Abstract
The endurance of memories of emotionally arousing events serves the adaptive role of minimizing future exposure to danger and reinforcing rewarding behaviors. However, following a traumatic event, a subset of individuals suffers from persistent pathological symptoms such as those seen in posttraumatic stress disorder (PTSD). Despite the availability of pharmacological treatments and evidence-based cognitive behavioral therapy, a considerable number of PTSD patients do not respond to the treatment, or show partial remission and relapse of the symptoms. In controlled laboratory studies, PTSD patients show deficient ability to extinguish conditioned fear. Failure to extinguish learned fear could be responsible for the persistence of PTSD symptoms such as elevated anxiety, arousal, and avoidance. It may also explain the high non-response and dropout rates seen during treatment. Animal models are useful for understanding the pathophysiology of the disorder and the development of new treatments. This review examines studies in a rodent model of PTSD with the goal of identifying behavioral and physiological factors that predispose individuals to PTSD symptoms. Single prolonged stress (SPS) is a frequently used rat model of PTSD that involves exposure to several successive stressors. SPS rats show PTSD-like symptoms, including impaired extinction of conditioned fear. Since its development by the Liberzon lab in 1997, the SPS model has been referred to by more than 200 published papers. Here we consider the findings of these studies and unresolved questions that may be investigated using the model.
Highlights
The focus of this Frontiers in Pharmacology Research Topic is the neural mechanisms of memory
A significant increase in GR expression was observed in the hippocampus and prefrontal cortex 7 days after partial Single prolonged stress (SPS) that did not impair extinction of conditioned fear (Knox et al, 2012b). These results indicate that glucocorticoid receptor expression must reach a threshold in order to interfere with the consolidation of extinction, or there is another SPS-related change that influences the extinction of conditioned fear
We have focused on factors contributing to extinction impairments, the SPS model can be used to investigate hypotheses about the biological causes of other debilitating symptoms such as social withdrawal, heightened anxiety, elevated startle response, hypervigilance, and sleep disturbances
Summary
The focus of this Frontiers in Pharmacology Research Topic is the neural mechanisms of memory. Acute changes in calmodulin (CaM) and calcium-CaM kinase II (CaMKII), two messengers involved in Ca2+ homeostasis and signaling processes related to learning and memory, were upand downregulated, respectively, within 1 day of SPS (Xiao et al, 2009), indicating that SPS disrupts fundamental mechanisms of cell signaling, which may lead to amygdala hyperactivity, enhanced fear expression and impaired extinction of conditioned fear. Consistent with the view that enhanced suppression of the HPA-axis and the resulting decrease in circulating glucocorticoids predisposes animals to the PTSD phenotype, Keller et al (2015b) found that inhibition of corticosterone synthesis prior to fear conditioning exacerbated the extinction impairment in SPS rats Taken together, these findings indicate that the SPS model is a useful tool for studying the role of the HPA-axis in PTSD. Further studies may be designed to determine whether HPA-axis dysfunction is a predisposing factor or a consequence of traumatic experience
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