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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
Acute stress activates basolateral amygdala neurons expressing corticotropin-releasing hormone receptor type 1 (CRHR1): Topographical distribution and projection-specific activation in male and female rats 急性应激可激活表达促肾上腺皮质激素释放激素受体 1 型 (CRHR1) 的杏仁核基底外侧神经元:雌雄大鼠的地形分布和投射特异性激活
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100694
Robert J. Aukema , Gavin N. Petrie , Samantha L. Baglot , Nicholas W. Gilpin , Matthew N. Hill
Although the basolateral amygdala (BLA) and corticotropin releasing hormone receptor type I (CRHR1) signaling are both central to the stress response, the spatial and circuit-specific distribution of CRHR1 have not been identified in the BLA at a high resolution. We used transgenic male and female CRHR1-Cre-tdTomato rats to topographically map the distribution of BLACRHR1 neurons and identify whether they are activated by acute stress. Additionally, we used the BLA circuits projecting to the central amygdala (CeA) and nucleus accumbens (NAc) as a model to test circuit-specific expression of CRHR1 in the BLA. We established several key findings. First, CRHR1 had the strongest expression in the lateral amygdala and in caudal portions of the BLA. Second, acute restraint stress increased FOS expression of CRHR1 neurons, and stress-induced activation was particularly strong in medial subregions of the BLA. Third, stress significantly increased FOS expression on BLA-NAc, but not BLA-CeA projectors, and BLA-NAc activation was more robust in males than females. Finally, CRHR1 was expressed on a subset of BLA-CeA and BLA-NAc projection neurons. Collectively, this expands our understanding of BLA molecular- and circuit-specific activation patterns following acute stress.
尽管杏仁基底外侧(BLA)和促肾上腺皮质激素释放激素受体 I 型(CRHR1)信号传导都是应激反应的核心,但 CRHR1 在杏仁基底外侧的空间和回路特异性分布尚未得到高分辨率的鉴定。我们利用转基因雄性和雌性 CRHR1-Cre-tdTomato 大鼠绘制了 BLACRHR1 神经元分布的地形图,并确定它们是否被急性应激激活。此外,我们还以投射到杏仁核中枢(CeA)和伏隔核(NAc)的BLA回路为模型,测试了CRHR1在BLA回路中的特异性表达。我们得出了几个重要发现。首先,CRHR1在杏仁核外侧和BLA尾部的表达最强。第二,急性束缚应激增加了CRHR1神经元的FOS表达,应激诱导的激活在BLA的内侧亚区尤其强烈。第三,应激明显增加了BLA-NAc上的FOS表达,但没有增加BLA-CeA突起上的FOS表达,而且男性的BLA-NAc激活比女性更强。最后,CRHR1在一部分BLA-CeA和BLA-NAc投射神经元上表达。总之,这拓展了我们对急性应激后BLA分子和回路特异性激活模式的理解。
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引用次数: 0
Sex specific gut-microbiota signatures of resilient and comorbid gut-brain phenotypes induced by early life stress 早期生活压力诱发的肠道-大脑表型的恢复力和合并症的性别特异性肠道微生物群特征
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100686
Lars Wilmes , Valentina Caputi , Thomaz F.S. Bastiaanssen , James M. Collins , Fiona Crispie , Paul D. Cotter , Timothy G. Dinan , John F. Cryan , Gerard Clarke , Siobhain M. O'Mahony

Background

Alterations in gut-brain axis communication pathways and the gut microbiota ecosystem caused by early life stress have been extensively described as critical players in the pathophysiology of stress-induced disorders. However, the extent to which stress-induced gut microbiota alterations manifest in early life and contribute to the sex-specific susceptibility to distinct gut-brain phenotypes in adulthood has yet to be defined.

Methods

Male and female Sprague-Dawley rat offspring underwent maternal separation (3h/day from postnatal day 2–12). Faecal samples were collected before weaning for gut microbiota 16S rRNA sequencing and metabolomic analysis. Visceral pain sensitivity and negative valence behaviours were assessed in adulthood using colorectal distension and the forced swim test respectively. Behavioural data were processed in a two-step cluster analysis to identify groupings within the dataset. Multi-omics analysis was carried out to investigate if the microbial signatures following early life stress were already defined according to the membership of the adult behavioural phenotypes.

