Stress Isn't The Same For Everyone: How It Affects Men And Women Differently

The study showed that stress affects males and females differently. Acute stress increased anxiety in males and weakened proteins that protect the brain in both sexes. Chronic stress provoked signs of depression only in males, while in females it appeared to activate a protective mechanism in the brain. These findings help understand how stress can impact the mental and physical health of the brain in different ways.

Stress is a major factor in several mood disorders, such as anxiety and depression. These problems are linked to changes in behavior and brain function. Furthermore, it is already known that men and women react differently to stress, which helps explain why these disorders appear more frequently in one sex than the other.

Another important point is that stress can also affect the blood vessels in the brain and the so-called blood-brain barrier, which acts as a kind of protective filter, controlling what enters and leaves the bloodstream to brain tissue. When this barrier is compromised, the risk of inflammation and neurological diseases increases.

In this study, scientists investigated how acute stress (short and intense) and chronic stress (mild, but repetitive and unpredictable) affect the behavior and brain health of male and female rats.

To do this, they used two types of behavioral tests. The first was the so-called "open field" test, in which rats are placed in a space to assess their activity, movement, and signs of anxiety. The second was the "forced swim test," in which the animal is placed in a container of water and observed for how long it swims toward an exit and how long it remains immobile, which is used as an indicator of despondency or depression-like behavior.

Animal experiments, like those conducted with rats in this study, serve as approximate models of what happens in humans. These animal studies don't provide definitive answers for humans, but they serve as initial roadmaps that guide clinical research. Of course, the human brain is much more complex, but there are several reasons why this research is useful:

- Biological similarities: Rats and humans share many basic nervous system processes, including blood-brain barrier proteins and stress response mechanisms. This allows us to observe trends that likely also occur in people.

- Experimental control: In animals, it is possible to control factors such as diet, environment, and type of stress, something impossible in humans. This helps isolate the specific effects of stress.

- Translation to human diseases: Behaviors such as "anxiety" or "low spirits" in rats are not identical to human symptoms, but there are validated tests (such as forced swimming) that indicate analogies with depression or coping strategies.

Open-field test

- Clues for new treatments: By identifying which proteins or brain regions change with stress in rats, scientists can investigate whether the same markers appear in people, and thus create prevention strategies or more targeted therapies.

In addition to behavior, the researchers also analyzed important brain proteins, especially in the prefrontal cortex, a region linked to decision-making, emotions, and anxiety control. To do this, they took brain tissue samples and measured the amount of proteins involved in both the blood-brain barrier and inflammation.

The results showed important differences. Acute stress increased anxiety only in male rats, but had no such effect in females. On the other hand, both males and females displayed a type of coping behavior while swimming, spending less time immobile. Chronic stress led to signs of depression only in males, while it had no clear effect in females.

When they looked at the proteins, the scientists found that acute stress reduced levels of some molecules important for the integrity of the blood-brain barrier, such as occludin and the protein known as VEGF. This suggests that even short episodes of stress can weaken the brain's protective barrier.

In contrast, chronic stress increased levels of a protein called claudin-5 in females, which may indicate that their brains are trying to compensate for the negative effects of prolonged stress.

Interestingly, neither type of stress had a significant impact on other proteins associated with inflammation, such as tumor necrosis factor and complement.

These results help us better understand how stress can affect males and females differently and how it alters not only behavior but also the structure that protects the brain. The study reinforces the idea that mental health cannot be separated from the physical health of the brain and that understanding these differences is essential to creating new forms of prevention and treatment for disorders such as depression and anxiety.

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Distinct behavioural and neurovascular signatures induced by acute and chronic stress in rats

Daniela M. Simões, José Carreira, Alexandre Henrique, Rita Gaspar, Eliane S. Sanches, Filipa I. Baptista, and Ana Paula Silva

Behavioural Brain Research, Volume 493, 13 September 2025, 115706

https://doi.org/10.1016/j.bbr.2025.115706

Abstract: 

Stress is a contributing factor for several mood disorders, including depression and anxiety which are associated with significant changes in behavioural and cellular domains. Additionally, sex differences in the prevalence of these neuropsychiatric disorders are well established. Emerging evidence suggests that stress is linked to cerebrovascular diseases and that blood-brain barrier (BBB) dysfunction contributes to the development and exacerbation of neuropathology and neuroinflammation. Despite these interesting findings, very little attention has been given to the effect of both acute and chronic stress (unpredictable chronic mild stress-uCMS) on the link between behavioural and BBB alterations. In this study we used the open field and forced swimming tests (FST) to evaluate locomotor activity, anxiety- and depressive-like behaviours in male and female Wistar rats. Western blotting or ELISA were used to quantify the levels of different proteins related to BBB components and neuroinflammation in the prefrontal cortex. We found that acute stress induced anxiety only in males, whereas uCMS had no effect. Additionally, acute stress decreased immobility time in the FST pointing to a coping strategy in both sexes. In contrast, uCMS increased immobility time only in males, indicating depressive-like behaviour. Additionally, both types of stress had no major impact on TNF-α, GFAP and C3/C3aR proteins. Nevertheless, acute stress significantly reduced occludin and VEGF protein levels in both sexes, highlighting significant alterations in the neurovasculature. Concerning uCMS, there was an upregulation in claudin-5 protein levels only in females suggesting a possible compensatory mechanism of the BBB in response to a prolonged situation of stress. In conclusion, acute and uCMS induce distinct behavioural and biochemical profiles, particularly affecting BBB proteins.