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Background Cognitive impairment is a distinguishing feature of many neurodegenerative diseases. The intra-dimensional (ID) extra-dimensional (ED) attentional set shift task is part of a clinical battery of tests used to evaluate executive function in Huntington’s and Alzheimer’s disease patients. The IDED task however has not translated well to pre-clinical rodent models of neurological disease. New method The ability to perform executive tasks coupled with a long lifespan makes sheep (Ovis aries) an ideal species for modelling cognitive decline in progressive neurodegenerative conditions. We describe the methodology for testing the performance of sheep in the IDED task using a semi-automated system in which visual stimuli are presented as coloured letters on computer screens. Results During each stage of IDED testing, all sheep (n = 12) learned successfully to discriminate between different colours and letters. Sheep were quick to learn the rules of acquisition at each stage. They required significantly more trials to reach criterion (p < 0.05) and made more errors (p < 0.05) following stimulus reversal, with the exception of the ED shift (p > 0.05). Comparison with existing method(s) Previous research shows sheep can perform IDED set shifting in a walk-through maze using solid objects with two changeable dimensions (colour and shape) as the stimuli. Presenting the stimuli on computer screens provides better validity, greater task flexibility and higher throughput than the walk-through maze. Conclusion All sheep completed each stage of the task, with a range of abilities expected in an outbred population. The IDED task described is ideally suited as a quantifiable and clinically translatable measure of executive function in sheep.

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... [13][14][15] To bridge the gap between rodent and non-human primate models, we have been investigating the use of sheep as a model species for functional brain research. In the behavioral domain, despite their reputation for limited cognitive ability, sheep perform better than rodents in many forms of cognitive testing [16][17][18] and have a high predicted levels of cognitive capacity that are comparable to those of other large mammals, such as pigs, dogs, and marmosets. 19 At a gross anatomical level, particularly with respect to the basal ganglia, the sheep brain is much more similar to the human brain, compared to that of rodents. ...
... Our proof-of-principle study shows that sheep are a docile and tractable species in which brain function can be studied longitudinally. The ability of sheep to perform complex cognitive tasks, 18 coupled with new technologies that would enable multiple simultaneous recording sites, offers exciting new possibilities for understanding the mechanisms underlying brain function in awake ''behaving'' animals. ...
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Although rodents are arguably the easiest animals to use for studying brain function, relying on them as model species for translational research comes with its own set of limitations. Here, we propose sheep as a practical large animal species to use for in vivo brain function studies performed in naturalistic settings. We conducted proof-of-principle deep brain electrophysiological recording experiments using unrestrained sheep during behavioral testing. Recordings were made from cortex and hippocampus, both while sheep performed goal-directed behaviors (two-choice discrimination tasks) and across states of vigilance, including sleep. Hippocampal and cortical oscillatory rhythms were consistent with those seen in rodents and non-human primates, and included cortical alpha oscillations and hippocampal sharp wave ripple oscillations (∼150 Hz) during immobility and hippocampal theta oscillations (5–6 Hz) during locomotion. Recordings were conducted over a period of many months during which time the animals participated willingly in the experiments. Over 3,000 putative neurons were identified, including examples whose activity was modulated by task, speed of locomotion, spatial position, reward and vigilance states, and one whose firing rate was potentially modulated by the sight of the investigator. Together, these experiments demonstrate that sheep are excellent experimental animals to use for longitudinal studies requiring a large-brained mammal and/or large-scale recordings across distributed neuronal networks. Sheep could be used safely for studying not only neural encoding of decision-making and spatial-mapping in naturalistic environments outside the confines of the traditional laboratory but also the neural basis of both intra- and inter-species social interactions.
... To bridge the gap between rodent and non-human primate animal models, we have been investigating the use of sheep as a model species for functional brain research. In the behavioural domain, despite their reputation for limited cognitive ability, sheep perform better than mice in many forms of cognitive testing (McBride et al., 2016;Nicol et al., 2016;Sorby-Adams et al., 2021) and have a high predicted level of cognitive capacity that approaches or equals that of nonhuman primates (McBride and Morton, 2018). At the gross anatomical level, particularly with respect to the basal ganglia, the sheep brain is much more similar to the human compared to that of rodents. ...
