Neurobiology of Stress最新文献

Neuroplacentology of stress: Novel frontiers linking maternal mental health to offspring neurodevelopment 压力的神经胎盘学：将母亲心理健康与后代神经发育联系起来的新前沿

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2026-01-01 DOI: 10.1016/j.ynstr.2025.100778

Cristiana Cruceanu

Neuroplacentology is an emerging interdisciplinary field integrating molecular neuroscience, placental biology, environmental modeling, and single-cell techniques to study stress-related neurodevelopmental programming. The placenta, once considered merely a conduit between mother and fetus, is now recognized as an important regulator of fetal brain development and a mediator of prenatal maternal stress and other exposures. To highlight this important aspect of the neurobiology of stress, this review outlines how maternal stress, genetic susceptibility, and environmental exposures converge at the placenta-brain axis to influence offspring psychiatric vulnerability.

Risk and resilience for psychiatric conditions are shaped by interactions between genetic predisposition and environmental exposures, including during the highly plastic prenatal period. Prenatal stress exposure can alter neuronal differentiation, transcription factor gene-regulatory networks, and excitation/inhibition neuronal balance. In parallel, maternal metabolic disorders, placental endocrine dysregulation, and psychotropic medication exposure modulate neuroactive pathways critical to brain development. The placenta responds to these exposures and synthesizes key stress molecules such as corticotropin-releasing hormone, serotonin and other neuromodulators, highlighting its neuroregulatory role.

To exemplify the promising future of neuroplacentology for our understanding of perinatal health and stress research, this review highlights innovative methodological approaches such as human-specific placental organoid systems and single-cell multi-omics. I propose that future research should focus on identifying placental biomarkers predictive of neurodevelopmental outcomes and refining in-vitro models for testing pharmacological interventions in a non-invasive manner. Elucidating the mechanisms at the placenta-brain interface, could lead to a better understanding of the developmental origins of mental illness and inform early intervention strategies.

神经胎盘学是一个新兴的跨学科领域，整合了分子神经科学、胎盘生物学、环境建模和单细胞技术来研究与压力相关的神经发育规划。胎盘，曾经被认为仅仅是母亲和胎儿之间的管道，现在被认为是胎儿大脑发育的重要调节器，也是产前母亲压力和其他暴露的中介。为了强调应激神经生物学的这一重要方面，本文概述了母体应激、遗传易感性和环境暴露如何汇聚在胎盘-脑轴上，从而影响后代的精神脆弱性。精神疾病的风险和恢复能力是由遗传易感性和环境暴露之间的相互作用形成的，包括在高度可塑性的产前时期。产前应激暴露可改变神经元分化、转录因子基因调控网络和兴奋/抑制神经元平衡。与此同时，母体代谢紊乱、胎盘内分泌失调和精神药物暴露也会调节对大脑发育至关重要的神经活性通路。胎盘对这些暴露做出反应，并合成关键的应激分子，如促肾上腺皮质激素释放激素、血清素和其他神经调节剂，突出其神经调节作用。为了说明神经胎盘学对围产期健康和应激研究的前景，本文重点介绍了人类特异性胎盘类器官系统和单细胞多组学等创新方法。我建议未来的研究应侧重于识别预测神经发育结果的胎盘生物标志物，并改进体外模型，以非侵入性方式测试药物干预。阐明胎盘-大脑界面的机制，可以更好地理解精神疾病的发育起源，并为早期干预策略提供信息。

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引用次数: 0

Central amygdala Fkbp5 expression correlates with faster submission and ethanol self-administration reacquisition: Benztropine reduces ethanol relapse-like reacquisition in stressed rats 中央杏仁核Fkbp5表达与更快的屈服和乙醇自我给药再习得相关：苯托品减少应激大鼠的乙醇复发样再习得

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2026-01-01 DOI: 10.1016/j.ynstr.2025.100770

Luisa B. Bertotto , Eleanna M. Sakoulas , Marian L. Logrip , Katrina Lin , Anastasia E. Pimentel , Lenwood Thompson , Bryan Cruz , Valentina Vozella , Cristiane A. Favoretto , Marisa Roberto , Eric P. Zorrilla

