Pub Date : 2025-11-01DOI: 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.
{"title":"Ventral hippocampal autophagy and mitophagy dynamics shape behavioral responses to chronic mild stress in adult male rats","authors":"Paola Brivio , Maria Teresa Gallo , Elena Volpari , Piotr Gruca , Magdalena Lason , Ewa Litwa , Fabio Fumagalli , Mariusz Papp , Francesca Calabrese","doi":"10.1016/j.ynstr.2025.100769","DOIUrl":"10.1016/j.ynstr.2025.100769","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100769"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145466304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 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).
{"title":"Electroacupuncture attenuates anxiety caused by chronic mild stress through inhibiting NOX2-derived oxidative stress in ventral hippocampus","authors":"Tong Yin , Yinxin Wang , Chuan'an Zhu , Yuanfang Lin , Weilin Wang , Jianpeng Huang , Kangwen Ming , Hang Lv","doi":"10.1016/j.ynstr.2025.100768","DOIUrl":"10.1016/j.ynstr.2025.100768","url":null,"abstract":"<div><div>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).</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100768"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145466303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01DOI: 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.
{"title":"Echoes of stress: From molecular whispers to social thunderstorms","authors":"Juan Pablo Lopez","doi":"10.1016/j.ynstr.2025.100766","DOIUrl":"10.1016/j.ynstr.2025.100766","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100766"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-19DOI: 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。
{"title":"Increased salivary oxytocin correlates with lower self-reported interoceptive accuracy in functional neurological disorders","authors":"Natascha Stoffel , Laure von der Weid , Josef Gross , Cristina Concetti , Rupert Bruckmaier , Selma Aybek","doi":"10.1016/j.ynstr.2025.100765","DOIUrl":"10.1016/j.ynstr.2025.100765","url":null,"abstract":"<div><h3>Introduction</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Discussion</h3><div>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.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100765"},"PeriodicalIF":3.6,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 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.
{"title":"Metabolic state shapes cortisol reactivity to acute stress: A systematic review and meta-analysis of metabolic and hormonal modulators","authors":"Madeleine Kördel , Maria Meier , Anne Kühnel , Nils B. Kroemer","doi":"10.1016/j.ynstr.2025.100764","DOIUrl":"10.1016/j.ynstr.2025.100764","url":null,"abstract":"<div><div>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 (<em>N</em> = 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 (<em>d</em> = 0.30, 95 % CI = [0.05, 0.60], BF<sub>10</sub> = 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.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100764"},"PeriodicalIF":3.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 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。
{"title":"Potential vulnerability and resilience to accelerated brain aging in women exposed to stressful life events: insights from the brain age prediction model","authors":"Hyeonseok Jeong , Yoonji Joo , Youngeun Shim , Yejin Kim , Hyeonji Lee , Yunjung Jin , Seog Ju Kim , Sujung Yoon , In Kyoon Lyoo","doi":"10.1016/j.ynstr.2025.100763","DOIUrl":"10.1016/j.ynstr.2025.100763","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100763"},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"FKBP5/FKBP51-mediated signaling pathways in neuropsychiatric diseases: Insights for biomarker development and targeted therapies","authors":"Yinglong Liu, Jiahe Lian, Youli Fu, Shishan Wang, Yongxin Liu, Rui Zhang, Huirong Han","doi":"10.1016/j.ynstr.2025.100762","DOIUrl":"10.1016/j.ynstr.2025.100762","url":null,"abstract":"<div><div>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 <em>FKBP5</em> (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 <em>FKBP5</em>/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 <em>FKBP5</em>/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.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100762"},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145100087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-16DOI: 10.1016/j.ynstr.2025.100761
Valentina Zonca , Moira Marizzoni , Samantha Saleri , Monica Mazzelli , Giulia Petrillo , Maria Grazia Di Benedetto , Floriana De Cillis , Marco Andrea Riva , Annamaria Cattaneo
Early-life stress (ELS) is a well-known risk factor for the development of several mental disorders later in life. The effect of ELS can be twofold: resilient individuals adapt by perceiving stress as minimal, while vulnerable ones struggle to cope with it and are predisposed to the onset of psychopathology. Although it is known that different brain regions play a role in determining ELS resilience or vulnerability, the specific mechanisms remain unclear. This preclinical study examines the effects of prenatal stress (PNS) on the functional connectivity of habenula (Hb) and insular cortex (IC) and whether these alterations predispose to stress vulnerability in adulthood. PNS was associated with reduced social interaction in both male and female animals, suggesting the onset of a potentially altered behavioural phenotype. Transcriptomic analysis of vulnerable and resilient animals revealed profound PNS-induced gene expression changes in both Hb and IC, with sex-specific patterns. In vulnerable males, pathway analysis identified a shared molecular signature between Hb and IC primarily involving the activation of inflammation and collagen-related processes. In females, vulnerability was linked to downregulation of serotonin signaling, indicating an alternative pathway to stress susceptibility compared with males. Co-expression network analysis confirmed these findings, highlighting sex-dependent biological mechanisms underlying vulnerability. These results suggest that vulnerability to stress may emerge from functional interactions between Hb and IC, mediated by distinct and sex-specific pathways.
