Control Circuitry for Fear Conditioning Associated with Post-Traumatic Stress Disorder (PTSD)

摘要

Post-Traumatic Stress Disorder (PTSD) is an anxiety disorder triggered by exposure to traumatic stressors. At a molecular level, traumatic stress triggers the release of neurotransmitter dopamine (DA), and the corresponding receptors take the role of sensors that signals the fear conditioning (FD) circuit. The proteins in the FD neuronal circuit in turn activate the transcription factor CREB in amygdala and Nucleus Accumbens (NAc) to counteract the stress in order to maintain the homeostasis of the system. However, a sustained excessive CREB level due to high stress results in long-lasting fear memory and social avoidance, typical symptoms of PTSD. Therefore, we hypothesize that an excessive production of CREB through the DA-CREB pathway may be one of the causes that lead to PTSD. In order to validate this hypothesis, we construct a chemical kinetic model of DA-CREB pathway in the FD circuit and subject it to both sensitivity and bifurcation analysis. Sensitivity analysis revealed a core positive feedback loop in the FD circuit that is responsible for sustained production of CREB under stressful conditions, and consistent with this analysis, bifurcation analysis also revealed the importance of this feedback loop by exhibiting bistability that causes several proteins in the FD circuit to sustain a high concentration level and attains a difficult to recovery state. This preliminary study underlines the importance of DA-CREB regulatory pathway, which when disrupted due to traumatic stress leads to PTSD symptoms.