ABS 057: Sex-Dependent Cognitive Deficits in APP Knock-in Mice Uncovered by Computational Analysis of the Restaurant Row Behavioral Task

Farhan Shaikh ¹ , Gavin Fuchs ¹ , Allison Alshouse ¹ , Sylvain Lesné ¹ , Mathew Sherman ¹

¹ University of Minnesota

Van Wickle (2025) Volume 1, ABS 057

Introduction: The APPNL (Swedish mutation) and APPNL-F (Swedish and Iberian mutations) knock-in mouselines are commonly used to study cognitive impairment in the context of Alzheimer’s Disease (AD). While both models express APP at endogenous levels, the APPNL-Fmice show cognitive deficits and amyloid deposition at 18 months, unlike their APPNL counterparts. To assess decision-making, we used the Restaurant Row (RRow) task, a neuroeconomic paradigm to characterize decision-making strategies in 12 to 15-month-old APPNL and APPNL-F mice and assess pathological and sex specific effects.
It was hypothesized that APPNL-F mice would show impaired decision making and perform poorly compared to compared to their APPNL counterparts for both sexes. (note: the NL and NL-F are to be in superscript throughout.

Methods: The RRow task, designed to evaluate foraging strategies under time constraints, spanned 51 days across four epochs with increasing food delays. Behavior was recorded using ANY-maze software, and while metrics such as earns, laps, and spatial data were readily available, a custom MATLAB script was developed to extract detailed decision-making patterns. We analyzed Pavlovian (stimulus-response), procedural (habitual learning), and deliberative (goal-directed contemplation) decision-making by examining “enter” and ”quit” probabilities, inter-earn intervals, and vicarious trial and error (VTE) scores. Due to the volume of data, supercomputing resources were utilized for processing.

Results: Male APPNL-F mice exhibited impaired decision-making compared to all other groups in the final stage of the task. They showed higher entry rates, reduced offer discrimination, and increased quitting probabilities. Consequently, they exhibited higher inter-earn intervals, reducing overall efficiency within the limited test duration.

Discussion: Our findings suggest that male APPNL-F mice demonstrate impaired deliberative decision-making, leading to inefficient foraging behavior in the RRow task. This behavior was supported by low VTE scores, indicating impulsive decisions rather than deliberative evaluation. These deficits were not observed in female APPNL-F mice of either sex of APPNL mice, suggesting a male-specific impairment in APPNL-F animals.These results highlight novel sex-specific vulnerabilities in neuroeconomic decision-making and provide a framework for future investigations into AD-related cognitive decline.