{"title":"Exposure to early-life stress uncovers shared biological signatures underlying vulnerability in the habenula and insular cortex of male and female adult rats","authors":"Valentina Zonca , Moira Marizzoni , Samantha Saleri , Monica Mazzelli , Giulia Petrillo , Maria Grazia Di Benedetto , Floriana De Cillis , Marco Andrea Riva , Annamaria Cattaneo","doi":"10.1016/j.ynstr.2025.100761","DOIUrl":"10.1016/j.ynstr.2025.100761","url":null,"abstract":"<div><div>Early-life stress (ELS) is a well-known risk factor for the development of several mental disorders later in life. The effect of ELS can be twofold: resilient individuals adapt by perceiving stress as minimal, while vulnerable ones struggle to cope with it and are predisposed to the onset of psychopathology. Although it is known that different brain regions play a role in determining ELS resilience or vulnerability, the specific mechanisms remain unclear. This preclinical study examines the effects of prenatal stress (PNS) on the functional connectivity of habenula (Hb) and insular cortex (IC) and whether these alterations predispose to stress vulnerability in adulthood. PNS was associated with reduced social interaction in both male and female animals, suggesting the onset of a potentially altered behavioural phenotype. Transcriptomic analysis of vulnerable and resilient animals revealed profound PNS-induced gene expression changes in both Hb and IC, with sex-specific patterns. In vulnerable males, pathway analysis identified a shared molecular signature between Hb and IC primarily involving the activation of inflammation and collagen-related processes. In females, vulnerability was linked to downregulation of serotonin signaling, indicating an alternative pathway to stress susceptibility compared with males. Co-expression network analysis confirmed these findings, highlighting sex-dependent biological mechanisms underlying vulnerability. These results suggest that vulnerability to stress may emerge from functional interactions between Hb and IC, mediated by distinct and sex-specific pathways.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100761"},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145119557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-15DOI: 10.1016/j.ynstr.2025.100758
Zhao-Xin Sun , Mao-Yang Zhou , Jin-Shan Li , Yun Zhao , Fang Xie , Xue Wang , Hong Feng , Zhao-Wei Sun , Ling-Jia Qian
Chronic stress-induced blood-brain barrier (BBB) dysfunction contributes to neurological disorders, with homocysteine (HCY) as a key risk factor. Considering pharmacotherapy limitations, non-invasive interventions like high-intensity interval training (HIIT) are promising. To determine whether HIIT improves stress-induced BBB dysfunction and cognitive impairment, we first established a chronic unpredictable mild stress (CUMS) model and assigned mice into four groups: Control (Ctrl), CUMS, HIIT, and HIIT + CUMS. Here, we found that HIIT significantly ameliorated cognitive impairment in male CUMS mice, as evidenced by reduced escape latency in morris water maze and increased memory performance in novel object recognition test. HIIT also preserved BBB integrity by ameliorating the tight junction disruption and BBB hyper-permeability in stressed mice. Subsequently, to clarify the role of HCY in the HIIT-mediated effects, we established an HHCY model and divided mice into four groups: Ctrl, HIIT, HHCY, and HIIT + HHCY. The results showed that HIIT normalized the plasma and hippocampal HCY levels by restoring the expression of related metabolic enzymes including CBS, MTHFR and MS, and alleviated HHCY-induced cognitive decline and BBB damage. Further, HIIT reversed HCY-induced Claudin-5 downregulation by inhibiting H3K27me3 enrichment at the Cldn5 (the encoding gene of Claudin-5) promoter region. In addition, HIIT restored the expression of ETS1, one of the transcriptional activators of Cldn5, to facilitate the transcription of Cldn5 gene and the stabilization of BBB. Collectively, these findings reveal that HIIT improves chronic stress-induced cognitive impairment via eliminating the disruptive effects of HHCY on the BBB integrity, offering a non-pharmacological intervention potential for stress-related cognitive deficits.
