New study shows brain circuit disruption mimics antidepressant effects

New research published in Psychopharmacology has found that damaging a specific brain region called the nucleus reuniens reduces depression-like behavior in both male and female rats. The study also showed that male and female brains respond differently to antidepressant treatments and brain circuit changes, highlighting the importance of considering sex as a biological factor in mental health research.

Depression is one of the most disabling health conditions worldwide and affects women at about twice the rate of men. While current antidepressants are helpful for many people, they often take several weeks to work and fail to relieve symptoms in up to one-third of patients. Researchers are actively exploring new targets in the brain that could lead to faster and more effective treatments.

One promising direction involves understanding the brain circuits that regulate stress and emotional processing. The nucleus reuniens, a small region in the thalamus, acts as a bridge between two areas heavily implicated in depression—the prefrontal cortex and the hippocampus.

Previous work by the same research group showed that disrupting the nucleus reuniens in male rats reduced depression-like behaviors and prevented stress-related brain changes. However, these earlier experiments were done only in males. Given the well-established sex differences in depression, the team sought to replicate their findings in females and compare how male and female rats respond to common antidepressants when this brain circuit is disrupted.

The study was conducted by Christina Dalla of the National and Kapodistrian University of Athens and her colleagues. They used adult male and female Wistar rats and divided them into multiple groups based on sex, surgery type (sham or nucleus reuniens lesion), and drug treatment (sertraline, clomipramine, or vehicle).

To disrupt the brain circuit, some rats received a precise lesion to the nucleus reuniens using a chemical (NMDA). The others underwent a sham surgery with no actual brain damage. After a recovery period, the animals were tested in the Forced Swim Test, a well-known behavioral assay used to evaluate antidepressant effects. In this test, rats are placed in water and their behavior is observed—immobility is seen as a sign of despair, while swimming and climbing suggest active coping.

The rats were either untreated or received one of two antidepressants before the test. Sertraline is a selective serotonin reuptake inhibitor, while clomipramine is a tricyclic antidepressant that affects both serotonin and norepinephrine. After testing, the researchers examined brain tissue to assess activity levels in key regions using a marker of neuronal activation called c-Fos.

The nucleus reuniens lesion produced antidepressant-like effects in both male and female rats. Animals with the lesion showed less immobility and more active behavior, particularly swimming, during the Forced Swim Test. These behavioral changes were similar in size to those seen with sertraline and clomipramine treatment, suggesting that disrupting this brain circuit has strong effects on mood-related behaviors.

However, the researchers also found important differences between sexes and between the effects of the two antidepressants.

In female rats, baseline behavior showed more immobility and less swimming compared to males, regardless of surgery or treatment. Both antidepressants reduced immobility and increased active behaviors in males and females, but only clomipramine increased climbing. Head shaking, a behavior linked to serotonin function, was increased by sertraline and the lesion in males, but only partly in females.

Looking at brain activation patterns, the researchers found that females showed higher activity in the prefrontal cortex and hippocampus than males after the swim test. This elevated activation was reduced by clomipramine in females, but not by sertraline. In contrast, male rats did not show these changes, suggesting that their brain response to stress and antidepressants is different.

In the nucleus reuniens itself, females had lower activation than males at baseline and after sertraline treatment. Clomipramine reduced activity in this brain region, but only in males. Interestingly, the lesion abolished many of the usual correlations between behavior and brain activity, suggesting that disrupting the circuit changes how the brain processes stress.

These results show that the same brain manipulation—damaging the nucleus reuniens—can produce similar behavioral outcomes in both sexes, but the underlying brain activity patterns differ. Serotonergic and noradrenergic antidepressants also affect brain regions differently depending on sex, even when they produce similar outward behavior.

The study sheds light on the importance of brain circuits and sex in depression, but it has some limitations. The researchers used the Forced Swim Test as their main behavioral measure. This test is widely used in antidepressant research but does not capture the full complexity of depression in humans. It measures behavioral responses to acute stress, which may not reflect long-term mood changes. Future studies should explore whether the same effects are seen in other models of depression, such as chronic stress paradigms.

Another area for future research is understanding how different neurotransmitter systems—such as glutamate, serotonin, and norepinephrine—interact within this brain circuit. The nucleus reuniens is known to use glutamate to communicate between brain regions, and it receives serotonin input but not much norepinephrine. This may explain why its lesioning mimics the effects of sertraline more than clomipramine.

Finally, the role of sex hormones in modulating these brain responses remains an open question. Estrogen and testosterone may influence how brain regions like the prefrontal cortex respond to stress and medication, especially in females.

“In conclusion, this study highlights the importance of sex as a factor when interpreting findings pertaining to circuits and their contribution to depressive-like phenotypes,” the researchers wrote. “Indeed, sex differences can emerge not only in behavioral tests and treatment response, but also in the contribution of infralimbic structures in depression. Importantly, we demonstrate that the [nucleus reuniens] is indeed crucially involved in the stress response.”

The study, “Prefrontal cortex—nucleus reuniens—hippocampus network exhibits sex-differentiated responses to stress and antidepressant treatment in rats,” was authored by V. Kafetzopoulos, N. Kokras, Filippos Katsaitis, N. Sousa, H. Leite‑Almeida, I. Sotiropoulos, and C. Dalla.