Stress-related emotional disorders, such as post-traumatic stress disorder (PTSD) and major depression, increase alcohol relapse risk. PTSD, depression, and alcohol use phenotypes associate with gene variants of FKBP prolyl isomerase 5 (FKBP5), a chaperone modulator of glucocorticoid receptors (GR). FKBP51 inhibitors can decrease ethanol intake, but FKBP51's role in recurrence of post-stress ethanol drinking is unknown. We tested the hypotheses that expression of Fkbp5 and immediate early genes (IEGs) in the central nucleus of the amygdala (CeA) is increased in rats with a history of defeat or foot-shock stress and associates with faster submission and increased reacquisition of ethanol self-administration. We tested if benztropine mesylate, an FDA-approved drug that inhibits FKBP51-GR binding, reduces reacquisition of ethanol self-administration in rats with a history of foot-shock stress. Wistar rats were studied after resident-intruder social defeat (n = 32) or in an ethanol self-administration reacquisition model, with or without repeated foot-shock history (n = 62). Acute social defeat stress increased CeA IEG expression within 1 h Fkbp5 expression by 6 h. CeA IEG activation correlated with Fkbp5 expression, and both correlated with faster submission to defeat. CeA Fkbp5 expression also associated with greater ethanol intake and blood ethanol concentration during reacquisition of ethanol self-administration. Benztropine (i.p., 5, 10 mg/kg) dose-dependently reduced relapse-like ethanol reacquisition, and sex-specific analyses suggest a more robust effect in males than females. The results warrant the study of CeA FKBP51 in passive stress coping and of drug-like selective FKBP51 inhibitors to reduce ethanol relapse after histories of repeated stress.

与压力相关的情绪障碍，如创伤后应激障碍（PTSD）和重度抑郁症，会增加酒精复发的风险。创伤后应激障碍、抑郁症和酒精使用表型与FKBP脯氨酸异构酶5 （FKBP5）基因变异相关，FKBP5是糖皮质激素受体（GR）的伴侣调节因子。FKBP51抑制剂可以减少乙醇摄入，但FKBP51在应激后乙醇饮酒复发中的作用尚不清楚。我们验证了以下假设：在有失败或足部休克应激史的大鼠中，杏仁核中央核（CeA）中Fkbp5和即时早期基因（IEGs）的表达增加，并与更快的屈服和增加的乙醇自我给药的重新获得有关。我们测试了甲磺酸苄托品（一种fda批准的抑制FKBP51-GR结合的药物）是否能减少有足部休克应激史的大鼠对乙醇自我给药的再获得。研究了Wistar大鼠在居民-入侵者社会失败后（n = 32）或在乙醇自我给药再获取模型中，有或没有重复足震史（n = 62）。急性社会失败应激使CeA IEG表达在1 h内增加6 h。CeA IEG激活与Fkbp5表达相关，两者都与更快地屈服于失败相关。CeA Fkbp5的表达也与乙醇自我给药过程中更高的乙醇摄入量和血乙醇浓度相关。苯托品（i.p, 5,10 mg/kg）剂量依赖性地减少了复发样乙醇再获得，性别特异性分析表明，男性比女性的效果更强。研究结果支持CeA FKBP51在被动应激应对中的作用，以及药物样选择性FKBP51抑制剂在反复应激史后减少乙醇复发的作用。

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引用次数: 0

Adolescent adversity persistently induces proinflammatory HMGB1 signaling and disrupts the basal forebrain cholinergic system in female rats 青春期逆境持续诱导雌性大鼠的促炎HMGB1信号传导并破坏基底前脑胆碱能系统

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2026-01-01 DOI: 10.1016/j.ynstr.2025.100779

Hayley Ross , Makayla Adelman , Juan E. Castillo , Ann Walker , Joseph Latham , Liya Qin , Victoria Macht , Fulton T. Crews , Ryan P. Vetreno

