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The importance of REM sleep fragmentation in the effects of stress on sleep: Perspectives from preclinical studies 快速眼动睡眠片段在压力对睡眠影响中的重要性:来自临床前研究的观点
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-14 DOI: 10.1016/j.ynstr.2023.100588
Laura Grafe , Katherine E. Miller , Richard J. Ross , Seema Bhatnagar

Psychological stress poses a risk for sleep disturbances. Importantly, trauma-exposed individuals who develop posttraumatic stress disorder (PTSD) frequently report insomnia and recurrent nightmares. Clinical studies have provided insight into the mechanisms of these sleep disturbances. We review polysomnographic findings in PTSD and identify analogous measures that have been made in animal models of PTSD. There is a rich empirical and theoretical literature on rapid eye movement sleep (REMS) substrates of insomnia and nightmares, with an emphasis on REMS fragmentation. For future investigations of stress-induced sleep changes, we recommend a focus on tonic, phasic and other microarchitectural REMS measures. Power spectral density analysis of the sleep EEG should also be utilized. Animal models with high construct validity can provide insight into gender and time following stressor exposure as moderating variables. Ultimately, preclinical studies with translational potential will lead to improved treatment for stress-related sleep disturbances.

心理压力会造成睡眠障碍。重要的是,创伤暴露的个体发展为创伤后应激障碍(PTSD)经常报告失眠和反复的噩梦。临床研究已经对这些睡眠障碍的机制提供了深入的了解。我们回顾了创伤后应激障碍的多导睡眠图发现,并确定了在创伤后应激障碍动物模型中所做的类似措施。关于快速眼动睡眠(REMS)对失眠和噩梦的影响,已有丰富的实证和理论文献,重点是REMS碎片化。对于未来压力诱发睡眠变化的研究,我们建议将重点放在紧张性、相位性和其他微结构性REMS测量上。还应利用睡眠脑电图的功率谱密度分析。具有高结构效度的动物模型可以提供性别和压力暴露时间作为调节变量的洞见。最终,具有转化潜力的临床前研究将改善与压力相关的睡眠障碍的治疗。
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引用次数: 0
Genomic glucocorticoid receptor effects guide acute stress-induced delayed anxiety and basolateral amygdala spine plasticity in rats 基因组糖皮质激素受体影响大鼠急性应激诱导的延迟性焦虑和杏仁核基底外侧脊柱可塑性
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-10 DOI: 10.1016/j.ynstr.2023.100587
Leonardo S. Novaes , Leticia M. Bueno-de-Camargo , Amadeu Shigeo-de-Almeida , Vitor A.L. Juliano , Ki Goosens , Carolina D. Munhoz

Anxiety, a state related to anticipatory fear, can be adaptive in the face of environmental threats or stressors. However, anxiety can also become persistent and manifest as anxiety- and stress-related disorders, such as generalized anxiety or post-traumatic stress disorder (PTSD). In rodents, systemic administration of glucocorticoids (GCs) or short-term restraint stress induces anxiety-like behaviors and dendritic branching within the basolateral complex of the amygdala (BLA) ten days later. Additionally, increased arousal-related memory retention mediated by elevated GCs requires concomitant noradrenaline (NE) signaling, both acting in the BLA. It is unknown whether GCs and NE play a role in the delayed acute stress-induced effects on behavior and BLA dendritic plasticity. Here, inhibiting corticosterone (CORT) elevation during 2 h of restraint stress prevents stress-induced increases in delayed anxiety-like behavior and BLA dendritic spine density in rats. Also, we show that the delayed acute stress-induced effects on behavior and morphological alterations are critically dependent on genomic glucocorticoid receptor (GR) actions in the BLA. Unlike CORT, the pharmacological enhancement of NE signaling in the BLA was insufficient to drive delayed anxiety-related behavior. Nonetheless, the delayed anxiety-like behavior ten days after acute stress requires NE signaling in the BLA during stress exposure. Therefore, we define the essential roles of two stress-related hormones for the late stress consequences, acting at two separate times: CORT, via GR, immediately during stress, and NE, via beta-adrenoceptors, during the expression of delayed anxiety.

