Neurobiology of Stress最新文献_第2页

From “Gig” to Genes: The enduring legacy of Seymour Levine in developmental stress neurobiology 从“Gig”到基因：西摩·莱文在发育应激神经生物学方面的不朽遗产

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-11-26 DOI: 10.1016/j.ynstr.2025.100772

Mathias V. Schmidt

The concept that early life experiences profoundly program adult physiology and behavior is now a cornerstone of neurobiology, a paradigm shift largely founded on the visionary work of Seymour “Gig” Levine. This review traces the intellectual lineage from Levine's pioneering behavioral and physiological studies to the modern molecular era, underscoring his indispensable contribution to understanding developmental stress. Levine's initial elegant experiments established the critical regulatory role of maternal care and the hypothalamic-pituitary-adrenal (HPA) axis, culminating in the discovery of the Stress Hyporesponsive Period (SHRP)—a crucial, sensitive window for developmental programming. Building on this legacy, subsequent research, including my own, has utilized advanced molecular tools to bridge the gap from these macroscopic observations to precise mechanistic detail. I highlight the role of gene-by-environment (G × E) interactions, particularly involving HPA axis modulators like FKBP51 and CRH signaling, in shaping vulnerability. Furthermore, I discuss how Levine's implicit recognition of individual differences has evolved into a central focus on biological sex differences, the match/mismatch hypothesis of adaptive programming, and the use of deep phenotyping to unravel the molecular bases of resilience and vulnerability. Ultimately, the journey from “Gig” to “Genes” provides a foundational understanding that is crucial for developing effective, targeted strategies to promote mental health and resilience across the lifespan.

早期生活经历深刻地影响了成人的生理和行为，这一概念现在是神经生物学的基石，这一范式转变很大程度上建立在西摩·“吉格”·莱文（Seymour“Gig”Levine）富有远见的工作之上。这篇综述追溯了从莱文的开创性行为和生理研究到现代分子时代的知识谱系，强调了他对理解发育压力的不可或缺的贡献。Levine最初的优雅实验确立了母性护理和下丘脑-垂体-肾上腺轴（HPA）的关键调节作用，最终发现了应激低反应期（SHRP）——发育程序的关键、敏感窗口。在这一遗产的基础上，后续的研究，包括我自己的研究，利用先进的分子工具来弥合从这些宏观观察到精确的机械细节的差距。我强调基因-环境（G × E）相互作用，特别是涉及HPA轴调节剂，如FKBP51和CRH信号，在形成脆弱性中的作用。此外，我还讨论了Levine对个体差异的隐性认识如何演变成对生物性别差异的中心关注，适应性编程的匹配/不匹配假设，以及使用深度表型来揭示弹性和脆弱性的分子基础。最终，从“Gig”到“Genes”的旅程提供了一个基本的理解，这对于制定有效的、有针对性的策略来促进整个生命周期的心理健康和恢复能力至关重要。

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引用次数: 0

Sensitive periods for the link between childhood maltreatment and brain aging during adulthood 儿童期虐待与成年期大脑老化之间关系的敏感期

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-11-01 DOI: 10.1016/j.ynstr.2025.100771

Leland L. Fleming , Kyoko Ohashi , Michelle Bosquet Enlow , Jennifer Khoury , Torsten Klengel , Karlen Lyons-Ruth , Martin Teicher , Kerry J. Ressler

Background

Childhood maltreatment (CM) is associated with the early onset of psychopathology and accelerated biological aging. However, outcomes vary widely among individuals with CM history. This variability may, in part, be explained by differences in age of exposure to CM. In this study, we examined whether CM was associated with accelerated brain aging, depending on the timing of exposure (i.e., ‘sensitive periods’).

Method

A machine learning algorithm of brain age trained prior to the current study in 3377 healthy individuals was employed in a CM dataset of 150 adult postnatal women, 92 of whom provided MRI data. CM history was retrospectively assessed from birth to age 18 years. Brain-predicted age was calculated from T1-weighted MRI scans. Brain age gap (BAG) was quantified as the disparity between brain-predicted age, relative to chronological age. Sensitive periods were identified using random forest regression with conditional inference trees.

