Stress, the body’s natural response to different types of challenges and daily problems, is an inherently harmless state experienced by most people worldwide. While short-term stress is a common experience and can even be beneficial, acute or prolonged stress responses are known to be linked with various neuropsychiatric disorders, including depression and anxiety disorders.
A key contributor to stress responses in humans and most other vertebrates is cortisol, a hormone released by the adrenal glands that regulates various physiological processes. This hormone binds to two proteins in the brain known as the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), which typically act in pairs, forming units known as dimers.
Dimers can be made up of two identical receptors (i.e., homodimers) or one MR and one GR (i.e., heterodimers). While neuroscientists had observed heterodimers in the past, their possible contribution to stress-related behavioral and brain changes so far remained poorly understood.
Researchers at Leiden University in the Netherlands recently carried out a study aimed at shedding new light on how MR/GR heterodimers could influence both the behavior and brain of zebrafish that are under stress.
Their findings, published in Molecular Psychiatry, suggest that the formation of dimers comprised of one MR and one GR receptor prompts changes in brain function and behavior upon stress in zebrafish, and potentially also in other vertebrates.
“The finding that inspired us to start this research was done by Erin Faught, when she was still a postdoc in the lab of Matt Vijayan (Univ. of Calgary),” Marcel JM Schaaf, senior author of the paper, told Medical Xpress.
“She found, using zebrafish larvae from MR and GR knockout lines, that both MR and GR were required for certain cortisol-induced changes in behavior. In a subsequent Marie Curie postdoc fellowship, she tested in my group at Leiden University (The Netherlands), the hypothesis that this effect was a result of heterodimerization between these receptors.”
The effects of stress on the zebrafish brain
As part of their study, Faught and Schaaf created genetically modified versions of stress hormone receptors that could form only homo- or heterodimers. This allowed them to genetically engineer zebrafish with specific combinations of MR and GR pairs, to then investigate how these combinations influenced their behavior and brain processes while under stress.
Zebrafish are commonly studied by neuroscientists, because observing their brain and monitoring their behavior is fairly simple. In addition, they can be genetically engineered to observe specific brain processes or explore the role of specific receptors in isolation.
“We managed to generate combinations of mutant MRs and GRs that were deficient in either homo- or heterodimerization,” explained Schaaf. “We could express these receptors in zebrafish larvae and study the effect of cortisol on their behavior.”
Interestingly, the researchers found that cortisol only altered the behavior of zebrafish when MR and GR receptors formed heterodimers. These pairs of different receptors appeared to control genes that enable communication between different parts of the brain via the excitatory neurotransmitter glutamate.
“We showed that the cortisol-induced effect on behavior was dependent on heterodimerization, which was the first time the physiological relevance of these heterodimers was demonstrated in an in vivo system,” said Schaaf.
“Furthermore, we found that the MR/GR heterodimers specifically modulated the transcription of genes involved in the glutamatergic system, which in turn affected other neurotransmitter systems such as the GABAergic and serotonergic systems.”
Deepening the understanding of mental health disorders
The results of this recent study offer new insight into the biological processes via which stress might contribute to some mental health disorders, particularly anxiety disorders.
Notably, the team also showed that disruption of a specific gene that encoded a specific glutamate receptor prevented the stress-induced change in zebrafish behavior.
If validated in other vertebrates and eventually in humans, the team’s observations could improve the present understanding of how stress drives the development of some psychiatric disorders or intensifies associated symptoms.
In the future, they could potentially also help to devise alternative treatments for specific disorders that target human analogs of the stress signaling pathways identified by the researchers.
“Our findings might explain certain stress-induced behavioral effects (e.g., anxiety-like behavior), and may therefore be helpful in development of therapies against stress-related mental disorders,” added Schaaf.
“We would now like to explore three distinct research directions. First, we plan to study the downstream effects of MR/GR heterodimer activation in the brain further. We also wish to investigate the role of heterodimers in other systems (e.g., the immune system), and see if other steroid receptors (e.g., AR) form similar heterodimers.”
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Publication details
Erin Faught et al, Mineralocorticoid and glucocorticoid receptor heterodimers mediate cortisol-induced behavioural changes via modulation of glutamatergic signalling, Molecular Psychiatry (2025). DOI: 10.1038/s41380-025-03389-z.
Journal information:
Molecular Psychiatry
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