Hippocampal-cortical interactions supporting memory and value-guided decision-making

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Project Summary/Abstract Prior experiences can profoundly shape subsequent decisions. Mental simulation of potential futures based on memories of prior actions and resultant outcomes is one strategy to support making adaptive decisions. Substantial evidence demonstrates that the hippocampus (HC) is involved in this process: planning and imagining future events based on previous spatial experiences. More specifically, the HC exhibits temporally compressed sequences of neural firing that are thought to internally represent prospective locations distinct from the animal’s current place in an environment. This “nonlocal” activity may enable consideration of alternate routes during learning, when the optimal choice is unclear. In order to make a decision about which trajectory to take, however, the brain must not only internally represent potential paths, but also the expected value of each choice. Neural activity in the prefrontal cortex (PFC) can encode the value of a choice’s outcome and is modulated by reward. This evidence makes the PFC a strong candidate site for the evaluation of potential spatial choices based on reward history. Despite substantial research on the respective functions of either the HC or PFC in memory or value-guided decisions, little is known about how these circuits interact to support behavior. Coordinated neural activity across these circuits may facilitate spatial evaluation in service of adaptive decisions and may be modulated by learning. Specifically, this project tests the hypothesis that nonlocal representations in the HC are a mechanism of spatial deliberation, and that they are coordinated with PFC value representations to support reward history-guided adaptive decisions. Testing this hypothesis requires uniting approaches typically used to study either the HC and spatial memory or the PFC and decision-making. The proposed experiments therefore comprise simultaneous recordings of the HC and PFC in rats during the performance of a spatial decision-making task with changing reward contingencies (Aims 1 and 2) and closed-loop optical inactivation of the HC based on neural feedback during behavior (Aim 3). By working at the intersection of established but often separate lines of investigation on memory and decisions, the proposed Specific Aims have the potential to test prominent hypotheses and elucidate the neural underpinnings of experience-based decision processes. Furthermore, understanding the neural substrates that enable memory-guided decision-making is critical to understanding related psychiatric disorders in which HC and PFC circuits malfunction, such as addiction, obsessive-compulsive disorder, and schizophrenia. The proposed research strategy is bolstered by a training plan with experimental and analytical strength and is necessarily guided by a sponsor who is a leader in the technical and conceptual aspects of the project. The research environment is accordingly equipped with mentorship, technology, and expertise, all within UCSF, a collaborative institution dedicated to advancing health worldwide.