT strategy was slightly less effective than the CSFS and would be a dominated strategy unless preclinical testing was cheaper than the threshold price of ￡6.28, but may be appropriate for flocks with particularly valuable livestock. Though the ST is not currently recommended, the proportion of susceptible genotypes in the national flock is likely to continue to decrease; this may eventually make it a cost-effective alternative to the MT or CSFS.     

Reduced Motivation in the BACHD Rat Model of Huntington Disease Is Dependent on the Choice of Food Deprivation Strategy

Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats'' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.     

Peripheral Blood Invariant Natural Killer T Cells of Pig-Tailed Macaques

In humans, invariant natural killer T (iNKT) cells represent a small but significant population of peripheral blood mononuclear cells (PBMCs) with a high degree of variability. In this study, pursuant to our goal of identifying an appropriate non-human primate model suitable for pre-clinical glycolipid testing, we evaluated the percentage and function of iNKT cells in the peripheral blood of pig-tailed macaques. First, using a human CD1d-tetramer loaded with α-GalCer (α-GalCer-CD1d-Tet), we found that α-GalCer-CD1d-Tet⁺ CD3⁺ iNKT cells make up 0.13% to 0.4% of pig-tailed macaque PBMCs, which are comparable to the percentage of iNKT cells found in human PBMCs. Second, we observed that a large proportion of Vα24⁺CD3⁺ cells are α-GalCer-CD1d-Tet⁺CD3⁺ iNKT cells, which primarily consist of either the CD4⁺ or CD8⁺ subpopulation. Third, we found that pig-tailed macaque iNKT cells produce IFN-γ in response to α-GalCer, as shown by ELISpot assay and intracellular cytokine staining (ICCS), as well as TNF-α, as shown by ICCS, indicating that these iNKT cells are fully functional. Interestingly, the majority of pig-tailed macaque iNKT cells that secrete IFN-γ are CD8⁺ iNKT cells. Based on these findings, we conclude that the pig-tailed macaques exhibit potential as a non-human animal model for the pre-clinical testing of iNKT-stimulating glycolipids.     

Attentional set-shifting deficit in Parkinson's disease is associated with prefrontal dysfunction: an FDG-PET study

The attentional set-shifting deficit that has been observed in Parkinson's disease (PD) has long been considered neuropsychological evidence of the involvement of meso-prefrontal and prefrontal-striatal circuits in cognitive flexibility. However, recent studies have suggested that non-dopaminergic, posterior cortical pathologies may also contribute to this deficit. Although several neuroimaging studies have addressed this issue, the results of these studies were confounded by the use of tasks that required other cognitive processes in addition to set-shifting, such as rule learning and working memory. In this study, we attempted to identify the neural correlates of the attentional set-shifting deficit in PD using a compound letter task and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography during rest. Shift cost, which is a measure of attentional set-shifting ability, was significantly correlated with hypometabolism in the right dorsolateral prefrontal cortex, including the putative human frontal eye field. Our results provide direct evidence that dysfunction in the dorsolateral prefrontal cortex makes a primary contribution to the attentional set-shifting deficit that has been observed in PD patients.     

Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet

Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.     

Transgenic nonhuman primates for neurodegenerative diseases

Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD), Parkinson's disease (PD) and Huntington's disease (HD) have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP) has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage) will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which genetic disorders play in the development of efficacious interventions and medications is foreseeable.     

Delayed procedural learning in α7-nicotinic acetylcholine receptor knockout mice

The α7-nicotinic acetylcholine receptor (nAChR) has long been a procognitive therapeutic target to treat schizophrenia. Evidence on the role of this receptor in cognition has been lacking, however, in part due to the limited availability of suitable ligands. The behavior of α7-nAChR knockout (KO) mice has been examined previously, but cognitive assessments using tests with cross-species translatability have been limited to date. Here, we assessed the cognitive performance of α7-nAChR KO and wild-type (WT) littermate mice in the attentional set-shifting task of executive functioning, the radial arm maze test of spatial working memory span capacity and the novel object recognition test of short-term memory. The reward motivation of these mutants was assessed using the progressive ratio breakpoint test. In addition, we assessed the exploratory behavior and sensorimotor gating using the behavioral pattern monitor and prepulse inhibition, respectively. α7-nAChR KO mice exhibited normal set-shifting, but impaired procedural learning (rule acquisition) in multiple paradigms. Spatial span capacity, short-term memory, motivation for food, exploration and sensorimotor gating were all comparable to WT littermates. The data presented here support the notion that this receptor is important for such procedural learning, when patterns in the environment become clear and a rule is learned. In combination with the impaired attention observed previously in these mice, this finding suggests that agonist treatments should be examined in clinical studies of attention and procedural learning, perhaps in combination with cognitive behavioral therapy.     

Characterisation of learning and memory deficits following NMDA receptor antagonism

Summary The effects of the non-competitive NMDA antagonist dizocilpine in tests of cognitive function have been compared with its effects on motor function in rats. Severe motor impairments were observed at doses above 0.1 mg/kg. Dizocilpine (0.075 mg/kg) had no effect on the acquisition of a spatial discrimination task in a Y-maze, but disrupted reversal learning. Both the acquisition and reversal of a visual discrimination task were impaired following dizocilpine (0.075 mg/kg). Dizocilpine (0.04 mg/kg) also disrupted performance of a fivechoice visual reaction time task. It is clear that dizocilpine can impair cognitive function at doses which do not induce pronounced motor dysfunction. The impairment induced by dizocilpine includes a disruption of spatial discrimination learning and a deficit in tasks with sustained attentional demands.     

