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Major depressive disorder is a heterogeneous disease with sex differences in prevalence, symptomology, and treatment response. For example, women are twice as likely to be diagnosed with major depressive disorder compared to men, and often have more symptoms, more severe symptoms, and higher likelihood of experiencing treatment-resistant depression. These sex differences are likely driven in part by biologic causes, though questions remain regarding the underlying source.

To gain clarity on sex differences in major depressive disorder, a team of scientists led by Marianne Seney, PhD (Associate Professor of Psychiatry and Bioengineering), investigated gene expression in two brain regions (the nucleus accumbens and the prefrontal cortex) important for stress in the Four Core Genotypes (FCG) mouse model. In most mammals, females have XX chromosomes and males have XY chromosomes. The Y chromosome contains a gene, SRY, which programs the development of testes, and in its absence the organism produces ovaries. In the FCG line, the SRY gene is removed from the Y chromosome and placed on an autosome, which produces animals with all of the possible combinations of sex chromosomes and gonads. Therefore, an FCG mouse could have XX chromosomes and have testes or have XY chromosomes and have ovaries. The expanded combinations possible with the FCG line enabled the scientists to disentangle how these two components of biologic sex (i.e., sex chromosomes and gonads) are associated with behavioral responses to stress.

Findings from the study, recently published in Proceedings of the National Academy of Sciences (PNAS), showed that in FCG mice exposed to stress, animals with XX chromosomes were vulnerable to stress regardless of whether they had ovaries or testes. In contrast, XY mice were resilient no matter what set of gonads they had. The investigators next profiled gene expression in the nucleus accumbens (central for encoding rewarding stimuli), and the prefrontal cortex (crucial for behavioral regulation and motor control). Across both regions, they found little overlap in the ways stress exposure changed gene expression between males and females. However, the effect of stress exposure was unique to the two regions. In the nucleus accumbens, the pattern of gene expression created by stress exposure was shared by mice who had the same sex chromosomes. However, in the prefrontal cortex, both sex chromosomes and gonad type contributed. 

“Our findings implicate both sex chromosomes and gonad type in understanding the effect of stress, suggesting that both factors should be explored in understanding risk for depression in humans and stress susceptibility in rodent models of disease,” said Dr. Seney, senior author of the study.

Impact of Sex Chromosomes and Gonad Type in Stress Susceptibility in Corticostriatal Brain Regions
Barko KN, Shelton MA, Kropp DR, Pham TQ, Rainville JR, Xue X, Teng GT, Hodes GE, Seney ML
Proceedings of the National Academy of Sciences. U.S.A. 123 (22) e2531920123, https://doi.org/10.1073/pnas.2531920123 (2026).