Biology session

Post-traumatic stress disorder (PTSD) is a psychiatric disorder in 10-20% of trauma survivors, characterised by persistent fear generalisation (marked anxiety reactions even in a safe environment). Although volume and/or activity abnormalities in certain brain areas (prefrontal cortex, amygdala and hippocampus) are known in PTSD, the network-level changes associated with specific symptoms, such as maladaptive fear generalisation, are not clear.

In this dissertation, I present a cellular resolution mapping of the whole brain network activity of fear generalization in a rodent model of PTSD. In our model, we exposed male Long-Evans rats to uncontrolled foot shock (trauma), followed by a measure of fear response both in the context of trauma (a measure of learning) and in a safe environment (a measure of generalization) 4 weeks later. Based on the latter test, we identified vulnerable and resilient groups (upper and lower 25% in proportion of freezing response), which were perfused at the time of fear generalization and immunohistochemically labeled coronal brain sections for the acute neuronal activity marker c-Fos protein. Using automated microscopy, we visualized and digitized the sections, which were placed in the volumetric atlas of the Waxholm Space Atlas for region identification. With the help of neural networks, c-Fos positive immunosignals were segmented, binarized and assigned to the atlas regions, thus quantifying the neuronal activity of brain regions.

These results partly confirm the activity differences in brain areas identified in the literature as key in PTSD (cingulate cortex, hippocampal CA1), but also reveal marked differences in activity in new regions (e.g. retrosplenial cortex, insular cortex). Furthermore, we showed that significant differences in overall network function were also apparent between the resilient and vulnerable groups, namely, we observed significantly stronger functional connectivity in activity correlations within modules in the resilient animals than in the vulnerable population. Our results may point to a new functional role for regions in the mechanism of fear generalization and may also point to broader network differences that are underlying these maladaptive alterations.