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Psychosocial stress-induced intestinal permeability in healthy humans: What is the evidence? 健康人的心理社会压力引起的肠道通透性:证据是什么?
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-06 DOI: 10.1016/j.ynstr.2023.100579
Danique La Torre , Lukas Van Oudenhove , Tim Vanuytsel , Kristin Verbeke

An impaired intestinal barrier function can be detrimental to the host as it may allow the translocation of luminal antigens and toxins into the subepithelial tissue and bloodstream. In turn, this may cause local and systemic immune responses and lead to the development of pathologies. In vitro and animal studies strongly suggest that psychosocial stress is one of the factors that can increase intestinal permeability via mast-cell dependent mechanisms. Remarkably, studies have not been able to yield unequivocal evidence that such relation between stress and intestinal permeability also exists in (healthy) humans. In the current Review, we discuss the mechanisms that are involved in stress-induced intestinal permeability changes and postulate factors that influence these alterations and that may explain the translational difficulties from in vitro and animal to human studies. As human research differs highly from animal research in the extent to which stress can be applied and intestinal permeability can be measured, it remains difficult to draw conclusions about the presence of a relation between stress and intestinal permeability in (healthy) humans. Future studies should bear in mind these difficulties, and more research into in vivo methods to assess intestinal permeability are warranted.

肠道屏障功能受损可能对宿主有害,因为它可能会使管腔抗原和毒素转移到上皮下组织和血液中。反过来,这可能会引起局部和系统免疫反应,并导致病理的发展。体外和动物研究强烈表明,心理社会压力是通过肥大细胞依赖机制增加肠道通透性的因素之一。值得注意的是,研究未能得出明确的证据,证明压力和肠道通透性之间的关系也存在于(健康)人类中。在目前的综述中,我们讨论了应激诱导的肠道通透性变化的机制,以及影响这些变化的假设因素,这些因素可能解释了从体外和动物到人类研究的转化困难。由于人类研究与动物研究在施加压力和测量肠道通透性的程度上有很大不同,因此很难得出关于(健康)人类压力与肠道通透性之间存在关系的结论。未来的研究应该考虑到这些困难,有必要对评估肠道通透性的体内方法进行更多的研究。
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引用次数: 0
Pre-COVID brain network topology prospectively predicts social anxiety alterations during the COVID-19 pandemic COVID-19前大脑网络拓扑可预测COVID-19大流行期间社交焦虑的变化
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-10-01 DOI: 10.1016/j.ynstr.2023.100578
Qingyuan Li , Xun Zhang , Xun Yang , Nanfang Pan , Xiao Li , Graham J. Kemp , Song Wang , Qiyong Gong

Background

Social anxiety (SA) is a negative emotional response that can lead to mental health issues, which some have experienced during the coronavirus disease 2019 (COVID-19) pandemic. Little attention has been given to the neurobiological mechanisms underlying inter-individual differences in SA alterations related to COVID-19. This study aims to identify neurofunctional markers of COVID-specific SA development.

Methods

110 healthy participants underwent resting-state magnetic resonance imaging and behavioral tests before the pandemic (T1, October 2019 to January 2020) and completed follow-up behavioral measurements during the pandemic (T2, February to May 2020). We constructed individual functional networks and used graph theoretical analysis to estimate their global and nodal topological properties, then used Pearson correlation and partial least squares correlations examine their associations with COVID-specific SA alterations.

Results

In terms of global network parameters, SA alterations (T2-T1) were negatively related to pre-pandemic brain small-worldness and normalized clustering coefficient. In terms of nodal network parameters, SA alterations were positively linked to a pronounced degree centrality pattern, encompassing both the high-level cognitive networks (dorsal attention network, cingulo-opercular task control network, default mode network, memory retrieval network, fronto-parietal task control network, and subcortical network) and low-level perceptual networks (sensory/somatomotor network, auditory network, and visual network). These findings were robust after controlling for pre-pandemic general anxiety, other stressful life events, and family socioeconomic status, as well as by treating SA alterations as categorical variables.

Conclusions

The individual functional network associated with SA alterations showed a disrupted topological organization with a more random state, which may shed light on the neurobiological basis of COVID-related SA changes at the network level.