焦虑是一种与预期恐惧相关的状态,在面对环境威胁或压力源时可以适应。然而,焦虑也可能持续存在,表现为焦虑和压力相关的疾病,如广泛性焦虑或创伤后应激障碍(PTSD)。在啮齿类动物中,全身给予糖皮质激素(GCs)或短期约束应激可在10天后诱导杏仁核基底外侧复合体(BLA)内的焦虑样行为和树突分支。此外,由GCs升高介导的觉醒相关记忆保留的增加需要伴随去甲肾上腺素(NE)信号,两者都在BLA中起作用。目前尚不清楚GCs和NE是否在延迟急性应力诱导的行为和BLA树突可塑性的影响中发挥作用。在本研究中,抑制抑制应激2小时时皮质酮(CORT)升高可防止应激诱导的延迟性焦虑样行为和大鼠BLA树突棘密度的增加。此外,我们还表明,延迟急性应激诱导的行为和形态改变的影响严重依赖于BLA中基因组糖皮质激素受体(GR)的作用。与CORT不同,BLA中NE信号的药理增强不足以驱动延迟的焦虑相关行为。然而,急性应激后10天的延迟焦虑样行为需要应激暴露期间BLA中的NE信号。因此,我们确定了两种与压力相关的激素在后期压力后果中的重要作用,它们在两个不同的时间起作用:CORT,通过GR,在压力期间立即起作用,NE,通过β -肾上腺素受体,在延迟焦虑的表达期间起作用。
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引用次数: 0
Estimating foraging behavior in rodents using a modified paradigm measuring threat imminence dynamics 用一种改进的测量威胁迫近动态的范式估计啮齿动物的觅食行为
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-07 DOI: 10.1016/j.ynstr.2023.100585
Xianzong Meng , Ping Chen , Andor Veltien , Tony Palavra , Sjors In't Veld , Joanes Grandjean , Judith R. Homberg

Animals need to respond to threats to avoid danger and approach rewards. In nature, these responses did not evolve alone but are always accompanied by motivational conflict. A semi-naturalistic threat imminence continuum model models the approach-avoidance conflict and is able to integrate multiple behaviors into a single paradigm. However, its comprehensive application is hampered by the lack of a detailed protocol and data about some fundamental factors including sex, age, and motivational level. Here, we modified a previously established paradigm measuring threat imminence continuum dynamics, involving modifications of training and testing protocols, and utilization of commercial materials combined with open science codes, making it easier to replicate. We demonstrate that foraging behavior is modulated by age, hunger level, and sex. This paradigm can be used to study foraging behaviors in animals in a more naturalistic manner with relevance to human approach-avoid conflicts and associated psychopathologies.

动物需要对威胁做出反应以避免危险并接近奖励。在自然界中,这些反应并不是单独进化的,而是总是伴随着动机冲突。一个半自然的威胁迫在眉睫的连续体模型对方法回避冲突进行建模,并能够将多种行为整合到一个单一的范式中。然而,由于缺乏关于性别、年龄和动机水平等一些基本因素的详细方案和数据,它的全面应用受到了阻碍。在这里,我们修改了之前建立的衡量威胁紧迫性连续动力学的范式,包括修改训练和测试协议,以及利用商业材料与开放科学代码相结合,使其更容易复制。我们证明,觅食行为受年龄、饥饿程度和性别的调节。该范式可用于以更自然的方式研究动物的觅食行为,并与人类避免冲突和相关精神病理学的方法相关。
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引用次数: 0
Cortical volume alteration in the superior parietal region mediates the relationship between childhood abuse and PTSD avoidance symptoms: A complementary multimodal neuroimaging study 上顶叶皮质体积改变介导童年虐待与PTSD回避症状之间的关系:一项互补的多模态神经影像学研究
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-07 DOI: 10.1016/j.ynstr.2023.100586
Richard Okyere Nkrumah , Claudius von Schröder , Traute Demirakca , Christian Schmahl , Gabriele Ende

Background

Adverse childhood experiences (ACE), which can be separated into abuse and neglect, contribute to the development of post-traumatic stress symptoms (PTSS). However, which brain structures are mainly affected by ACE as well as the mediating role these brain structures play in ACE and PTSS relationship are still being investigated. The current study tested the effect of ACE on brain structure and investigated the latter's mediating role in ACE-PTSS relationship.

