Comparison between touchscreen operant chambers and water maze to detect early prefrontal dysfunction in mice

Abstract

The relative lack of sensitive and clinically valid tests of rodent behavior might be one of the reasons for the limited success of the clinical translation of preclinical Alzheimer's disease (AD) research findings. There is a general interest in innovative behavioral methodology, and protocols have been proposed for touchscreen operant chambers that might be superior to existing cognitive assessment methods. We assessed and analyzed touchscreen performance in several novel ways to examine the possible occurrence of early signs of prefrontal (PFC) functional decline in the APP/PS1 mouse model of AD. Touchscreen learning performance was compared between APP/PS1‐21 mice and wildtype littermates on a C57BL/6J background at 3, 6 and 12 months of age in parallel to the assessment of spatial learning, memory and cognitive flexibility in the Morris water maze (MWM). We found that older mice generally needed more training sessions to complete the touchscreen protocol than younger ones. Older mice also displayed defects in MWM working memory performance, but touchscreen protocols detected functional changes beginning at 3 months of age. Histological changes in PFC of APP/PS1 mice indeed occurred as early as 3 months. Our results suggest that touchscreen operant protocols are more sensitive to PFC dysfunction, which is of relevance to the use of these tasks and devices in preclinical AD research and experimental pharmacology.

A Preclinical Model of Computerized Cognitive Training: Touchscreen Cognitive Testing Enhances Cognition and Hippocampal Cellular Plasticity in Wildtype and Alzheimer’s Disease Mice

“…Additionally, reversal learning tasks have been sensitive to cognitive flexibility impairments in AD mouse models as they age ( Piiponniemi et al, 2017 ; Shepherd et al, 2019 ; Van den Broeck et al, 2019 ) and attention and executive control have also been scrutinized and shown to be sensitive to donepezil ( Romberg et al, 2011 ), a drug commonly used clinically for AD. Recently, Van den Broeck et al (2021) showed that touchscreen tests were more sensitive in picking up memory impairments in an AD model compared to traditional maze-based tests. Although this is promising for early detection of impairments, and thus insight into early disease mechanisms, not all studies have shown early detection of impairments, with one reporting no differences in aged mice expressing a mutation in Tau ( Kent et al, 2018 ).…”

Longitudinal Assessment of Working Memory Performance in the APPswe/PSEN1dE9 Mouse Model of Alzheimer’s Disease Using an Automated Figure-8-Maze

“…Similar to the F8M procedure described here, touchscreen tasks minimize stress, allow for a high degree of automation and standardization, and thus facilitate longitudinal testing. In addition, they have been successfully used to detect early cognitive deficits starting at 3 moa in APP/PS1-21 mice ( Van den Broeck et al, 2021 ), suggesting higher sensitivity than the DAT. The preferred use of different procedures will depend on the aim of the study.…”

Using touchscreen-delivered cognitive assessments to address the principles of the 3Rs in behavioral sciences

“…In addition to representing a welfare concern, the stress induced by this task can interfere with the interpretation of results and animal performance 83,84 . Two independent studies compared the performance of two Alzheimer's mouse models (APP-KI and APP/PS1) on the MWM to the performance of touchscreen PAL, location discrimination (LD) and visual discrimination and reversal tasks; these studies reported that the touchscreen tasks detected significant performance impairments in the model animals compared to wild-type controls at an earlier age (and so under conditions of lesser pathological burden) than the MWM 52,85 . These findings suggest that the touchscreen approach can offer higher sensitivity assessment with lower stressor exposure, consistent with a substantial refinement.…”

“…More importantly, these assays have persistent negative effects on animal welfare 140,141 . In addition, given the increased sensitivity of touchscreen tasks relative to the MWM 52,85 , in which animals are also exposed to stress, touchscreen tasks might also show enhanced sensitivity compared to FST and TST, although to our knowledge this important comparison remains to be completed.…”