{"title":"High-intensity interval training improves cognitive dysfunction in chronically stressed mice through alleviating homocysteine-induced transcriptional repression of Cldn5","authors":"Zhao-Xin Sun , Mao-Yang Zhou , Jin-Shan Li , Yun Zhao , Fang Xie , Xue Wang , Hong Feng , Zhao-Wei Sun , Ling-Jia Qian","doi":"10.1016/j.ynstr.2025.100758","DOIUrl":"10.1016/j.ynstr.2025.100758","url":null,"abstract":"<div><div>Chronic stress-induced blood-brain barrier (BBB) dysfunction contributes to neurological disorders, with homocysteine (HCY) as a key risk factor. Considering pharmacotherapy limitations, non-invasive interventions like high-intensity interval training (HIIT) are promising. To determine whether HIIT improves stress-induced BBB dysfunction and cognitive impairment, we first established a chronic unpredictable mild stress (CUMS) model and assigned mice into four groups: Control (Ctrl), CUMS, HIIT, and HIIT + CUMS. Here, we found that HIIT significantly ameliorated cognitive impairment in male CUMS mice, as evidenced by reduced escape latency in morris water maze and increased memory performance in novel object recognition test. HIIT also preserved BBB integrity by ameliorating the tight junction disruption and BBB hyper-permeability in stressed mice. Subsequently, to clarify the role of HCY in the HIIT-mediated effects, we established an HHCY model and divided mice into four groups: Ctrl, HIIT, HHCY, and HIIT + HHCY. The results showed that HIIT normalized the plasma and hippocampal HCY levels by restoring the expression of related metabolic enzymes including CBS, MTHFR and MS, and alleviated HHCY-induced cognitive decline and BBB damage. Further, HIIT reversed HCY-induced Claudin-5 downregulation by inhibiting H3K27me3 enrichment at the Cldn5 (the encoding gene of Claudin-5) promoter region. In addition, HIIT restored the expression of ETS1, one of the transcriptional activators of Cldn5, to facilitate the transcription of Cldn5 gene and the stabilization of BBB. Collectively, these findings reveal that HIIT improves chronic stress-induced cognitive impairment via eliminating the disruptive effects of HHCY on the BBB integrity, offering a non-pharmacological intervention potential for stress-related cognitive deficits.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100758"},"PeriodicalIF":3.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145100033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-13DOI: 10.1016/j.ynstr.2025.100760
Eva Fellinger , Tom Brandt , Andrea Schittenhelm , Eric Quarg , Matthias Pröll , Gregor Domes , Annette Schmidt
Background
The Trier Social Stress Test (TSST) is a widely used tool for inducing and measuring stress responses in a controlled environment. In this study, we aimed to explore the effectiveness of a virtual TSST (TSST-VR) in eliciting stress responses across multiple physiological and psychological markers.
Methods
A sample of 24 participants underwent the TSST-VR, during which salivary cortisol, alpha-amylase (AA), blood glucose levels, heart rate (HR), root mean square of successive differences (RMSSD) as a measure of heart rate variability (HRV), and subjective stress ratings (NRS) were collected at multiple time points.
Results
In a baseline-to-peak analysis, significant increases were observed in HR (MDiff = 13.04, 95 %-CI [8.19–17.90], p < .001), RMSSD (MDiff = 17.75, 95 %-CI [3.28–32.22], p < .001), AA (p < .001, r = 1.07), and NRS (p < .001, r = 1.31) measures following the TSST-VR. While no significant changes in cortisol levels were found in the baseline-to-peak analysis across all participants, a secondary cluster analysis identified distinct cortisol responders (baseline-to-peak rise >1.5 mmol/l). Within this group, high cortisol responders (HCR) showed significantly higher cortisol (Wald χ2(7) = 118.03, p < .001), HR (Wald χ2(8) = 17.91, p = .022), and AA levels (Wald χ2(7) = 17.13, p = .017) compared to low cortisol responders (LCR). Area-under-the-curve analysis further confirmed a more robust cortisol stress response in HCR.