Methods

A total of 78 adults with self-reported ACE were included in this study. Participants completed the childhood trauma questionnaire (CTQ) and a Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) to ascertain ACE history and PTSS, respectively. T1w images and diffusion MRI scans were then acquired to assess cortical morphometry and white matter (WM) integrity in fibre tracts connecting key areas where ACE-related cortical volume alterations were observed.

Results

The combined effect of ACE was negatively associated with total grey matter volume and local cortical area in the right superior parietal region (rSP). Childhood abuse was negatively related to right superior parietal volume after controlling for neglect and overall psychological burden. The right superior parietal volume significantly mediated the relationship between childhood abuse and avoidance-related PTSS. Post-hoc analyses showed that the indirect relation was subsequently moderated by dissociative symptoms. Lastly, a complementary examination of the WM tracts connected to abuse-associated cortical GM regions shows that abuse was negatively related to the normalised fibre density of WM tracts connected to the right superior parietal region.

Conclusion

We provide multimodal structural evidence that ACE in the first years of life is related to alterations in the right superior brain region, which plays a crucial role in spatial processing and attentional functioning. Additionally, we highlight that the cortical volume alteration in this region may play a role in explaining the relationship between childhood abuse and avoidance symptoms.

不良的童年经历(ACE)可分为虐待和忽视,有助于创伤后应激症状(PTSS)的发展。然而,ACE主要影响哪些脑结构以及这些脑结构在ACE与ptsd关系中的中介作用仍在研究中。本研究检验ACE对脑结构的影响,并探讨后者在ACE- ptss关系中的中介作用。方法本研究共纳入78例自报ACE的成人。参与者分别完成童年创伤问卷(CTQ)和创伤后应激障碍检查表(PCL-5)以确定ACE病史和创伤后应激障碍。然后获得T1w图像和弥散MRI扫描,以评估连接关键区域的纤维束的皮层形态测量和白质(WM)完整性,在这些区域观察到与ace相关的皮质体积改变。结果ACE的联合作用与脑灰质总量和右侧顶叶上区局部皮质面积呈负相关。在控制忽视和整体心理负担后,儿童虐待与右顶叶上容积呈负相关。右顶叶上容积显著调节儿童虐待与回避相关性ptsd之间的关系。事后分析表明,这种间接关系随后被分离症状所缓和。最后,对与虐待相关的皮质GM区域相连的WM束的补充检查表明,虐待与与右顶叶上区相连的WM束的正常化纤维密度呈负相关。结论我们提供的多模态结构证据表明,1岁时ACE与右脑上区改变有关,右脑上区在空间加工和注意功能中起着至关重要的作用。此外,我们强调该区域的皮质体积改变可能在解释儿童虐待和回避症状之间的关系中起作用。
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引用次数: 0
Acute stress selectively blunts reward anticipation but not consumption: An ERP study 急性压力选择性地削弱了奖励预期,而不是消耗:一项ERP研究
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-01 DOI: 10.1016/j.ynstr.2023.100583
Wei Yi , Yantao Chen , Linlin Yan , Nils Kohn , Jianhui Wu

Stress-induced dysfunction of reward processing is documented to be a critical factor associated with mental illness. Although many studies have attempted to clarify the relationship between stress and reward, few studies have investigated the effect of acute stress on the temporal dynamics of reward processing. The present study applied event-related potentials (ERP) to examine how acute stress differently influences reward anticipation and consumption. In this study, seventy-eight undergraduates completed a two-door reward task following a Trier Social Stress Task (TSST) or a placebo task. The TSST group showed higher cortisol levels, perceived stress, anxiety, and negative affect than the control group. For the control group, a higher magnitude of reward elicited a reduced cue-N2 but increased stimulus-preceding negativity (SPN), suggesting that controls were sensitive to reward magnitude. In contrast, these effects were absent in the stress group, suggesting that acute stress reduces sensitivity to reward magnitude during the anticipatory phase. However, the reward positivity (RewP) and P3 of both groups showed similar patterns, which suggests that acute stress has no impact on reward responsiveness during the consummatory phase. These findings suggest that acute stress selectively blunts sensitivity to reward magnitude during the anticipatory rather than the consummatory phase.

