Project Summary: The primary clinical treatment for maladaptive fear is extinction—repeated exposure to a fearful stimulus in the absence of threat. Extinction does not permanently eliminate maladaptive fear. Extinguished fear resurfaces with the passage of time or if a new trauma is experienced. The transience of extinction suggests that it does not erase learned fear but, instead, establishes a new memory that competes with the fear memory for expression. To understand why fear returns, we must know more about the mechanisms controlling the retrieval or expression of extinction. Here we propose a highly novel approach to elucidate these mechanisms. Our proposal focuses on the dentate gyrus (DG), a region of the hippocampus that plays a critical role in acquisition of context fear memory—fear of a place in which an aversive experience occurred. We recently discovered that DG neural activity is also required for context fear extinction. Under this award, we will use using activity-dependent neural tagging, a technique that allows us to tag (and later manipulate) neural ensembles that are active during a behavioral experience, to investigate how neural ensembles in DG orchestrate the expression of fear and extinction memories. Our central hypothesis is that extinction causes DG to generate a new context representation, and activation of this extinction representation suppresses fear. Consistent with this hypothesis, our preliminary studies indicate (1) that fear learning and fear extinction activate distinct ensembles of “fear neurons” and “extinction neurons” in DG in mice, and (2) the activity of these ensembles modulates expression of fear and extinction. The proposed studies will leverage these findings to (1) test the hypothesis that the recovery of fear after extinction reflects changes in the activity of DG fear and extinction ensembles, (2) identify mechanisms through which these ensembles modulate fear, and (3) visualize the processing of fear and extinction memory in real-time using in vivo imaging with head-mounted miniature microscopes. We anticipate that the proposed research will uncover mechanisms controlling the expression of fear and extinction, reveal why fear recovers after extinction, and identify strategies for making extinction more durable.

Public Health Relevance In the clinic, the most effective method for suppressing pathological fear is extinction training, a form of exposure therapy in which repeated presentations of a fearful stimulus in the absence of threat gradually reduce fear. Unfortunately, extinction does not permanently suppress learned fear. The proposed experiments are aimed at understanding why fear returns after extinction. We will use innovative imaging and gain-of- function experiments to determine how activity in the hippocampus modulates fear and reveal how changes in hippocampal mechanisms contribute to the recovery of extinguished fear.