Results

CM severity was associated with greater BAG (β = 0.34, p < 0.001). The most robust type/time risk factors for greater BAG were parental verbal abuse between ages 7 and 15 years, parental physical abuse between ages 4 and 6 years, witnessing sibling violence between ages 4 and 15 years, and sexual abuse between ages 4–6. Parental verbal abuse (7–15 years) and parental physical abuse (4–6) were the variables that were the most important predictors above and beyond duration, multiplicity (number of exposures), and cumulative maltreatment severity.

Conclusion

These findings suggest a link between CM and accelerated brain aging, with certain developmental periods appearing more sensitive to these effects. To the best of our knowledge, this study is the first to identify sensitive periods for the link between CM and brain aging in adults, and the first to examine the link between CM and brain aging in postnatal women. Together, these results suggest that CM's association with brain development is complex and warrants nuanced approaches to investigating the possible mechanisms underlying its effects.

儿童虐待（CM）与精神病理的早期发病和生物老化的加速有关。然而，有CM病史的个体的预后差异很大。这种差异部分可以用暴露于CM的年龄差异来解释。在这项研究中，我们根据暴露的时间（即“敏感期”）研究了CM是否与加速大脑衰老有关。方法将3377名健康个体在本研究之前训练的脑年龄机器学习算法应用于150名成年产后妇女的CM数据集，其中92名提供MRI数据。回顾性评估从出生到18岁的CM病史。通过t1加权MRI扫描计算脑预测年龄。脑年龄差距（BAG）被量化为大脑预测年龄与实际年龄之间的差距。利用随机森林回归和条件推理树识别敏感期。结果scm严重程度与BAG加重相关（β = 0.34,p <； 0.001）。最显著的类型/时间风险因素是7 - 15岁之间父母的言语虐待，4 - 6岁之间父母的身体虐待，4 - 15岁之间目睹兄弟姐妹暴力，以及4 - 6岁之间的性虐待。父母言语虐待（7-15岁）和父母身体虐待（4-6岁）是最重要的预测变量，超过了持续时间、多样性（暴露次数）和累积虐待严重程度。这些发现表明CM与大脑加速衰老之间存在联系，某些发育时期对这些影响更为敏感。据我们所知，这项研究是第一个确定成人CM和大脑衰老之间联系的敏感期，也是第一个检查产后女性CM和大脑衰老之间联系的研究。总之，这些结果表明CM与大脑发育的关系是复杂的，需要细致入微的方法来研究其影响的可能机制。

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引用次数: 0

Ventral hippocampal autophagy and mitophagy dynamics shape behavioral responses to chronic mild stress in adult male rats 成年雄性大鼠腹侧海马自噬和有丝自噬动力学影响慢性轻度应激的行为反应

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-11-01 DOI: 10.1016/j.ynstr.2025.100769

Paola Brivio , Maria Teresa Gallo , Elena Volpari , Piotr Gruca , Magdalena Lason , Ewa Litwa , Fabio Fumagalli , Mariusz Papp , Francesca Calabrese

Major depressive disorder (MDD) is a highly prevalent psychiatric condition characterized by a range of symptoms that often lead to reduced quality of life. Although chronic stress is a major risk factor for the development of MDD, only a subset of individuals exposed to stress develop depressive symptoms, while others remain resilient. Emerging evidence suggests that autophagy and mitophagy, key cellular processes involved in maintaining homeostasis and energy balance, may play a critical role in the response to stress. In this study, we investigated the impact of 6 weeks of chronic mild stress (CMS) on autophagy and mitophagy pathways in adult male rats, aiming to explore their potential association with vulnerability or resilience to stress-induced anhedonic-like behavior. By analyzing key autophagy and mitophagy markers in the dorsal (dHip) and ventral hippocampus (vHip), we describe region- and phenotype-specific alterations that may reflect distinct neurobiological adaptations to stress. In particular, we observed enhanced mitophagy alongside an overall impairment of autophagy in the vHip of vulnerable rats, while resilient animals showed preserved activity. These findings provide new insights into the molecular mechanisms associated with stress susceptibility and may inform future studies aimed at identifying novel therapeutic targets for MDD.