应激诱导的奖励处理功能障碍是与精神疾病相关的一个关键因素。尽管许多研究试图澄清压力和奖励之间的关系,但很少有研究调查急性压力对奖励加工的时间动态的影响。本研究应用事件相关电位(ERP)研究急性应激对奖赏预期和消费的不同影响。在这项研究中,78名大学生在完成特里尔社会压力任务(TSST)或安慰剂任务后完成了双门奖励任务。与对照组相比,TSST组表现出更高的皮质醇水平、感知压力、焦虑和负面情绪。在对照组中,较高的奖励强度引起的线索- n2减少,但刺激前负性(SPN)增加,表明对照组对奖励强度敏感。相反,这些影响在应激组中不存在,这表明急性应激降低了预期阶段对奖励大小的敏感性。然而,两组的奖励积极性(RewP)和P3表现出相似的模式,这表明急性应激对完满期的奖励反应没有影响。这些发现表明,急性应激在预期阶段而不是完成阶段选择性地减弱了对奖励大小的敏感性。
{"title":"Acute stress selectively blunts reward anticipation but not consumption: An ERP study","authors":"Wei Yi ,&nbsp;Yantao Chen ,&nbsp;Linlin Yan ,&nbsp;Nils Kohn ,&nbsp;Jianhui Wu","doi":"10.1016/j.ynstr.2023.100583","DOIUrl":"https://doi.org/10.1016/j.ynstr.2023.100583","url":null,"abstract":"<div><p>Stress-induced dysfunction of reward processing is documented to be a critical factor associated with mental illness. Although many studies have attempted to clarify the relationship between stress and reward, few studies have investigated the effect of acute stress on the temporal dynamics of reward processing. The present study applied event-related potentials (ERP) to examine how acute stress differently influences reward anticipation and consumption. In this study, seventy-eight undergraduates completed a two-door reward task following a Trier Social Stress Task (TSST) or a placebo task. The TSST group showed higher cortisol levels, perceived stress, anxiety, and negative affect than the control group. For the control group, a higher magnitude of reward elicited a reduced cue-N2 but increased stimulus-preceding negativity (SPN), suggesting that controls were sensitive to reward magnitude. In contrast, these effects were absent in the stress group, suggesting that acute stress reduces sensitivity to reward magnitude during the anticipatory phase. However, the reward positivity (RewP) and P3 of both groups showed similar patterns, which suggests that acute stress has no impact on reward responsiveness during the consummatory phase. These findings suggest that acute stress selectively blunts sensitivity to reward magnitude during the anticipatory rather than the consummatory phase.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289523000711/pdfft?md5=c85d53b17bd67afd5e53bd423c3cfc77&pid=1-s2.0-S2352289523000711-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92099723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The double-edged sword of the hippocampus-ventromedial prefrontal cortex resting-state connectivity in stress susceptibility and resilience: A prospective study 海马体-腹内侧前额叶皮层静息状态连接在应激易感性和恢复力中的双刃剑:一项前瞻性研究
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-01 DOI: 10.1016/j.ynstr.2023.100584
Jingjing Chang , Di Song , Rongjun Yu