Results

Maternal separation resulted in increased visceral hypersensitivity while showing a trend for a sex-dependent increase in negative valence behaviour in adulthood. The cluster analysis revealed four clusters within the dataset representing distinct pathophysiological domains reminiscent of the behavioural consequences of early-life stress: 1. resilient, 2. pain, 3. immobile and 4. comorbid. The early life gut microbiota of each of these clusters show distinct alterations in terms of diversity, genus level differential abundance, and functional modules. Multi-omic integrations points towards a role for different metabolic pathways underlying each cluster-specific phenotype.

Conclusion

Our study is the first to identify distinct phenotypes defined by susceptibility or resilience to gut-brain dysfunction induced by early life stress. The gut microbiota in early life shows sex-dependent alterations in each cluster that precede specific behavioural phenotypes in adulthood. Future research is warranted to determine the causal relationship between early-life stress-induced changes in the gut microbiota and to understand the trajectory leading to the manifestation of different behavioural phenotypes in adulthood.
背景早期生活压力引起的肠道-大脑轴沟通途径和肠道微生物群生态系统的改变已被广泛描述为压力诱发疾病的病理生理学中的关键因素。然而,应激诱导的肠道微生物群改变在生命早期的表现程度,以及在成年期对不同肠道-大脑表型的性别特异性易感性的贡献程度尚未确定。方法对雌雄Sprague-Dawley大鼠后代进行母鼠分离(从出生后第2-12天,每天3小时)。断奶前收集粪便样本,进行肠道微生物群 16S rRNA 测序和代谢组学分析。成年后,分别使用结肠直肠胀气和强迫游泳测试评估内脏痛敏感性和负价行为。对行为数据进行了两步聚类分析,以确定数据集中的分组情况。结果 母体分离导致内脏超敏性增加,同时成年后负价行为的增加趋势与性别有关。聚类分析揭示了数据集中的四个聚类,它们代表了不同的病理生理领域,让人联想到早期生活压力的行为后果:1.适应力强;2.疼痛;3.行动不便;4.合并症。这些群组中每个群组的生命早期肠道微生物群在多样性、属级丰度差异和功能模块方面都显示出不同的变化。我们的研究首次发现了不同的表型,这些表型由生命早期压力诱发的肠道-大脑功能障碍的易感性或恢复力所定义。生命早期的肠道微生物群在每个群中都显示出性别依赖性改变,这些改变先于成年期的特定行为表型。未来的研究需要确定早期生活压力诱导的肠道微生物群变化之间的因果关系,并了解导致成年后表现出不同行为表型的轨迹。
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引用次数: 0
Transient impact of chronic social stress on effort-based reward motivation in non-food restricted mice: Involvement of corticosterone 慢性社会应激对非食物限制小鼠基于努力的奖赏动机的短暂影响皮质酮的参与
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100690
Danina Evertse , Pilar Alves-Martinez , Giulia Treccani , Marianne B. Müller , Frank J. Meye , Michael A. van der Kooij
Chronic stress has been connected to a reduced effort and motivational deficits. To study effort-based motivation in rodents, operant conditioning is often employed. However, caloric restriction is typically imposed simultaneously. Since caloric restriction is a stressor in its own right, this procedure interferes with data interpretation. Here, we investigate whether chronic social defeat stress (CSD), lasting 10 consecutive days, would alter effort-based reward motivation in mice trained under ad libitum food conditions. Utilizing operant FED3 boxes in home cages, mice were trained within eight days to nose poke for palatable food. After training completion, operant memory was retained for at least 16 days, and mice demonstrated sustained effort, as assessed with a progressive ratio schedule, to obtain reward pellets. Directly after CSD exposure (10th day), mice exhibited reduced effort for palatable food rewards, but also displayed reduced nose poking in general. The effects of CSD on effort were short-lived, with no lasting impact on effort-based reward motivation one week post-stress. As corticosterone (CORT) levels were increased at day 10 of CSD, but not at day 17, we hypothesized that CORT might mediate the acute effects of CSD on effort-based reward motivation. Indeed, CORT administration [100 μg/ml], supplied via the drinking water, mirrored the CSD-induced CORT spike and temporarily reduced reward motivation. Our findings emphasize that CSD does not result in long-term deficits in reward motivation, suggesting a resilient adaptive response in mice under unrestricted feeding conditions. This study underscores the necessity of considering temporal dynamics of stress impacts and highlights the modulating effects of CORT. These insights contribute to a deeper understanding of the resilience mechanisms in motivational impairments and pave the way for further research into factors facilitating this resilience.