重度抑郁症（MDD）是一种非常普遍的精神疾病，其特征是一系列症状，往往导致生活质量下降。虽然慢性压力是MDD发展的主要风险因素，但只有一小部分暴露于压力下的个体会出现抑郁症状，而其他人则保持弹性。新的证据表明，自噬和有丝自噬是维持体内平衡和能量平衡的关键细胞过程，可能在应激反应中起关键作用。在这项研究中，我们研究了6周的慢性轻度应激（CMS）对成年雄性大鼠自噬和有丝自噬途径的影响，旨在探讨它们与应激诱导的快感缺乏样行为的脆弱性或恢复力的潜在关联。通过分析背侧海马（dHip）和腹侧海马（vHip）中关键的自噬和有丝自噬标记物，我们描述了区域和表型特异性的改变，这些改变可能反映了不同的神经生物学适应压力。特别是，我们观察到，在脆弱的大鼠的vHip中，有丝分裂增强，同时自噬整体受损，而有弹性的动物则表现出保留的活性。这些发现提供了与应激易感性相关的分子机制的新见解，并可能为未来旨在确定MDD新治疗靶点的研究提供信息。

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引用次数: 0

Intergenerational influences of paternal combat-related trauma on offspring behavioral and brain function 父亲战斗相关创伤对后代行为和脑功能的代际影响

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-11-01 DOI: 10.1016/j.ynstr.2025.100767

Glenn R. Yamakawa , James Freeman , Sydney Harris , Marissa Sgro , Elaina Vlassopoulos , Crystal N. Li , Josep Roman-Juan , Melanie Noel , Sabrina Salberg , Richelle Mychasiuk

Post-traumatic stress (PTS) is a debilitating mental health condition that is highly prevalent in Veteran populations owing to their increased exposure to combat-related trauma. PTS is associated with numerous comorbid conditions including major depressive disorder, anxiety, and chronic pain. Although the causal mechanisms are currently unknown, paternal trauma has been linked to an increased risk for pathology in their offspring. Therefore, using a preclinical model of combat trauma, we examined the relationship between paternal PTS and offspring socio-emotional functioning, pain perception, and gene expression changes pertinent to HPA-axis functioning, reward processing, and epigenetic regulation. Paternally experienced trauma produced persistent changes in sire anxiety, anhedonia, and sociability, as well as elevated levels of corticosterone and changes to gene expression. In addition, the paternal experiences prior to conception changed offspring behaviour and gene expression but did not modify the offspring's stress response in adolescence. Offspring born to fathers who experienced trauma exhibited changes to nociceptive sensitivity, social and anxiety-like behaviour, as well as changes in expression of 5HT1A, 5HT2A, Comt, Dnmt3a, Drd2, FKBP5, NR3C1, Maoa, and Mecp2 in the adrenal gland, hippocampus, hypothalamus, prefrontal cortex, and thalamus. These results suggest that trauma in fathers may alter expression of genes that contribute to an increased risk for the development of mental health conditions, such as PTS and chronic pain, in their offspring. This model of paternally induced intergenerational transmission could be used to explore the efficacy of future therapeutic strategies to ameliorate some risk imparted upon offspring by Veteran fathers living with PTS.

创伤后应激（PTS）是一种使人衰弱的精神健康状况，在退伍军人中非常普遍，因为他们越来越多地接触与战斗有关的创伤。PTS与许多合并症有关，包括重度抑郁障碍、焦虑和慢性疼痛。虽然因果机制目前尚不清楚，但父亲创伤与后代患病风险增加有关。因此，我们利用战斗创伤的临床前模型，研究了父亲PTS与后代社会情绪功能、痛觉以及与hpa轴功能、奖励加工和表观遗传调控相关的基因表达变化之间的关系。父亲经历的创伤会产生持续的焦虑、快感缺乏和社交能力的变化，以及皮质酮水平的升高和基因表达的变化。此外，受孕前的父亲经历改变了后代的行为和基因表达，但没有改变后代在青春期的应激反应。经历过创伤的父亲所生的后代表现出伤害敏感性、社交行为和焦虑样行为的变化，以及肾上腺、海马、下丘脑、前额叶皮层和丘脑中5HT1A、5HT2A、Comt、Dnmt3a、Drd2、FKBP5、NR3C1、Maoa和Mecp2表达的变化。这些结果表明，父亲的创伤可能会改变基因的表达，从而增加其后代患精神健康状况（如PTS和慢性疼痛）的风险。这种父亲诱导的代际遗传模型可以用来探索未来治疗策略的有效性，以改善患有PTS的退伍军人父亲传给后代的一些风险。

