Search strategy analysis reveals sex‐specific deficits in spatial reference memory in 5xFAD mice

Abstract

AbstractBackgroundSpatial disorientation is one of the earliest symptoms in Alzheimer’s disease. Search strategy classification systems to study navigational deficits in Alzheimer disease have been developed but aren’t widely available. Hence, we studied the navigational strategies in the 5xFAD murine model and evaluated differences between sexes.MethodWe studied spatial reference memory in 3‐month‐, 7‐month‐ and 12‐month‐old female and male 5xFAD mice and their aged‐matched controls in the Morris water maze. Furthermore, a detailed analysis of the swimming strategies using “Pathfinder” was performed. Navigational strategies were classified in spatial (“direct path”, “directed search”, “focal search”, “indirect search”) and non‐spatial categories (“chaining”, “scanning”, “random search”, thigmotaxis”).ResultEscape latency was prolonged in 5xFAD mice compared to WT, only at 7 and 12 months, with greater magnitude in females than males. Regarding search strategies during acquisition training, the most common spatial strategy was “indirect search” whereas “random search” was the most frequent non‐spatial strategy. At 3 months, no clear difference was seen between 5xFAD and WT animals. However, at 7 months, 5xFAD mice used more frequently non‐spatial strategies. Although transgenic mice progressively shifted to more spatial strategies as they learned (mainly “indirect search”), WT animals applied more frequently spatial strategies with higher cognitive value such as “direct path”, “directed search” and “focal search”. In comparison, 12 month‐old 5xFAD mice used more non‐spatial strategies, mainly “random search”, than the WT and their transition to “indirect search” occurred more rarely than in younger mice. Overall, all animals increased the use of non‐spatial strategies as they aged but this increment was greater and earlier in 5xFAD females than in 5xFAD males. Lastly, in the probe trial, 5xFAD female mice at 3 and 12 months applied “random search” more often, while the WT chose “indirect search” with higher frequency. No difference was seen in males during probe trial.ConclusionConventional behavior analysis of escape latencies revealed spatial reference memory deficits in 7m and 12m 5XFAD mice. Deficits in spatial memory were more pronounced in female 5XFAD mice than in male mice. 5XFAD mice, regardless of sex, used a qualitatively and quantitatively different search strategy pattern than WT animals.