The ε4 allele of the primary cholesterol carrier in the brain - Apolipoprotein E (apoE4) is the most prevalent genetic risk factor of Alzheimer’s disease (AD). Despite a substantial body of evidence linking cognitive symptoms of AD to cellular and molecular apoE4 pathologies, studies on the neuronal activity underlying these phenomena are scarce.

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Human and murine data repeatedly show that APOE ε4 carriers are particularly sensitive to stress. Despite robust data highlighting molecular alterations of apoE4 pathology following stressful tasks requiring many trials and handling, such as the Morris Water Maze and fear-conditioning paradigms, they are currently the golden standard in the world of apoE4 research.

 

To provide a novel window to the neuronal activity underlying apoE4 pathological behavior, we utilize miniaturized fluorescence microscopes that call for behavioral paradigms fit for assessing learning and memory in a naturalistic manner.

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With this overarching goal, we were driven to implement a "one-shot" stress-reduced task suited for imaging, specifically an automated binary complex maze recently developed by the Cal-Tech based Meister laboratory.

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This assay is based on the finding that behaviors regarding ecologically relevant tasks are learned in the most efficient manner, such as mice exploring a burrow-like rewarded maze. 

 

We have gathered many data from naive male and female apoE4 and control mice in this apparatus and developed a python-based analysis pipeline termed "MazeMaster" to automate post analysis and generate complex evaluation metrics.

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We observed intriguing phenotypes, among them that both control and apoE4 female and male mice quickly learn to access the reward during only one learning session and develop strong spatial memory-devoid of visual cues.

 

Yet seemingly, apoE4 mice display impaired long-term memory relative to controls. Utilizing this paradigm, we are currently in the process of uncovering neuronal activity and network-based effects underlying these clinically relevant cognitive symptoms of apoE4-pathology.