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Corticosterone-induced postpartum depression induces depression-like behavior and impairs hippocampal neurogenesis in adolescent offspring via HPA axis and BDNF-mTOR pathway 皮质酮诱导的产后抑郁通过HPA轴和BDNF-mTOR通路诱导抑郁样行为,损害青春期子代海马神经发生。
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2025.100708
Hongxiao Xie , Yanning Jiang , Xiumeng Zhang , Xinran Min , Jiuseng Zeng , Li Chen , Nan Zeng , Rong Liu
Postpartum depression (PPD) adversely affects the growth and development of the offspring, increasing the risk of various internalizing behaviorsduring adolescence. Studies have shown that corticosterone (CORT)-induced PPD affects neurogenesis in the offspring, which is closely related to the onset of depression. However, the underlying mechanisms of these changes in the offspring of PPD mothers remain unexplored. In this study, we demonstrated postpartum mice treated with high CORT experienced activation of the hypothalamic-pituitary-adrenal (HPA) axis, which induced depressive-like behavior and impaired maternal caring behavior. Furthermore, adolescent offspring of PPD mice exhibited depression-like behavior, and learning and memory deficits. These offspring also showed diminished levels of DCX+, decreased levels of synaptic proteins, and reduced dendritic spine density and length in hippocampus. Additionally, we detected increased serum stressed hormones and decreased hippocampal glucocorticoid receptor (GR) protein level in the offspring. We also found the offspring exhibited reduced expression of brain-derived neurotrophic factor (BDNF) and the phosphorylation tyrosine kinase receptor B (TrkB), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins in hippocampus. These results indicated that the behavioral deficits and neuronal damage observed in the offspring of PPD mice may be related to HPA axis dysfunction and inhibition of the BDNF-mTOR pathway. In conclusion, our findings confirm that CORT induces depression-like behavior and impairs maternal caring behavior in maternal mice, which in turn affects their offspring's emotion and cognitive behavior. This impact is characterized by the activation of the HPA axis and inhibition of the BDNF-mTOR pathway.
产后抑郁症(PPD)对后代的生长发育产生不利影响,增加了青春期各种内化行为的风险。研究表明,皮质酮(CORT)诱导的PPD影响后代的神经发生,这与抑郁症的发病密切相关。然而,PPD母亲的后代中这些变化的潜在机制仍未被探索。在这项研究中,我们证明了高CORT处理的产后小鼠下丘脑-垂体-肾上腺(HPA)轴被激活,从而导致抑郁样行为和母性关怀行为受损。此外,PPD小鼠的青春期后代表现出类似抑郁的行为,以及学习和记忆缺陷。这些后代也表现出DCX+水平降低,突触蛋白水平降低,海马树突棘密度和长度减少。此外,我们检测到后代血清应激激素升高,海马糖皮质激素受体(GR)蛋白水平降低。我们还发现后代海马中脑源性神经营养因子(BDNF)、磷酸化酪氨酸激酶受体B (TrkB)、蛋白激酶B (AKT)和哺乳动物雷帕霉素靶蛋白(mTOR)的表达减少。这些结果表明,PPD小鼠后代的行为缺陷和神经元损伤可能与HPA轴功能障碍和BDNF-mTOR通路的抑制有关。综上所述,我们的研究结果证实了CORT诱导母鼠抑郁样行为并损害母鼠关爱行为,进而影响其后代的情绪和认知行为。这种影响的特征是HPA轴的激活和BDNF-mTOR通路的抑制。
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引用次数: 0
Mothering matters: Towards a better understanding of disrupted infant-caregiver relationships in both mother and offspring 母性问题:更好地理解母亲和子女之间被破坏的婴儿照顾者关系。
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2024.100701
Millie Rincón-Cortés
The mother-infant bond is among the strongest social relationships formed in humans and nonhuman mammals. As such, disrupted infant-caregiver relationships have the capacity to result in potent adverse effects not only in the offspring, but also in the mother. Here, I provide a brief overview of my prior work showing adversity-induced alterations in offspring and maternal behavioral and brain function. I also share my vision for future directions for developmental and maternal neurobiology research in the context of stress and/or adversity exposure.
