Contextual processing elicits sex differences in dorsal hippocampus activation following footshock and context fear retrieval

Establishing a contextual representation of an environment places specific spatial-temporal processing demands on the mammalian hippocampus, a region showing sex-differences in processing capabilities. However, evidence for sex differences in these processing demands during contextual fear learning remains limited. Here, we examined the relationship among contextual processing, timing of footshock, and activation of the dorsal hippocampus and basolateral amygdalar nuclei (BLA) in male and female mice (C57Bl/6 J). We modified the initial exposure time to the conditioning context prior to administration, or not, of a single footshock. We then quantified Fos- ir neurons activated by acquisition or retrieval of contextual fear memories in the rostral half of the dorsal CA1 (proximal – distal regions), CA3, Dentate Gyrus and basolateral amygdalar nuclei corresponding to atlas levels of the Allen Reference Atlas. In experiment 1, we found that sex differences in context elicited freezing were evident at the longest context placement-to-shock interval and that context fear retrieval with increasing contextual exposure periods increased CA1 Fos-ir in males, but not females. In experiment 2, we observed that an aversive footshock in males potentiated CA1 activation, while it downregulated CA1 activation in females. We also found that an aversive footshock independent of sex moderated Dentate Gyrus activation that normally showed increased activation with greater context exposure periods. Lastly, we identified a heightened responsiveness in BLA neurons to both footshock and length of context exposure in females compared to males. Overall, our findings suggest that sex differences in contextual fear conditioning may arise from marked sex differences in the contextual processing demands of the dorsal hippocampus subfields largely modulated by aversive outcomes.