背景社交焦虑(SA)是一种负面情绪反应,可能导致心理健康问题,一些人在2019冠状病毒病(新冠肺炎)大流行期间曾经历过这种情况。很少关注与新冠肺炎相关的SA改变个体间差异的神经生物学机制。本研究旨在确定新冠肺炎特异性SA发展的神经功能标志物。方法110名健康参与者在疫情前(2019年10月T1至2020年1月)接受了静息状态磁共振成像和行为测试,并在疫情期间(2020年2月T2至5月)完成了后续行为测量。我们构建了单个函数网络,并使用图论分析来估计它们的全局和节点拓扑性质,然后使用Pearson相关性和偏最小二乘相关性来检查它们与新冠病毒特异性SA变化的关联。结果在全局网络参数方面,SA改变(T2-T1)与疫情前大脑小世界度和归一化聚类系数呈负相关。在节点网络参数方面,SA的改变与显著的程度中心性模式呈正相关,包括高级认知网络(背侧注意网络、扣带回盖任务控制网络、默认模式网络、记忆检索网络、额顶叶任务控制网络和皮层下网络)和低级感知网络(感觉/体动网络、听觉网络和视觉网络)。在控制了疫情前的普遍焦虑、其他压力生活事件和家庭社会经济地位,并将SA变化视为分类变量后,这些发现是有力的。结论与SA改变相关的个体功能网络表现出一种更随机的拓扑组织破坏,这可能为新冠肺炎相关SA改变在网络水平上的神经生物学基础提供线索。
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引用次数: 0
Greater maltreatment severity is associated with smaller brain volume with implication for intellectual ability in young children 虐待程度越严重,大脑体积越小,这对幼儿的智力有影响。
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-23 DOI: 10.1016/j.ynstr.2023.100576
Judith Joseph , Claudia Buss , Andrea Knop , Karin de Punder , Sibylle M. Winter , Birgit Spors , Elisabeth Binder , John-Dylan Haynes , Christine Heim

Background

Childhood maltreatment profoundly alters trajectories of brain development, promoting markedly increased long-term health risks and impaired intellectual development. However, the immediate impact of maltreatment on brain development in children and the extent to which altered global brain volume contributes to intellectual development in children with maltreatment experience is currently unknown. We here utilized MRI data obtained from children within 6 months after the exposure to maltreatment to assess the association of maltreatment severity with global brain volume changes. We further assessed the association between maltreatment severity and intellectual development and tested for the mediating effect of brain volume on this association.

Method

We used structural MRI (3T) in a sample of 49 children aged 3–5 years with maltreatment exposure, i.e. emotional and physical abuse and/or neglect within 6 months, to characterize intracranial and tissue-specific volumes. Maltreatment severity was coded using the Maternal Interview for the Classification of Maltreatment. IQ was tested at study entry and after one year using the Snijders Oomen Nonverbal Test.

Results

Higher maltreatment severity was significantly correlated with smaller intracranial volume (r = -.393, p = .008), which was mainly driven by lower total brain volume (r = -.393, p = .008), which in turn was primarily due to smaller gray matter volume (r = -.454, p = .002). Furthermore, smaller gray matter volume was associated with lower IQ at study entry (r = -.548, p < .001) and predicted IQ one year later (r = -.493, p = .004). The observed associations were independent of potential confounding variables, including height, socioeconomic status, age and sex.

Importance

We provide evidence that greater maltreatment severity in early childhood is related to smaller brain size at a very young age with significant consequences for intellectual ability, likely setting a path for far-reaching long-term disadvantages. Insights into the molecular and neural processes that underlie the impact of maltreatment on brain structure and function are urgently needed to derive mechanism-driven targets for early intervention.

背景:儿童时期的虐待严重改变了大脑发育的轨迹,导致长期健康风险显著增加,智力发育受损。然而,目前尚不清楚虐待对儿童大脑发育的直接影响,以及有虐待经历的儿童的整体大脑容量变化在多大程度上促进了智力发育。在这里,我们利用从暴露于虐待后6个月内的儿童身上获得的MRI数据来评估虐待严重程度与整体脑容量变化的关系。我们进一步评估了虐待严重程度与智力发展之间的关系,并测试了脑容量对这种关系的中介作用。方法:我们对49名3-5岁的虐待儿童(即6个月内的情感和身体虐待和/或忽视)进行了结构MRI(3T),以表征颅内和组织特异性体积。使用母亲访谈法对虐待行为的严重程度进行编码。在研究开始时和一年后使用Snijders-Oomen非言语测试对IQ进行了测试,研究开始时,灰质体积越小,智商越低(r=-0.548,p=0.004)。观察到的相关性与潜在的混杂变量无关,包括身高、社会经济地位、年龄和性别。重要性:我们提供的证据表明,儿童早期虐待的严重程度越高,与很小的时候大脑体积越小有关,这对智力产生了重大影响,可能会导致深远的长期不利影响。迫切需要深入了解虐待对大脑结构和功能影响的分子和神经过程,以获得早期干预的机制驱动目标。
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引用次数: 0
Chronic stress promotes basal ganglia disinhibition by increasing the excitatory drive of direct-pathway neurons 慢性应激通过增加直接通路神经元的兴奋驱动来促进基底神经节的去抑制
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-22 DOI: 10.1016/j.ynstr.2023.100571
Diana Rodrigues , Patricia Monteiro

