Fifty years ago, Bruce McEwen and colleagues published the first report of glucocorticoid receptors in brain (McEwen et al., 1968). This report, which showed concentrated uptake of tritiated corticosterone in the hippocampus of adult rats, was followed 4 years later by another paper using in vivo autoradiography to show that neurons in the dentate gyrus and CA fields of the hippocampus concentrated the steroid when it was injected into adrenalectomized rats (Gerlach and McEwen, 1972). Since these groundbreaking studies, the study of glucocorticoid and stress effects on the hippocampus and other parts of the brain has grown exponentially. A considerable amount of this work came directly from McEwen’s laboratory at The Rockefeller University, as well as from the labs of innumerable trainees whose careers McEwen helped to launch. Over the years, substantial progress has been made and McEwen has played an indispensable role in our advanced understanding in the field. Of course there continues to be much to learn about the neurobiology, neuroendocrinology, and psychology of stress, and many scientific debates continue. McEwen’s research has always been at the forefront of new findings, ideas, and resolutions in the field. Thus it is only fitting that this special issue of Frontiers in Neuroendocrinology is dedicated to the contributions McEwen has made to the field of stress research. The collection includes a paper by McEwen himself, as well as by his collaborators and trainees from virtually all epochs of his career. The volume represents research presented at a meeting entitled “Stress: Past, Present and Future Directions”, which took place at Princeton University in 2017 and included a Festschrift event to honor McEwen’s career thus far. As former postdoctoral fellows of McEwen, we have enjoyed overseeing the compilation of these illuminating articles to honor a scientist of such outstanding caliber, who has made such important contributions to the field, as well as to the lives and careers of so many other scientists, ourselves included. The articles in this issue span multiple levels of analysis, which fittingly reflects the overarching approach taken by McEwen throughout his career. Indeed, reviews in this special issue tackle research on stress influencing outcomes at the population level (Epel et al., 2018) to the deep genome (Barlett and Hunter, 2018). Some of the papers summarize findings on stress effects in human populations, using behavioral, neuroimaging and biochemical analyses (Lupien et al. 2018; Epel et al.,2018; Dhabar et al., 2018), while others consider animal models to investigate clinical conditions, such as diabetes, autism spectrum disorder and mood disorders (Magarinos et al., 2018; Spencer et al., 2018; Cameron and Schoenfeld, 2018). Many reviews center on stress effects in otherwise healthy animal models, focusing on cellular processes, including microglial reactivity, neurogenesis, dendritic spine plasticity (Macht and Reagan, 2018; Karatsoreos, 2018; Ortiz and Conrad, 2018; Cameron and Schoenfeld, 2018) and molecular mechanisms, including stress effects on telomeres, epigenetics, receptor expression, mitochondrial enzymes, and non-coding elements of the genome called retrotransposons (Epel et al., 2018; Romeo et al., 2018; Picard et al., 2018; Bartlett and Hunter, 2018; de Kloet et al., 2018). The collected papers span stress effects on all aspects of the lifespan, including development, adolescence, early adulthood and old age and almost all consider both sexes, pointing out notable similarities and differences that emerge at different life stages, which create both vulnerabilities and strengths. Given the known sex differences in human diseases, such as autism spectrum disorder, major depressive disorder and drug addiction, understanding how stress impacts males and females seems increasingly relevant. Here again, McEwen has been a pioneer, studying sex difference in the context of stress as well as under other conditions, long before it was considered universally important to do so. While the vast majority of research on stress effects on the body and brain has focused on the downside, the upside of stress, including stress resilience, has become increasingly recognized as worthy of study. Many experiences with hedonic value produce physiological stress responses, and by some definitions can be deemed “stressful”, and most of these, somewhat surprisingly given the hormonal milieu, lead to beneficial outcomes in terms of brain plasticity, behavior, and overall health. Furthermore, experiences that are aversive in nature, more classically defined as “stressful” which not surprisingly produce physiological stress responses, often produce resilience or even resistance to subsequent stressors, as so-called “stress inoculation” effects. Understanding the mechanisms that promote prolonged health despite high levels of “stress” molecules either under rewarding or aversive conditions may provide clues about the processes that can be invoked in order to prevent or correct stress-induced illness. Many of the papers in this collection reflect this important trend, with an aim toward balancing the good with the bad and extracting information about healthy function to help elucidate and treat unhealthy states. As with much of the work on deleterious effects of stress on the brain and body, McEwen, his collaborators and trainees, have been at the forefront of these studies on the benefits of short-term stress (see Dhabhhar et al., this issue). Indeed, the commentary in this issue by Karatsoreos (2018) suggests several steps to enable stress researchers to reframe questions in order to guide us to new “universal principles” of stress. It is likely that these efforts, in combination with those designed to understand stress-induced illness, will provide a comprehensive view of the myriad of experience-dependent changes that shape individuals and contribute to health outcomes. Given the generative nature of McEwen’s career to this date, both in terms of publications and the students he has trained and continues to

