Woman sitting in front of laptop with head in hands to illustrate depression
Credit: Jamie Grill/Getty Images

A key mediator may help explain why women are more likely to experience depression than men. A multi-institutional team found that regulator of G-protein signaling 2 (RGS2) was downregulated in stressed female mice and women with major depressive disorder. Overexpression of the protein restored social approach in stressed mice.

The team’s study was published this month in Biological Psychiatry.

Women experience higher rates of depression than men, yet the cause for this difference is unknown, making their illnesses, at times, more complicated to treat.

University of California, Davis, researchers teamed up with scientists from Mt. Sinai Hospital, Princeton University, and Laval University, Quebec, to try to understand how the nucleus accumbens is affected during depression. The nucleus accumbens is part of the brain important for motivation and response to rewarding experiences and social interactions, which are affected by depression.

Previous analyses within the nucleus accumbens showed that different genes were turned on or off in women, but not in men diagnosed with depression. These changes could have caused symptoms of depression, or alternatively, the experience of being depressed could have changed the brain. To differentiate between these possibilities, the researchers studied mice that had experienced negative social interactions, which induce stronger depression-related behavior in females than males.

This group looked at the impact of stress on transcriptional profiles in male and female California mouse the nucleus accumbens and compared these results with data from post-mortem samples of the nucleus accumbens from men and women diagnosed with major depressive disorder.

Their cross-species computational analyses identified Rgs2 as a transcript downregulated by defeat stress in female California mice and in women with major depression. This protein plays a key role in signal regulation of neuropeptide and neurotransmitter receptors.

“These high-throughput analyses are very informative for understanding long-lasting effects of stress on the brain. In our rodent model, negative social interactions changed gene expression patterns in female mice that mirrored patterns observed in women with depression,” said Alexia Williams, a doctoral researcher and recent UC Davis graduate who designed and led these studies. “This is exciting because women are understudied in this field, and this finding allowed me to focus my attention on the relevance of these data for women’s health.”

Study of sex differences in depression is a new and growing field.  Another research group recently identified a female-specific biomarker—soluble E-selectin—that may identify women with neurovascular signs of depression.

“In humans, less stable versions of the Rgs2 protein are associated with increased risk of depression, so we were curious to see whether increasing Rgs2 in the nucleus accumbens could reduce depression-related behaviors,” said Brian Trainor, UC Davis professor of psychology and senior author on the study.

When the researchers increased Rgs2 protein in the nucleus accumbens of female mice, they effectively reversed the effects of stress—social approach and preferences for preferred foods increased to levels observed in females without stress. Notably, Rgs2 also controls the expression of a protein that regulates neurotransmitter receptors that are targeted by antidepressant medications such as Prozac and Zoloft.

“These results highlight a molecular mechanism contributing to the lack of motivation often observed in depressed patients. Reduced function of proteins like Rgs2 may contribute to symptoms that are difficult to treat in those struggling with mental illnesses,” Williams said.

“Our hope is that by doing studies such as these, which focus on elucidating mechanisms of specific symptoms of complex mental illnesses, we will bring science one step closer to developing new treatments for those in need,” added Williams.

Also of Interest