The Role of the Prefrontal Cortex in Aversive Memory Formation: Contribution of Sex and Circuit

Adaptive learning and responding to threat is crucial for survival. Maladaptive fear memory formation likely contributes to the development and maintenance of anxiety and fear disorders. However, we have little understanding of how executive and cognitive systems interact at the time of fear memory formation. Given that these same systems are implicated in human fear processing and dysfunction within these circuits contributes to anxiety and fear disorders, it is imperative to determine how these systems promote the acquisition of fear memory. Moreover, given the increased prevalence of these disorders in women, it is critical to determine how key nodes of the fear memory network differentially contribute to learning in each sex. Trace fear conditioning (TFC) is an associative learning paradigm which engages the same episodic and emotional memory systems implicated in pathological fear. The overarching goal of my dissertation was to determine how the prefrontal cortex and its interaction with the amygdala supports the initial formation of fear memories. In addition, I sought to determine whether males and females differentially engage the prefrontal cortex in support of memory.The prelimbic area of the medial prefrontal cortex (PL) and amygdala are required for TFC, and we tested the hypothesis that direct PL to amygdala communication is required for learning. We found that direct PL to amygdala communication is required under limited training. These results highlight that within a distributed cognitive network, direct neuronal interactions can uniquely contribute to the formation of complex fear memories. We next hypothesized that there would be sex-differences in the requirement of neurmodulatory signaling at muscarinic and PACAP receptors in the PL to form trace fear associations. We found that estrous stage influences the strength of fear memories, and that muscarinic and PACAPergic activity interacts with ovarian hormonal state to regulate the strength of TFC. My dissertation research advances our understanding of how the PL participates within distributed brain networks to form fear memories, and uncovered estrous cycle dependent sex-differences in the neurobiological mechanisms which support the involvement of the PL in fear memory formation