Discriminations, reversals, and extra-dimensional shifts in the Göttingen minipig

G?ttingen minipigs were trained on a set-shifting procedure involving discriminations, reversals, and extra-dimensional shifts. The discriminations used were black-white discriminations and right-left discriminations. The initial visual and spatial discrimination seemed equally difficult, and only for the visual modality was reversal found to be more difficult than the initial discrimination. Visual reversal was more difficult than spatial reversal, and a larger number of perseverative sessions were found for visual reversal compared to spatial reversal. The acquisition of the extra-dimensional shift from the visual to the spatial dimension was not inferior to the learning of spatial reversal. Neither was the acquisition of the extra-dimensional shift from the spatial to the visual dimension inferior to the learning of visual reversal. Thus, no evidence was found for attention to stimulus dimensions in discrimination learning of the pigs.     

Effect of context on the plasticity of cognitive activity

The hypotheses that the plasticity or flexibility of cognitive activity substantially depends on the ability to replace the previous cognitive sets by new sets that are more appropriate to new conditions is substantiated. Working memory overload results in a decrease in set-shifting and, as a consequence, increased erroneous stimuli recognition. The plasticity of set-shifting is changed depending on the context of cognitive activity. On the basis of the data from the analysis of the coherence function and induced synchronization/desynchronization responses of potentials in the θ (4–7 Hz) and low-frequency α (8–10 Hz) bands, the roles of the tonic and phasic forms of activity of the cortico-hippocampal and fronto-thalamic functional systems of cerebral integration in changes of plasticity of cognitive functions are discussed.     

Cdk5 Contributes to Huntington’s Disease Learning and Memory Deficits via Modulation of Brain Region-Specific Substrates

Cognitive deficits are a major hallmark of Huntington’s disease (HD) with a great impact on the quality of patient’s life. Gaining a better understanding of the molecular mechanisms underlying learning and memory impairments in HD is, therefore, of critical importance. Cdk5 is a proline-directed Ser/Thr kinase involved in the regulation of synaptic plasticity and memory processes that has been associated with several neurodegenerative disorders. In this study, we aim to investigate the role of Cdk5 in learning and memory impairments in HD using a novel animal model that expresses mutant huntingtin (mHtt) and has genetically reduced Cdk5 levels. Genetic reduction of Cdk5 in mHtt knock-in mice attenuated both corticostriatal learning deficits as well as hippocampal-dependent memory decline. Moreover, the molecular mechanisms by which Cdk5 counteracts the mHtt-induced learning and memory impairments appeared to be differentially regulated in a brain region-specific manner. While the corticostriatal learning deficits are attenuated through compensatory regulation of NR2B surface levels, the rescue of hippocampal-dependent memory was likely due to restoration of hippocampal dendritic spine density along with an increase in Rac1 activity. This work identifies Cdk5 as a critical contributor to mHtt-induced learning and memory deficits. Furthermore, we show that the Cdk5 downstream targets involved in memory and learning decline differ depending on the brain region analyzed suggesting that distinct Cdk5 effectors could be involved in cognitive impairments in HD.     

The short and long term effects of docetaxel chemotherapy on rodent object recognition and spatial reference memory

Aims

Previous animal studies have examined the potential for cytostatic drugs to induce learning and memory deficits in laboratory animals but, to date, there is no pre-clinical evidence that taxanes have the potential to cause cognitive impairment. Therefore our aim was to explore the short- and long-term cognitive effects of different dosing schedules of the taxane docetaxel (DTX) on laboratory rodents.

Main methods

Healthy male hooded Wistar rats were treated with DTX (6 mg/kg, 10 mg/kg) or physiological saline (control), once a week for 3 weeks (Experiment 1) or once only (10 mg/kg; Experiment 2). Cognitive function was assessed using the novel object recognition (NOR) task and spatial water maze (WM) task 1 to 3 weeks after treatment and again 4 months after treatment.

Key findings

Shortly after DTX treatment, rats perform poorly on NOR regardless of treatment regimen. Treatment with a single injection of 10 mg/kg DTX does not appear to induce sustained deficits in object recognition or peripheral neuropathy.

Significance

Overall these findings show that treatment with the taxane DTX in the absence of cancer and other anti-cancer treatments causes cognitive impairment in healthy rodents.     

The performance of ravens on simple discrimination tasks: a preliminary study

Recent studies suggest the existence of primate-like cognitive abilities in corvids. Although the learning abilities of corvids in comparison to other species have been investigated before, little is known on how corvids perform on simple discrimination tasks if tested in experimental settings comparable to those that have been used for studying complex cognitive abilities. In this study, we tested a captive group of 12 ravens (Corvus corax) on four discrimination problems and their reversals. In contrast to other studies investigating learning abilities, our ravens were not food deprived and participation in experiments was voluntary. This preliminary study showed that all ravens successfully solved feature and position discriminations and several of the ravens could solve new tasks in a few trials, making very few mistakes.     

Learning ability and retention performance of a weanling squirrel monkey (Saimiri sciureus)

The visual discrimination and delayed-response tests and the test of conditioned-avoidance response were adapted and administered to a weanling squirrel monkey to determine its learning ability and retention performance. The data show that the weanling learned to perform all the tests successfully, indicating that the tractable squirrel monkey is a potentially satisfactory animal model for a comparative and developmental study of learning ability and retention performance during the early stages of life.