Adolescence is a critical period of neurodevelopment characterized by heightened neuroplasticity and refinement of executive functioning and cognition. Basal forebrain cholinergic neurons mature during this period, coinciding with development of adult cognitive function. Exposure to adolescent adversity has been linked to long-lasting neurobiological and cognitive consequences, yet the mechanisms underlying these outcomes remain poorly understood. Using a preclinical model of adolescent intermittent restraint stress (AIRS), we tested the hypothesis that adolescent adversity induces lasting proinflammatory innate immune signaling, loss of basal forebrain cholinergic neurons, and cognitive deficits in adult female rats. We report that AIRS elevated plasma levels of corticosterone and proinflammatory high mobility group box 1 (HMGB1), consistent with HPA axis activation and systemic inflammation. In the late adolescent (P55) basal forebrain, AIRS caused an increase of the proinflammatory signaling molecule HMGB1, the HMGB1 receptors TLR4 and RAGE, the downstream proinflammatory transcription activation marker pNF-κB p65, and proinflammatory cytokines that persisted into adulthood (P95). This was accompanied by persistent adult increases of microglial activation markers, Iba-1 and CD11b. Importantly, AIRS caused a reduction of ChAT+ and TrkA + basal forebrain cholinergic neurons that persisted into adulthood, paralleling significant impairments in recognition memory on the novel object recognition memory test. Together, these findings suggest that adolescent adversity induces persistent proinflammatory HMGB1-TLR4/RAGE-pNF-κB signaling, microglial priming, and reductions of basal forebrain cholinergic neurons as well as enduring cognitive impairment. The HMGB1 proinflammatory pathway may represent a promising therapeutic target for mitigating the long-term neurobiological and behavioral consequences of adolescent adversity.

青春期是神经发育的关键时期，其特点是神经可塑性增强，执行功能和认知能力得到完善。基底前脑胆碱能神经元在此期间成熟，与成人认知功能的发育一致。暴露于青少年逆境与长期的神经生物学和认知后果有关，但这些结果背后的机制仍然知之甚少。利用青春期间歇性约束应激（AIRS）的临床前模型，我们验证了青春期逆境诱导成年雌性大鼠持久的促炎先天免疫信号、基底前脑胆碱能神经元的丧失和认知缺陷的假设。我们报道，AIRS升高血浆皮质酮水平和促炎高流动性组框1 （HMGB1）水平，与HPA轴激活和全身性炎症一致。在青少年晚期（P55）基底前脑，AIRS引起促炎信号分子HMGB1、HMGB1受体TLR4和RAGE、下游促炎转录激活标志物pNF-κB p65和促炎细胞因子的增加，并持续到成年（P95）。这伴随着成人小胶质细胞激活标记物Iba-1和CD11b的持续增加。重要的是，AIRS导致ChAT+和TrkA +基底前脑胆碱能神经元的减少，这种减少持续到成年，在新的物体识别记忆测试中，识别记忆的显著损伤是平行的。综上所述，这些研究结果表明，青少年逆境诱导了持续的促炎HMGB1-TLR4/RAGE-pNF-κB信号传导、小胶质启动、基底前脑胆碱能神经元的减少以及持久的认知障碍。HMGB1促炎通路可能是缓解青少年逆境长期神经生物学和行为后果的一个有希望的治疗靶点。

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引用次数: 0

Developmental and early-life stress-induced effects on 5-HT3R-expressing interneurons within auditory cortex 发育和早期生活应激诱导对听觉皮层中表达5- ht3r的中间神经元的影响

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2026-01-01 DOI: 10.1016/j.ynstr.2026.100780

James T. Moore , Matthew J. Sunthimer , Ethan White , Jeffrey G. Mellott , Merri J. Rosen

Early life stress (ELS) is a well-known predictor of neuropsychiatric disease and contributes to the development of sensory processing deficits that persist throughout life. Organisms are particularly susceptible to the deleterious effects of stress during critical periods, when neuroplasticity is heightened, and initial representations of the sensory environment are mapped to cortex. When ELS is induced during the auditory cortical (ACx) critical period, it impairs both neural and behavioral responses to a variety of auditory stimuli that rely on temporal processing. Mechanisms by which ELS may alter critical period plasticity are of particular interest in understanding ELS-related pathology, including the 5-HT3R interneuron system, which has been implicated in regulating neural activity during critical periods. Here we examined two principal subpopulations of interneurons in primary ACx: VIP and NDNF cells, which account for a majority of cortical neurons expressing 5-HT3R. The expression of the Htr3a gene during normal development and under ELS conditions was quantified using multiplex fluorescent in situ hybridization. We show that densities of cells expressing NDNF and VIP decrease following ear opening and across the ACx critical period, and that ELS results in the maintenance of elevated cell densities compared to age-matched controls. Further, Htr3a in VIP neurons is developmentally upregulated, and its expression is further increased by ELS beyond normal physiologic levels. Stress-induced shifts in these serotonergic interneurons may contribute to deficits that arise in auditory cortical and perceptual responses via effects on local cortical circuitry.

