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

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.

Impaired Reversal Learning in APPPS1-21 Mice in the Touchscreen Visual Discrimination Task.

Preclinical-clinical translation of cognitive functions has been difficult in Alzheimer's disease (AD) research but is crucial to the (predictive) validity of AD animal models. Reversal learning, a representation of flexibility and adaptability to a changing environment, might represent such a translatable feature of human cognition. We, therefore, examined visual discrimination (VD) and reversal learning in the APPPS1-21 mouse model of amyloid-based AD pathology. We used touchscreen operant cages in novel and translationally valid, as well as objective testing methodology that minimizes within- or between-trial handling. Mice were trained to associate a visual cue with a food reward (VD learning), and subsequently learned to adjust their response when this rule changed (reversal learning). We assessed performance at two different ages, namely at 6 months of age, considered an early disease stage, and at 9 months, a stage of established pathology. Both at 6 and 9 months, transgenic animals needed more sessions to reach criterion performance, compared to wild-type controls. Overall, transgenic animals do not show a general cognitive, motivational or motor deficit, but experience specific difficulties to adapt to reward contingency changes, already at an early pathology stage.