Variability in response to severe stress: highly reactive rats exhibit changes in fear and anxiety-like behavior related to distinct neuronal co-activation patterns.

There is an important individual variability in development of posttraumatic stress disorder (PTSD) and this feature needs to be better addressed in preclinical studies. Previously we showed that only rats that explored the context before a foot shock (delayed shock group) exhibited long-lasting behavioral changes. In this study the delayed shock group was segregated using the freezing response upon re-exposure to the shock-paired context and we investigated whether higher reactivity would be related to behavioral alterations and to activation of brain regions using Fos immunoreactivity. The latter allowed the analysis of co-activity patterns among brain regions within each group, by creating connectivity maps. High responder rats (HR) displayed heightened freezing response upon context re-exposure, anxiety-like behavior, impaired exploratory behavior and fear sensitization. Fos analysis showed that HR displayed a negative correlation between the medial prefrontal cortex and the ventral hippocampus (vHPC) after the first context re-exposure. After the second context re-exposure, HR displayed reduced Fos expression in vHPC CA1 area, whereas low responders (LR) showed increased Fos in the paraventricular nucleus of the thalamus. Pearson correlation analyses revealed positive associations between freezing and Fos in the dorsal the periaqueductal gray and vHPC after exposure to unfamiliar acoustic stimulus in a novel environment. Thus, assessment of individual variability allowed the identification of a subset of reactive animals that displayed behavioral modifications relevant to PTSD. Fos correlation and network analyses revealed co-activity patterns in HR rats that may point out to associations of brain areas relevant to the behavioral outcomes.