母子关系是人类和非人类哺乳动物中形成的最牢固的社会关系之一。因此,被破坏的婴儿-照顾者关系不仅会对后代产生严重的不利影响,也会对母亲产生不利影响。在这里,我简要概述了我之前的工作,展示了逆境诱导的后代和母亲行为和大脑功能的改变。我还分享了我对未来在压力和/或逆境暴露背景下发育和母亲神经生物学研究方向的看法。
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引用次数: 0
Stress reactivity moderates the association between early experiences of unpredictability and emotional problems in adolescents 应激反应缓和了青少年早期不可预测性经历与情绪问题之间的联系。
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2024.100706
J.L. Buthmann , C. Antonacci , J.P. Uy , L.R. Borchers , J.G. Miller , I.H. Gotlib
Researchers have documented that exposure to different kinds of psychosocial stressors can lead to emotional difficulties and, further, that heightened reactivity to stress can moderate these associations. Recently, investigators have distinguished among threat, deprivation, and unpredictability as different dimensions of early life stress (ELS). It is not clear, however, whether reactivity in specific stress response systems functions as a diathesis to lead to emotional difficulties following exposure to these dimensions of ELS. In this study (N = 154) we examined whether stress reactivity, assessed across different psychobiological systems during the Trier Social Stress Test, is a unitary or multidimensional construct, and if reactivity differentially moderates the associations between ELS dimensions and adolescents’ susceptibility to emotional and behavioral problems two years later. A factor analysis conducted on stress reactivity measures yielded two factors: one composed of reactivity in heart rate, heart rate variability, and cortisol, and one composed of reactivity in skin conductance and self-reported mood. These two factors independently moderated the associations between early unpredictability and subsequent emotional problems. For each factor, the combination of higher unpredictability and higher stress reactivity predicted higher emotional problems; stress reactivity factors were not significant moderators of the effects of threat and deprivation. Our findings suggest that increased stress reactivity, assessed across several domains of functioning, functions as a diathesis that interacts with ELS characterized by unpredictability to predict subsequent mental health difficulties in adolescents and, further, that low stress reactivity buffers against mental health difficulties in adolescents who have experienced unpredictability early in life.
研究人员已经证明,暴露于不同类型的社会心理压力源会导致情绪困难,而且,对压力的高度反应可以缓和这些关联。最近,研究者区分了威胁、剥夺和不可预测性作为早期生活压力(ELS)的不同维度。然而,目前尚不清楚,特定应激反应系统中的反应性是否作为一种素质,在暴露于ELS的这些维度后导致情绪困难。在这项研究中(N = 154),我们考察了在Trier社会压力测试中通过不同的心理生物学系统评估的压力反应性是一个单一的还是多维的结构,以及反应性是否在两年后不同程度地调节ELS维度与青少年对情绪和行为问题的易感性之间的关联。对压力反应性测量进行的因素分析得出了两个因素:一个由心率、心率变异性和皮质醇的反应性组成,另一个由皮肤电导和自我报告情绪的反应性组成。这两个因素独立地调节了早期不可预测性和随后的情绪问题之间的联系。对于每个因素,较高的不可预测性和较高的压力反应性的组合预示着较高的情绪问题;应激反应因素对威胁和剥夺的影响无显著调节作用。我们的研究结果表明,在多个功能领域中,压力反应性的增加作为一种素质,与以不可预测性为特征的ELS相互作用,以预测青少年随后的心理健康困难,此外,低压力反应性缓冲了在生命早期经历不可预测性的青少年的心理健康困难。
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引用次数: 0
Retrotransposons and the brain: Exploring a complex relationship between mobile elements, stress, and neurological health 反转录转座子与大脑:探索移动元件、压力和神经系统健康之间的复杂关系
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2025.100709
Amelia Cuarenta
Environmental experiences during early life, including stress, can significantly impact brain development and behavior. Early life stress (ELS) is linked to an increased risk for various psychiatric disorders including anxiety, depression, and substance use disorders. Epigenetic mechanisms have increasingly been of interest to understand how environmental factors contribute to reprogramming the brain and alter risk and resilience to developing psychiatric disorders. However, we know very little about mobile elements or the regulation of mobile elements and their contribution to psychiatric disorders. Recently, advances in genomics have contributed to our understanding of mobile elements, including the retrotransposon LINE-1 (L1) and their potential role in mediating environmental experiences. Yet we still do not understand how these elements may contribute to psychiatric disorders. Future research leveraging cutting-edge technologies will deepen our understanding of these mobile elements. By elucidating their role in development and how stress may impact them, we may unlock new avenues for therapeutic and diagnostic innovations.
