Abstract A hallmark of drug addiction is the uncontrollable urge to seek drug despite negative consequences— drug seeking individuals become resistant to punishment. Punishment resistance has also been observed in an animal model of addiction. In this model, some rats continue to seek cocaine despite a footshock outcome (i.e., punishment), whereas other rats instead reduce their cocaine seeking to avoid footshock. The propensity to reduce cocaine seeking to avoid a negative consequence may require behavioral flexibility, an adaptive form of learning that allows changes in behavior in response to new features in the environment. Previous work using measures of behavioral flexibility, such as reversal learning and strategy shifting, have shown that striatal circuits are essential for expressing behavioral flexibility. Specifically, frontal cortex areas such as the orbitofrontal cortex (OFC) and thalamic areas such as the parafascicular thalamus (PF) target the dorsal striatum (DS) and help track events in the environment that are important for updating behavior. One striatal cell type that is important for the role of PF and OFC in behavioral flexibility are cholinergic interneurons (CIN). However, the role of be- havioral flexibility and its neural substrates in punishment resistance is poorly understood. The proposed work will test the hypothesis that punishment-resistant cocaine seeking results from reduced behavioral flexibility when faced with negative consequences. Specific Aim 1 (F99, dissertation phase) will identify a DS CIN mechanism that supports behavioral flexibility during punishment of cocaine seeking in rats, using immunohistochemistry, behavioral pharmacological, and optogenetics. Specific Aim 2 (K00, postdoctoral phase) proposes a research direction that will focus on the role of OFC in driving vs suppressing punishment-resistant cocaine seeking, which serves as an extension of the dissertation work that will be completed in Aim 1. I will acquire technical skills related to a measure of neurotransmission, such as in vivo calcium imaging, to fully investigate OFC activity patterns related to cocaine seeking in the face of negative outcomes. In addition, Aim 2 describes the qualities I will seek in a postdoctoral mentor and research environment that can support my research interests, technical training goals, and growth as an independent neuroscientist. Overall, the proposed research in this training fel- lowship aims to define the neural mechanisms underlying reduced behavioral flexibility, which will contribute to identifying targeted treatment strategies for drug addiction.

Project Narrative A defining feature of drug addiction is the uncontrollable urge to seek drugs despite negative conse- quences. The proposed work will test the hypothesis that this behavior results from reduced flexibility when faced with new outcomes. These studies will investigate the neural mechanisms underlying reduced behavioral flexi- bility with the aim of uncovering potential treatment targets for addiction.