Linking memories through hippocampal ensemble reactivation

Project Summary Post-traumatic stress disorder (PTSD) is a debilitating condition characterized by persistent and intrusive memories of a traumatic event. Understanding the mnemonic processes through which fear is triggered by environmental stimuli is therefore paramount to PTSD treatment. That said, the most widely employed models of associative fear conditioning used to study PTSD only assess cues directly paired with an aversive event and do not capture the spread of fear beyond these stimuli. This represents a critical gap in our knowledge of the etiology of the disorder. This proposal seeks to increase our understanding of how aversive memories propagate to other memories and could fundamentally change our view of how fear spreads in PTSD. We recently demonstrated that when animals are exposed to two neutral environments within several hours of each other they are capable of being linked in memory (they activate overlapping cell populations), providing a tool for understanding how events across time come to be related. Moreover, we found that when one of these environments was subsequently paired with an aversive event, fear spread to the linked (neutral) environment as well, providing a novel mechanism for the spread of fear. However, it is unknown how strength of an aversive experience affects the propensity for memories to be linked. Moreover, it is unknown how neuronal activity after learning supports the integration of distinct episodic memories. I have collected extensive preliminary data suggesting that aversive events are able to extend the window of linking, such that fear is transferred from an aversive event to a neutral memory formed days before. These findings are remarkable because they could potentially explain how so many stimuli come to trigger PTSD symptoms. The unifying goal of this proposal is to understand how aversive experience links distinct memories encoded across days, and to identify a circuit mechanism that explains how this occurs. In the first aim, I will examine how the strength of aversive experience modifies the ability of stimuli to be linked across time, while simultaneously imaging calcium dynamics in the hippocampus, a brain structure known to be altered in PTSD. I will record during learning, the period directly following learning, and retrieval of neutral and aversive experiences. In the second aim, I will selectively inhibit the hippocampal ensemble of the neutral memory after learning of the aversive experience. This will enable me to test whether co-reactivation of the neutral- and aversive-encoding ensembles in the hippocampus after learning is necessary for the two experiences to become linked in memory. Integrating advanced behavioral assays, in vivo calcium imaging, and cell-specific neuronal manipulation strategies, this work promises to shed light on how fear spreads in PTSD, and how this spread might be prevented.