PTSD: From Neurons to Networks

Abstract

Animal models of post-traumatic stress disorder (PTSD) must not only capture salient features of the disorder at the behavioral level but also provide insights into the underlying neuronal, physiological, and endocrine mechanisms. The fact that exposure to severe stress leads to the development of PTSD in humans provides the basic rationale for all rodent models of the disorder. The early focus of many of these models was on studying the debilitating effects of chronic or repeated stress on the hippocampus, a key component of the stress-inhibitory circuit that is reduced in volume in PTSD. Neuroimaging and clinical studies, however, also implicate two other brain areas, the amygdala and the prefrontal cortex, in PTSD. Moreover, structural and functional changes in all three brain structures appear to differ from each other in PTSD. These findings from human studies pose a challenge for animal models of PTSD: can the same stressful experience elicit contrasting cellular effects in the hippocampus, amygdala, and prefrontal cortex? Another striking characteristic of PTSD, which is not fully reflected in commonly used animal models of chronic stress, lies in the temporal domain. While PTSD is triggered by a single intensely traumatic event, some symptoms persist well beyond the original event. Can animal studies on the delayed, long-term impact of brief, but severe, stressors shed any light on these temporal features of human PTSD? Finally, while the hippocampus, amygdala, and prefrontal cortex are distinct in their associations with the severity of PTSD symptoms, there are significant neuroanatomical interconnections between the three areas. Can stress-induced modulation of structure and function in one of these brain areas affect changes in another? If so, can we construct new animal models that expand the scope of their analyses by studying stress-induced changes distributed across a wider network encompassing all three brain areas implicated in PTSD? In this review, we address these key questions by summarizing findings from various rodent models of stress. We focus on the morphological, electrophysiological, endocrine and molecular effects of stress in the hippocampus, amygdala, and prefrontal cortex. We end by discussing some of the gaps in our current understanding and explore experimental strategies that may lead to more powerful animal models in the future.