早期生活中的环境经历,包括压力,会对大脑发育和行为产生重大影响。早期生活压力(ELS)与各种精神疾病的风险增加有关,包括焦虑、抑郁和物质使用障碍。表观遗传机制越来越引起人们的兴趣,以了解环境因素如何促进大脑的重新编程,并改变发展精神疾病的风险和恢复能力。然而,我们对移动元素或移动元素的调节及其对精神疾病的贡献知之甚少。最近,基因组学的进展有助于我们了解包括逆转录转座子LINE-1 (L1)在内的可移动元件及其在介导环境体验中的潜在作用。然而,我们仍然不明白这些因素是如何导致精神疾病的。利用尖端技术的未来研究将加深我们对这些移动元素的理解。通过阐明它们在发展中的作用以及压力如何影响它们,我们可能会为治疗和诊断创新开辟新的途径。
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引用次数: 0
Integrative approaches to studying sleep, stress, and related disorders 研究睡眠、压力和相关疾病的综合方法
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2024.100700
Thomas C. Neylan, Gina R. Poe, Victoria B. Risbrough
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引用次数: 0
Brain receptor dynamics in early and adult life stress: Gateways to maladaptive coping strategies 早期和成年生活压力中的脑受体动态:适应不良应对策略的途径。
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2025.100707
Sora Shin
Stress plays a significant role in the onset of numerous psychiatric disorders. Depending on individual resilience or stressor's nature, long-term changes to stress in the brain can lead to a wide range of behavioral symptoms, including social withdrawal, feelings of helplessness, and emotional overeating. The brain receptor molecules are key mediators of these processes, translating neuromodulatory signals into neuronal responses or circuit activity changes that ultimately shape behavioral outcomes. Here, I highlight several of my previous studies that reveal the pivotal role of receptor molecules in critical brain regions such as the nucleus accumbens, lateral hypothalamus, and lateral septum. I identified how mGluR5 signaling in the nucleus accumbens promotes stress resilience through pathways involving ΔFosB and SRF, while leptin receptor or glucocorticoid receptor signaling within lateral hypothalamic circuits contributes to stress eating. Additionally, I uncovered the role of dopamine receptor 3 signaling in the lateral septum in mediating the impact of early life stress on social behaviors. These findings underscore the functional relevance of brain receptor molecules in transducing stress—from early life through adulthood—into maladaptive coping behaviors. As druggable targets, these receptor-mediated pathways provide a critical foundation for developing targeted interventions to alleviate stress-related psychiatric symptoms.
