Mapping entorhinal cortex circuitry in mouse models of Alzheimer’s Disease

Abstract Background Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide that comes with significant personal and economic burdens. Unfortunately, the brain circuitry underlying AD pathophysiology is yet to be fully understood. Elucidating the circuits that change before the onset of cognitive deficits would help to identify neuronal populations that change early in disease progression. After the identification of these brain regions and cell types, they can be selectively targeted to reverse both the anatomical pathology and eventual behavioral decline. Method Here we used a novel viral‐genetic method, rabies virus (RABV) tracing, which maps the inputs of targeted starter cell populations. We utilized this method in two mouse models of AD to measure circuit changes in the entorhinal cortex, which is one of the earliest brain regions to degenerate in Alzheimer’s. We implemented RABV mapping at three different time points, using aging as a key measure of comparison between circuit states. In using RABV tracing throughout disease progression, we were able to capture how these circuits look before any overt behavioral or histopathological deficits, as well as at a more advanced stage of the disease when both cognitive and pathological deficits are present. Result Our preliminary results have identified key cells and circuits that are disrupted related to AD pathogenesis as targets to slow or prevent the development of the disease. Conclusion Key cells and circuits change early on in AD pathogenesis elucidated by rabies virus tracing.