Impact of Sex Chromosomes and Gonad Type in Stress Susceptibility in Corticostriatal Brain Regions

To gain insight into these sex differences, we utilized the subchronic variable stress paradigm (SCVS) in which female mice are susceptible, while males are behaviorally resilient. We used the Four Core Genotypes mice to differentiate between sex chromosome complement (XX vs. XY) and gonad type (ovaries vs. testes) in stress susceptibility, uncoupling these factors by removing the testes-determining SRY gene from the Y chromosome.

Mice were subjected to SCVS followed by assays to assess anxiety-/depressive-like behaviors. Regardless of gonads, XX mice were stress susceptible, while XY mice were stress resilient, underscoring the importance of sex chromosome effects to sex differences in susceptibility to SCVS, independent of gonad type. We then performed RNA-sequencing of the prefrontal cortex (PFC) and nucleus accumbens (NAc).