中文翻译：

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五十年的压力和更多的压力：向布鲁斯·麦克尤恩致敬

五十年前，Bruce McEwen 及其同事发表了关于大脑中糖皮质激素受体的第一份报告（McEwen 等，1968）。这份报告显示成年大鼠海马中氚化皮质酮的集中吸收，4 年后另一篇论文使用体内放射自显影显示海马齿状回和 CA 区的神经元在注射时浓缩了类固醇进入肾上腺切除的大鼠（Gerlach 和 McEwen，1972）。由于这些开创性的研究，糖皮质激素和压力对海马体和大脑其他部分的影响的研究呈指数增长。大量的这项工作直接来自麦克尤恩在洛克菲勒大学的实验室，以及麦克尤恩帮助他们开展职业生涯的无数受训人员的实验室。这些年来，取得了实质性进展，麦克尤恩在我们对该领域的深入理解方面发挥了不可或缺的作用。当然，关于神经生物学、神经内分泌学和压力心理学还有很多需要学习的地方，许多科学争论仍在继续。McEwen 的研究一直处于该领域新发现、想法和解决方案的前沿。因此，本期《神经内分泌学前沿》特刊专门介绍 McEwen 对压力研究领域的贡献，这再合适不过了。该系列包括麦克尤恩本人以及他几乎所有职业生涯的合作者和学员的论文。该卷代表了在题为“压力：过去、现在和未来方向”的会议上提出的研究，该活动于 2017 年在普林斯顿大学举行，其中包括一项纪念 McEwen 迄今为止的职业生涯的 Festschrift 活动。作为 McEwen 的前博士后研究员，我们很高兴监督这些具有启发性的文章的汇编，以表彰一位如此杰出的科学家，他对该领域以及许多其他科学家的生活和事业做出了如此重要的贡献，包括我们自己。本期文章涵盖多个层次的分析，恰如其分地反映了 McEwen 在其整个职业生涯中所采取的总体方法。事实上，本特刊中的评论涉及压力影响人口水平（Epel 等人，2018 年）到深层基因组（Barlett 和 Hunter，2018 年）结果的研究。一些论文总结了人类压力影响的发现，使用行为，神经影像学和生化分析（Lupien 等人，2018 年；Epel 等人，2018 年；Dhabar 等人，2018 年），而其他人则考虑使用动物模型来研究糖尿病、自闭症谱系障碍和情绪障碍等临床状况（Magarinos 等人，2018 年） .，2018 年；Spencer 等人，2018 年；Cameron 和 Schoenfeld，2018 年）。许多评论都集中在健康动物模型中的压力效应，重点关注细胞过程，包括小胶质细胞反应性、神经发生、树突棘可塑性（Macht 和 Reagan，2018 年；Karatsoreos，2018 年；Ortiz 和 Conrad，2018 年；Cameron 和 Schoenfeld，2018 年）和分子机制，包括对端粒、表观遗传学、受体表达、线粒体酶和称为逆转录转座子的基因组非编码元件的压力影响（Epel 等，2018；Romeo 等，2018；Picard 等，2018；Bartlett和猎人，2018 年；de Kloet 等人，2018 年）。收集的论文涵盖了对生命周期各个方面的压力影响，包括发育、青春期、成年早期和老年，几乎都考虑了两性，指出了在不同生命阶段出现的显着相似之处和差异，这会产生脆弱性和优势。鉴于人类疾病中已知的性别差异，例如自闭症谱系障碍、重度抑郁症和毒瘾，了解压力如何影响男性和女性似乎越来越重要。在这里，麦克尤恩再次成为先驱，在压力和其他条件下研究性别差异，早在普遍认为这样做很重要之前。虽然绝大多数关于压力对身体和大脑影响的研究都集中在负面影响上，压力的好处，包括抗压能力，越来越被认为值得研究。许多具有享乐价值的体验会产生生理压力反应，并且根据某些定义可以被视为“压力”，而其中大部分体验，在考虑到荷尔蒙环境的情况下，会在大脑可塑性、行为和整体健康方面带来有益的结果。此外，本质上令人厌恶的体验，更经典地定义为“压力”，这并不奇怪会产生生理压力反应，通常会对随后的压力源产生弹性甚至抵抗力，即所谓的“压力接种”效应。了解在奖励性或厌恶性条件下尽管存在高水平“压力”分子但促进长期健康的机制可能会提供有关可以调用以预防或纠正压力引起的疾病的过程的线索。本集中的许多论文都反映了这一重要趋势，旨在平衡好与坏，并提取有关健康功能的信息，以帮助阐明和治疗不健康的状态。与许多关于压力对大脑和身体的有害影响的工作一样，麦克尤恩、他的合作者和受训者一直处于这些关于短期压力益处的研究的前沿（参见 Dhabhhar 等人，本期） . 确实，Karatsoreos (2018) 在这个问题上的评论提出了几个步骤，使压力研究人员能够重新构建问题，以指导我们了解压力的新“普遍原则”。这些努力与旨在了解压力引起的疾病的努力相结合，很可能会全面了解塑造个人并有助于健康结果的无数依赖于经验的变化。考虑到 McEwen 迄今为止的职业生涯，无论是在出版物方面还是在他培训并继续培养的学生方面，