The sexually divergent cFos activation map of fear extinction.

ABSTRACT

Objective: Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that can develop after experiencing or witnessing a traumatic event. Exposure therapy is a common treatment for PTSD, but it has varying levels of efficacy depending on sex. In this study, we aimed to compare the sexual dimorphism in brain activation during the extinction of fear conditioning in male and female rats by detecting the c-fos levels in the whole brain. Methods: Thirty-two rats (Male n = 16; Female n = 16) were randomly separated into the extinction group as well as the non-extinction group, and fear conditioning was followed by extinction and non-extinction, respectively. Subsequently, brain sections from the sacrificed animal were performed immunofluorescence and the collected data were analyzed by repeated two-way ANOVAs as well as Pearson Correlation Coefficient. Results: Our findings showed that most brain areas activated during extinction were similar in both male and female rats, except for the reuniens thalamic nucleus and ventral hippocampi. Furthermore, we found differences in the correlation between c-fos activation levels and freezing behavior during extinction between male and female rats. Specifically, in male rats, c-fos activation in the anterior cingulate cortex was negatively correlated with the freezing level, while c-fos activation in the retrosplenial granular cortex was positively correlated with the freezing level; but in female rats did not exhibit any correlation between c-fos activation and freezing level. Finally, the functional connectivity analysis revealed differences in the neural networks involved in extinction learning between male and female rats. In male rats, the infralimbic cortex and insular cortex, anterior cingulate cortex and retrosplenial granular cortex, and dorsal dentate gyrus and dCA3 were strongly correlated after extinction. In female rats, prelimbic cortex and basolateral amygdala, insular cortex and dCA3, and anterior cingulate cortex and dCA1 were significantly correlated. Conclusion: These results suggest divergent neural networks involved in extinction learning in male and female rats and provide a clue for improving the clinical treatment of exposure therapy based on the sexual difference.