Corticoamygdalar regulation of stimulus-outcome memory

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Project Summary/Abstract Substance use disorder is a chronic, relapsing brain disease characterized by poor decision making, often in the presence of drug-associated cues. Indeed, such cues can elicit cravings and drug seeking, despite known negative consequences of drug use (e.g., illness, overdose). Addictive substances are thought to hijack the brain systems that normally support adaptive motivated behavior, resulting in maladaptive drug-seeking behavior. Thus they may produce maladaptive drug seeking by causing dysfunction in the brain’s ability to retrieve the stimulus-outcome associative memories that are crucial for mentally simulating (i.e., representing) possible future rewarding and aversive outcomes. But very little is known of the neural circuitry that enables these stimulus-outcome memories and even less about the systems that allow these memories to adapt following a shift in the predicted outcome’s value. In order to gain insight into how pathological states arise and determine what can be done to combat them, the goal of this research is to elucidate the brain mechanisms that support the retrieval of stimulus-outcome value memories and the use of such memories to promote adaptive behavior following a negative experience with the predicted reward. Recent studies in rodents and humans have indicated that the basolateral amygdala is a brain region crucial for stimulus-outcome associative memories, but the neural circuitry through which it achieves this function is unknown. I will conduct a critical, in-depth, and hypothesis-driven investigation of the contribution of the basolateral amygdala and its reciprocal connections with the medial orbitofrontal cortex, a region critical for considering potential future outcomes during decision making, in the retrieval of stimulus-outcome memories and use of these memories to guide adaptive behavior when a once-pleasurable event has become aversive. I will receive training in projection-specific chemogenetic manipulation, projection-specific activity monitoring, and behavioral procedures with translational relevance to symptoms of human mental illness to uncover the function of basolateral amygdala-medial orbitofrontal cortex loops in adaptive motivated behavior. I have selected sponsors to provide training on each technical and intellectual aspect of the project, and on career advancement more broadly. Further, completing this project at UCLA ensures I will have access to a highly collaborative network of leading neuroscientists to receive project feedback and any additional training as needed. This award will provide training to help launch me into an independent career as an addiction neuroscientist studying how addictive substances hijack the brain systems that evolved to support adaptive motivated behavior.