Women are twice as likely as men to develop Post-Traumatic Stress Disorder (PTSD) after a trauma, but the neurobiological basis for this discrepancy is poorly understood. While there is a great deal of evidence that trauma itself can impact the male and female brain in discrete ways, less attention has been paid to the potential for PTSD treatments to work in a sex-dependent manner. A better understanding of the mechanisms that specifically mediate PTSD recovery in women could lead to improved therapeutics and a higher success rate for symptom reduction. In particular, the neural processes by which ovarian hormones modulate extinction learning represent a promising area of focus. Here, we will investigate the influence of circulating estrogen on the structure and function of neural circuitry connecting the ventral tegmental area (VTA), infralimbic area (IL) of the medial prefrontal cortex (mPFC), and basolateral area of the amygdala (BLA) in rats. We propose a system by which high estrogen states facilitate IL-BLA connectivity and enhanced extinction retention through upstream modulation of VTA-IL DA release during extinction learning. To test this hypothesis, we will use a combination of neuroanatomical tracers, intersectional viral techniques, and 3D reconstructions, thereby defining fear extinction-associated neural activity and plasticity across the estrous cycle. This work will result in a multi-synaptic map of extinction circuitry in the female brain, potentially identifying novel mechanisms by which estrogen can modulate learning processes.
Women are twice as likely as men to develop Post-Traumatic Stress Disorder, but the neurobiology underlying this discrepancy is poorly understood. The proposed work will specifically investigate how estrogen can modulate extinction of conditioned fear, a learning paradigm that is relevant to exposure therapy. This work may identify novel, estrogen-dependent mechanisms that drive extinction, providing insight into potential new therapeutic targets for women.