Disruption of hippocampal-prefrontal neural dynamics and risky decision-making in a mouse model of Alzheimer’s disease

This study investigates how amyloid pathology influences hippocampal-prefrontal neural dynamics and decision-making in Alzheimer’s disease (AD) using 5XFAD mice, a well-established model system characterized by pronounced early amyloid pathology. Utilizing ecologically-relevant “approach food-avoid predator” foraging tasks, we observed that 5XFAD mice exhibited persistent risk-taking behaviors and reduced adaptability to changing threat conditions, indicative of impaired decision-making. Multi-regional neural recordings revealed rigid hippocampal CA1 place-cell fields, decreased sharp-wave ripple (SWR) frequencies, and disrupted medial prefrontal-hippocampal connectivity, all of which corresponded with deficits in behavioral flexibility during spatial risk scenarios. These findings highlight the critical role of SWR dynamics and corticolimbic circuit integrity in adaptive decision-making, with implications for understanding cognitive decline in AD in naturalistic contexts. By identifying specific neural disruptions underlying risky decision-making deficits, this work provides insights into the neural basis of cognitive dysfunction in AD and suggests potential targets for therapeutic intervention.