Translating a rodent behavioral assay for humans
While animal models of neurodegenerative diseases exhibit many of the features observed in patients, it remains a challenge to translate laboratory findings to effective clinical therapies. In this episode, Steve Finkbeiner, Pascal Sanchez, and Kate Possin discuss their collaboration to develop and evaluate a virtual version of the Morris water maze, which is frequently used to assess spatial learning and memory in rodents, for use in patients with mild Alzheimer’s disease-associated cognitive impairment. Careful comparison between a mouse model of Alzheimer’s disease in the Morris maze and patients with Alzheimer’s disease in the virtual version of the test revealed that with proper sample size and the evaluation of appropriate performance measures the Morris maze is a sensitive assay for detecting Alzheimer’s disease-related impairments across species.
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Abstract
Analogous behavioral assays are needed across animal models and human patients to improve translational research. Here, we examined the extent to which performance in the Morris water maze — the most frequently used behavioral assay of spatial learning and memory in rodents — translates to humans. We designed a virtual version of the assay for human subjects that includes the visible-target training, hidden-target learning, and probe trials that are typically administered in the mouse version. We compared transgenic mice that express human amyloid precursor protein (hAPP) and patients with mild cognitive impairment due to Alzheimer’s disease (MCI-AD) to evaluate the sensitivity of performance measures in detecting deficits. Patients performed normally during visible-target training, while hAPP mice showed procedural learning deficits. In hidden-target learning and probe trials, hAPP mice and MCI-AD patients showed similar deficits in learning and remembering the target location. In addition, we have provided recommendations for selecting performance measures and sample sizes to make these assays sensitive to learning and memory deficits in humans with MCI-AD and in mouse models. Together, our results demonstrate that with careful study design and analysis, the Morris maze is a sensitive assay for detecting AD-relevant impairments across species.
Authors
Katherine L. Possin, Pascal E. Sanchez, Clifford Anderson-Bergman, Roland Fernandez, Geoffrey A. Kerchner, Erica T. Johnson, Allyson Davis, Iris Lo, Nicholas T. Bott, Thomas Kiely, Michelle C. Fenesy, Bruce L. Miller, Joel H. Kramer, Steven Finkbeiner
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)