Neuroscience
Elucidating PTSD Gene-Environment Interactions in Veteran Stem Cell-Derived GABAergic Neurons via Glucocorticoid-Induced Gene Expression
Kelly Deng
Neuroscience
Kelly Deng
Post-traumatic stress disorder (PTSD) is a debilitating disorder characterized by damaged stress adaptation and repeated flashbacks to trauma. 65-89% of all individuals face a traumatic event in their lifetime, yet only 10-12% develop PTSD. However, in veteran populations, this statistic surges to 30%. Previous genome-wide association studies reveal that genetic predispositions may contribute to PTSD risk; however, the molecular mechanisms remain unknown, ultimately hindering risk protection and tailored treatment. Recent studies have established chronic glucocorticoid-induced stress exposure increases GABAergic neuron activity, subsequently stimulating PTSD development. Thus, drugs that modulate the glucocorticoid and GABAergic systems represent potential avenues for pharmacological intervention. Since PTSD is rooted in the brain, stem cells can provide a patient-specific, noninvasive look into the brain, possibly uncovering genetic interactions underlying PTSD. The goal of this study is to dissect how disease risk variants interact with the environment in GABAergic neurons and to subsequently identify genes that contribute to a PTSD-dependent glucocorticoid stress response. Stem-cell-derived GABAergic neurons will be generated by reprogramming skin cells biopsied from recruited veterans with or without PTSD, then exposing the neurons to varying levels of stress hormone glucocorticoid to simulate trauma exposure. After RNA-sequencing, sets of genes particularly active in PTSD-prone neurons, as well as specific differential gene networks following exposure, will be identified. With gene targets identified, a vast avenue opens up for improved diagnostics and predictions of clinical trajectories to minimize the likelihood of PTSD following trauma exposure – a particularly valuable outcome for military personnel who are particularly vulnerable to PTSD.