The hippocampus has long been considered a pivotal region implicated in both stress susceptibility and resilience. A wealth of evidence from animal and human studies underscores the significance of hippocampal functional connectivity with the ventromedial prefrontal cortex (vmPFC) in these stress-related processes. However, there remains a scarcity of research that explores and contrasts the roles of hippocampus-vmPFC connectivity in stress susceptibility and resilience when facing a real-life traumatic event from a prospective standpoint. In the present study, we investigated the contributions of undirected and directed connectivity between the hippocampus and vmPFC to stress susceptibility and resilience within the context of the COVID-19 pandemic. Our findings revealed that the left hippocampus-left vmPFC connectivity prior to the pandemic exhibited a negative correlation with both stress susceptibility and resilience. Specifically, individuals with stronger left hippocampus-left vmPFC connectivity reported experiencing fewer stress-related feelings during the outbreak period of the epidemic but displayed lower levels of stress resilience five months later. Our application of spectral dynamic causal modeling unveiled an additional inhibitory connectivity pathway from the left hippocampus to the left vmPFC in the context of stress susceptibility, which was notably absent in stress resilience. Furthermore, we observed a noteworthy positive association between self-inhibition of the vmPFC and stress susceptibility, with this effect proving substantial enough to predict an individual's susceptibility to stress; conversely, these patterns did not manifest in the realm of stress resilience. These findings enrich our comprehension of stress susceptibility and stress resilience and might have implications for innovative approaches to managing stress-related disorders.

长期以来,海马体一直被认为是影响压力敏感性和恢复力的关键区域。来自动物和人类研究的大量证据强调了海马与腹内侧前额叶皮层(vmPFC)功能连接在这些应激相关过程中的重要性。然而,从前瞻性的角度探索和对比海马体- vmpfc连接在面对现实生活创伤事件时压力易感性和恢复力中的作用的研究仍然很少。在本研究中,我们研究了在COVID-19大流行背景下,海马和vmPFC之间的定向和定向连接对应激敏感性和恢复力的贡献。我们的研究结果显示,在大流行之前,左侧海马体-左侧vmPFC的连通性与压力敏感性和恢复力都呈负相关。具体来说,左侧海马体-左侧vmPFC连通性较强的个体报告说,在疫情爆发期间,与压力相关的感受较少,但五个月后表现出较低的压力恢复能力。我们应用谱动态因果模型揭示了应激易感性背景下从左侧海马体到左侧vmPFC的额外抑制连接通路,这在应激恢复力中是明显缺失的。此外,我们观察到vmPFC的自我抑制与压力易感性之间存在显著的正相关,这种影响足以预测个体对压力的易感性;相反,这些模式并没有在压力恢复能力领域表现出来。这些发现丰富了我们对压力易感性和压力恢复力的理解,并可能对管理压力相关疾病的创新方法产生影响。
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引用次数: 0
Controlling intrusive thoughts of future fears under stress 在压力下控制对未来恐惧的侵入性想法
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-11-01 DOI: 10.1016/j.ynstr.2023.100582
Stephanie M. Ashton , Tom Smeets , Conny W.E.M. Quaedflieg

Negative outlooks of our future may foster unwanted and intrusive thoughts. To some extent, individuals have control over their ability to suppress intrusions and downregulate their frequency. Acute stress impairs intentional suppression, leading to an increased frequency of intrusions. The aim of this study was to gain insight into the mechanism underlying stress-induced impairments in intentional suppression of intrusions by investigating the combined and independent roles of the two major stress hormones, noradrenaline and cortisol. Healthy participants (N = 181) were administered propranolol (to block the noradrenergic response), metyrapone (to block the cortisol response), or a placebo before being exposed to the Maastricht Acute Stress Test. Intrusive thoughts of autobiographical future fears were then measured via the Imagine/No-Imagine task. Results demonstrated that the stress response was successfully altered because of the drug and stress manipulations. In all groups, repeated suppression of future fears reduced intrusions. Across the sample, an enhanced decrease over time was associated with greater attenuation of anxiety towards the related fears. The groups did not differ in the total frequency of intrusions. Though, trait anxiety increased the total number of intrusions. Our findings show that stress hormones did not influence the ability to suppress intrusions. However, our results do add support to previous research linking anxiety to memory control deficits. When using autobiographical content, future research should focus on the quality and characteristics of the individual memories to explain more of the variation observed in intentional memory control.