Chronic stress (CS) is a well-recognized triggering factor in obsessive-compulsive disorder (OCD) and Tourette's syndrome (TS), two neuropsychiatric disorders characterized by the presence of stereotypic motor symptoms. Planning and execution of motor actions are controlled by the dorsal striatum, a brain region that promotes or suppresses motor movement by activating striatal neurons from the direct- or indirect-pathway, respectively. Despite the dorsal striatum being affected in motor disorders and by CS exposure, how CS affects the two opposing pathways is not fully understood. Here, we report that CS in mice selectively potentiates the direct-pathway, while sparing the indirect-pathway. Specifically, we show that CS both increases excitation and reduces inhibition over direct-pathway neurons in the dorsomedial striatum (DMS). Furthermore, inhibitory interneurons located in the DMS also display reduced excitatory drive after chronic stress, thus amplifying striatal disinhibition. Altogether, we propose a model where both increased excitatory drive and decreased inhibitory drive in the striatum causes disinhibition of basal ganglia's motor direct pathway - a mechanism that might explain the emergence of motor stereotypies and tic disorders under stress.

慢性压力(CS)是公认的强迫症(OCD)和抽动秽语综合征(TS)的触发因素,这两种神经精神疾病的特征是存在刻板的运动症状。运动动作的计划和执行由背侧纹状体控制,背侧纹状体是一个大脑区域,通过分别从直接或间接途径激活纹状体神经元来促进或抑制运动。尽管背侧纹状体在运动障碍和CS暴露中受到影响,但CS如何影响两种相反的途径尚不完全清楚。在这里,我们报道了CS在小鼠中选择性地增强直接途径,同时保留间接途径。具体而言,我们发现CS既增加了对背内侧纹状体(DMS)直接通路神经元的兴奋,又减少了对其的抑制。此外,位于DMS中的抑制性中间神经元在慢性应激后也表现出兴奋性驱动减弱,从而增强纹状体的去抑制作用。总之,我们提出了一个模型,在该模型中,纹状体中兴奋性驱动的增加和抑制性驱动的减少都会导致基底神经节运动直接通路的去抑制,这一机制可能解释了压力下运动刻板印象和抽动障碍的出现。
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引用次数: 0
Effect of acetate supplementation on traumatic stress-induced behavioral impairments in male rats 醋酸盐补充对创伤应激性大鼠行为障碍的影响
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-19 DOI: 10.1016/j.ynstr.2023.100572
Arax Tanelian , Bistra Nankova , Furong Hu , Jordan D. Sahawneh , Esther L. Sabban

Gut microbiota and their metabolites have emerged as key players in the pathogenesis of neuropsychiatric disorders. Recently, we demonstrated that animals susceptible to Single Prolonged Stress (SPS) have an overall pro-inflammatory gut microbiota and significantly lower cecal acetate levels than SPS-resilient rats, which correlated inversely with the anxiety index. Here, we investigated whether the microbial metabolite, acetate, could ameliorate SPS-triggered impairments. Male rats were randomly divided into unstressed controls or groups exposed to SPS. The groups received continued oral supplementation of either 150 mM of sodium acetate or 150 mM of sodium chloride-matched water. Two weeks after SPS, a battery of behavioral tests was performed, and the animals were euthanized the following day. While not affecting the unstressed controls, acetate supplementation reduced the impact of SPS on body weight gain and ameliorated SPS-induced anxiety-like behavior and the impairments in social interaction, but not depressive-like behavior. These changes were accompanied by several beneficial effects of acetate supplementation. Acetate alleviated the stress response by reducing urinary epinephrine levels, induced epigenetic modification by decreasing histone deacetylase (HDAC2) gene expression, inhibited neuroinflammation by reducing the density of Iba1+ cells and the gene expression of IL-1ß in the hippocampus, and increased serum β-hydroxybutyrate levels. The findings reveal a causal relationship between oral acetate treatment and mitigation of several SPS-induced behavioral impairments. Mechanistically, it impacted neuronal and metabolic pathways including changes in stress response, epigenetic modifications, neuroinflammation and showed novel link to ketone body production. The study demonstrates the preventive-therapeutic potential of acetate supplementation to alleviate adverse responses to traumatic stress.