慢性压力与努力减少和动机缺陷有关。为了研究啮齿类动物基于努力的动机,通常会采用操作性条件反射。不过,通常会同时实施热量限制。由于热量限制本身就是一种压力源,因此这种程序会干扰数据解释。在此,我们研究了连续10天的慢性社会挫败应激(CSD)是否会改变在自由食物条件下接受训练的小鼠基于努力的奖赏动机。利用家用笼子中的操作性 FED3 盒,在八天内训练小鼠用鼻子捅可口的食物。训练完成后,操作性记忆至少保留了 16 天,而且小鼠表现出了持续的努力(通过累进比率计划进行评估),以获得奖励颗粒。直接暴露于 CSD 后(第 10 天),小鼠在获得适口食物奖励时表现出的努力程度降低,但戳鼻子的行为也普遍减少。CSD对努力程度的影响是短暂的,在应激一周后对基于努力程度的奖励动机没有持续影响。由于皮质酮(CORT)水平在CSD第10天升高,但在第17天没有升高,我们假设CORT可能会介导CSD对努力奖赏动机的急性影响。事实上,通过饮用水提供的 CORT [100 μg/ml] 反映了 CSD 诱导的 CORT 激增,并暂时降低了奖赏动机。我们的研究结果强调,CSD 不会导致奖赏动机的长期缺陷,这表明小鼠在无限制喂养条件下的适应性反应具有弹性。这项研究强调了考虑压力影响的时间动态的必要性,并突出了CORT的调节作用。这些见解有助于更深入地了解动机损伤的恢复机制,并为进一步研究促进这种恢复的因素铺平了道路。
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引用次数: 0
Opposing effects of pre-encoding stress on neural substrates of item and emotional contextual source memory retrieval 编码前压力对项目和情感语境源记忆检索神经基质的相反影响
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100691
Carlos Ventura-Bort , Janine Wirkner , Julia Wendt , Lars Schwabe , Florin Dolcos , Alfons O. Hamm , Mathias Weymar
Although the mediating role of the stress hormone systems in memory for single— especially emotional— events is well-stablished, less is known about the influence of stress on memory for associated contextual information (source memory). Here, we investigated the impact of acute stress on the neural underpinnings of emotional contextual source memory. Participants underwent a stress or a control manipulation before they encoded objects paired with pleasant, neutral, or unpleasant backgrounds. One week later, item and contextual source memory were tested. Acute stress modulated the neural signature of item and contextual source memory in an opposite fashion: stressed participants showed larger activation in the precuneus and the medial prefrontal cortex (mPFC) during the retrieval of items, while the retrieval of contextual unpleasant information was associated with lower activation in the angular gyrus (AG) and mPFC. Furthermore, as revealed by cross-region representational similarity analyses, stress also reduced the memory reinstatement of the previously encoded visual cortex representations of object/unpleasant background pairings in the AG and mPFC. These results suggest that pre-encoding stress induction increases the activity of memory-related regions for single items but reduces the activity of these regions during the retrieval of contextual unpleasant information. Our findings provide new insights into the dissociative effects of stress on item and contextual source memory which could have clinical relevance for stress-related disorders.