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引用次数: 0

Electroacupuncture attenuates anxiety caused by chronic mild stress through inhibiting NOX2-derived oxidative stress in ventral hippocampus 电针通过抑制海马腹侧nox2来源的氧化应激，减轻慢性轻度应激引起的焦虑

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-11-01 DOI: 10.1016/j.ynstr.2025.100768

Tong Yin , Yinxin Wang , Chuan'an Zhu , Yuanfang Lin , Weilin Wang , Jianpeng Huang , Kangwen Ming , Hang Lv

Anxiety disorders are highly prevalent and often triggered or worsened by chronic stress, yet current pharmacological treatments have limitations. Electroacupuncture (EA), a modern adaptation of traditional acupuncture, has shown promise as an alternative therapy for anxiety, though its mechanisms remain unclear. In this study, we investigated whether EA can alleviate anxiety-like behaviors induced by chronic mild stress (CMS) in mice, focusing on the role of NOX2-mediated oxidative stress and synaptic function in the ventral hippocampus. CMS exposure led to increased anxiety-like behavior, enhanced excitatory synaptic transmission, and elevated oxidative stress specifically in the ventral CA1 (vCA1) region. EA treatment was associated with normalization of excitatory/inhibitory synaptic balance and reduction in oxidative stress markers and NOX2 expression. Furthermore, overexpression of NOX2 in vCA1 induced anxiety-like behaviors, which EA partially ameliorated. These findings suggest that EA's anxiolytic effects may involve NOX2-related oxidative stress pathways and hippocampal excitability modulation, providing mechanistic insights that warrant further investigation for potential therapeutic applications (Graphical Abstract).

焦虑障碍非常普遍，并且经常由慢性压力引发或恶化，但目前的药物治疗有局限性。电针（EA）是传统针灸的现代改编，虽然其机制尚不清楚，但已显示出作为治疗焦虑的替代疗法的希望。在本研究中，我们研究了EA是否可以缓解小鼠慢性轻度应激（CMS）诱导的焦虑样行为，重点关注nox2介导的氧化应激和腹侧海马突触功能的作用。CMS暴露导致焦虑样行为增加，兴奋性突触传递增强，特别是腹侧CA1 （vCA1）区域氧化应激升高。EA治疗与兴奋性/抑制性突触平衡正常化、氧化应激标志物和NOX2表达降低有关。此外，vCA1中NOX2的过表达诱导了焦虑样行为，EA部分改善了这种行为。这些发现表明，EA的抗焦虑作用可能涉及nox2相关的氧化应激途径和海马兴奋性调节，为进一步研究潜在的治疗应用提供了机制见解（图摘要）。

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引用次数: 0

Echoes of stress: From molecular whispers to social thunderstorms 压力的回声：从分子耳语到社会风暴

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-11-01 DOI: 10.1016/j.ynstr.2025.100766

Juan Pablo Lopez

Stress is often described as a fleeting feeling, a momentary surge of tension or anxiety, but in my work as a neurobiologist, I have come to understand it as something far more enduring and complex. It is not merely a reaction to external pressure, it is a biological echo that resonates through our cells, brain circuits, and peripheral systems, ultimately shaping behavior and health. These echoes begin as molecular whispers, subtle shifts in hormonal regulation, gene expression, epigenetic marks, and synaptic plasticity, but over time, they can build into thunderstorms, manifesting as psychiatric and other stress-related disorders. My research has focused on detecting and translating these echoes into meaningful biological insight. Through this perspective article, I describe how early-life adversity, sex differences, and individual variability shape susceptibility and resilience. It highlights the promise of precision tools, from single-cell technologies to AI-driven behavioral tracking, to decode stress in motion and across systems. Through studies spanning human molecular genetics, animal models, and systems neuroscience, I envision a future of stress research that embraces biological complexity, prioritizes translational relevance, and aspires to personalize mental health care by decoding the molecular and circuit-level biology of lived experience.

