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

Abstract Background Context-fear memory dysregulation is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). The hippocampus and prelimbic subregion (PrL) of the medial prefrontal cortex (mPFC) have been linked with context fear memory retrieval in rodents, but the mechanisms by which hippocampal-prelimbic circuitry regulates this process remains poorly understood. Methods Spatial and genetic targeting of hippocampal-prelimbic circuitry for RNA-sequencing (n = 31), chemo-genetic stimulation (n = 44), in vivo calcium imaging (n = 20), ex vivo electrophysiology (n = 8), and molecular regulation of plasticity cascades during fear behavior (context fear retrieval; n = 16). Results We show that hippocampal neurons with projections to the PrL (vHC-PrL projectors) are a transcriptomically-distinct sub-population compared to adjacent non-projecting neurons, and show complementary enrichment for diverse neuronal processes and CNS-related clinical gene sets. We further show that stimulation of this population of vHC-PrL projectors suppresses context fear memory retrieval 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 associated with brain-derived neurotrophic factor (BDNF) signaling within vHC-PrL projectors causally regulate activity in excitatory and inhibitory PrL neurons during context fear memory retrieval. Conclusions Together, our data show that activity-dependent BDNF release from molecularly-distinct vHC-PrL projection neurons modulates post-synaptic signaling in both inhibitory and excitatory PrL neurons, modifying activity in discrete populations of PrL neurons to suppress freezing during context fear memory retrieval.