Simões Daniela M, Carreira José, Henriques Alexandre, Gaspar Rita, Sanches Eliane S, Baptista Filipa I, Silva Ana Paula
Univ Coimbra, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra, Portugal; Univ Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal; Univ Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal.
Univ Coimbra, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra, Portugal.
Behav Brain Res. 2025 Jun 16;493:115706. doi: 10.1016/j.bbr.2025.115706.
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.
应激是多种情绪障碍的一个促成因素，包括抑郁症和焦虑症，这些疾病与行为和细胞领域的显著变化有关。此外，这些神经精神疾病患病率的性别差异已得到充分证实。新出现的证据表明，应激与脑血管疾病有关，血脑屏障（BBB）功能障碍会导致神经病理学和神经炎症的发展与加剧。尽管有这些有趣的发现，但急性和慢性应激（不可预测的慢性轻度应激-uCMS）对行为和血脑屏障改变之间联系的影响却很少受到关注。在本研究中，我们使用旷场试验和强迫游泳试验（FST）来评估雄性和雌性Wistar大鼠的运动活动、焦虑样和抑郁样行为。采用蛋白质免疫印迹法或酶联免疫吸附测定法（ELISA）来定量前额叶皮质中与血脑屏障成分和神经炎症相关的不同蛋白质的水平。我们发现，急性应激仅在雄性大鼠中诱发焦虑，而uCMS则没有影响。此外，急性应激缩短了FST中的不动时间，表明两性都有应对策略。相比之下，uCMS仅在雄性大鼠中增加了不动时间，表明出现了抑郁样行为。此外，两种应激对肿瘤坏死因子-α（TNF-α）、胶质纤维酸性蛋白（GFAP）和补体C3/C3a受体（C3/C3aR）蛋白均无重大影响。然而，急性应激显著降低了两性的闭合蛋白和血管内皮生长因子（VEGF）蛋白水平，突出了神经血管系统的显著改变。关于uCMS，仅在雌性大鼠中claudin-5蛋白水平上调，表明血脑屏障可能存在一种应对长期应激情况的补偿机制。总之，急性应激和uCMS诱导了不同的行为和生化特征，尤其影响血脑屏障蛋白。