虽然压力荷尔蒙系统在单一事件(尤其是情绪事件)记忆中的中介作用已得到公认,但人们对压力对相关情境信息记忆(源记忆)的影响却知之甚少。在这里,我们研究了急性应激对情绪情境源记忆神经基础的影响。受试者在编码与愉快、中性或不愉快背景配对的对象之前,会接受压力或对照操作。一周后,对项目记忆和情境源记忆进行测试。急性应激以相反的方式调节了物品记忆和背景来源记忆的神经特征:在检索物品时,应激参与者的楔前叶和内侧前额叶皮层(mPFC)显示出更大的激活,而检索背景不愉快信息时,角回(AG)和mPFC的激活较低。此外,跨区域表征相似性分析表明,压力还降低了 AG 和 mPFC 中先前编码的物体/不愉快背景配对的视觉皮层表征的记忆恢复。这些结果表明,编码前的压力诱导会增加记忆相关区域对单个项目的活动,但在检索背景不愉快信息时会降低这些区域的活动。我们的研究结果为压力对项目记忆和情境源记忆的分离效应提供了新的见解,这可能对压力相关障碍具有临床意义。
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引用次数: 0
Dopamine and D1 receptor in hippocampal dentate gyrus involved in chronic stress-induced alteration of spatial learning and memory in rats 多巴胺和海马齿状回中的 D1 受体参与慢性应激诱导的大鼠空间学习和记忆改变
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-24 DOI: 10.1016/j.ynstr.2024.100685
Linping Wang , Weiyao Wang , Yingshun Li , Hua Jin , Bin Xiao , Qinghua Jin
There is increasing evidence that chronic stress (CS), which occurs when the body is exposed to prolonged stressors, significantly impairs learning and memory. Dopamine (DA) plays a critical role in learning and memory in the hippocampus through the activation of D1-like receptors (D1R). However, the specific roles of DA and D1R in the hippocampal dentate gyrus (DG), particularly in CS-induced changes in spatial learning and memory, are not well understood. In this study, we established a CS rat model through the random application of various stressors. We assessed spatial learning and memory using the Morris water maze (MWM) and measured DA concentration and the amplitude of field excitatory postsynaptic potentials (fEPSP) in the DG during the MWM test in freely moving rats. We also examined the involvement of D1R in spatial learning and memory by microinjecting its antagonist (SCH23390) into the DG, and then analyzed the expressions of phosphorylated (p-) Ca2+/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), and cAMP-response element binding protein (CREB) in the DG using Western blot. During the MWM test, compared with the control group, the escape latency was increased, and the percentage of distance in target quadrant and the number of platform crossings were decreased, in addition, the increase of fEPSP amplitude in the DG was significantly attenuated in CS group. In the control group, the DA concentration in the DG was significantly increased during the MWM test, and this response was enhanced in the CS group. Microinjection of SCH23390 into the DG significantly improved the spatial learning and memory impairments in CS rats, and reversed the inhibitory effect of CS on increase of fEPSP amplitude in the DG during the MWM test. Furthermore, SCH23390 partially reversed the inhibitory effects of CS on the expressions of p-CaMKII, p-PKA, and p-CREB in the DG. Our findings suggest that overactivation of the DA-D1R system in the hippocampal DG impairs spatial learning and memory and related synaptic plasticity in CS rats via downregulation of PKA-CREB signaling pathway.
越来越多的证据表明,慢性应激(CS),即人体长期处于应激状态时发生的现象,会严重损害学习和记忆能力。多巴胺(DA)通过激活 D1 类受体(D1R)在海马的学习和记忆中发挥着关键作用。然而,DA和D1R在海马齿状回(DG)中的具体作用,尤其是在CS诱导的空间学习和记忆变化中的作用,还不是很清楚。在本研究中,我们通过随机施加各种应激源建立了 CS 大鼠模型。我们利用莫里斯水迷宫(MWM)评估了大鼠的空间学习和记忆能力,并测量了自由活动的大鼠在MWM测试中DG的DA浓度和场兴奋突触后电位(fEPSP)的振幅。我们还通过向DG显微注射D1R拮抗剂(SCH23390)研究了D1R参与空间学习和记忆的情况,然后用Western印迹分析了DG中磷酸化(p-)的Ca2+/钙调蛋白依赖性蛋白激酶II(CaMKII)、蛋白激酶A(PKA)和cAMP反应元件结合蛋白(CREB)的表达。在MWM试验中,与对照组相比,CS组的逃逸潜伏期增加,目标象限距离百分比和平台穿越次数减少,此外,DG中fEPSP振幅的增加在CS组明显减弱。在MWM测试中,对照组DG中的DA浓度明显增加,而在CS组中这一反应增强。向DG显微注射SCH23390可明显改善CS组大鼠的空间学习和记忆障碍,并逆转CS对MWM测试中DG中fEPSP振幅增加的抑制作用。此外,SCH23390还部分逆转了CS对DG中p-CaMKII、p-PKA和p-CREB表达的抑制作用。我们的研究结果表明,海马DG中DA-D1R系统的过度激活会通过下调PKA-CREB信号通路损害CS大鼠的空间学习和记忆以及相关的突触可塑性。
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引用次数: 0
