Footshock Stress Activates the HPA Axis to Change Neurotransmitter Identity

After experiencing traumatic stress, people may develop stress-induced anxiety disorders such as post-traumatic stress disorder (PTSD). One of the major symptoms of PTSD is the overgeneralization of fear. Our unpublished data demonstrated that this behavior can be caused by foodshock stress of adult mice through transmitter switching in the lateral wings of dorsal raphe (lwDR), but the mechanism triggering this neuroplasticity remained unknown. Because the hypothalamic-pituitary-adrenal (HPA) axis regulates stress, we hypothesized that traumatic stress would activate the HPA axis to induce the switch of the co-expressing neurotransmitter from glutamate to gamma-aminobutyric acid (GABA) in serotonergic (5-HT-expressing) neurons located in the lateral wings of the dorsal raphe (lwDR). To test our hypothesis, we first measured following footshock, the c-fos expression by neurons in the paraventricular nucleus of the hypothalamus (PVN) that release corticotropin-releasing hormone (CRH) and assayed the plasma corticosterone level. We then blocked the activity of the CRHPVN neurons or glucocorticoid receptors in the lwDR using viral tools. Further, we performed intraperitoneal (IP) injections of metyrapone, RU486, or corticosterone-HBC to either temporarily weaken corticosterone’s efficacy or introduce exogenous corticosterone. Analysis of transmitter switching and behavior revealed that the activity of the HPA axis was necessary and sufficient (when accompanied by weak shock) to cause the transmitter switch and change in behavior. These results show that the HPA axis plays an essential role in regulating neuroplasticity, which then generates fearful behavior. Thus, the HPA axis could be a target for treating stress-induced anxiety disorders