Fear responses to environmental threats are critical for survival. However, enhanced fear responses are a hallmark of anxiety disorders, such as posttraumatic stress disorder (PTSD), due in part to increased activity in the dorsal anterior cingulate (dACC). Rodents are widely used for to study mechanisms of fear expression due to the numerous anatomical similarities that exist with humans. In rodents, the functional analog of dACC is the prelimbic (PL) subdivision of the medial prefrontal cortex which also exhibits increased activity after fear memory formation. However, a complete understanding of how PL participates in fear memory formation as well as the details of the circuit-based mechanisms supporting this function are lacking. PL exhibits a highly organized laminar structure composed of excitatory projection-specific output neurons as well as a prominent network of inhibitory interneurons. Both classes of neurons receive layer-specific inputs from another fear- related structure, the basolateral amygdala (BLA). However, it is unclear how BLA inputs and PL laminar organization participate in memory formation. Preliminary data suggest that a sparse PL neural ensemble is recruited during fear memory formation, that optogenetic ensemble reactivation induces fear- and anxiety-like behaviors, and that excitatory inputs onto specific excitatory and inhibitory neurons exhibit fear memory-related synaptic plasticity. Based on these data, I propose that a PL neural ensemble contributes to fear memory storage and is selectively recruited by joint plasticity of excitatory and inhibitory circuits after fear learning. To test this hypothesis, I will pursue the following two aims: 1) Characterize a fear-related PL neural ensemble using activity-dependent ensemble tagging, confocal imaging, and in vivo optogenetic ensemble manipulation. 2) Identify the plasticity of BLA inputs and PL microcircuits ensuring the selective recruitment of the fear memory ensemble by using intersectional- and optogenetics-assisted cell type-specific dual patch-clamp recordings in mouse brain slices. Results from this proposal will be the first to identify plasticity mechanisms underlying selective PL fear memory ensemble recruitment. Moreover, these findings will afford a more comprehensive understanding of PL-mediated fear expression and therefore mechanisms underlying pathologic fear expression in PTSD and will lay the foundation for interrogating mechanisms of ensemble recruitment in many diverse behaviors and brain regions.
The medial prefrontal cortex has been linked to fear expression and exhibits abnormal activity in anxiety disorders including posttraumatic stress disorder, where fear expression is greatly enhanced. The proposed work will identify the circuit-based plasticity mechanisms underlying fear and anxiety behaviors. Overall, results will afford a deeper understanding of fear encoding and expression in the medial prefrontal cortex with important implications for anxiety disorders.