Basal cortisol level modulates stress-induced opioid-seeking behavior 基础皮质醇水平调节应激诱导的阿片寻求行为
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-24 DOI: 10.1016/j.ynstr.2024.100684
Mark K. Greenwald , Eric A. Woodcock , Tabitha E.H. Moses , Leslie H. Lundahl
In preclinical studies and our human laboratory, the α2-noradrenergic autoreceptor antagonist yohimbine was found to promote drug-seeking behavior. This study evaluated effects of dose-combinations of yohimbine and the glucocorticoid receptor agonist hydrocortisone to model intensity-dependent effects of stimulating each neurochemical system, alone and together, on stress-reactivity and opioid-seeking. Twelve regular heroin-using participants diagnosed with opioid use disorder (OUD) were stabilized on sublingual buprenorphine (8-mg/day), then passed a hydromorphone 18-mg vs. placebo intramuscular reinforcement screen. Across 9 experimental conditions (3 × 3 within-subject, randomized crossover, placebo-controlled, double-blind design) during inpatient buprenorphine maintenance, combinations of oral pretreatment doses of yohimbine (0, 27, 54-mg; t = 0 min) then hydrocortisone (0, 20, 40-mg; t = 45 min) were administered. In each condition, subjective drug and mood effects, cardiovascular responses, and saliva cortisol and α-amylase levels were assessed to evaluate stress-reactivity, and participants completed a 12-trial choice progressive ratio task during which they could earn units of hydromorphone (1.5-mg intramuscular) and/or money ($2.00). Yohimbine dose-dependently increased blood pressure, α-amylase, and anxiety scores, and decreased opioid agonist symptoms; hydrocortisone dose-dependently increased cortisol levels. Yohimbine/hydrocortisone dose-combinations significantly shifted within-session responding from money to opioid-seeking among participants with lower basal cortisol levels. These findings replicate yohimbine effects on stress biomarkers and demonstrate that noradrenergic/glucocorticoid-potentiated opioid-seeking is modulated by basal cortisol level. In persons with OUD stabilized on buprenorphine, basal HPA-axis activity and acute stressors can enhance opioid relative reinforcing efficacy. These factors may limit OUD treatment efficacy and highlight the need for novel interventions that prevent stress-induced opioid-seeking.
在临床前研究和我们的人体实验室中,发现α2-去甲肾上腺素能自体受体拮抗剂育亨宾能促进觅药行为。本研究评估了育亨宾和糖皮质激素受体激动剂氢化可的松的剂量组合效应,以模拟单独或同时刺激每种神经化学系统对应激反应和阿片觅药行为的强度依赖效应。12 名被诊断为阿片类药物使用障碍(OUD)的定期吸食海洛因的参与者在舌下含服丁丙诺啡(8 毫克/天)稳定后,通过了 18 毫克氢吗啡酮与安慰剂的肌肉注射强化筛选。在住院丁丙诺啡维持治疗期间的 9 个实验条件(3 × 3 受试者内、随机交叉、安慰剂对照、双盲设计)中,分别给予口服预处理剂量育亨宾(0、27、54 毫克;t = 0 分钟)和氢化可的松(0、20、40 毫克;t = 45 分钟)的组合。在每种条件下,都会对主观药物和情绪效应、心血管反应、唾液皮质醇和α-淀粉酶水平进行评估,以评价应激反应性,参与者还完成了一项 12 次选择累进比率任务,在该任务中,他们可以获得氢吗啡酮单位(1.5 毫克肌肉注射)和/或金钱(2 美元)。育亨宾剂量依赖性地增加了血压、α-淀粉酶和焦虑评分,并减少了阿片激动症状;氢化可的松剂量依赖性地增加了皮质醇水平。在基础皮质醇水平较低的参与者中,育亨宾/氢化可的松的剂量组合能显著地将会话期内的反应从金钱转向阿片寻求。这些发现复制了育亨宾对应激生物标志物的影响,并证明了去甲肾上腺素能/糖皮质激素促进的阿片类药物寻求受基础皮质醇水平的调节。对于服用丁丙诺啡后病情稳定的 OUD 患者,基础 HPA 轴活动和急性应激因素会增强阿片类药物的相对强化效果。这些因素可能会限制对 OUD 的治疗效果,并凸显了对新型干预措施的需求,以防止压力引起的阿片类药物寻求。
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引用次数: 0
Stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses 压力复原力是一个活跃的多因素过程,表现为突触的结构、功能和分子变化
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-22 DOI: 10.1016/j.ynstr.2024.100683
E. Bączyńska , M. Zaręba-Kozioł , B. Ruszczycki , A. Krzystyniak , T. Wójtowicz , K. Bijata , B. Pochwat , M. Magnowska , M. Roszkowska , I. Figiel , J. Masternak , A. Pytyś , J. Dzwonek , R. Worch , K.H. Olszyński , A.D. Wardak , P. Szymczak , J. Labus , K. Radwańska , P. Jahołkowski , J. Włodarczyk
Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subregion of the hippocampus.