压力在许多精神疾病的发病中起着重要作用。根据个人的适应能力或压力源的性质,大脑中压力的长期变化会导致各种各样的行为症状,包括社交退缩、无助感和情绪性暴饮暴食。脑受体分子是这些过程的关键介质,将神经调节信号转化为神经元反应或电路活动变化,最终形成行为结果。在这里,我重点介绍了我之前的几项研究,这些研究揭示了受体分子在大脑关键区域(如伏隔核、外侧下丘脑和外侧隔膜)中的关键作用。我确定了伏隔核中的mGluR5信号传导如何通过ΔFosB和SRF通路促进应激恢复,而下丘脑外侧回路中的瘦素受体或糖皮质激素受体信号传导有助于应激进食。此外,我还发现了侧隔膜中多巴胺受体3信号在调节早期生活压力对社会行为的影响中的作用。这些发现强调了大脑受体分子在从早期生活到成年期的应激转导到适应不良应对行为中的功能相关性。作为药物靶点,这些受体介导的途径为开发有针对性的干预措施以减轻压力相关的精神症状提供了重要的基础。
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引用次数: 0
Neuroanatomical prediction of individual anxiety problems level using machine learning models: A population-based cohort study of young adults 使用机器学习模型的个体焦虑问题水平的神经解剖学预测:一项基于人群的年轻人队列研究。
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2024.100705
Hui Xu , Jing Xu , Dandong Li
Anxiety, a mental state in healthy individuals, is characterized by apprehension of potential future threats. Though the neurobiological basis of anxiety has been investigated widely in the clinical populations, the underly mechanism of neuroanatomical correlates with anxiety level in healthy young adults is still unclear. In this study, 1080 young adults were enrolled from the Human Connectome Project Young Adult dataset, and machine learning-based elastic net regression models with cross validation, together with linear mix effects (LME) models were adopted to investigate whether the neuroanatomical profiles of structural magnetic resonance imaging indicators associated with anxiety level in healthy young adults. We found multi-region neuroanatomical profiles predicted anxiety problems level and it was still robust in an out-of-sample. The neuroanatomical profiles had widespread brain nodes, including the dorsal lateral prefrontal cortex, supramarginal gyrus, and entorhinal cortex, which implicated in the default mode network and frontoparietal network. This finding was further supported by LME models, which showed significant univariate associations between brain nodes with anxiety. In sum, it's a large sample size study with multivariate analysis methodology to provide evidence that individual anxiety problems level can be predicted by machine learning-based models in healthy young adults. The neuroanatomical signature including hub nodes involved theoretically relevant brain networks robustly predicts anxiety, which could aid the assessment of potential high-risk of anxiety individuals.
焦虑是健康人的一种精神状态,其特征是对未来潜在威胁的忧虑。尽管焦虑的神经生物学基础已经在临床人群中得到了广泛的研究,但健康年轻人焦虑水平与神经解剖学相关的潜在机制仍不清楚。在这项研究中,从人类连接组计划的年轻人数据集中招募了1080名年轻人,并采用基于交叉验证的机器学习弹性网络回归模型和线性混合效应(LME)模型来研究结构磁共振成像指标的神经解剖学特征是否与健康年轻人的焦虑水平相关。我们发现多区域神经解剖图谱预测焦虑问题水平,并且在样本外仍然是稳健的。神经解剖学特征显示广泛的脑淋巴结,包括背外侧前额叶皮层、边缘上回和内嗅皮层,这些淋巴结涉及默认模式网络和额顶叶网络。这一发现进一步得到了LME模型的支持,该模型显示脑节点与焦虑之间存在显著的单变量关联。总之,这是一项大样本研究,采用多变量分析方法,为健康年轻人的个体焦虑问题水平可以通过基于机器学习的模型预测提供证据。包括枢纽节点在内的神经解剖学特征涉及理论相关的脑网络,可以有效预测焦虑,有助于评估焦虑个体的潜在高危性。
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引用次数: 0
Elevated GABAergic neurotransmission prevents chronic intermittent ethanol induced hyperexcitability of intrinsic and extrinsic inputs to the ventral subiculum of female rats 升高的gaba能神经传递可防止慢性间歇乙醇诱导的雌性大鼠腹侧下背内外输入的高兴奋性。
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1016/j.ynstr.2024.100696
Eva C. Bach, Jeff L. Weiner
With the recent rise in the rate of alcohol use disorder (AUD) in women, the historical gap between men and women living with this condition is narrowing. While there are many commonalities in how men and women are impacted by AUD, an accumulating body of evidence is revealing sex-dependent adaptations that may require distinct therapeutic approaches. Preclinical rodent studies are beginning to shed light on sex differences in the effects of chronic alcohol exposure on synaptic activity in a number of brain regions. Prior studies from our laboratory revealed that, while withdrawal from chronic intermittent ethanol (CIE), a commonly used model of AUD, increased excitability in the ventral hippocampus (vHC) of male rats, this same treatment had the opposite effect in females. A follow-up study not only expanded on the synaptic mechanisms of these findings in male rats, but also established a CIE-dependent increase in the excitatory-inhibitory (E-I) balance of a glutamatergic projection from the basolateral amygdala to vHC (BLA-vHC). This pathway modulates anxiety-like behavior and could help explain the comorbid occurrence of anxiety disorders in individuals suffering from AUD. The present study sought to conduct a similar analysis of CIE effects on both synaptic mechanisms in the vHC and adaptations in the BLA-vHC pathway of female rats. Our findings indicate that CIE increases the strength of inhibitory neurotransmission in the vHC and that this sex-specific adaptation blocks, or at least delays, the increases in intrinsic vHC excitability and BLA-vHC synaptic transmission observed in males. Our findings establish the BLA-vHC pathway and the vHC as important circuitry to consider for future studies directed at identifying sex-dependent therapeutic approaches to AUD.
