Molecularly-Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Recall

Associating fearful events with the context in which they occur is critical for survival. Dysregulation of context-fear memory processing is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Both the hippocampus and prelimbic subregion (PrL) of the medial prefrontal cortex (mPFC) have been linked with context fear memory recall in rodents, but the mechanisms by which hippocampal-prelimbic circuitry regulates this process remains poorly understood. Spatial and genetic targeting of this circuit in mice allowed us to use molecular profiling to show that hippocampal neurons with projections to the PrL (vHC-PrL projectors) are a transcriptomically-distinct sub-population that is enriched for expression of genes associated with both GAD and PTSD. We further show that stimulation of this population of vHC-PrL projectors suppresses context fear memory recall and impairs the ability of PrL neurons to dynamically distinguish between distinct phases of fear learning. Using transgenic and circuit-specific molecular targeting approaches, we demonstrate that unique patterns of activity-dependent gene transcription within vHC-PrL projectors causally regulate excitatory/inhibitory balance in the PrL during context fear memory recall. Together, our data illuminate the molecular mechanisms by which hippocampal-prelimbic circuitry regulates the retrieval of contextually-mediated fear memories.