肠道微生物群及其代谢产物已成为神经精神疾病发病机制的关键参与者。最近,我们证明,与SPS弹性大鼠相比,易受单次长期应激(SPS)影响的动物具有整体的促炎肠道微生物群,盲肠乙酸盐水平显著较低,这与焦虑指数呈负相关。在这里,我们研究了微生物代谢产物乙酸盐是否可以改善SPS引发的损伤。雄性大鼠被随机分为无应激对照组或暴露于SPS的组。各组继续口服补充150mM乙酸钠或150mM氯化钠匹配水。SPS后两周,进行了一系列行为测试,第二天对动物实施安乐死。虽然不影响未应激的对照组,但补充乙酸盐减少了SPS对体重增加的影响,并改善了SPS诱导的焦虑样行为和社交障碍,但没有改善抑郁样行为。这些变化伴随着补充乙酸盐的一些有益效果。醋酸盐通过降低尿肾上腺素水平来缓解应激反应,通过降低组蛋白脱乙酰酶(HDAC2)基因表达来诱导表观遗传学修饰,通过降低海马中Iba1+细胞密度和IL-1ß基因表达来抑制神经炎症,并提高血清β-羟丁酸水平。研究结果揭示了口服乙酸盐治疗与减轻SPS诱导的几种行为障碍之间的因果关系。从机制上讲,它影响了神经元和代谢途径,包括应激反应的变化、表观遗传学修饰、神经炎症,并显示出与酮体产生的新联系。该研究证明了补充乙酸盐以减轻创伤应激的不良反应的预防性治疗潜力。
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引用次数: 0
The mineralocorticoid receptor and extra-synaptic NMDA receptor in the lateral habenula involve in the vulnerability to early life stress in the maternal separation model 在母亲分离模型中,侧缰中矿化皮质激素受体和突触外NMDA受体参与了早期生活应激的易感性
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-18 DOI: 10.1016/j.ynstr.2023.100570
Miseon Kang , Jun-mo Chung , Jihyun Noh , Jeongyeon Kim

The lateral habenula (LHb) plays a pivotal role in regulating emotional responses during stress reactions, and its hyperactivity has been associated with depression. Recently it has been demonstrated that chronic early-life stress results in individual differences in stress vulnerability among rodents. However, how synaptic function in the LHb varies between susceptibility and resilience to early life stress remains elusive. In this study, we used a maternal separation model to assign animals with different stress vulnerabilities into groups and investigated the synaptic responses in the LHb. Our findings indicate that synaptic long-term depression (LTD) was impaired and extra-synaptic LTD was enhanced in the LHb of the susceptible group. To mimic the synaptic alteration in stress situations, when administered corticosterone, a stress hormone, the intervention appeared to impair synaptic LTD in the LHb of the control group, through the activation of mineralocorticoid receptors (MR). Indeed, there was an up-regulation of MR mRNA observed in the susceptible group. Following there was an up-regulation of both NR2A and NR2B subunits in the LHb. These results indicated that MR and extra-synaptic NMDA receptors in LHb are critically engaged in the susceptibilities to stress. Furthermore, our findings propose potential therapeutic targets for alleviating stress-related symptoms.

