Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, Rehovot, Israel.
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Eur J Neurosci. 2022 May;55(9-10):2777-2793. doi: 10.1111/ejn.15481. Epub 2021 Oct 15.
Chronic stress creates an allostatic overload that may lead to mood disorders such as anxiety and depression. Modern causes of chronic stress in humans are mostly social in nature, relating to work and relationship stress. Research into neural and molecular mechanisms of vulnerability and resilience following chronic social stress (CSS) is ongoing and uses animal models to discover efficient prevention strategies and treatments. To date, most CSS studies have neglected the female sex and used male-focused aggression-based animal models such as chronic social defeat stress (CSDS). Accumulating evidence on sex differences suggests differences in the stress response, the prevalence of stress-related illness and in response to treatment, indicating that researchers should expand CSS investigation to include female-focused protocols alongside the popular CSDS protocols. Here, we describe a novel female mouse model of CSS and a parallel modified male mouse model of CSDS in C57BL/6 mice. These new models enable the investigation of vulnerability, coping and downstream effectors mediating short-term and long-term consequences of CSS in both sexes. Our data demonstrate differential effects on male and female mice during, soon after, and many weeks after CSS. Female mice are more prone to body weight loss during CSS and hyperactive anxious behaviour following CSS. Both sexes show reduced social interaction, but only stressed male mice show long-term changes in emotional memory and neuroendocrine function. We further discuss future avenues of research using these models to investigate mechanisms pertaining to sensitivity to CSS and treatment response profiles, in a sex-appropriate manner.
慢性应激会导致适应负荷过重，从而可能导致焦虑和抑郁等情绪障碍。现代人类慢性应激的主要原因是与工作和人际关系有关的社会压力。对慢性社会应激（CSS）后易感性和弹性的神经和分子机制的研究正在进行中，并使用动物模型来发现有效的预防策略和治疗方法。迄今为止，大多数 CSS 研究都忽略了女性，并且使用了基于雄性的以攻击性为重点的动物模型，例如慢性社会挫败应激（CSDS）。越来越多的关于性别差异的证据表明，应激反应、应激相关疾病的患病率以及对治疗的反应存在差异，这表明研究人员应该扩大 CSS 研究范围，将女性为重点的方案与流行的 CSDS 方案结合起来。在这里，我们描述了一种新型的慢性社会应激雌性小鼠模型和一种平行的改良的慢性社会挫败应激雄性小鼠模型。这些新模型能够研究易感性、应对策略以及 CSS 短期和长期后果的下游效应器，同时适用于两性。我们的数据表明，在 CSS 期间、CSS 后不久以及 CSS 后数周内，雄性和雌性小鼠的影响存在差异。在 CSS 期间，雌性小鼠更容易出现体重减轻和 CSS 后出现过度活跃的焦虑行为。两种性别的小鼠的社交互动都减少了，但只有应激的雄性小鼠表现出长期的情绪记忆和神经内分泌功能变化。我们进一步讨论了使用这些模型以适当的性别方式研究与 CSS 敏感性和治疗反应谱相关的机制的未来研究途径。
