Abstract
To generate meaningful information, translational research must employ paradigms that allow extrapolation from animal models to humans. However, few studies have evaluated translational paradigms on the basis of defined validation criteria. We outline three criteria for validating translational paradigms. We then evaluate the Hebb–Williams maze paradigm (Hebb and Williams, 1946; Rabinovitch and Rosvold, 1951) on the basis of these criteria using Fragile X syndrome (FXS) as model disease. We focused on this paradigm because it allows direct comparison of humans and animals on tasks that are behaviorally equivalent (criterion #1) and because it measures spatial information processing, a cognitive domain for which FXS individuals and mice show impairments as compared to controls (criterion #2). We directly compared the performance of affected humans and mice across different experimental conditions and measures of behavior to identify which conditions produce comparable patterns of results in both species. Species differences were negligible for Mazes 2, 4, and 5 irrespective of the presence of visual cues, suggesting that these mazes could be used to measure spatial learning in both species. With regards to performance on the first trial, which reflects visuo-spatial problem solving, Mazes 5 and 9 without visual cues produced the most consistent results. We conclude that the Hebb–Williams mazes paradigm has the potential to be utilized in translational research to measure comparable cognitive functions in FXS humans and animals (criterion #3).
Highlights
“By carefully selecting tasks for animals with high construct validity to human tasks, reliability and accuracy of translational efforts will not be lost and meaningful progress can be made in ameliorating the cognitive deficits that affect the lives of those suffering from mental illness.”
Gandhi et al (2014a) showed that a metabotropic glutamate receptor antagonist (i.e., MPEP) reversed these deficits in KO mice. These findings suggest that the Hebb–Williams paradigm meets two of the criteria for validating translational paradigms: it allows for direct comparison of humans and animals on a paradigm that is behaviorally equivalent, and it measures cognitive functions and underlying neural mechanisms that are fundamental to the disorder
Using Fragile X syndrome (FXS) as a model disease, we examined the potential utility of the Hebb–Williams maze paradigm (Hebb and Williams, 1946; Rabinovitch and Rosvold, 1951) for translational and drug discovery research on the basis of three validation criteria
Summary
“By carefully selecting tasks for animals with high construct validity to human tasks, reliability and accuracy of translational efforts will not be lost and meaningful progress can be made in ameliorating the cognitive deficits that affect the lives of those suffering from mental illness.”. The silencing of the FMR1 gene results in several significant behavioral and cognitive impairments including deficits in attention (Backes et al, 2002; Baumgardner et al, 1995), visual-spatial cognition (Crowe and Hay, 1990; Cornish et al, 1998, 1999), working memory (Schapiro et al, 1995; Jakala et al, 1997), and visual-perceptual processing (Kogan et al, 2004a) Because it is the outcome of a single gene defect, FXS offers a remarkable opportunity to investigate the validity and feasibility of translational paradigms by comparing the animal model with affected individuals. Two studies (Frankland et al, 2004; Koekkoek et al, 2005) employed paradigms that measure prepulse inhibition, a function that is thought to be impaired in
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