Conclusion
These findings suggest that the TSST-VR can effectively induce measurable stress responses and may provide insights into individual differences in physiological and metabolic stress reactions. The study highlights the potential of virtual stress paradigms in stress research and underscores the advantages of a virtual setting in terms of standardization and economic considerations.
Trier社会压力测试（TSST）是一种在受控环境中诱导和测量压力反应的广泛使用的工具。在这项研究中，我们的目的是探讨虚拟TSST （TSST- vr）在多种生理和心理标记中引发应激反应的有效性。方法对24名参与者进行TSST-VR，在此期间，在多个时间点收集唾液皮质醇、α -淀粉酶（AA）、血糖水平、心率（HR）、连续差异均方根（RMSSD）作为心率变异性（HRV）的测量指标，以及主观应激评分（NRS）。结果基线-峰值分析显示，TSST-VR后患者的HR （MDiff = 13.04, 95% -CI [8.19-17.90], p < 0.001）、RMSSD （MDiff = 17.75, 95% -CI [3.28-32.22], p < 0.001）、AA （p < 0.001, r = 1.07）和NRS （p < 0.001, r = 1.31）指标均显著升高。虽然在所有参与者的基线-峰值分析中没有发现皮质醇水平的显著变化，但二次聚类分析确定了不同的皮质醇应答者（基线-峰值升高>；1.5 mmol/l）。在该组中，高皮质醇应答者（HCR）的皮质醇（Wald χ2(7) = 118.03, p < 0.001）、HR （Wald χ2(8) = 17.91, p = 0.022）和AA水平（Wald χ2(7) = 17.13, p = 0.017）均显著高于低皮质醇应答者（LCR）。曲线下面积分析进一步证实了HCR中更强的皮质醇应激反应。结论TSST-VR可有效诱导可测量的应激反应，为揭示生理和代谢应激反应的个体差异提供依据。该研究强调了虚拟应力范式在应力研究中的潜力，并强调了虚拟环境在标准化和经济考虑方面的优势。
{"title":"Virtual stress testing: Analyzing endocrine, metabolic, cardiovascular, and psychological responses to the TSST-VR","authors":"Eva Fellinger , Tom Brandt , Andrea Schittenhelm , Eric Quarg , Matthias Pröll , Gregor Domes , Annette Schmidt","doi":"10.1016/j.ynstr.2025.100760","DOIUrl":"10.1016/j.ynstr.2025.100760","url":null,"abstract":"<div><h3>Background</h3><div>The Trier Social Stress Test (TSST) is a widely used tool for inducing and measuring stress responses in a controlled environment. In this study, we aimed to explore the effectiveness of a virtual TSST (TSST-VR) in eliciting stress responses across multiple physiological and psychological markers.</div></div><div><h3>Methods</h3><div>A sample of 24 participants underwent the TSST-VR, during which salivary cortisol, alpha-amylase (AA), blood glucose levels, heart rate (HR), root mean square of successive differences (RMSSD) as a measure of heart rate variability (HRV), and subjective stress ratings (NRS) were collected at multiple time points.</div></div><div><h3>Results</h3><div>In a baseline-to-peak analysis, significant increases were observed in HR (M<sub>Diff</sub> = 13.04, 95 %-CI [8.19–17.90], p < .001), RMSSD (M<sub>Diff</sub> = 17.75, 95 %-CI [3.28–32.22], p < .001), AA (p < .001, r = 1.07), and NRS (p < .001, r = 1.31) measures following the TSST-VR. While no significant changes in cortisol levels were found in the baseline-to-peak analysis across all participants, a secondary cluster analysis identified distinct cortisol responders (baseline-to-peak rise >1.5 mmol/l). Within this group, high cortisol responders (HCR) showed significantly higher cortisol (Wald χ<sup>2</sup>(7) = 118.03, p < .001), HR (Wald χ<sup>2</sup>(8) = 17.91, p = .022), and AA levels (Wald χ<sup>2</sup>(7) = 17.13, p = .017) compared to low cortisol responders (LCR). Area-under-the-curve analysis further confirmed a more robust cortisol stress response in HCR.</div></div><div><h3>Conclusion</h3><div>These findings suggest that the TSST-VR can effectively induce measurable stress responses and may provide insights into individual differences in physiological and metabolic stress reactions. The study highlights the potential of virtual stress paradigms in stress research and underscores the advantages of a virtual setting in terms of standardization and economic considerations.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100760"},"PeriodicalIF":3.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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