Differentiating fear generalization and extinction neuronal ensembles in prefrontal cortex

About This Grant

PROJECT SUMMARY/ABSTRACT It is estimated that 6.8% of U.S. adults have suffered from post-traumatic stress disorder (PTSD) in their lifetime. PTSD symptoms can be attributed, in part, to dysfunction in extinction and generalization—key learning and memory processes that regulate fear responses. Interestingly, generalization and extinction processes may not be mutually exclusive. It has long been proposed that generalization processes may contribute to extinction performance, although this hypothesis has never been directly tested. The infralimbic cortex (IL) is a small region of the ventromedial prefrontal cortex that processes both extinction and generalization. Whether extinction and generalization interact in IL is unknown. The goal of this proposal is to determine whether fear generalization and extinction are processed in mutually exclusive, or overlapping, neuronal substrates in IL. The human homologue of rodent IL is the subgenual anterior cingulate cortex which has been shown to be dysregulated in PTSD, making the preclinical study of IL translationally important. In Aim 1, we leverage ArcCreERT2 x eYFP transgenic mice to visualize and measure neurons activated during the expression of generalization for quantitative comparison with neurons activated during extinction. In a second experiment, fiber photometry will be used to gather a high-resolution temporal signature of functional activity during the expression of generalization and extinction. Together, these data will provide a first glimpse into whether fear generalization and extinction represent separate, or common, neuronal processes in IL. In Aim 2, an activity-dependent, multiplexed chemogenetic system will be used to bi-directionally modify extinction performance by manipulating neurons that were previously engaged during generalization. These data will provide causal evidence into whether generalization processes contribute to extinction performance. A full factorial experimental design that includes individual differences is a key strength of this proposal. This research plan was carefully thought-out with undergraduate neuroscience research in mind and designed to be completed within the proposed timeline. It is anticipated that this project will strengthen the research environment at Vassar College by exposing undergraduates to exciting new research opportunities, and lead to a greater understanding of fear generalization and extinction neurobehavioral processes, with the hope of advancing treatment options for PTSD.