压力通常被描述为一种短暂的感觉，一种瞬间的紧张或焦虑，但在我作为神经生物学家的工作中，我已经开始理解它是一种更持久、更复杂的东西。它不仅仅是对外界压力的反应，它是一种生物回声，通过我们的细胞、大脑回路和外围系统产生共鸣，最终塑造行为和健康。这些回声开始是分子的低语，荷尔蒙调节、基因表达、表观遗传标记和突触可塑性的微妙变化，但随着时间的推移，它们可以形成雷暴，表现为精神疾病和其他与压力相关的疾病。我的研究重点是检测并将这些回声转化为有意义的生物学见解。通过这篇透视文章，我描述了早期生活中的逆境、性别差异和个体差异是如何塑造易感性和弹性的。它强调了精密工具的前景，从单细胞技术到人工智能驱动的行为跟踪，以解码运动和跨系统的压力。通过对人类分子遗传学、动物模型和系统神经科学的研究，我设想了一个未来的压力研究，包括生物复杂性，优先考虑转化相关性，并渴望通过解码生活经验的分子和电路水平生物学来个性化精神卫生保健。

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引用次数: 0

Increased salivary oxytocin correlates with lower self-reported interoceptive accuracy in functional neurological disorders 在功能性神经疾病中，唾液催产素增加与自我报告的内感受准确性降低相关

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-10-19 DOI: 10.1016/j.ynstr.2025.100765

Natascha Stoffel , Laure von der Weid , Josef Gross , Cristina Concetti , Rupert Bruckmaier , Selma Aybek

Introduction

Functional Neurological Disorder (FND) is shaped by psychosocial stress, early adversity, and neuroendocrine dysregulation. Oxytocin (OXT), a hormone central to stress regulation and interoception, remains largely unexplored in FND.

Methods

In this cross-sectional study, salivary OXT was assessed at four timepoints across 87 participants (42 FND and 45 sex-age-matched healthy controls), including appetite and satiety and hormonal factors (intake of hormonal contraception or menstrual cycle phases) as covariates. Self-reported interoception, attachment style, childhood trauma and sexual functioning were assessed allowing analysis for association.

Results

Patients with FND exhibited higher OXT concentrations (averaged across four timepoints: d = 0.55, p = 0.031), which remained when controlling for covariates. Appetite and satiety specifically modulated OXT levels at different timepoints, underlying the group difference after lunch (p = 0.006) and at the end of the study visit (p = 0.035). Self-reported interoceptive accuracy was negatively correlated with OXT (r = −0.31, p = 0.014) and insecure attachment was positively correlated with OXT in controls (r = 0.42, p = 0.005), but not in FND. No associations of OXT and childhood trauma or sexual functioning reports were found.

Discussion

The elevated salivary OXT levels observed in patients with FND may reflect a dysregulated or compensatory neuroendocrine response. The combination of higher OXT and lower self-reported interoceptive accuracy suggests that OXT may be upregulated as an attempt to modulate bodily stress or restore homeostatic balance. The absent association of OXT with attachment style in FND specifically supports its role in dealing with socio-affiliative stress.

功能性神经障碍（FND）是由社会心理压力、早期逆境和神经内分泌失调形成的。催产素（OXT）是一种应激调节和内感受的核心激素，在FND中仍未得到充分研究。在这项横断面研究中，87名参与者（42名FND和45名性别年龄匹配的健康对照）的唾液OXT在四个时间点进行评估，包括食欲和饱腹感以及激素因素（激素避孕药的摄入或月经周期阶段）作为协变量。对自我报告的内感受、依恋类型、童年创伤和性功能进行了评估，以便进行关联分析。结果FND患者表现出较高的OXT浓度（四个时间点的平均值：d = 0.55, p = 0.031），在控制协变量后仍然存在。食欲和饱腹感在不同时间点特异性地调节了OXT水平，这是午餐后（p = 0.006）和研究访问结束时（p = 0.035）的组差异的基础。自我报告的内感受准确性与OXT呈负相关（r = - 0.31, p = 0.014），不安全依恋与对照组的OXT呈正相关（r = 0.42, p = 0.005），但在FND中没有。没有发现OXT与儿童创伤或性功能报告的关联。FND患者唾液OXT水平升高可能反映了失调或代偿性神经内分泌反应。较高的OXT和较低的自我报告的内感受准确性的结合表明，OXT可能作为调节身体压力或恢复内稳态平衡的一种尝试而上调。在FND中，情感行为与依恋类型之间不存在关联，这特别支持了情感行为在处理社会附属压力中的作用。

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引用次数: 0

Metabolic state shapes cortisol reactivity to acute stress: A systematic review and meta-analysis of metabolic and hormonal modulators 代谢状态影响皮质醇对急性应激的反应：代谢和激素调节剂的系统回顾和荟萃分析