随着最近女性酒精使用障碍(AUD)率的上升,患有这种疾病的男性和女性之间的历史差距正在缩小。虽然男性和女性受到AUD影响的方式有许多共同点,但越来越多的证据表明,性别依赖的适应可能需要不同的治疗方法。临床前啮齿类动物研究开始揭示慢性酒精暴露对大脑许多区域突触活动影响的性别差异。我们实验室之前的研究表明,虽然从慢性间歇性乙醇(CIE)中退出(一种常用的AUD模型)会增加雄性大鼠腹侧海马(vHC)的兴奋性,但同样的治疗在雌性大鼠中却有相反的效果。一项后续研究不仅在雄性大鼠中扩展了这些发现的突触机制,而且还建立了从基底外侧杏仁核到vHC (BLA-vHC)的谷氨酸能投射的兴奋-抑制(E-I)平衡依赖于cie的增加。这一通路调节焦虑样行为,有助于解释AUD患者焦虑障碍的共病发生。本研究试图对CIE对雌性大鼠vHC突触机制和BLA-vHC通路适应性的影响进行类似的分析。我们的研究结果表明,CIE增加了vHC中抑制性神经传递的强度,这种性别特异性适应阻断或至少延迟了在男性中观察到的vHC内在兴奋性和BLA-vHC突触传递的增加。我们的研究结果确定了BLA-vHC通路和vHC是未来研究中重要的回路,这些研究旨在确定AUD的性别依赖性治疗方法。
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引用次数: 0
Transcriptome dynamics in mouse amygdala under acute and chronic stress revealed by thiol-labeled RNA sequencing 硫醇标记的 RNA 测序揭示急性和慢性应激下小鼠杏仁核转录组的动态变化
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100688
Dan Zhao , Lu Zhang , Yang Yang
Both acute and chronic stress have significant impact on brain functions. The amygdala is essential in mediating stress responses, but how its transcriptomic dynamics change under stress remains elusive. To overcome the difficulties in detecting subtle stress-induced changes by evaluating total RNA using classic RNA sequencing, we conducted thiol-labeled RNA sequencing (SLAM-seq). We injected 4-thiouridine (4sU) into mouse amygdala followed by SLAM-seq to detect nascent mRNA induced by acute and chronic restraint stress, and found that SLAM-seq could label actively transcribed genes in the major neuronal and glial subtypes. Using SLAM-seq, we found that chronic stress led to higher turnover of a group of genes associated with myelination, and this finding is confirmed by immunostaining which showed increased myelination in the chronically stressed amygdala. Additionally, genes detected by SLAM-seq and RNA-seq only partially overlapped, suggesting that SLAM-seq and RNA-seq are complementary in identifying stress-responsive genes. By applying SLAM-seq in vivo, we obtained a rich dataset of genes with higher turnover in the amygdala under stress.
