Brain‐wide cellular mapping of acute stress‐induced activation in male and female mice

Mood disorders are more prevalent and often reported to be more severe in women; however, little is known about the underlying mechanisms of this sexual prevalence. To gain insight into the functional differences in female brains in response to stress, we systemically compared brain activation in male and female C57BL/6N mice after acute stress exposure. We measured c-Fos expression levels in 18 brain areas related to stress responses after a 3-h long restraint stress and found that activation was sexually dimorphic in several brain areas, including the nucleus accumbens, ventral tegmental area, nucleus reuniens, and medial part of the lateral habenula. Moreover, stress-activated a substantial number of cells in the medial prefrontal cortex, amygdala, and lateral part of the lateral habenula; however, the levels of activation were comparable in males and females, suggesting that the core stress responding machineries are largely shared. Pearson correlation analysis revealed several interesting connections between the analyzed areas that are implicated in stress responses and depression. Overall, stress strengthened intra-circuitries in the hippocampus, amygdala, and prefrontal cortex in female mice, whereas more longer-range connections were highlighted in stressed male mice. Our study provides a highly valuable neuroanatomical framework for investigating the circuit mechanism underlying the higher vulnerability to depression in women.