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While rodents are arguably the easiest animals to use for studying brain function, relying on them as model species for translational research comes with its own sets of limitations. Here, we propose sheep as a practical large animal species for in vivo brain function studies performed in naturalistic settings. To demonstrate their experimental usefulness, we performed proof-of-principle deep brain electrophysiological recording experiments from unrestrained sheep. Recordings were made from cortex and hippocampus both whilst sheep performed goal-directed behaviours (two-choice discrimination tasks), and across states of vigilance that included natural sleep. Hippocampal and cortical oscillatory rhythms were consistent with those seen in rodents and non-human primates, and included cortical alpha oscillations during immobility, hippocampal theta oscillations (5-6Hz) during locomotion and hippocampal sharp wave ripple oscillations (~150 Hz) during immobility. Moreover, we found clear examples of neurons whose activity was modulated by task, speed of locomotion, spatial position, reward and vigilance states. Recordings were conducted over a period of many months. Due to the exceptional stability of individual electrodes we were able to record from some neurons continuously for more than 1 month. Together these experiments demonstrate that sheep are an excellent experimental animal model to use in longitudinal electrophysiological and imaging studies, particularly those requiring a large brained mammal, large scale recordings across distributed neuronal networks, experimentation outside the confounds of the traditional laboratory, or all the above concomitantly.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the sixth leading cause of death and the most common cause of dementia worldwide. Over the last few decades, significant advancements have been made in our understanding of AD by investigating the molecular mechanisms underlying amyloid-β and tau pathology. Despite this progress, no disease-modifying treatments exist for AD, an issue that will exacerbated by the rising costs and prevalence of the disorder. Moreover, effective therapies to address the devastating cognitive and behavioral symptoms are also urgently needed. This perspective focuses on the value of nonhuman primate (NHP) models in bridging the molecular, circuit, and behavioral levels of analysis to better understand the complex genetic and environmental/lifestyle factors that contribute to AD pathogenesis. These investigations could provide an opportunity for translating our understanding of the pathogenesis and physiological mechanisms underlying AD and related disorders into new diagnostic approaches and disease-modifying therapies to prevent disease or restore brain function for symptomatic individuals.
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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'. However, we suspect that there may be inconsistent data that is unpublished or perhaps 'failed experiments' that may have been caused by unintended deviations from effective protocols. The purpose of this review is to describe our approach and the rationale behind certain aspects of the protocol, including common pitfalls that are encountered when establishing an effective local protocol.
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A unifying function associated with the default mode network (DMN), which is more active during rest than under active task conditions, has been difficult to define. The DMN is activated during monitoring the external world for unexpected events, as a sentinel, and when humans are engaged in high-level internally focused tasks. The existence of DMN correlates in other species, such as mice, challenge the idea that internally focused, high-level cognitive operations, such as introspection, autobiographical memory retrieval, planning the future, and predicting someone else’s thoughts, are evolutionarily preserved defining properties of the DMN. A recent human study demonstrated that demanding cognitive shifts could recruit the DMN, yet it is unknown whether this holds for nonhuman species. Therefore, we tested whether large changes in cognitive context would recruit DMN regions in female and male nonhuman primates. Such changes were measured as displacements of spatial attentional weights based on internal rules of relevance (spatial shifts) compared with maintaining attentional weights at the same location (stay events). Using fMRI in macaques, we detected that a cortical network, activated during shifts, largely overlapped with the DMN. Moreover, fMRI time courses sampled from independently defined DMN foci showed significant shift selectivity during the demanding attention task. Finally, functional clustering based on independent resting state data revealed that DMN and shift regions clustered conjointly, whereas regions activated during the stay events clustered apart. We therefore propose that cognitive shifting in primates generally recruits DMN regions. This might explain a breakdown of the DMN in many neurological diseases characterized by declined cognitive flexibility.
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Objective: Cognitive deficits following stroke are well documented, but less is known about problems with social skills such as understanding others' thoughts and feelings. This study investigated the effect of stroke on a visual-affective measure of social understanding: the Reading the Mind in the Eyes test (RMET). The aims were to investigate whether right hemisphere stroke was particularly detrimental to this aspect of Theory of Mind (ToM), and investigate the relationship between ToM ability and executive function following stroke. Methods: Performance of stroke patients (right hemisphere stroke, n = 15; left hemisphere stroke, n = 15) was compared to that of controls (n = 40) matched for age, years of education, and IQ on tasks measuring ToM and executive functioning. Results: Right hemisphere stroke was associated with impaired ToM ability, but left hemisphere stroke was not. There was no effect of stroke on a matched non-ToM control task. High correlations were found between performance on the RMET and some measures of executive functioning in participants with right hemisphere stroke only. Further analyses suggested that deficits in executive functioning could not statistically explain all of the difficulties shown by stroke participants on the RMET. Conclusions: A reduction in the ability to attribute mental states to others following right hemisphere stroke may adversely affect psychosocial functioning, disrupt interpersonal relationships, and lead to reduced quality of life. The clinical importance of these findings, implications for clinical practice and future research are discussed.
