Biologic sex plays a complex role in vulnerability to stress

What is it about?

While everyone no matter their age, sex, or ethnicity can become depressed, globally, women are twice as likely to be diagnosed with depression. Further, women with depression often have more symptoms, more severe symptoms, and more likely to find that the front-line pharmaceutical treatments aren't effective in treating their symptoms; a condition which is clinically described as "treatment-resistant" depression. While one might immediately think this is based on cultural factors such as men not seeking help or the ways that living in a patriarchal society impacts women's emotional health, evidence suggests that there are biologic causes as well. For example, this disparity in depression rates between men and women is paralleled in rodent models as well. Female mice show anxiety and depressive-like responses to short, intense stress paradigms whereas male mice do not. However, the underlying source of those differences are in question. Here we investigated gene expression in two brain regions important for stress in a mouse line called the Four Core Genotypes (FCG) model. FCG mice are genetically engineered in a manner that allows us to separate sex chromosomes (XX, XY) from gonads. In most mammals, females have two copies of the X chromosome while males have one copy of the X chromosome and one copy of the Y chromosome. 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 in another place in the genome which produces animals with all of the possible combinations of sex chromosomes and gonads. So, while the FCG line produces the typical combinations (e.g. XY mice with testes), an FCG mouse could also have two XX chromosomes and have testes or have XY chromosomes and have ovaries. This is really useful because it allows us to disentangle how these two components of biologic sex play a role in behavioral responses to stress. First, we exposed all four combinations of the FCG mice to the same short, intense stress paradigm mentioned above. In typical mice, females are susceptible while males are resilient. In FCG mice, we found that animals with two XX chromosomes were vulnerable to stress no matter whether they had ovaries or testes. On the other hand, XY mice were resilient no matter what set of gonads they had. This sets up how important sex chromosome complement is in understanding the relationship between biologic sex and stress effects. After stress, we profiled gene expression in two regions which are important for modulating the effect of stress: the nucleus accumbens (NAc), a region which is central for encoding rewarding stimuli, and the prefrontal cortex (PFC), a region crucial for behavioral regulation and motor control. Across both of these two regions, we found little overlap in the ways stress exposure changed gene expression between males and females. This parallels what our team and other teams have demonstrated in human depression. In humans, depression leads to divergent patterns of gene expression in brain regions important for the depression disease process. Here in this present work, stress exposure altered pathways related to immune function in stress susceptible XX mice. While in stress resilient XY mice, stress exposure altered pathways involved in neuronal function. However, the effect of stress exposure was unique to the two regions we investigated. In the NAc, the pattern of gene expression created by stress exposure was shared by mice who had the same complement of sex chromosomes. However, in the PFC sex chromosomes and gonad type both contributed. In total, our findings implicate both sex chromosomes and gonad type in understanding the effect of stress and both factors need to be explored in understanding risk for depression in humans and stress susceptibility in rodent models of disease.

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Photo by digitale.de on Unsplash

Photo by digitale.de on Unsplash

Why is it important?

This work is a crucial addition to the field because the history of medicine is marked by a one size fits all approach to depression studies. We've long believed that depression in men and women operates through the same physical mechanisms and should be treated using the same remedies. So many studies in the past used only male subjects or only male rodents to our detriment. Depression and stress susceptibility are complex, nuanced processes and this work underscores the idea that we need to be just as nuanced in our strategies to help those who suffer.

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