应激恢复能力是指神经元网络在面临应激时仍能保持其功能的能力。我们利用小鼠模型研究了应激恢复现象。为了评估小鼠在长期不可预测的应激诱导后产生的恢复能力和失调行为表型,我们结合使用了蛋白质组学、电生理学和成像方法,对海马兴奋性突触的结构和功能可塑性进行了定量表征。我们的研究结果表明,应激复原力是一个活跃的多因素过程,表现为突触的结构、功能和分子变化。我们发现,慢性应激会影响突触蛋白的棕榈酰化,而有应激恢复能力的动物和无应激恢复能力的动物的棕榈酰化情况各不相同。棕榈酰化的变化主要与谷氨酸受体信号传导有关,从而影响突触传递和树突棘的相关结构。我们的研究表明,应激恢复能力与海马 CA1 亚区突触后部分的结构补偿可塑性有关。
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引用次数: 0
Stress-induced cortisol response predicts empathy for pain: The role of task-based connectivity between the insula and sensorimotor cortex during acute stress 压力引起的皮质醇反应可预测对疼痛的移情作用急性应激期间脑岛和感觉运动皮层之间基于任务的连接的作用
IF 4.3 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-18 DOI: 10.1016/j.ynstr.2024.100682
Zihan Tang , Yadong Liu , Xiaolin Zhao , Weiyu Hu , Mengning Zhang , Yipeng Ren , Zhenni Wei , Juan Yang
Empathy for pain is a key driver of prosocial behavior and is influenced by acute psychosocial stress. However, the role of task-based brain connectivity during acute stress have been neglected. Hence, we aimed to explore the relationship between the magnitude of cortisol response to acute stress and empathy for pain, as well as the neural connectivity mechanisms involved. In this study, 80 healthy participants (37 women and 43 men) were exposed to the acute psychosocial stress paradigm (ScanSTRESS) and were scanned by functional magnetic resonance imaging. Saliva samples were collected to measure the magnitude of cortisol stress response. Subsequently, the participants took part in a pain-video task to assess their empathy for pain. Six participants were excluded because of physical discomfort or excessive head movement in all runs during the task-dependent fMRI scan. Therefore, 33 women and 41 men were included in data analysis. We found that empathy for pain was negatively correlated with the magnitude of cortisol stress response (r = -0.268, p = 0.018) and that the task-based connectivity between the salience network and sensorimotor network, including its sub-network and sub-region, was negatively correlated with the magnitude of cortisol stress response, and positively correlated with empathy for pain. Furthermore, task-based connectivity between the insula and the paracentral lobule mediates the effect of the stress-induced cortisol response on empathy for pain (indirect effect = -0.0152, 95% CI = [-0.036, -0.001], p = 0.036). Our research suggests that empathy is not only correlated with stress-induced glucocorticoids but also tied to the stress-induced reduced communication between basic and higher brain regions.
对疼痛的同情是亲社会行为的一个关键驱动因素,并受到急性社会心理压力的影响。然而,基于任务的大脑连通性在急性应激中的作用却一直被忽视。因此,我们旨在探索皮质醇对急性应激反应的程度与对疼痛的移情之间的关系,以及其中涉及的神经连接机制。在这项研究中,80 名健康参与者(37 名女性和 43 名男性)接受了急性社会心理应激范式(ScanSTRESS)的训练,并进行了功能磁共振成像扫描。采集唾液样本以测量皮质醇应激反应的程度。随后,参与者参加了疼痛视频任务,以评估他们对疼痛的移情能力。有六名参与者因身体不适或在任务相关的 fMRI 扫描过程中头部过度移动而被排除在外。因此,33 名女性和 41 名男性被纳入数据分析。我们发现,对疼痛的移情与皮质醇应激反应的程度呈负相关(r = -0.268,p = 0.018),并且显著性网络和感觉运动网络(包括其子网络和子区域)之间基于任务的连通性与皮质醇应激反应的程度呈负相关,而与对疼痛的移情呈正相关。此外,脑岛和旁中心小叶之间基于任务的连接介导了压力引起的皮质醇反应对疼痛移情的影响(间接效应 = -0.0152,95% CI = [-0.036,-0.001],p = 0.036)。我们的研究表明,移情不仅与压力诱导的糖皮质激素相关,还与压力诱导的基础脑区和高级脑区之间的交流减少有关。
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Neurobiology of Stress
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