Sex differences in contextual pattern separation, neurogenesis, and functional connectivity within the limbic system

Background Females are more likely to present with anxiety disorders such as post-traumatic stress disorder (PTSD) compared to males, which are associated with disrupted hippocampal integrity. Sex differences in the structure and function of hippocampus exist. Here, we examined sex differences in contextual pattern separation, functional connectivity, and activation of new neurons during fear memory. Methods Two-month-old male and female Sprague-Dawley rats were injected with the DNA synthesis markers, iododeoxyuridine (IdU) and chlorodeoxyuridine (CldU) 3 weeks and 4 weeks before perfusion, respectively. One week after CldU injection, the rats underwent a context discrimination task in which rats were placed in context A (shock) and context A’ (no shock) every day for 12 days. On the test day, rats were placed in the shock context (context A) to measure fear memory and expression of zif268, an immediate early gene across 16 different limbic and reward regions. Repeated-measures or factorial analysis of variance was conducted on our variables of interest. Pearson product-moment calculations and principal component analyses on zif268 expression across regions were also performed. Results We found that females, but not males, showed contextual discrimination during the last days of training. On the test day, both sexes displayed similar levels of freezing, indicating equivalent fear memory for context A. Despite similar fear memory, males showed more positive correlations of zif268 activation between the limbic regions and the striatum, whereas females showed more negative correlations among these regions. Females showed greater activation of the frontal cortex, dorsal CA1, and 3-week-old adult-born dentate granular cells compared to males. Conclusions These results highlight the importance of studying sex differences in fear memory and the contribution of adult neurogenesis to the neuronal network and may contribute to differences in susceptibility to fear-related disorders such as post-traumatic stress disorder. Highlights Female rats, but not male rats, show faster discrimination during a contextual pattern separation task. Three-week-old adult-born neurons are more active in response to fear memory in females compared to males. Females had greater neural activation compared to males in the frontal cortex and dorsal CA1 region of the hippocampus in response to fear memory. Males and females show distinct patterns in functional connectivity for fear memory across limbic regions. Males have many positive correlations between activated new neurons of different ages between the dorsal and ventral hippocampus, while females show more correlations between activated new neurons and other limbic regions.Arts, Faculty ofMedicine, Faculty ofPsychology, Department ofReviewedFacultyResearche