急性和慢性压力都会对大脑功能产生重大影响。杏仁核是介导应激反应的重要器官,但其转录组动态如何在应激下发生变化仍是一个未知数。为了克服用传统的RNA测序方法评估总RNA来检测应激诱导的微妙变化的困难,我们进行了硫醇标记RNA测序(SLAM-seq)。我们向小鼠杏仁核注射了4-硫代硫甙(4sU),然后用SLAM-seq检测急性和慢性束缚应激诱导的新生mRNA,结果发现SLAM-seq可以标记主要神经元和神经胶质亚型中的活跃转录基因。通过使用 SLAM-seq,我们发现慢性应激导致一组与髓鞘化相关的基因更替率升高,这一发现得到了免疫染色的证实,免疫染色显示慢性应激杏仁核中的髓鞘化增加。此外,SLAM-seq和RNA-seq检测到的基因只有部分重叠,这表明SLAM-seq和RNA-seq在鉴定应激反应基因方面是互补的。通过在体内应用 SLAM-seq,我们获得了在应激状态下杏仁核中周转率较高的基因的丰富数据集。
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引用次数: 0
Behavioral coping with chronic defeat stress in mice: A systematic review of current protocols 小鼠对慢性失败压力的行为应对:当前方案的系统回顾
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100689
Alina Díez-Solinska , Zurine De Miguel , Garikoitz Azkona , Oscar Vegas
Social stress is the most significant source of chronic stress in humans and is commonly associated with health impairment. Individual differences in the behavioral coping responses to stress have been proposed to mediate the negative effects of stress on physical, behavioral and mental health. Animal models, particularly mice, offer valuable insights into the physiological and neurobiological correlates of behavioral coping strategies in response to chronic social stress. Here we aim to identify differences and similarities among stress protocols in mice, with particular attention to how neuroendocrine and/or behavioral responses vary according to different coping strategies, while highlighting the need for standardized approaches in future research. A systematic review was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA statement). A total of 213 references were identified by electronic search, and after the screening, 18 articles were found to meet all the established criteria. We analyzed differences in the stress protocol, the characterization and classification of coping strategies and the physiological and behavioral differences according to coping. The results show that differences in behavioural expression under chronic social stress (coping) may also be associated with physiological differences and differential susceptibility to disease. However, this review also underlines the importance of a cautious interpretation of the results obtained. The lack of consistency in the nomenclature and procedures associated with the study of coping strategies for social stress, as well as the absence of a uniform classification, highlight the importance of using a common language when approaching the study of coping strategies. Thereby, this review encourages the development of a more defined method and criteria for assessing coping strategies, based on both behavioral and biological indicators.
社会压力是人类最主要的慢性压力来源,通常与健康受损有关。有人提出,个体在应对压力的行为反应方面存在差异,这可能是压力对身体、行为和心理健康产生负面影响的中介因素。动物模型,尤其是小鼠,为我们深入了解应对慢性社会压力的行为策略的生理和神经生物学相关性提供了宝贵的资料。在此,我们旨在找出小鼠应激方案之间的异同,特别关注神经内分泌和/或行为反应如何根据不同的应对策略而变化,同时强调在未来研究中采用标准化方法的必要性。我们按照《系统综述和元分析首选报告项目》(PRISMA 声明)进行了系统综述。通过电子检索共找到 213 篇参考文献,经过筛选,发现 18 篇文章符合所有既定标准。我们分析了压力协议的差异、应对策略的特征和分类以及应对策略的生理和行为差异。结果表明,慢性社会压力(应对)下的行为表现差异也可能与生理差异和对疾病的不同易感性有关。不过,本综述也强调了谨慎解释所获结果的重要性。与社会压力应对策略研究相关的术语和程序缺乏一致性,也没有统一的分类方法,这突出了在研究应对策略时使用共同语言的重要性。因此,本综述鼓励根据行为和生物指标,制定更加明确的应对策略评估方法和标准。
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引用次数: 0
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Neurobiology of Stress
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