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In this review we summarize the progress that has been made in the research on attentional and executive deficits in Alzheimer's disease. Like memory, attention is now recognized as consisting of subtypes that differ in their function and anatomical basis. We base our review upon a classification of three subtypes of attention: selective, sustained and divided. This model derives from lesion studies, animal electrophysiological recordings and functional imaging. We examine how these sub-components of attention can be reconciled with neuropsychological models of attentional control, particularly the Supervisory Attentional System and the Central Executive System of Shallice and Baddeley, respectively. We also discuss the relationship of attention to the concept of executive function. Current evidence suggests that after an initial amnesic stage in Alzheimer's disease, attention is the first non-memory domain to be affected, before deficits in language and visuospatial functions. This is consistent with the possibility that
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Introduction: Pathophysiological mechanisms underlying Alzheimer's disease (AD) remain insufficiently documented for the identification of accurate diagnostic markers and purposeful target discovery and development. Nonhuman primates (NHPs) have important translational value given their close phylogenetic relationship to humans and similar developmental paths in (neuro)anatomy, physiology, genetics, and neural functions, as well as cognition, emotion, and social behavior. Areas covered:This review deals with the past and future role of NHP-based research in AD pathophysiology, diagnosis and drug discovery, and touches upon ethical and legal aspects. Expert opinion:Aging NHPs are not complete phenocopies of human AD. Conceivably, no other species or experimental model will ever develop the full spectrum of AD-typical alterations. Nevertheless, partial - and even negative - models can increase knowledge of disease mechanisms. Modeling complex brain disorders should not be based on a single model or species. Understanding brain diseases relies on knowledge of healthy brain functioning, and given their close phylogenetic relationship to humans, NHPs serve excellent tools in this respect. NHP-based studies remain essential in the development and validation of radiopharmaceuticals for early diagnostic imaging biomarkers, as well as in the efficacy and safety evaluation of new therapeutic approaches, with active immunization or vaccination approaches as front runners.
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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.
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For reasons of cost and ethical concerns, models of neurodegenerative disorders such as Huntington's disease (HD) are currently being developed in farm animals, as an alternative to non-human primates. Developing reliable methods of testing cognitive function is essential to determining the usefulness of such models. Nevertheless, cognitive testing of farm animal species presents a unique set of challenges. The primary aims of this study were to develop and validate a mobile operant system suitable for high throughput cognitive testing of sheep. We designed a semi-automated testing system with the capability of presenting stimuli (visual, auditory) and reward at six spatial locations. Fourteen normal sheep were used to validate the system using a two choice visual discrimination task (2CVDT). Four stages of training devised to acclimatise animals to the system are also presented. All sheep progressed rapidly through the training stages, over eight sessions. All sheep learned the 2CVDT and performed at least one reversal stage. The mean number of trials the sheep took to reach criterion in the first acquisition learning was 13.9±1.5 and for the reversal learning was 19.1±1.8. This is the first mobile semi-automated operant system developed for testing cognitive function in sheep. We have designed and validated an automated operant behavioural testing system suitable for high throughput cognitive testing in sheep and other medium-sized quadrupeds, such as pigs and dogs. Sheep performance in the two-choice visual discrimination task was very similar to that reported for non-human primates and strongly supports the use of farm animals as pre-clinical models for the study of neurodegenerative diseases. Copyright © 2015. Published by Elsevier B.V.
