EARLY-STAGE ALTERATIONS IN ADAPTIVE NAVIGATION STRATEGIES IN A TGF344-AD RAT MODEL OF ALZHEIMER’S DISEASE

Identifying sensitive behavioral paradigms capable of capturing early-stage alterations in Alzheimer’s disease (AD) remains a challenge. In this study, we used the TgF344-AD rat model and tested male and female animals at 6 months of age. We developed a rodent analog of a human task, termed Crossroads, designed to assess sequential spatial decision making at navigational intersections. The task consisted of a water maze with four sequential intersections, where animals were required to make navigational choices to reach a hidden escape platform. Rats were tested across four consecutive days with eight trials per day. Across testing days, rats exhibited a robust reduction in response latencies, demonstrating successful acquisition of the task. At the end of day 3, a probe trial introduced a newly available shortcut to the goal; neither TgF344-AD nor wild-type rats preferentially used this shortcut, indicating reliance on learned action sequences rather than formation of a cognitive map. A second probe trial at the end of day 4 altered the release location to dissociate motor-based strategies from landmark-guided navigation. In this condition, most male rats, irrespective of genotype, adopted a landmark-based strategy, whereas female rats showed a divergence, with wild-type animals preferentially using landmark-guided choices and TgF344-AD animals relying more on motor-based strategies. Overall, task acquisition was comparable across genotypes; however, exploratory analyses suggest genotype- and sex-dependent modulation of navigational strategy selection. These findings indicate that the Crossroads task provides a sensitive and relevant approach for probing subtle alterations in spatial decision making in early stages of AD.