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Absolute Winding Number Differentiates Mouse Spatial Navigation Strategies With Genetic Risk for Alzheimer's Disease.

ABSTRACT: Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer's disease, and even in cognitively normal individuals at risk for Alzheimer's disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer's disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric supported increased vulnerability in APOE4 females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer's disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer's disease.

SUBMITTER: Badea A

PROVIDER: S-EPMC9247395 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The hybrid model of number magnitude processing suggests that multi-digit numbers are simultaneously processed holistically (whole number magnitudes) and in a decomposed manner (digit magnitudes). Thus, individual tendencies and situational factors may affect which type of processing becomes dominant in a certain individual in a given situation. The unit-decade compatibility effect has been described as indicative of stronger decomposed number processing. This effect occurs during the comparison of two-digit numbers. Compatible items in which the larger number contains the larger unit digit are easier to solve than incompatible items in which the larger number contains the smaller unit digit. We have previously described women show a larger compatibility effect than men. Furthermore, the compatibility effect is modulated by situational factors like the vertical spacing of the presented numbers. However, it has not been addressed whether situational factors and sex affect the unit-decade compatibility effect interactively. We have also demonstrated that the unit-decade compatibility effects relates to global-local processing, which in turn also affects spatial processing strategies. However, a link between spatial processing strategies and the unit-decade compatibility effect has not yet been established. In the present study we investigate, whether sex differences in the unit-decade compatibility effect (i) depend on the vertical spacing between numbers, (ii) are mediated via sex hormone levels of participants, and (iii) relate to sex differences in spatial processing strategies. 42 men and 41 women completed a two-digit number comparison task as well as a spatial navigation task. The number comparison task modulates compatibility and vertical spacing in a 2 × 2 design. The results confirm a larger compatibility effect in women compared to men and with dense compared to sparse spacing. However, no interactive effect was observed, suggesting that these factors modulate number magnitude processing independently. The progesterone/testosterone ratio was related to the compatibility effect, but did not mediate the sex difference in the compatibility effect. Furthermore, spatial processing strategies were related to the compatibility effect and did mediate the sex difference in the compatibility effect. Participants with a stronger focus on landmarks in the spatial navigation task showed a larger compatibility effect.

Project description:Spatial navigation is a universal behavior that varies depending on goals, experience and available sensory stimuli. Spatial navigational tasks are routinely used to study learning, memory and goal-directed behavior, in both animals and humans. One popular paradigm for testing spatial memory is the Morris water maze, where subjects learn the location of a hidden platform that offers escape from a pool of water. Researchers typically express learning as a function of the latency to escape, though this reveals little about the underlying navigational strategies. Recently, a number of studies have begun to classify water maze search strategies in order to clarify the precise spatial and mnemonic functions of different brain regions, and to identify which aspects of spatial memory are disrupted in disease models. However, despite their usefulness, strategy analyses have not been widely adopted due to the lack of software to automate analyses. To address this need we developed Pathfinder, an open source application for analyzing spatial navigation behaviors. In a representative dataset, we show that Pathfinder effectively characterizes the development of highly-specific spatial search strategies as male and female mice learn a standard spatial water maze. Pathfinder can read data files from commercially- and freely-available software packages, is optimized for classifying search strategies in water maze paradigms, and can also be used to analyze 2D navigation by other species, and in other tasks, as long as timestamped xy coordinates are available. Pathfinder is simple to use, can automatically determine pool and platform geometry, generates heat maps, analyzes navigation with respect to multiple goal locations, and can be updated to accommodate future developments in spatial behavioral analyses. Given these features, Pathfinder may be a useful tool for studying how navigational strategies are regulated by the environment, depend on specific neural circuits, and are altered by pathology.

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Absolute Winding Number Differentiates Mouse Spatial Navigation Strategies With Genetic Risk for Alzheimer's Disease.

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