早期生活压力（ELS）是一种众所周知的神经精神疾病的预测因子，并有助于持续一生的感觉处理缺陷的发展。生物体在关键时期特别容易受到压力的有害影响，此时神经可塑性增强，感觉环境的初始表征被映射到皮层。当ELS在听觉皮质（ACx）关键时期被诱导时，它会损害依赖于时间加工的各种听觉刺激的神经和行为反应。ELS可能改变关键时期可塑性的机制对理解ELS相关病理特别感兴趣，包括在关键时期调节神经活动的5-HT3R中间神经元系统。在这里，我们研究了原代ACx中两个主要的中间神经元亚群：VIP和NDNF细胞，它们占表达5-HT3R的皮层神经元的大多数。采用多重荧光原位杂交法定量测定正常发育和ELS条件下Htr3a基因的表达。我们发现，表达nndnf和VIP的细胞密度在打开耳后和ACx关键时期下降，与年龄匹配的对照组相比，ELS导致细胞密度维持在较高水平。此外，Htr3a在VIP神经元中发育上调，ELS使其表达水平进一步升高，超出正常生理水平。应激诱导的5 -羟色胺能中间神经元的变化可能通过对局部皮层回路的影响导致听觉皮层和知觉反应出现缺陷。

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引用次数: 0

Multi-omics reveals associations between the microbiota-gut-brain axis and antidepressant effects of vagus nerve stimulation 多组学揭示了微生物-肠-脑轴与迷走神经刺激的抗抑郁作用之间的联系

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-12-10 DOI: 10.1016/j.ynstr.2025.100777

Dan Pan , Mingchen Jiang , Ying Wang , Junyuan He , Jumei Tang , Siyu Liu , Mingxia Li , Xing Jiang , Qiuyue Xu

Background

Major depressive disorder is a severe mental health condition characterized by persistent depressed mood and loss of interest. Current first-line pharmacotherapies often exhibit limited therapeutic performance and adverse side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising, safe, and noninvasive alternative intervention with demonstrated neuromodulatory efficacy. Nevertheless, its mechanisms remain unclear. This study investigated whether the antidepressant properties of taVNS are associated with the microbiota-gut-brain axis, focusing on the potential crosstalk between differentially expressed hippocampal proteins and the gut microbiota.

Methods

A chronic unpredictable mild stress (CUMS) rat model of depression was established, and taVNS was administered for 14 days. Hippocampal proteomic profiling was performed using data-independent acquisition. Fecal metagenomic sequencing was conducted to characterize alterations in gut microbial communities. Key signaling pathways were validated using Western blot, qRT-PCR, HE staining, and transmission electron microscopy, all of which were employed to systematically assess behavioral, proteomic, microbial, and molecular changes.

Results

Proteomics and molecular analyses revealed that taVNS upregulated hippocampal expression of glutamate ionotropic receptor N-methyl-D-aspartate type subunit 1 (GluN1) and brain-derived neurotrophic factor (BDNF), while simultaneously restoring mitogen-activated protein kinase (MAPK) signaling activity. Metagenomic profiling demonstrated that taVNS increased the abundance of Akkermansia muciniphila and reduced Ligilactobacillus reuteri. Ligilactobacillus levels were positively correlated with synaptogyrin-1 (Syngr1), indicating their potential association in enhancing the antidepressant effects mediated by the GluN1/MAPK/BDNF signaling cascade.

Conclusion

TaVNS significantly alleviated depression-like behaviors in CUMS-exposed rats. The underlying mechanism may involve the restoration of synaptic function of glutamatergic neurons by regulating the GluN1/MAPK/BDNF signaling pathway. In addition, taVNS reshaped the gut microbiota, markedly increasing the abundance of Akkermansia muciniphila and Ligilactobacillus murinus while reducing Limosilactobacillus reuteri and Lactobacillus johnsonii. The positive correlation between Syngr1 protein level and Ligilactobacillus abundance in the hippocampus suggests that the microbiota-gut-brain axis may play a key role in the antidepressant effects of taVNS.