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-10-09 DOI: 10.1016/j.ynstr.2025.100764

Madeleine Kördel , Maria Meier , Anne Kühnel , Nils B. Kroemer

Individual variability in cortisol stress responses is shaped by multiple physiological factors. Yet the interaction with metabolic and hormonal states remains poorly understood. Therefore, we conducted a systematic review and meta-analysis to examine how metabolic factors (particularly glucose) and sex hormone levels (progesterone and estradiol) influence cortisol reactivity to acute stress. We identified 21 studies (N = 1216 participants) and conducted random-effects meta-analyses for metabolic and hormonal states. Across studies, glucose administration was associated with a significant increase in cortisol responses to acute stress compared to fasting or non-glucose control conditions (d = 0.30, 95 % CI = [0.05, 0.60], BF₁₀ = 2.42, NNT = 10.63). In contrast, the effects of sex hormones on cortisol responses were smaller and more variable, with both progesterone and estradiol showing weak and inconsistent associations. Our results highlight a robust modulatory role of metabolic state, specifically glucose availability, on HPA axis reactivity, while evidence for sex hormone effects remains inconclusive. Future research should focus on better harmonization of designs concerning sex hormones and systematically examine interactions between metabolic and hormonal states to better explain sex differences in the prevalences of metabolic and stress-related disorders.

皮质醇应激反应的个体差异是由多种生理因素形成的。然而，与代谢和激素状态的相互作用仍然知之甚少。因此，我们进行了系统回顾和荟萃分析，以研究代谢因素（特别是葡萄糖）和性激素水平（黄体酮和雌二醇）如何影响皮质醇对急性应激的反应。我们确定了21项研究（N = 1216名参与者），并对代谢和激素状态进行了随机效应荟萃分析。在所有研究中，与禁食或非葡萄糖控制条件相比，葡萄糖给药与皮质醇对急性应激反应的显著增加相关（d = 0.30, 95% CI = [0.05, 0.60], BF10 = 2.42, NNT = 10.63）。相比之下，性激素对皮质醇反应的影响更小，变化更大，黄体酮和雌二醇都表现出微弱且不一致的关联。我们的研究结果强调了代谢状态（特别是葡萄糖可用性）对HPA轴反应性的强大调节作用，而性激素作用的证据仍不确定。未来的研究应侧重于更好地协调性激素的设计，并系统地检查代谢和激素状态之间的相互作用，以更好地解释代谢和压力相关疾病患病率的性别差异。

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引用次数: 0

Potential vulnerability and resilience to accelerated brain aging in women exposed to stressful life events: insights from the brain age prediction model 面对压力生活事件的女性大脑加速老化的潜在脆弱性和复原力：来自大脑年龄预测模型的见解

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-09-23 DOI: 10.1016/j.ynstr.2025.100763

Hyeonseok Jeong , Yoonji Joo , Youngeun Shim , Yejin Kim , Hyeonji Lee , Yunjung Jin , Seog Ju Kim , Sujung Yoon , In Kyoon Lyoo

Brain age prediction models consistently reveal accelerated brain aging in psychiatric disorders, yet associations with stress, independent of formal psychiatric diagnoses, remain uncertain. This study investigated the relationships of emotional and alcohol-use symptoms, common and often comorbid stress-related symptoms, and resilience with brain aging using high-resolution structural MRI data from 520 women who experienced stressful life events. Participants were divided into four groups based on the presence of emotional and alcohol-use symptoms: no symptoms (n = 287), emotional symptoms only (n = 93), alcohol-use symptoms only (n = 79), or both symptoms (n = 61). Individual brain age gap (BAG)—the difference between predicted brain age and chronological age—was calculated using a deep learning-based brain age prediction model. Individual and interactive associations of the presence of two symptoms with BAG were assessed using two-way ANCOVA. Relationships of a continuous composite symptom score integrating both symptoms and resilience with BAG were evaluated. Participants with both symptoms exhibited significantly larger BAG than the other groups, with a statistically significant interaction between two symptom domains (p = 0.017). Across the full sample, composite symptom scores were positively associated with BAG (β = 0.16, p = 0.004), with an even stronger association within individuals with both symptoms (β = 0.34, p < 0.001). Conversely, higher resilience was linked to smaller BAG across all participants (β = −0.10, p = 0.046). The negative association between resilience and BAG was statistically mediated by the composite symptom score (b = −0.011, p = 0.010). These findings may suggest a synergistic, more-than-additive association between stress-related symptoms and accelerated brain aging, as well as a potentially buffering association of resilience.

