Temporal factors and ensemble coding of contextual fear and extinction memories in the hippocampus

Abstract

Fearful experiences create long-term memories that involve acquiring a negative association to the surrounding context. Exposure to the same context at a later time elicits a fearful response, but this learned behavior will diminish in the absence of threat, a process known as extinction. Extinguished fear often relapses; thus, a better understanding of the behavioral and neural mechanisms that influence how fear and extinction memories are acquired and expressed is crucial to develop better therapies. The goals of the experiments in this dissertation were to understand the temporal factors and ensemble coding mechanisms that govern the enhancement or suppression of contextual fear learning. First, we investigated the influence of postshock context exposure in contextual fear conditioning (CFC). We found that prolonging the amount of postshock context exposure reduced conditioned fear. The reduction was more effective than an equivalent amount of context exposure the following day, but required low levels of freezing during the postshock period. Thus, unique mechanisms may play a role in attenuating context fear depending on the timing of the exposure and the emotional state of the animal. Next, we determined if the interval between context pre-exposure and conditioning affected one-trial CFC. Increasing the time between pre-exposure and conditioning by at least 1 h led to enhanced conditioned fear, indicative of a trial spacing effect. Spacing the sessions increased reactivation of CA3 ensembles associated with fear acquisition, suggesting this may be a potential neural correlate of the spacing effect. Finally, we investigated the neural mechanisms governing expression of competitive fear and extinction memories in the dentate gyrus (DG), a region known to play an important role in acquiring both fear and extinction memories. Using an activity-dependent neural tagging system, we demonstrate that extinction training suppresses reactivation of fear-associated DG neurons, while activating a unique population of extinction-associated DG neurons. Optogenetically silencing extinction-associated neurons impairs extinction memory retrieval, while silencing fear-associated neurons prevents spontaneous recovery of fear. Our results suggest that extinction training creates a unique DG extinction engram whose activity is necessary for extinction expression. We hypothesize that interactions between the fear and extinction engrams in the DG govern the expression of fear and extinction memories