NEURAL CIRCUITRY MEDIATING BEHAVIORAL FLEXIBILITY

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Project Summary Balancing habitual and flexible strategies for navigating the environment is necessary for behavior that is both cognitively efficient yet adaptive to change, and perturbations that disrupt this balance can result in significant cognitive impairments. Significant work has focused on how patients with substance abuse disorders (SUD) often shown difficulty altering their behavior to respond to changing outcomes, leading to poor decision-making and disrupted cognitive function. These deficits in cognitive function are linked to dampened prefrontal activity. The parent award is aimed to determine how a history of cocaine alters the corticostriatal neural network signaling that drives impaired cognitive flexibility. Critically, chronic history with drugs often leads to forms of dementia, but little is known about how drugs of abuse and dementia are linked. This current administrative supplement is aimed at examining how these circuits are altered in rat model of Alzheimer’s disease (AD, TgF344-AD). Patients with AD show decreased grey matter in the same brain regions linked to impaired cognitive flexibility in SUDs. We hypothesize that these changes contribute to deficits in cognition and decision-making in AD. For example, early signs of AD include both deficits in judgment, which may reflect changes to brain circuitry necessary for behavioral flexibility and difficulties in familiar tasks, which may reflect changes in brain circuitry necessary for habitual control of behavior. For this supplement, we propose to characterize the neural signaling changes in the Transgenic AD rat (TgF344-AD) in the corticostriatal pathways during behavioral flexibility. Specifically, similar to the parent grant we will explore the medial prefrontal cortex subregions (prelimbic and infralimbic) linked to ventral (i.e., nucleus accumbens) and dorsal striatum subregions. We will also link alterations in neurophysiology and behavioral to neurochemical and histopathological changes in AD rats. Data obtained through this administrative supplemental mechanism will drive future studies and grant applications that will examine how alterations in neurophysiology in corticostrial circuits link to behavior to more accurately predict the progression of AD, and in combination with the parent award, how drugs of abuse affect this progression.