PROJECT SUMMARY The natural process of aging is also the leading risk factor for Alzheimer’s disease (AD), a prevalent form of dementia that has devastating effects on the quality of human life and health care costs. As cognitive functions progressively deteriorate with AD, a neurobiological understanding of how AD alters brain cells and their circuit functions is one of the great challenges facing modern biomedical research with broad implications for advancing the nation’s health as well as stimulating the economy. Considerable human and animal AD research has focused on relating ‘physical’ (macroscopic, microscopic) changes in the brain with destructive loss of memory (i.e., anterograde and retrograde amnesias). In contrast, significantly less is known about the impact of AD on other cognitive functioning, such as risky decision-making which plays pervasive role in daily life, and how AD-afflicted neurons operate in ‘real-time’ as cognitive functioning is taking place. The primary goal of this application is to understand the dynamics of prelimbic cortex-hippocampus (PL-HPC) circuit functions in decision-making in a murine model of AD, utilizing an ecologically-relevant behavioral paradigm. We will test the general hypothesis that AD causes coordinated PL-HPC neural activities and risky decision- making abilities to decline as a function of the amyloid plaque accumulation in the two structures. There are two specific aims of the project: (1) an ETHOBEHAVIORAL ANALYSIS will investigate the scope of amyloid plaque effects on the animal’s ability to discern safety-danger boundary and make optimal risky foraging decisions; and (2) a SYSTEMS-LEVEL ANALYSIS will determine the neural synchrony in the PL-HPC network as AD mice perform risky foraging and also probe whether decision-making deficits can be alleviated by optogenetic intervention. Information generated from this project would be of significance (1) from a basic scientific perspective because it will provide novel data pertaining to AD-associated changes neural coding and decision-making; and (2) from an applied perspective because it provides a new avenue of naturalistic-based preclinical research that can potentially lead to developing successful treatments of AD-related declines in cognitive functions.