侧缰核(LHb)在调节应激反应中的情绪反应中发挥着关键作用,其多动与抑郁症有关。最近有研究表明,长期的早期生活压力会导致啮齿类动物压力脆弱性的个体差异。然而,LHb的突触功能如何在对早期生活压力的易感性和恢复力之间变化仍然难以捉摸。在这项研究中,我们使用母体分离模型将具有不同应激脆弱性的动物分组,并研究LHb中的突触反应。我们的研究结果表明,易感组LHb的突触长期抑制(LTD)受损,突触外LTD增强。为了模拟应激情况下的突触改变,当给予皮质酮(一种应激激素)时,干预似乎通过激活盐皮质激素受体(MR)来损害对照组LHb中的突触LTD。事实上,在易感组中观察到MR mRNA的上调。随后,LHb中的NR2A和NR2B亚基均上调。这些结果表明,LHb中的MR和突触外NMDA受体与应激易感性密切相关。此外,我们的研究结果提出了缓解压力相关症状的潜在治疗靶点。
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引用次数: 0
Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model 创伤后应激障碍大鼠额叶基因表达谱的时程分析及与条件恐惧模型的比较
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-18 DOI: 10.1016/j.ynstr.2023.100569
Shao-Han Chang , Yao-Ming Chang , Huan-Yuan Chen , Fu-Zen Shaw , Bai-Chuang Shyu

Posttraumatic stress disorder (PTSD) is a complex disorder that involves physiological, emotional, and cognitive dysregulation that may occur after exposure to a life-threatening event. In contrast with the condition of learned fear with resilience to extinction, abnormal fear with impaired fear extinction and exaggeration are considered crucial factors for the pathological development of PTSD. The prefrontal cortex (mPFC) is considered a critical region of top-down control in fear regulation, which involves the modulation of fear expression and extinction. The pathological course of PTSD is usually chronic and persistent; a number of studies have indicated temporal progression in gene expression and phenotypes may be involved in PTSD pathology. In the current study, we use a well-established modified single-prolonged stress (SPS&FS) rat model to feature PTSD-like phenotypes and compared it with a footshock fear conditioning model (FS model); we collected the frontal tissue after extreme stress exposure or fear conditioning and extracted RNA for transcriptome-level gene sequencing. We compared the genetic profiling of the mPFC at early (<2 h after solely FS or SPS&FS exposure) and late (7 days after solely FS or SPS&FS exposure) stages in these two models. First, we identified temporal differences in the expressional patterns between these two models and found pathways such as protein synthesis factor eukaryotic initiation factor 2 (EIF2), transcription factor NF-E2-related factor 2 (NRF2)-mediated oxidative stress response, and acute phase responding signaling enriched in the early stage in both models with significant p-values. Furthermore, in the late stage, the sirtuin signaling pathway was enriched in both models; other pathways such as STAT3, cAMP, lipid metabolism, Gα signaling, and increased fear were especially enriched in the late stage of the SPS&FS model. However, pathways such as VDR/RXR, GP6, and PPAR signaling were activated significantly in the FS model's late stage. Last, the network analysis revealed the temporal dynamics of psychological disorder, the endocrine system, and also genes related to increased fear in the two models. This study could help elucidate the genetic temporal alteration and stage-specific pathways in these two models, as well as a better understanding of the transcriptome-level differences between them.

创伤后应激障碍(PTSD)是一种复杂的障碍,涉及生理、情绪和认知失调,可能发生在接触危及生命的事件后。与习得性恐惧具有消退韧性的情况相反,异常恐惧具有受损的恐惧消退和夸大被认为是PTSD病理发展的关键因素。前额叶皮层(mPFC)被认为是恐惧调节中自上而下控制的关键区域,涉及恐惧表达和消退的调节。创伤后应激障碍的病理过程通常是慢性和持续的;许多研究表明,基因表达和表型的时间进展可能与PTSD病理有关。在目前的研究中,我们使用了一种成熟的改良单次延长应激(SPS和FS)大鼠模型来表征PTSD样表型,并将其与脚跳恐惧条件模型(FS模型)进行了比较;我们收集了极端压力暴露或恐惧条件下的额叶组织,并提取RNA用于转录组水平的基因测序。我们比较了这两个模型中mPFC在早期(仅FS或SPS和FS暴露后<;2小时)和晚期(仅FS和SPS和FS接触后7天)阶段的遗传图谱。首先,我们确定了这两个模型之间表达模式的时间差异,并发现了蛋白质合成因子真核起始因子2(EIF2)、转录因子NF-E2相关因子2(NRF2)介导的氧化应激反应和急性期反应信号传导等途径,这些途径在两个模型的早期阶段都富集,具有显著的p值。此外,在晚期,sirtuin信号通路在两种模型中都富集;其他途径如STAT3、cAMP、脂质代谢、Gα信号传导和恐惧增加在SPS的晚期尤其丰富;FS模型。然而,在FS模型的晚期,VDR/RXR、GP6和PPAR信号通路被显著激活。最后,网络分析揭示了两个模型中心理障碍、内分泌系统的时间动态,以及与恐惧增加相关的基因。这项研究有助于阐明这两个模型中的遗传时间变化和阶段特异性途径,并更好地了解它们之间的转录组水平差异。
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引用次数: 0
Immersive virtual plus-maze to examine behavior and psychophysiological-related variables in young people with problematic alcohol and cannabis consumption 沉浸式虚拟加迷宫,以检查有问题的酒精和大麻消费的年轻人的行为和心理生理相关变量
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-01 DOI: 10.1016/j.ynstr.2023.100564
R.D. Moreno-Fernández , D. García-León , G. Peñas , R. Martín-Romero , F. Buades-Sitjar , P. Sampedro-Piquero

