Prefrontal Modulators of Stress-induced Extinction Impairment in Female Rats - Project Summary Abstract: Although women have twice the incidence of developing post-traumatic stress disorder (PTSD), the identified neurobiological mechanisms that increase the susceptibility of female animals to stress-induced fear extinction impairment are limited. Abundant studies show that the infralimbic cortex (IL) is critical for proper fear extinction recall. To begin to address this gap, adult female rats were exposed to single prolonged stress (SPS) and the animals that showed impaired extinction recall were identified. The rats that were susceptible to stress-induced extinction impairment exhibited distinct proteomic changes in IL compared to rats that showed good extinction recall. Although many of the identified proteins, including neurogranin and microtubule associated protein tau (MAPT), are involved in neuronal function and synaptic plasticity, their role in stress-induced extinction impairment is unknown. In this proposal, we will build on our preliminary findings to further validate the proteomic findings and examine the role of IL neurogranin and MAPT in susceptibility to impaired extinction recall after exposure to traumatic stress in female rats. The goal of this proposal is to compare, through robust experimentation, the mechanisms by which prefrontal neurogranin and MAPT expression contribute to impaired fear extinction after traumatic stress in female rats as an important step toward understanding prefrontal mechanisms that alter susceptibility to impaired extinction after exposure to traumatic stress in females. Our central hypothesis is that exposure to traumatic stress alters neurogranin or MAPT expression in the IL of susceptible rats leading to reduced excitability of IL neurons and impaired fear extinction recall in females. To address this hypothesis, the team will examine the relationship between IL neurogranin and MAPT expression and impaired fear extinction after SPS exposure in Aim 1. In Aim 2, they will determine if reducing the expression of neurogranin or MAPT in IL enhances fear extinction and alters IL neuronal excitability. The overall impact of these Aims will greatly increase the understanding of the mechanisms by which exposure to traumatic stress can hinder fear extinction and highlight the role of changes in neurogranin, MAPT, and the IL proteome in this process. This data will enhance NIH’s mission to identify the neurobiological basis for complex behavioral responses to trauma and potentially lead to novel treatments.
