Elsevier

Biochemical Pharmacology

Volume 81, Issue 12, 15 June 2011, Pages 1356-1366
Biochemical Pharmacology

Review
Translating cognition from animals to humans

https://doi.org/10.1016/j.bcp.2010.12.028Get rights and content

Abstract

Many clinical disorders, whether neurological (e.g. Alzheimer's disease) or neuropsychiatric (e.g. schizophrenia and depression), exhibit cognitive symptoms that require pharmacological treatment. Cognition is multi-faceted and includes processes of perception, attention, working memory, long-term memory, executive function, language and social cognition. This article reviews how it is feasible to model many aspects of human cognition with the use of appropriate animal models and associated techniques, including the use of computer controlled tests (e.g. touch-screens), for optimising translation of experimental research to the clinic. When investigating clinical disorders, test batteries should aim to profile cognitive function in order to determine which aspects are impaired and which are preserved. In this review we have paid particular attention to the validation of translational methods; this may be done through the application of common theoretical principles, by comparing the effects of psychological manipulations and, wherever feasible, with the demonstration of homologous neural circuitry or equivalent pharmacological actions in the animal and human paradigms. Of particular importance is the use of ‘back-translation’ to ensure that the animal model has validity, for example, in predicting the effects of therapeutic drugs already found in human studies. It is made clear that the choice of appropriate behavioral tests is an important element of animal models of neuropsychiatric or neurological disorder; however, of course it is also important to select appropriate manipulations, whether genetic, neurodevelopmental, neurotoxic, or pharmacological, for simulating the neural substrates relevant to the disorders that lead to predictable behavioral and cognitive impairments, for optimising the testing of candidate compounds.

Introduction

Translational neuroscience has now become crucial to drug discovery. The vast expense of Phase 3 trials and relative lack of success of developing effective new compounds in psychiatry has necessitated a new approach to the use of animal models and preclinical strategies. Some of this lack of success is attributable to the lack of reporting of failed clinical studies which would allow more rigorous analysis and comparison across the human and animal data. Concern has also been raised relating to the short-comings of animal models, with a failure to robustly guide the use of new compounds in the clinic, although we would suggest that there may also have been deficiencies in implementation and interpretation of the animal models themselves. Thus, for example, pragmatic requirements have often resulted in the use of less rigorous procedures or a reliance on only a single behavioral assay. Moreover, we find insufficient evidence of ‘back-translation’ (from humans to animals) of the fate of new drugs for us to be confident that any ‘failures’ are necessarily a result of inadequate animal models. Nevertheless, we believe that the new emphasis on translation has brought focus onto ‘construct validity’—whether the identified cognitive processes are adequately homologous between species. This is distinct from ‘predictive validity’ which remains useful for predicting, for example whether a drug has an anti-depressant like action, but will too often result in another ‘me-too’ compound with the same basic failings as its relatives [1]. Clearly it is important to be sure that the predictive validity does not merely identify compounds that produce a particular effect if that effect is not convincingly linked to therapeutic benefit [2]. Additionally, progress in genetics and developmental biology has resulted in emphasis on the use of transgenic techniques as a new approach to understanding the aetiology of neuropsychiatric disorders and the identification of endophenotypes [3].

Section snippets

Test batteries for cognitive disorders

There are now an overwhelming number of clinical disorders requiring treatment of cognitive dysfunction, including not only obvious examples such as Alzheimer's disease, but also other neurodegenerative conditions such as Parkinson's and Huntington's disease, brain damage resulting from stroke or other injury, schizophrenia and bipolar disorder, depression, the sequelae of addiction, and developmental disorders such as autism and attention deficit hyperactivity disorder. It is important to

Perception

Perception is the ‘on-line’ representation of the world by the sensory systems and must ultimately be used to make decisions. This percept of the world is the result of current sensory stimulation which is temporally bound together over transient time- and space-windows and combined with longer term memory systems. Perception is generally tested in experimental animals and humans by means of discrimination learning and recognition, whereby responding in the presence of one stimulus is

Conclusions

In this survey, we have mainly discussed how it is feasible to model specific aspects of cognition in experimental animals that may bear some approximation to the greater complexity often observed in human patients. As cognition is not a unitary construct, it is necessary to focus on specific aspects, for example, of memory that are highlighted by the patient's deficits. It is often important to test cognition in humans and other animals in ways that are as similar as possible, for example,

Acknowledgements

This work has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115008. IMI is a public–private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. This work was carried out at The Behavioral and Clinical Neuroscience Institute (BCNI), a joint award from the Medical Research Council (MRC) and Wellcome Trust (G0001354) to Prof TW Robbins (Director) and Prof ET Bullmore

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