Stressful events appear to be risky situations that can precipitate the consumption of drugs. One way to recreate stressful contexts, in an ecological and controlled method, is through immersive virtual reality (VR). In our study, we designed the scenario of an elevated plus-maze (EPM) using VR, which is widely used in animal models to assess unconditioned anxiety. This task allowed us to analyze the behavioral, psychophysiological (heart rate and electrodermal activity), and hormonal response (salivary cortisol and Alpha-amylase) to this stressful situation in different moments (before VR task (anticipation), at the end of the task and 10 minutes later) in young people with problematic alcohol use (AU, n = 27), alcohol combined with cannabis consumption (AU + C, n = 10), as well as in a control group (CO, n = 33). Behavioral analysis revealed that the AU group displayed fewer entries into open arms than the CO group, whereas both experimental groups spent less time at the end of the open arms, as well as lower time by look down index compared to the CO group. Moreover, our VR EPM induced different psychophysiological responses in the different moments measured. In general, electrodermal activity seemed to be a good biomarker of recovery from a stressful situation, as once the exposure to the stressful situation ended, the AU + C group took longer to recover compared to the CO group. Regarding hormonal analyses, we observed a similar response pattern in all groups suggesting that our VR task was able to activate both stress systems. The alpha-amylase to cortisol ratio, proposed as a biomarker of stress systems dysregulation, was higher in the group of young participants with alcohol abuse. Interestingly, our VR EPM was able to induce a slight alcohol craving in both experimental groups. In conclusion, our results suggest certain subtle behavioral and physiological differences that could be used to detect young individuals at risk of future severe addictions or other stress-related comorbidities. Moreover, it could help us to develop prevention strategies focused on emotional, cognitive, and psychophysiological aspects.

压力事件似乎是有风险的情况,可以促使药物的消费。一种以生态和可控的方式重现压力环境的方法是通过沉浸式虚拟现实(VR)。在我们的研究中,我们使用VR设计了一个高架+迷宫(EPM)的场景,该场景在动物模型中广泛用于评估无条件焦虑。这项任务使我们能够分析有问题饮酒的年轻人(AU,n=27)在不同时刻(VR任务(预期)之前、任务结束时和10分钟后)对这种压力情况的行为、心理生理(心率和皮肤电活动)和激素反应(唾液皮质醇和α-淀粉酶),酒精与大麻消费相结合(AU+C,n=10),以及对照组(CO,n=33)。行为分析显示,与CO组相比,AU组张开双臂的次数更少,而两个实验组在张开双臂结束时花费的时间更少,并且通过向下看指数计算的时间也更低。此外,我们的VR EPM在测量的不同时刻诱导了不同的心理生理反应。总的来说,皮肤电活动似乎是从紧张状态中恢复的一个很好的生物标志物,因为一旦暴露于紧张状态结束,与CO组相比,AU+C组需要更长的时间才能恢复。关于激素分析,我们在所有组中都观察到了类似的反应模式,这表明我们的VR任务能够激活两个压力系统。作为压力系统失调的生物标志物,α-淀粉酶与皮质醇的比率在酗酒的年轻参与者中更高。有趣的是,我们的VR EPM能够在两个实验组中诱导轻微的酒精渴求。总之,我们的研究结果表明,某些细微的行为和生理差异可用于检测未来有严重成瘾或其他压力相关合并症风险的年轻人。此外,它可以帮助我们制定专注于情绪、认知和心理生理方面的预防策略。
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引用次数: 0
Sex and hormonal status influence the anxiolytic-like effect of oxytocin in mice 性别和荷尔蒙状态影响催产素在小鼠体内的抗焦虑作用
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-01 DOI: 10.1016/j.ynstr.2023.100567
Khalin E. Nisbett , Luis A. Gonzalez , Marina Teruel , C. Sue Carter , Leandro F. Vendruscolo , Michael E. Ragozzino , George F. Koob

