Nalepa Isabella Flor, Nielsen Vibeke, Wolf Tanja Esther, Touma Chadi, Grupe Morten, Asuni Ayodeji A, Ratner Cecilia
Department of Preclinical Fluid Biomarkers & Occupancy, H. Lundbeck A/S, Valby, Denmark.
Osnabrück University, Behavioural Biology, Osnabrück, Germany.
Stress. 2025 Dec;28(1):2447079. doi: 10.1080/10253890.2024.2447079. Epub 2024 Dec 30.
Chronic stress and stress-related mental illnesses such as major depressive disorder (MDD) constitute some of the leading causes of disability worldwide with a higher prevalence in women compared to men. However, preclinical research into stress and MDD is heavily biased toward using male animals only. Aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to the development of MDD and several animal models of MDD have been established based on HPA axis dysregulation. In the present study, we compared stress biomarkers and behavior of male and female mice after acute and chronic restraint stress to investigate potential effects of sex differences in the stress response. Further, the validity of the interrupted repeated restraint stress (IRRS) model as an animal model for the HPA axis disturbances seen in MDD was assessed. After acute stress, female mice showed increased corticosterone secretion and changes in molecular markers suggesting increased HPA axis feedback sensitivity. Acute stress-induced signs of anxiety-like behavior were observed in male mice only suggesting that female mice may be more resilient to the anxiogenic effects of acute stress. Males and females responded similarly to IRRS with no sustained perturbations in HPA axis biomarkers. The IRRS model did not adequately translate to the changes reported in MDD with HPA axis overactivity and more severe perturbation models are likely needed. However, in alignment with previous studies, these data support that there are important sex differences in the HPA axis and that these may contribute to the etiology of stress-related psychiatric disorders.
慢性应激以及与应激相关的精神疾病，如重度抑郁症（MDD），是全球致残的一些主要原因，女性的患病率高于男性。然而，应激和MDD的临床前研究严重偏向于仅使用雄性动物。下丘脑 - 垂体 - 肾上腺（HPA）轴的异常活动与MDD的发生有关，并且已经基于HPA轴失调建立了几种MDD动物模型。在本研究中，我们比较了急性和慢性束缚应激后雄性和雌性小鼠的应激生物标志物和行为，以研究应激反应中性别差异的潜在影响。此外，评估了间断重复束缚应激（IRRS）模型作为MDD中所见HPA轴紊乱的动物模型的有效性。急性应激后，雌性小鼠表现出皮质酮分泌增加和分子标志物变化，提示HPA轴反馈敏感性增加。仅在雄性小鼠中观察到急性应激诱导的焦虑样行为迹象，表明雌性小鼠可能对急性应激的致焦虑作用更具抵抗力。雄性和雌性对IRRS的反应相似，HPA轴生物标志物没有持续的扰动。IRRS模型不能充分转化为MDD中报道的HPA轴过度活跃的变化，可能需要更严重的扰动模型。然而，与先前的研究一致，这些数据支持HPA轴存在重要的性别差异，并且这些差异可能导致与应激相关的精神疾病的病因。
