Project Summary Alzheimer’s disease (AD) is characterized by memory impairments and underlying neuropathology, including plaques, amyloid-β peptides, tau, in conjunction with neuroinflammation, and neuronal injury/loss. Recent studies suggest that alterations in neurophysiology are evident in patients with AD prior to gross neuropathology. Given that the prefrontal cortex contributes to top-down control of memory processing necessary for optimal decision-making, dysfunction within the PFC may contribute to suboptimal decision-making which often precedes gross memory loss in AD patients. Optimal decision-making requires functioning behavioral flexibility (the ability to shift behavior in response to changing consequences). The rat prelimbic cortex (PrL), and its connection with the nucleus accumbens (NAc), is heavily implicated in behavioral flexibility as measured by the ability to shift behavior after following outcome devaluation. The parent award is aimed to determine how a history of cocaine alters the corticostriatal neural network signaling that drives impaired behavioral flexibility (i.e., post outcome devaluation). We recently have found that transgenic AD rat (TgF344-AD) show impaired behavioral flexibility in this task compared to wild type litter mate control rats. Critically, AD rats show aberrant neurophysiological processing in the PrL to reward predictive cues. Specifically, PrL neuronal firing in the AD rats is hyper- responsive to reward predictive cues following outcome devaluation (i.e., PrL neurons in AD rats increase their firing rates to devalued reward predictive-cues where as PrL neurons in WT rats decrease firing rates to these cues). This current administrative supplement will aim at examining how these aberrant neurophysiological signatures are linked to impairments in behavioral flexibility. Specifically, we will utilize optogenetic techniques to determine if increased PrL input into the NAc is causally linked to impaired expression of behavioral flexibility in AD rats. Findings obtained through this supplement will allow for circuit level mechanistic insight into the AD impaired expression of behavioral flexibility following changes in outcome value in order to guide future therapeutics for impaired valued based decision-making in AD patients.