Anxiety and depression are highly prevalent psychiatric disorders, affecting approximately 18% of the United States population. Evidence indicates that central oxytocin mediates social cognition, social bonding, and social anxiety. Although it is well-established that oxytocin ameliorates social deficits, less is known about the therapeutic effects of oxytocin in non-social contexts. We hypothesized that positive effects of oxytocin in social contexts are attributable to intrinsic effects of oxytocin on neural systems that are related to emotion regulation. The present study investigated the effect of intracerebroventricular (ICV) oxytocin administration (i.e., central action) on anxiety- and depression-like behavior in C57Bl/6J mice using non-social tests. Male and female mice received an ICV infusion of vehicle or oxytocin (100, 200, or 500 ng), then were tested in the elevated zero maze (for anxiety-like behavior) and the tail suspension test (for depression-like behavior). Oxytocin dose-dependently increased open zone occupancy and entries in the elevated zero maze and reduced immobility duration in the tail suspension test in both sexes. Oxytocin decreased anxiety and depression-like behavior in male and female mice. The observed effect of oxytocin on anxiolytic-like behavior appeared to be driven by the males. Given the smaller anxiolytic-like effect of oxytocin in the female mice and the established interaction between oxytocin and reproductive hormones (estrogen and progesterone), we also explored whether oxytocin sensitivity in females varies across estrous cycle phases and in ovariectomized females that were or were not supplemented with estrogen or progesterone. Oxytocin reduced anxiety-like behavior in female mice in proestrus/estrus, ovariectomized females (supplemented or not with estrogen or progesterone), but not females in metestrus/diestrus. Additionally, oxytocin reduced depression-like behavior in all groups tested with slight differences across the various hormonal statuses. These results suggest that the effect of oxytocin in depression- and anxiety-like behavior in mice can be influenced by sex and hormonal status.

焦虑和抑郁是非常普遍的精神疾病,影响着大约18%的美国人口。有证据表明,中枢催产素介导社会认知、社会联系和社会焦虑。尽管众所周知,催产素可以改善社交缺陷,但人们对催产素在非社交环境中的治疗效果知之甚少。我们假设催产素在社会环境中的积极作用可归因于催产素对与情绪调节相关的神经系统的内在影响。本研究使用非社会测试研究了侧脑室内(ICV)催产素给药(即中枢作用)对C57Bl/6J小鼠焦虑和抑郁样行为的影响。雄性和雌性小鼠接受ICV输注载体或催产素(100、200或500 ng),然后在升高的零迷宫中测试(焦虑样行为)和尾部悬吊测试(抑郁样行为)。在尾悬试验中,催产素剂量依赖性地增加了开放区的占有率和进入高架零迷宫的次数,并缩短了两性的不动时间。催产素降低雄性和雌性小鼠的焦虑和抑郁样行为。观察到的催产素对焦虑样行为的影响似乎是由雄性驱动的。考虑到催产素在雌性小鼠中较小的抗焦虑作用,以及催产素与生殖激素(雌激素和孕激素)之间已建立的相互作用,我们还探讨了雌性小鼠的催产素敏感性是否在发情周期阶段以及补充或未补充雌激素或孕激素的去卵巢雌性小鼠中有所不同。催产素降低了发情前期/发情期雌性小鼠、去卵巢雌性小鼠(补充或不补充雌激素或黄体酮)的焦虑样行为,但没有降低发情期/发情期的雌性小鼠的焦虑样表现。此外,催产素降低了所有测试组的抑郁样行为,不同激素状态之间略有差异。这些结果表明,催产素对小鼠抑郁和焦虑样行为的影响可能受到性别和激素状态的影响。
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引用次数: 0
Nucleus accumbens deep brain stimulation improves depressive-like behaviors through BDNF-mediated alterations in brain functional connectivity of dopaminergic pathway 伏隔核深部脑刺激通过BDNF介导的多巴胺能通路脑功能连接的改变改善抑郁样行为
IF 5 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-01 DOI: 10.1016/j.ynstr.2023.100566
Ssu-Ju Li , Yu-Chun Lo , Hsin-Yi Tseng , Sheng-Huang Lin , Chao-Hung Kuo , Ting-Chieh Chen , Ching-Wen Chang , Yao-Wen Liang , Yi-Chen Lin , Chih-Yu Wang , Tsai-Yu Cho , Mu-Hua Wang , Ching-Te Chen , You-Yin Chen