重度抑郁症是一种严重的精神健康状况，其特征是持续的抑郁情绪和兴趣丧失。目前的一线药物治疗往往表现出有限的治疗效果和不良副作用。经皮耳迷走神经刺激（taVNS）是一种有前途的、安全的、无创的替代干预方法，具有良好的神经调节效果。然而，其机制仍不清楚。本研究探讨了taVNS的抗抑郁特性是否与微生物-肠-脑轴相关，重点研究了差异表达的海马蛋白与肠道微生物群之间的潜在串扰。方法建立慢性不可预知轻度应激（CUMS）大鼠抑郁模型，给予taVNS治疗14 d。海马蛋白质组学分析采用数据独立采集。进行粪便宏基因组测序以表征肠道微生物群落的变化。通过Western blot、qRT-PCR、HE染色和透射电镜验证关键信号通路，所有这些都被用来系统地评估行为、蛋白质组学、微生物和分子变化。结果蛋白质组学和分子分析显示，taVNS上调海马谷氨酸离子化受体n-甲基-d -天冬氨酸亚型亚基1 （GluN1）和脑源性神经营养因子（BDNF）的表达，同时恢复丝裂原活化蛋白激酶（MAPK）信号活性。宏基因组分析表明，taVNS增加了嗜粘液阿克曼氏菌的丰度，减少了罗伊氏乳杆菌。Ligilactobacillus水平与synaptogygrin -1 （Syngr1）呈正相关，表明它们可能通过GluN1/MAPK/BDNF信号级联介导增强抗抑郁作用。结论tavns可显著减轻cums暴露大鼠抑郁样行为。其潜在机制可能涉及通过调节GluN1/MAPK/BDNF信号通路来恢复谷氨酸能神经元的突触功能。此外，taVNS重塑了肠道微生物群，显著增加了嗜粘阿克曼氏杆菌和鼠脂乳酸杆菌的丰度，同时减少了罗伊氏乳酸杆菌和约氏乳杆菌。海马中Syngr1蛋白水平与Ligilactobacillus丰度呈正相关，提示微生物-肠-脑轴可能在taVNS的抗抑郁作用中发挥关键作用。

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引用次数: 0

Hair stress hormones in individuals with a recent suicide attempt experiencing a depressive episode 最近有自杀企图并经历抑郁发作的个体的毛发应激激素

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-12-02 DOI: 10.1016/j.ynstr.2025.100776

Lejla Colic , Anna Karoline Seiffert , Lydia Bahlmann , Ani Zerekidze , Johanna Walther , Larissa McClain , Bianca Besteher , Fabricio Pereira , Mocrane Abbar , Martin Walter , Fabrice Jollant , Gerd Wagner

Background

Stressful events and dysregulation of the hypothalamic-pituitary-adrenal (HPA)- axis contribute to the risk of suicide attempt (SA) in persons in depressive episodes. Hair cortisol, cortisone and dehydroepiandrosterone (DHEA) concentrations may serve as reliable indicators of HPA axis dysregulation prior to SA.

Methods

Participants (n = 75; mean age [standard deviation] = 30.0 [10.2] years; n = 49 [65 %] women; Jena site) comprised three groups: individuals with a history of SA approximately one month (SA; n = 22); individuals with a current depressive episode without SA history (CC; n = 31) and healthy individuals (HC; n = 22). SA was defined as self-initiated, potentially injurious behavior accompanied by some intent to die. Stress hormones were measured using LC-MS/MS protocol (days from sampling to analysis = 342 [171]) and logarithmic transformed. Group differences in hair stress hormones with hair segments representing time were tested using linear mixed models on a p < .05 threshold. Exploratory models further examined the effects of childhood abuse, frequency of SAs, suicide intent level and impulsiveness of the last SA of mean hormone levels, on a corrected p_corr< .012 threshold.

Results

There was a main effect of group for the DHEA-log (p = .02) and post-hoc tests indicated that SA group had higher DHEA compared to CC (p_corr = .01) and HC (p_corr = .08) in the peri-suicidal period. There were no significant (p < .05) interaction or group effects on cortisol-log and cortisone-log. Preliminary exploratory analyses showed that SA with multiple attempts had higher mean DHEA-log compared to SA with a single suicide attempt (p_uncorr = .05). Furthermore, there were positive associations between level of suicide intent and both mean cortisol-log (p_uncorr = .02) and mean cortisone-log (p_uncorr = .02). Childhood abuse and impulsiveness of the last SA were not related to hair stress hormones.

Conclusions

Individuals with a recent history of SA showed alterations in the DHEA hair levels. These results partially support dysregulation of the HPA axis as a biopsychosocial feature of SA. Future longitudinal and experimental studies should investigate whether hair HPA axis hormones can serve as markers of suicidal crisis and vulnerability.