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Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States' Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient's right. The panel agreed on the following specific findings: (1) validated screening tests are available that take 3 to 7 minutes to administer; (2) a combination of patient- and informant-based screens is the most appropriate approach for identifying early cognitive impairment; (3) early cognitive impairment may have treatable components; and (4) emerging data support a combination of medical and lifestyle interventions as a potential way to delay or reduce cognitive decline. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
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Cognitive impairment, particularly involving dysfunction of circuitry within the prefrontal cortex (PFC), represents a core feature of many neuropsychiatric and neurodevelopmental disorders, including depression, post-traumatic stress disorder, schizophrenia and autism spectrum disorder. Deficits in cognitive function also represent the most difficult symptom domain to successfully treat, as serotonin reuptake inhibitors and tricyclic antidepressants have only modest effects. Functional neuroimaging studies and postmortem analysis of human brain tissue implicate the PFC as being a primary region of dysregulation in patients with these disorders. However, preclinical behavioral assays used to assess these deficits in mouse models which can be readily manipulated genetically and could provide the basis for studies of new treatment avenues have been underutilized. Here we describe the adaptation of a behavioral assay, the attentional set shifting task (AST), to be performed in mice to assess prefrontal cortex mediated cognitive deficits. The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents, providing excellent face, construct and predictive validity.
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Total body hypothermia is an established neuroprotectant in global cerebral ischemia. The role of hypothermia in acute ischemic stroke remains uncertain. Selective application of hypothermia to a region of focal ischemia may provide similar protection with more rapid cooling and elimination of systemic side effects. We studied the effect of selective endovascular cooling in a focal stroke model in adult domestic swine. After craniotomy under general anesthesia, a proximal middle cerebral artery branch was occluded for 3 h, followed by 3 h of reperfusion. In half of the animals, selective hypothermia was induced during reperfusion using a dual lumen balloon occlusion catheter placed in the ipsilateral common carotid artery. Following reperfusion, the animals were sacrificed. Brain MRI and histology were evaluated by experts who were blinded to the intervention. 25 animals were available for analysis. Using selective hypothermia, hemicranial temperature was successfully cooled to a mean of 26.5°C. Average time from start of perfusion to attainment of moderate hypothermia (<30°C) was 25 min. Mean MRI stroke volumes were significantly reduced by selective cooling (0.050±0.059 control, 0.005±0.011 hypothermia (ratio stroke:hemisphere volume) (p=0.046). Stroke pathology volumes were reduced by 42% compared with controls (p=0.256). Selective moderate hypothermia was rapidly induced using endovascular techniques in a clinically realistic swine stroke model. A significant reduction in stroke volume on MRI was observed. Endovascular selective hypothermia can provide neuroprotection within time frames relevant to acute ischemic stroke treatment. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Aging dogs and cats show neurodegenerative features that are similar to human aging and Alzheimer disease. Neuropathologic changes with age may be linked to signs of cognitive dysfunction both in the laboratory and in a clinic setting. Less is known about cat brain aging and cognition and this represents an area for further study. Neurodegenerative diseases such as lysosomal storage diseases in dogs and cats also show similar features of human aging, suggesting some common underlying pathogenic mechanisms and also suggesting pathways that can be modified to promote healthy brain aging. Copyright © 2014 Elsevier Inc. All rights reserved.
Article
Preclinical detection of Alzheimer’s disease is critical to determining at-risk individuals in order to improve patient and caregiver planning for their futures, and to identify individuals likely to benefit from treatment as advances in therapeutics develop over time. Identification of olfactory dysfunction at the preclinical and early stages of the disease is a potentially useful method to accomplish these goals. We first review basic olfactory circuitry. We then evaluate the evidence of pathophysiological change in the olfactory processing pathways during aging and Alzheimer’s disease in both human and animal models. We also review olfactory behavioral studies during these processes in both types of models. In doing so, we suggest hypotheses about the localization and mechanisms of olfactory dysfunction and identify important avenues for future work.
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We investigated the viability of psychometrically robust executive function measures as markers for premanifest Huntington's disease (HD). Fifteen premanifest HD subjects and 42 controls were compared on the NIH EXAMINER executive function battery. This battery yields an overall executive composite score, plus working memory, cognitive control, and fluency scores that are measured on psychometrically matched scales. The scores were correlated with two disease markers, disease burden and striatal volumes, in the premanifest HD subjects. The premanifest HD subjects scored significantly lower on the working memory score. The executive composite positively correlated with striatal volumes, and the working memory score negatively correlated with disease burden. The cognitive control and fluency scores did not differ between the groups or correlate significantly with the disease markers. The NIH EXAMINER executive composite and working memory scores are sensitive markers of cognitive dysfunction, striatal volume, and disease burden in premanifest HD. © 2013 International Parkinson and Movement Disorder Society.