对未来的消极看法可能会滋生不想要的和侵入性的想法。在某种程度上,个体可以控制自己抑制干扰和下调频率的能力。急性应激损害有意抑制,导致入侵频率增加。本研究的目的是通过研究两种主要应激激素去甲肾上腺素和皮质醇的联合和独立作用,来深入了解应激诱导的损伤在故意抑制入侵中的机制。健康参与者(N = 181)在接受马斯特里赫特急性压力测试之前被给予心得安(阻断去甲肾上腺素能反应)、美替拉酮(阻断皮质醇反应)或安慰剂。然后通过想象/不想象任务测量自传式未来恐惧的侵入性想法。结果表明,由于药物和压力的操纵,应激反应成功地改变了。在所有的小组中,反复抑制对未来的恐惧减少了干扰。在整个样本中,随着时间的推移,这种增强的减少与对相关恐惧的焦虑的更大衰减有关。两组在入侵的总频率上没有差异。然而,特质焦虑增加了入侵的总数。我们的研究结果表明,应激激素不影响抑制入侵的能力。然而,我们的结果确实支持了先前将焦虑与记忆控制缺陷联系起来的研究。当使用自传体内容时,未来的研究应该关注个体记忆的质量和特征,以解释在有意记忆控制中观察到的更多变化。
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引用次数: 0
Prenatal infection and adolescent social adversity affect microglia, synaptic density, and behavior in male rats 产前感染和青少年社会逆境对雄性大鼠小胶质细胞、突触密度和行为的影响
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-19 DOI: 10.1016/j.ynstr.2023.100580
Cyprien G.J. Guerrin , Kavya Prasad , Daniel A. Vazquez-Matias , Jing Zheng , Maria Franquesa-Mullerat , Lara Barazzuol , Janine Doorduin , Erik F.J. de Vries

Maternal infection during pregnancy and childhood social trauma have been associated with neurodevelopmental and affective disorders, such as schizophrenia, autism spectrum disorders, bipolar disorder and depression. These disorders are characterized by changes in microglial cells, which play a notable role in synaptic pruning, and synaptic deficits. Here, we investigated the effect of prenatal infection and social adversity during adolescence – either alone or in combination – on behavior, microglia, and synaptic density. Male offspring of pregnant rats injected with poly I:C, mimicking prenatal infection, were exposed to repeated social defeat during adolescence. We found that maternal infection during pregnancy prevented the reduction in social behavior and increase in anxiety induced by social adversity during adolescence. Furthermore, maternal infection and social adversity, alone or in combination, induced hyperlocomotion in adulthood. Longitudinal in vivo imaging with [11C]PBR28 positron emission tomography revealed that prenatal infection alone and social adversity during adolescence alone induced a transient increase in translocator protein TSPO density, an indicator of glial reactivity, whereas their combination induced a long-lasting increase that remained until adulthood. Furthermore, only the combination of prenatal infection and social adversity during adolescence induced an increase in microglial cell density in the frontal cortex. Prenatal infection increased proinflammatory cytokine IL-1β protein levels in hippocampus and social adversity reduced anti-inflammatory cytokine IL-10 protein levels in hippocampus during adulthood. This reduction in IL-10 was prevented if rats were previously exposed to prenatal infection. Adult offspring exposed to prenatal infection or adolescent social adversity had a higher synaptic density in the frontal cortex, but not hippocampus, as evaluated by synaptophysin density. Interestingly, such an increase in synaptic density was not observed in rats exposed to the combination of prenatal infection and social adversity, perhaps due to the long-lasting increase in microglial density, which may lead to an increase in microglial synaptic pruning. These findings suggest that changes in microglia activity and cytokine release induced by prenatal infection and social adversity during adolescence may be related to a reduced synaptic pruning, resulting in a higher synaptic density and behavioral changes in adulthood.

