Summary: Stress affects everyone, but its impact on the brain depends on the type and duration. A recent rat study shows that brief, acute stress tends to trigger anxiety-like behaviours—particularly in males—while prolonged, unpredictable mild stress is more closely associated with depressive-like symptoms. The research also reveals stress-related changes in blood-brain barrier (BBB) proteins, with distinct patterns for acute versus chronic stress and notable sex differences. These results highlight the need for prevention and treatment strategies that account for both the kind of stress and biological sex.
Researchers report alterations in key proteins that maintain the blood-brain barrier, indicating that different stress exposures compromise brain vascular defenses in different ways. Recognizing how acute and chronic stress diverge in their behavioural and neurovascular effects can improve how we prevent and treat anxiety, depression, and related neuropsychiatric conditions.
Key Facts
- Acute stress: Provokes anxiety-like behaviours, with stronger effects observed in male rats.
- Chronic stress (unpredictable mild chronic stress, uCMS): More closely linked to depressive-like behaviour and distinct changes in BBB-associated proteins.
- Sex differences: Male and female brains respond differently to stress, suggesting interventions should consider biological sex.
Source: BIAL Foundation
Study overview: This study evaluated how acute and chronic stress affect behaviour and neurovascular markers in male and female Wistar rats, revealing that short-term stress and prolonged unpredictable stress produce separate behavioural and biochemical signatures.
Stress is a well-known risk factor for mood disorders such as anxiety and depression, conditions that impose a major public health and economic burden worldwide. Epidemiological data show that mental health disorders affect a substantial portion of the global population. There are also established sex differences: women commonly represent a larger share of diagnosed stress-related disorders, while men account for a higher proportion of completed suicides, underscoring the complex interplay between sex, stress responses, and mental health outcomes.
Although moderate stress can be adaptive, excessive or prolonged stress harms the brain and can contribute to cerebrovascular and neuroinflammatory processes. The blood-brain barrier—responsible for protecting the brain from harmful substances—is particularly vulnerable to stress. While previous research has linked stress to BBB dysfunction and neuroinflammation, the cellular and molecular mechanisms driving these effects, and how they differ between acute and chronic stress or between sexes, have remained unclear.
To address these gaps, a team at the University of Coimbra led by Ana Paula Silva, supported by the BIAL Foundation, performed behavioural and biochemical analyses in rats. They used standard behavioural assays—the open field test to assess locomotion and anxiety-related activity and the forced swimming test to measure coping and depressive-like behaviour. The study compared responses after a single acute stress episode and after a regimen of unpredictable chronic mild stress (uCMS), in both male and female animals.
Behavioural results showed that acute stress elicited anxiety-like behaviour in male rats, while uCMS did not produce the same anxiety responses. In the forced swimming test, acute stress reduced immobility time in both sexes, a pattern interpreted as an active coping strategy. In contrast, uCMS increased immobility time in males only, consistent with depressive-like behaviour. These distinctions emphasize that brief and prolonged stressors do not simply differ by intensity but also by the type of behavioural response they provoke and by sex-specific vulnerability.
At the molecular level, the researchers measured protein levels in the prefrontal cortex that are related to the BBB and to neuroinflammation, using western blot and ELISA techniques. They observed that acute stress significantly reduced occludin and VEGF protein levels in both sexes, pointing to rapid neurovascular alterations. Chronic unpredictable stress produced a different pattern: claudin-5 protein levels were increased only in females, which the authors suggest may reflect a compensatory reaction of the BBB to persistent stress. Other inflammatory markers examined—TNF-α, GFAP and components of the complement system (C3/C3aR)—showed no major changes under either condition, indicating that BBB protein alterations can arise independently of overt neuroinflammatory marker shifts in this experimental context.
Overall, the findings demonstrate that acute and chronic stress produce distinct behavioural and biochemical profiles, with specific impacts on BBB-associated proteins and clear sex-dependent differences. These insights are important for neuroscience research and for clinical strategies aimed at preventing and treating stress-related psychiatric disorders: interventions might be more effective if tailored to the type of stress exposure and to sex-specific biological responses.
About this stress and mental health research news
Author: Sandra Pinto
Source: BIAL Foundation
Contact: Sandra Pinto – BIAL Foundation
Image: The image is credited to Neuroscience News
Original Research: Open access. “Distinct behavioural and neurovascular signatures induced by acute and chronic stress in rats” by Ana Paula Silva et al., Behavioural Brain Research.
Abstract
Distinct behavioural and neurovascular signatures induced by acute and chronic stress in rats
Stress contributes to the development of mood disorders, including depression and anxiety, and is associated with significant behavioural and cellular alterations. Sex differences in the prevalence and manifestation of these disorders are well documented. Emerging evidence links stress to cerebrovascular disease and implicates blood-brain barrier (BBB) dysfunction in neuroinflammation and neuropathology. Yet, the differential effects of acute versus chronic unpredictable mild stress (uCMS) on behavioural outcomes and BBB integrity have received limited attention.
This study applied the open field and forced swimming tests to evaluate locomotor activity, anxiety-like and depressive-like behaviours in male and female Wistar rats. Western blot and ELISA assays quantified levels of proteins related to the BBB and to neuroinflammatory processes in the prefrontal cortex. Results indicated that acute stress induced anxiety-like behaviour in males only, while uCMS did not produce the same anxiety response. Acute stress decreased immobility time in the forced swimming test in both sexes, suggesting an active coping response, whereas uCMS increased immobility time in males, indicating a depressive-like state.
Regarding molecular markers, neither form of stress produced major changes in TNF-α, GFAP, or C3/C3aR protein levels. However, acute stress significantly reduced occludin and VEGF protein expression in both sexes, highlighting acute impacts on neurovascular components. Under uCMS, claudin-5 expression increased in females only, possibly reflecting a compensatory BBB response to prolonged stress. In summary, acute and unpredictable chronic mild stress produce distinct behavioural and biochemical signatures, with particular effects on BBB-associated proteins and evident sex differences.