背景：应激事件和下丘脑-垂体-肾上腺（HPA）轴的失调与抑郁症患者自杀企图（SA）的风险有关。毛发皮质醇、可的松和脱氢表雄酮（DHEA）浓度可作为SA前HPA轴失调的可靠指标。MethodsParticipants (n = 75;平均年龄(标准差) = 30.0(10.2)年;n = 49[65 %]女性;耶拿网站)由三组:个人历史的SA大约一个月(SA); n = 22);目前无SA病史的抑郁发作个体（CC, n = 31）和健康个体（HC, n = 22）。SA被定义为自我发起的，潜在的伤害行为，伴随着一些死亡的意图。采用LC-MS/MS方案测量应激激素（从取样到分析的天数 = 342[171]）并进行对数变换。毛发段代表时间的毛发应激激素的组间差异采用p上的线性混合模型 <； 进行检验。05年阈值。探索性模型进一步检验了童年虐待、SA频率、自杀意图水平和最后一次SA的冲动性对平均激素水平的影响，校正后的阈值为0.012。结果实验组DHEA-log有主效应（p = .02），事后检验表明，SA组在自杀期DHEA高于CC组（pcorr = .01）和HC组（pcorr = .08）。皮质醇-log和皮质醇-log之间没有显著的相互作用或组效应（p <； .05）。初步探索性分析显示，多次自杀未遂的SA比一次自杀未遂的SA有更高的平均DHEA-log （puncorr = .05）。此外，自杀意图水平与平均皮质醇-log （puncorr = .02）和平均皮质醇-log （puncorr = .02）之间存在正相关。最后一个SA的童年虐待和冲动与头发应激激素无关。结论近期有SA病史的个体表现出脱氢表雄酮毛发水平的改变。这些结果部分支持HPA轴失调作为SA的生物心理社会特征。未来的纵向和实验研究应该探讨头发HPA轴激素是否可以作为自杀危机和脆弱性的标志。

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引用次数: 0

Age-dependent effects of chronic traumatic and social isolation stress on mice social behavior 慢性创伤和社会隔离应激对小鼠社会行为的年龄依赖性影响

IF 3.6 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2025-11-27 DOI: 10.1016/j.ynstr.2025.100773

Moonseok Choi , Jisu Jeong , Dongsoo Kim , Hong Seok Choi , Junghwa Ryu , Hye Jin Choi , Mookyung Cheon , Yun Ha Jeong

Modern people are exposed to various stressful situations. Stress is a significant factor in emotional changes and social behavior and is associated with imbalances in physiological and psychological homeostasis, including brain function and structure. Stress has multiple causes, each of which has different impacts on social behavior throughout life. However, little is known about how stress influences social behavior across the life cycle. To understand this further, this study exposed mice to chronic stress at three different ages: adolescence, early adulthood, and adulthood. Chronic stresses were induced by combining chronic traumatic and isolation stress. Chronic stress has been shown to enhance social dominance behavior, especially in adolescence, and changes in the expression of genes and proteins, including Fabp7 and Cxcl12, were observed to change in the opposite direction compared to adulthood, confirming that it is related to changes in social dominance behavior. This study may provide important insights into factors related to adolescence social behavior abnormalities.

现代人面临着各种各样的压力。压力是情绪变化和社会行为的重要因素，与生理和心理稳态失衡有关，包括脑功能和结构。压力有多种原因，每种原因对一生中的社会行为都有不同的影响。然而，人们对压力如何影响整个生命周期的社会行为知之甚少。为了进一步理解这一点，这项研究将小鼠暴露在三个不同年龄的慢性压力下：青春期，成年早期和成年期。慢性应激是由慢性创伤性应激和孤立性应激共同引起的。慢性压力已被证明可以增强社会支配行为，特别是在青春期，并且观察到包括Fabp7和Cxcl12在内的基因和蛋白质的表达变化与成年期相反，证实了它与社会支配行为的变化有关。这项研究可能为了解青少年社会行为异常的相关因素提供重要的见解。

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引用次数: 0

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。

{"title":"Sensitive periods for the link between childhood maltreatment and brain aging during adulthood","authors":"Leland L. Fleming , Kyoko Ohashi , Michelle Bosquet Enlow , Jennifer Khoury , Torsten Klengel , Karlen Lyons-Ruth , Martin Teicher , Kerry J. Ressler","doi":"10.1016/j.ynstr.2025.100771","DOIUrl":"10.1016/j.ynstr.2025.100771","url":null,"abstract":"<div><h3>Background</h3><div>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’).</div></div><div><h3>Method</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"39 ","pages":"Article 100771"},"PeriodicalIF":3.6,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614864","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}

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