妊娠期和儿童期的母亲感染社会创伤与神经发育和情感障碍有关,如精神分裂症、自闭症谱系障碍、双相情感障碍和抑郁症。这些疾病的特征是小胶质细胞的变化,小胶质细胞在突触修剪和突触缺陷中发挥着显著作用。在这里,我们研究了产前感染和青春期社会逆境(单独或联合)对行为、小胶质细胞和突触密度的影响。注射poly I:C的怀孕大鼠的雄性后代,模仿产前感染,在青春期暴露于反复的社会失败中。我们发现,怀孕期间的母亲感染阻止了青春期社会逆境引起的社交行为的减少和焦虑的增加。此外,母亲感染和社会逆境,无论是单独还是组合,都会导致成年后的过度运动。[11C]PBR28正电子发射断层扫描的纵向体内成像显示,单独的产前感染和青春期的社会逆境诱导了转运蛋白TSPO密度的短暂增加,TSPO密度是神经胶质反应性的指标,而它们的组合诱导了持续到成年的长期增加。此外,只有产前感染和青春期社会逆境的结合才导致额叶皮层小胶质细胞密度增加。在成年期,产前感染增加了海马中的促炎细胞因子IL-1β蛋白水平,而社会逆境降低了海马中抗炎细胞因子IL-10蛋白水平。如果大鼠先前暴露于产前感染,则可以防止IL-10的这种减少。根据突触素密度评估,暴露于产前感染或青少年社会逆境的成年后代额叶皮层的突触密度较高,但海马体的突触密度不高。有趣的是,在暴露于产前感染和社会逆境的大鼠中没有观察到突触密度的这种增加,可能是由于小胶质细胞密度的长期增加,这可能导致小胶质细胞突触修剪的增加。这些发现表明,产前感染和青春期社会逆境诱导的小胶质细胞活性和细胞因子释放的变化可能与突触修剪减少有关,从而导致成年后突触密度和行为变化增加。
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引用次数: 0
High emotional reactivity is associated with activation of a molecularly distinct hippocampal-amygdala circuit modulated by the glucocorticoid receptor 高情绪反应性与糖皮质激素受体调节的分子不同的海马杏仁核回路的激活有关
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-16 DOI: 10.1016/j.ynstr.2023.100581
Qiang Wei , Vivek Kumar , Shannon Moore, Fei Li, Geoffrey G. Murphy, Stanley J. Watson , Huda Akil

Emotions are characterized not only by their valence but also by whether they are stable or labile. Yet, we do not understand the molecular or circuit mechanisms that control the dynamic nature of emotional responses. We have shown that glucocorticoid receptor overexpression in the forebrain (GRov) leads to a highly reactive mouse with increased anxiety behavior coupled with greater swings in emotional responses. This phenotype is established early in development and persists into adulthood. However, the neural circuitry mediating this lifelong emotional lability remains unknown. In the present study, optogenetic stimulation in ventral dentate gyrus (vDG) of GRov mice led to a greater range and a prolonged duration of anxiety behavior. cFos expression analysis showed that the amplified behavioral response to vDG activation in GRov mice is coupled to increased neuronal activity in specific brain regions. Relative to wild type mice, GRov mice displayed glutamatergic/GABAergic activation imbalance in ventral CA1 (vCA1) and selectively increased glutamatergic activation in the basal posterior amygdaloid complex. Moreover, forebrain GR overexpression led to increased activation of molecularly distinct subpopulations of neurons within the hippocampus and the posterior basolateral amygdala (pBLA) as evident from the increased cFos co-labeling in the calbindin1+ glutamatergic neurons in vCA1 and in the DARPP-32/Ppp1r1b+ glutamatergic neurons in pBLA. We propose that a molecularly distinct hippocampal-amygdala circuit is shaped by stress early in life and tunes the dynamics of emotional responses.