Major depressive disorder (MDD), a common psychiatric condition, adversely affects patients’ moods and quality of life. Despite the development of various treatments, many patients with MDD remain vulnerable and inadequately controlled. Since anhedonia is a feature of depression and there is evidence of leading to metabolic disorder, deep brain stimulation (DBS) to the nucleus accumbens (NAc) might be promising in modulating the dopaminergic pathway. To determine whether NAc-DBS alters glucose metabolism via mitochondrial alteration and neurogenesis and whether these changes increase neural plasticity that improves behavioral functions in a chronic social defeat stress (CSDS) mouse model. The Lab-designed MR-compatible neural probes were implanted in the bilateral NAc of C57BL/6 mice with and without CSDS, followed by DBS or sham stimulation. All animals underwent open-field and sucrose preference testing, and brain resting-state functional MRI analysis. Meanwhile, we checked the placement of neural probes in each mouse by T2 images. By confirming the placement location, mice with incorrect probe placement (the negative control group) showed no significant therapeutic effects in behavioral performance and functional connectivity (FC) after receiving electrical stimulation and were excluded from further analysis. Western blotting, seahorse metabolic analysis, and electron microscopy were further applied for the investigation of NAc-DBS. We found NAc-DBS restored emotional deficits in CSDS-subjected mice. Concurrent with behavioral amelioration, the CSDS DBS-on group exhibited enhanced FC in the dopaminergic pathway with increased expression of BDNF- and NeuN-positive cells increased dopamine D1 receptor, dopamine D2 receptors, and TH in the medial prefrontal cortex, NAc, ventral hippocampus, ventral tegmental area, and amygdala. Increased pAMPK/total AMPK and PGC-1α levels, functions of oxidative phosphorylation, and mitochondrial biogenesis were also observed after NAc-DBS treatment. Our findings demonstrate that NAc-DBS can promote BDNF expression, which alters FC and metabolic profile in the dopaminergic pathway, suggesting a potential strategy for ameliorating emotional processes in individuals with MDD.

重性抑郁障碍(MDD)是一种常见的精神疾病,会对患者的情绪和生活质量产生不利影响。尽管有各种治疗方法的发展,许多MDD患者仍然很脆弱,控制不足。由于快感缺乏是抑郁症的一个特征,并且有证据表明它会导致代谢紊乱,因此对伏隔核(NAc)的脑深部刺激(DBS)可能有希望调节多巴胺能通路。在慢性社交失败应激(CSDS)小鼠模型中,确定NAc-DBS是否通过线粒体改变和神经发生改变葡萄糖代谢,以及这些变化是否增加神经可塑性,从而改善行为功能。将实验室设计的MR兼容神经探针植入有和没有CSDS的C57BL/6小鼠的双侧NAc中,然后进行DBS或假刺激。所有动物都接受了开放视野和蔗糖偏好测试,以及大脑静息状态功能MRI分析。同时,我们通过T2图像检查了神经探针在每只小鼠中的位置。通过确认放置位置,探针放置不正确的小鼠(阴性对照组)在接受电刺激后,在行为表现和功能连接(FC)方面没有显示出显著的治疗效果,因此被排除在进一步分析之外。蛋白质印迹、海马代谢分析和电子显微镜进一步应用于NAc-DBS的研究。我们发现NAc-DBS恢复了CSDS小鼠的情绪缺陷。在行为改善的同时,CSDS-DBS组在多巴胺能通路中表现出FC增强,BDNF-和NeuN阳性细胞的表达增加,内侧前额叶皮层、NAc、腹侧海马、腹侧被盖区和杏仁核中的多巴胺D1受体、多巴胺D2受体和TH增加。NAc-DBS治疗后,还观察到pAMPK/总AMPK和PGC-1α水平增加、氧化磷酸化功能和线粒体生物发生。我们的研究结果表明,NAc-DBS可以促进BDNF的表达,从而改变多巴胺能通路中的FC和代谢谱,这表明了改善MDD患者情绪过程的潜在策略。
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引用次数: 0
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Neurobiology of Stress
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