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Authors & Affiliations
Grace Cunliffe, Li Yang Tan, Sarah Luo, Jonathan Turner, Sangyong Jung, John Gigg
Abstract
Executive dysfunction encompasses altered decision-making, excessive risk-taking behaviours and inefficient planning. Alongside memory loss, these cognitive deficits are amongst the most frequently reported symptoms of Alzheimer’s disease (AD). Normal executive function depends on connectivity between the ventral hippocampus (vHIP) and medial prefrontal cortex (mPFC), yet how abnormalities in this pathway lead to cognitive dysfunction in AD has yet to be elucidated. As the Iowa Gambling task effectively measures executive function in the clinic, the rodent 4-Choice Gambling task (4CGT) touchscreen version was used to assess decision-making in 6-month-old male control and 3xTgAD mice. All groups successfully trained to criterion; however, during testing 3xTg mice were unable to choose significantly more advantageous (lower risk) over disadvantageous (higher risk) options, indicative of abnormal executive function. In a separate cohort of male 3xTgAD and control mice, underlying modifications to hippocampal-mPFC connectivity at this age were explored using extracellular or patch-clamp electrophysiology on infralimbic cortex layer II/III and V neurons receiving hippocampal input. 3xTg neurons displayed a reduced action potential amplitude and shorter AHP latency in layer V and II/III, respectively. Local field potentials exhibited paired pulse depression in layer V, and reduced input-output connectivity in layer II/III. Bulk RNA sequencing of the mPFC is ongoing to identify gene expression changes associated with these network alterations. Overall, these results support a platform for testing executive function in AD models and provide insight into how early-stage excitability changes in the hippocampal-prefrontal pathway may underlie executive dysfunction in AD.