Post Traumatic Stress Disorder (PTSD) is a devastating neuropsychiatric disorder that develops after trauma. A previous history of stress exposure significantly increases the likelihood of developing PTSD after a traumatic event. Deficits in extinction learning are a debilitating and core symptom of PTSD. This inability to learn that stimuli previously linked to trauma are no longer threatening causes maladaptive fear expression toward these stimuli. Efforts to reduce stress-induced deficits in extinction learning have included identifying stress-induced perturbations of molecular pathways in the brain. Most of this work has either treated brain regions as a homogeneous population of cells or mainly focused on neurons. While glia are the most populous cells in the nervous system, we have little appreciation for their contribution to stress-induced deficits in extinction learning. In this proposal, we examine how molecular events in astrocytes (the most predominant glial cell population) influence stress-induced deficits in extinction learning. More specifically, we study the relationship between astrocytes in the infra-limbic prefrontal cortex, a brain region important for extinction learning and stress-induced deficits in extinction learning. We hypothesize that in the adult brain, stress- induced deficits in extinction learning are, in part, mediated by stress hormone action and increased activity of developmental signaling pathways, in astrocytes of the infra-limbic prefrontal cortex. To test this hypothesis, we will study stress-induced deficits in extinction learning after manipulating stress hormone receptor function and the activity of developmental signaling cascades in astrocytes of the infra-limbic prefrontal cortex. Successful outcomes from our work will shed new light on how molecular function in astrocytes contribute to stress-induced impairments in extinction learning. Additionally, our work has the potential to recommend new cell-type specific molecular pathways that could be targeted to mitigate a highly prevalent and debilitating memory-related dimension of PTSD.
Prior exposure to stress is a risk-factor that biases the development of Post-Traumatic Stress Disorder (PTSD) after future trauma. Stress-induced deficits in extinction learning are characterized by the inability to learn that stimuli previously linked to trauma are no longer threatening and cause maladaptive fear expression toward these stimuli. This proposal will shed light on how astrocytes ? the predominant cell population in the brain, influence stress-induced deficits in extinction learning and inform new therapeutic approaches to mitigate this core pathology of PTSD.