情绪的特征不仅在于它们的价态,还在于它们是稳定的还是不稳定的。然而,我们不了解控制情绪反应动态性质的分子或电路机制。我们已经表明,前脑中的糖皮质激素受体过度表达(GRov)会导致高度反应性小鼠焦虑行为增加,情绪反应波动更大。这种表型在发育早期就形成了,并一直持续到成年。然而,介导这种终生情绪不稳定的神经回路仍然未知。在本研究中,GRov小鼠腹侧齿状回(vDG)的光遗传学刺激导致焦虑行为的范围更大,持续时间更长。cFos表达分析表明,GRov小鼠对vDG激活的放大行为反应与特定脑区神经元活性的增加有关。与野生型小鼠相比,GRov小鼠在腹侧CA1(vCA1)表现出谷氨酸能/GABA能激活失衡,并选择性增加基底后杏仁核复合体的谷氨酸能激活。此外,前脑GR过表达导致海马和后基底外侧杏仁核(pBLA)内神经元的分子不同亚群的激活增加,这从vCA1中的钙结合蛋白1+谷氨酸能神经元和pBLA中的DARPP-32/Pp1r1b+谷氨酸能神经元中的cFos共标记增加中可以明显看出。我们提出,一个分子上不同的海马杏仁核回路是由生命早期的压力形成的,并调节情绪反应的动力学。
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引用次数: 0
Epigenetic age acceleration as a biomarker for impaired cognitive abilities in adulthood following early life adversity and psychiatric disorders 表观遗传年龄加速作为成年早期生活逆境和精神障碍后认知能力受损的生物标志物
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-15 DOI: 10.1016/j.ynstr.2023.100577
John M. Felt , Natan Yusupov , Karra D. Harrington , Julia Fietz , Zhenyu “Zach” Zhang , Martin J. Sliwinski , Nilam Ram , Kieran J. O'Donnell , BeCOME Working Group , Michael J. Meaney , Frank W. Putnam , Jennie G. Noll , Elisabeth B. Binder , Chad E. Shenk

Background

Early life adversity and psychiatric disorders are associated with earlier declines in neurocognitive abilities during adulthood. These declines may be preceded by changes in biological aging, specifically epigenetic age acceleration, providing an opportunity to uncover genome-wide biomarkers that identify individuals most likely to benefit from early screening and prevention.

Methods

Five unique epigenetic age acceleration clocks derived from peripheral blood were examined in relation to latent variables of general and speeded cognitive abilities across two independent cohorts: 1) the Female Growth and Development Study (FGDS; n = 86), a 30-year prospective cohort study of substantiated child sexual abuse and non-abused controls, and 2) the Biological Classification of Mental Disorders study (BeCOME; n = 313), an adult community cohort established based on psychiatric disorders.

Results

A faster pace of biological aging (DunedinPoAm) was associated with lower general cognitive abilities in both cohorts and slower speeded abilities in the BeCOME cohort. Acceleration in the Horvath clock was significantly associated with slower speeded abilities in the BeCOME cohort but not the FGDS. Acceleration in the Hannum clock and the GrimAge clock were not significantly associated with either cognitive ability. Accelerated PhenoAge was associated with slower speeded abilities in the FGDS but not the BeCOME cohort.

Conclusions

The present results suggest that epigenetic age acceleration has the potential to serve as a biomarker for neurocognitive decline in adults with a history of early life adversity or psychiatric disorders. Estimates of epigenetic aging may identify adults at risk of cognitive decline that could benefit from early neurocognitive screening.

背景早期生活中的逆境和精神障碍与成年期神经认知能力的早期下降有关。在这些下降之前,生物衰老可能会发生变化,特别是表观遗传学年龄加速,这为揭示全基因组生物标志物提供了机会,这些生物标志物可以识别最有可能从早期筛查和预防中受益的个体。方法在两个独立的队列中,检测了来自外周血的五个独特的表观遗传学年龄加速时钟与一般和加速认知能力的潜在变量的关系:1)女性生长发育研究(FGDS;n=86),这是一项为期30年的前瞻性队列研究,对证实的儿童性虐待和非虐待对照进行研究,和2)精神障碍生物学分类研究(BeCOME;n=313),一个基于精神障碍建立的成人社区队列。结果生物衰老速度较快(DunedinPoAm)与两个队列中较低的一般认知能力和BeCOME队列中较慢的加速能力有关。Horvath时钟的加速与BeCOME队列中较慢的加速能力显著相关,但与FGDS无关。Hannum时钟和GrimAge时钟的加速与这两种认知能力都没有显著关联。在FGDS中,加速表型年龄与较慢的加速能力有关,但在BeCOME队列中则不然。结论目前的研究结果表明,表观遗传年龄加速有可能成为有早期生活逆境或精神障碍史的成年人神经认知能力下降的生物标志物。表观遗传学衰老的估计可能会识别出有认知能力下降风险的成年人,这可能受益于早期神经认知筛查。
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引用次数: 0
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Neurobiology of Stress
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