脑年龄预测模型一致地揭示了精神疾病中加速的脑衰老，但与压力的关联，独立于正式的精神病学诊断，仍然不确定。这项研究利用520名经历过压力生活事件的女性的高分辨率结构MRI数据，调查了情绪和酒精使用症状、常见的和经常共病的压力相关症状以及恢复力与大脑衰老的关系。根据情绪和酒精使用症状的存在将参与者分为四组：无症状（n = 287）、只有情绪症状（n = 93）、只有酒精使用症状（n = 79）或两种症状都有（n = 61）。个体脑年龄差距（BAG）——预测脑年龄与实足年龄之间的差异——使用基于深度学习的脑年龄预测模型进行计算。使用双向ANCOVA评估两种症状与BAG存在的个体和相互关联。综合症状和恢复力的连续复合症状评分与BAG的关系进行评估。两种症状的参与者表现出明显大于其他组的BAG，两种症状域之间的相互作用具有统计学意义（p = 0.017）。在整个样本中，综合症状评分与BAG呈正相关（β = 0.16, p = 0.004），在具有两种症状的个体中，相关性更强（β = 0.34, p < 0.001）。相反，所有参与者的高弹性与较小的BAG相关（β = - 0.10, p = 0.046）。心理弹性与BAG的负相关被综合症状评分介导（b = - 0.011, p = 0.010）。这些发现可能表明，压力相关症状与大脑加速衰老之间存在一种协同作用，而不是相加的关联，以及一种潜在的缓冲关联。

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引用次数: 0

FKBP5/FKBP51-mediated signaling pathways in neuropsychiatric diseases: Insights for biomarker development and targeted therapies 神经精神疾病中FKBP5/ fkbp51介导的信号通路：生物标志物开发和靶向治疗的见解

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-09-18 DOI: 10.1016/j.ynstr.2025.100762

Yinglong Liu, Jiahe Lian, Youli Fu, Shishan Wang, Yongxin Liu, Rui Zhang, Huirong Han

The FK506-binding protein 5 gene encodes FKBP51, a molecular chaperone linked to the pathogenesis of neuropsychiatric diseases. Recent evidence shows that FKBP51 modulates activity of the HPA axis and GR-mediated feedback via dynamic interactions with GR, thereby influencing stress adaptation, inflammatory responses, and neuronal survival. This review systematically analyzes the mechanisms by which FKBP5 (and its encoded FKBP51) contributes to neuropsychiatric diseases and identifies shared pathways across these conditions. We further highlight key factors mediating disease variability and susceptibility: sex-, region-, and cell type-specific expression patterns of FKBP5/FKBP51, their temporal dynamics, genetic variants, epigenetic regulation, and gene–environment interactions. Additionally, we propose a “biphasic stress-response model” to conceptualize the temporal dynamics of FKBP5/FKBP51 expression during disease progression. Finally, we explore the translational potential of targeting FKBP51 signaling, and outline pharmacological strategies to modulate chaperone-dependent protein folding and stress pathways as novel therapeutic interventions.

fk506结合蛋白5基因编码FKBP51，这是一种与神经精神疾病发病机制相关的分子伴侣。最近的证据表明，FKBP51通过与GR的动态相互作用调节HPA轴的活性和GR介导的反馈，从而影响应激适应、炎症反应和神经元存活。本综述系统分析了FKBP5（及其编码的FKBP51）参与神经精神疾病的机制，并确定了这些疾病的共享途径。我们进一步强调了介导疾病变异性和易感性的关键因素：FKBP5/FKBP51的性别、区域和细胞类型特异性表达模式，它们的时间动态、遗传变异、表观遗传调控和基因-环境相互作用。此外，我们提出了一个“双相应激反应模型”来概念化疾病进展过程中FKBP5/FKBP51表达的时间动态。最后，我们探讨了靶向FKBP51信号的翻译潜力，并概述了调节伴侣依赖蛋白折叠和应激途径的药理学策略，作为新的治疗干预措施。

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