A new study has found that the hormone estrogen plays a protective role against stress-induced, depression-like behaviors in male mice, a function previously thought to be primarily associated with testosterone. The research identified that estrogen’s effects are mediated through a specific protein called estrogen receptor beta within a distinct brain circuit linked to reward processing. The findings were published in the scientific journal Molecular Psychiatry.
The investigation was prompted by an existing puzzle in psychiatry. While low testosterone is linked to depression in some men, and testosterone replacement therapy can sometimes help, the treatment comes with serious side effects, and its exact mechanism in the brain has remained unclear.
A team of researchers led by Polymnia Georgiou wanted to explore an alternative explanation. In the male brain, an enzyme called aromatase converts a significant amount of testosterone into the potent estrogen known as 17β-estradiol. In females, estrogen is well-known to be involved in regulating mood and reward sensitivity.
The scientists hypothesized that the antidepressant effects attributed to testosterone in males might not come from testosterone itself, but from the estrogen it gets converted into within the brain. The team set out to determine if estrogen was responsible, which specific receptor it used, and what brain pathways were involved in protecting against stress.
To examine the interplay between hormones, stress, and behavior, the researchers employed a “two-hit” model in mice. The first “hit” was the reduction of sex hormones, and the second was exposure to a mild form of social stress. To lower hormone levels, male mice underwent an orchiectomy, a procedure to remove the testes, which are the primary source of testosterone. These mice were then subjected to a brief, subthreshold social defeat stress, a mild stressor that does not typically cause behavioral changes in healthy animals.
The researchers found that the combination of low hormones and stress made the male mice susceptible to developing maladaptive behaviors. Specifically, they exhibited social avoidance and anhedonia, which is a reduced interest in pleasurable activities. Anhedonia was measured by a test of the mice’s preference for the scent of female urine over male urine. It is important to note that mice with low hormones that were not stressed, and mice with normal hormone levels that were stressed, did not develop these behaviors. This suggests that both factors were needed to trigger the negative outcome.
Having established this link, the team tested whether estrogen could prevent these effects. In low-hormone male mice, a single administration of 17β-estradiol before the mild stress exposure successfully prevented the development of both social avoidance and anhedonia. This provided the first piece of evidence that estrogen was directly involved in stress resilience in males. The next step was to identify which of the body’s estrogen receptors was responsible for this protective effect.
The scientists used mice that were genetically modified to lack either estrogen receptor alpha or estrogen receptor beta. When exposed to stress, male mice without estrogen receptor alpha showed some social deficits but did not develop anhedonia. In contrast, male mice lacking estrogen receptor beta developed both social avoidance and anhedonia, mirroring the effects seen in the low-hormone mice.
This finding pointed to estrogen receptor beta as the key mediator of estrogen’s protective actions against stress in males. In a notable sex-specific difference, female mice that lacked estrogen receptor beta were found to be more resilient to stress, suggesting the receptor’s function differs between males and females.
The investigation then moved to pinpoint the exact brain circuitry involved. Using advanced viral tracing techniques, the researchers identified a strong neural pathway composed of cells containing estrogen receptor beta that extends from the basolateral amygdala, a brain region central to emotion processing, to the nucleus accumbens, a critical hub for reward and motivation.
To confirm that this circuit was directly involved, they used a combination of sophisticated methods. Using a technique called optogenetics, which uses light to control brain cells, they found that activating this specific basolateral amygdala to nucleus accumbens pathway was inherently rewarding for male mice. The animals would spend more time in a chamber where they received the light stimulation. This rewarding effect was not observed in female mice.
To further test the circuit’s role in stress, the team used a technology called fiber photometry to measure the real-time activity of these specific neurons in awake, behaving mice. They found that in low-hormone mice subjected to stress, the activity of the estrogen receptor beta pathway from the basolateral amygdala to the nucleus accumbens was significantly reduced during social interactions. This reduction in activity correlated with the animals’ social avoidance behaviors.
The scientists then showed they could directly manipulate these outcomes. Using optogenetics to artificially activate the circuit in low-hormone mice before stress exposure prevented the onset of social avoidance. Conversely, using a chemical method called chemogenetics to inhibit the circuit in healthy, unstressed mice made them vulnerable to social stress, causing them to develop social deficits. This established a causal link between the activity of this specific brain pathway and resilience to stress.
Finally, the researchers performed a series of pharmacological experiments to definitively separate the effects of testosterone from those of estrogen. They confirmed that giving testosterone back to low-hormone mice prevented the stress-induced behavioral problems. However, when they blocked the action of testosterone at its own receptors, the androgen receptors, in healthy mice, it had no effect on their resilience to stress.
In a critical experiment, they used a drug called letrozole, which blocks the aromatase enzyme that converts testosterone into estrogen. When healthy male mice were treated with letrozole, they became susceptible to stress and developed social avoidance and anhedonia, just like the low-hormone mice. This demonstrated that it is the absence of estrogen, not testosterone itself, that creates vulnerability to stress in males.
Recognizing that estrogen therapy is not a practical treatment for men due to side effects like gynecomastia, the team explored a novel therapeutic strategy. They tested a compound known as DHED, which is a prodrug that is inactive in the body but is converted into 17β-estradiol specifically within the brain. When they administered this brain-selective estrogen prodrug to low-hormone, stressed mice, it effectively prevented the development of social deficits and anhedonia. This was achieved without producing the peripheral side effects associated with standard estrogen treatment, offering a proof-of-concept for a new therapeutic approach.
The study has some limitations. The findings are based on rodent models, and further work is needed to determine if these mechanisms translate to humans. The research focused on one specific neural pathway, and while it proved to be a major player, other brain circuits containing estrogen receptor beta may also contribute to stress regulation.
Future research could explore the roles of these other pathways and examine how they might interact. Studies could also investigate the development of selective estrogen receptor beta activators as potential new antidepressants for men, particularly for those with depression linked to low hormone levels. This work provides a new framework for understanding the biological basis of stress vulnerability in males and opens new avenues for developing targeted, sex-specific treatments for reward-related psychiatric disorders.
The study, “Estradiol, via estrogen receptor β signaling, mediates stress susceptibility in the male brain,” was authored by Polymnia Georgiou, Abagail F. Postle, Ta-Chung M. Mou, Liam E. Potter, Xiaoxian An, Panos Zanos, Michael S. Patton, Katherine J. Pultorak, Sarah M. Clark, Vien Ngyuyen, Chris F. Powels, Katalin Prokai-Tatrai, Antonis Kirmizis, Istvan Merchenthaler, Laszlo Prokai, Margaret M. McCarthy, Brian N. Mathur, and Todd D. Gould.
