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Background Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Methods Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Results Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Conclusions Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD., United States. Dept. of Defense. Congressionally Directed Medical Research Programs Posttraumatic Stress Disorder Program, Human Frontier Science Program (Strasbourg, France), McGovern Institute for Brain Research at MIT, McGovern Institute for Brain Research at MIT. Neurotechnology Program, Massachusetts Institute of Technology. Media Laboratory, Massachusetts Institute of Technology. Mind-Machine Project, National Alliance for Research on Schizophrenia and Depression, National Institutes of Health (U.S.) (Director's New Innovator Award 1DP2OD002002), National Institutes of Health (U.S.) (Grant 1R01DA029639), National Institutes of Health (U.S.) (Grant 1R43NS070453), National Institutes of Health (U.S.) (Grant 1RC1MH088182), Alfred P. Sloan Foundation, National Institute of Mental Health (U.S.) (R01 MH084966), United States. Army Research Laboratory, United States. Army Research Office (Grant 58076-LS-DRP)

Though growth hormone (GH) is synthesized by hippocampal neurons, where its expression is influenced by stress exposure, its function is poorly characterized. Here, we show that a regimen of chronic stress that impairs hippocampal function in rats also leads to a profound decrease in hippocampal GH levels. Restoration of hippocampal GH in the dorsal hippocampus via viral-mediated gene transfer completely reversed stress-related impairment of two hippocampus-dependent behavioral tasks, auditory trace fear conditioning, and contextual fear conditioning, without affecting hippocampal function in unstressed control rats. GH overexpression reversed stress-induced decrements in both fear acquisition and long-term fear memory. These results suggest that loss of hippocampal GH contributes to hippocampal dysfunction following prolonged stress and demonstrate that restoring hippocampal GH levels following stress can promote stress resilience., National Institute of Mental Health (U.S.) (NIMH (R01 MH084966)), United States. Army Research Office, United States. Defense Advanced Research Projects Agency (grant W911NF-10-1-0059)