Neurobiology of Stress最新文献_第3页

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

Neurobiology of Stress

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

Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children 产前暴露和细胞类型比例是畸形儿童和非畸形儿童 FKBP5 DNA 甲基化的主要驱动因素

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100687

Vera N. Karlbauer , Jade Martins , Monika Rex-Haffner , Susann Sauer , Simone Roeh , Katja Dittrich , Peggy Doerr , Heiko Klawitter , Sonja Entringer , Claudia Buss , Sibylle M. Winter , Christine Heim , Darina Czamara , Elisabeth B. Binder

DNA methylation in peripheral tissues may be a relevant biomarker of risk for developing mental disorders after exposure to early life adversity. Genes involved in HPA axis regulation, such as FKBP5, might play a key role. In this study, we aimed to identify the main drivers of salivary FKBP5 methylation in a cohort of 162 maltreated and non-maltreated children aged 3–5 years at two measurement timepoints. We combined data from a targeted bisulfite sequencing approach for fine-mapping 49 CpGs in regulatory regions of FKBP5 and epigenetic scores for exposure to alcohol, cigarette smoke, and glucocorticoids derived from the EPICv1 microarray.

Most variability of methylation in the FKBP5 locus was explained by estimated cell type proportions as well as epigenetic exposure scores, most prominently by the glucocorticoid exposure score. While not surviving correction for multiple testing, we replicated previously reported associations of FKBP5 methylation with CM. We also detected synergistic effects of both rs1360780 genotype and the glucocorticoid exposure score on FKBP5 hypomethylation. These effects were identified in the 3′TAD, a distal regulatory region of FKBP5 which is not extensively covered in Illumina arrays, emphasizing the need for fine mapping approaches. Additionally, the epigenetic glucocorticoid exposure score was associated with childhood maltreatment, maternal mental disorders, and pregnancy complications, thereby highlighting the role of glucocorticoid signaling in the epigenetic consequences of early adversity.

These results underscore the need to assess cell type heterogeneity in targeted assessments of DNA methylation and show the impact of exposures beyond just childhood maltreatment such as glucocorticoid exposure.

外周组织中的 DNA 甲基化可能是一种相关的生物标志物，可用于衡量早期生活逆境后罹患精神障碍的风险。参与 HPA 轴调控的基因（如 FKBP5）可能在其中发挥了关键作用。在这项研究中，我们的目的是在一组 162 名 3-5 岁受虐待和未受虐待的儿童中，在两个测量时间点找出唾液 FKBP5 甲基化的主要驱动因素。我们结合了来自靶向亚硫酸氢盐测序方法的数据和EPICv1微阵列得出的酒精、香烟烟雾和糖皮质激素暴露的表观遗传评分，对FKBP5基因座的49个CpGs进行了精细图谱分析。虽然没有通过多重检验校正，但我们重复了之前报道的 FKBP5 甲基化与 CM 的关系。我们还发现了 rs1360780 基因型和糖皮质激素暴露评分对 FKBP5 低甲基化的协同效应。这些效应是在 3′TAD 中发现的，该区域是 FKBP5 的远端调控区，Illumina 阵列并未广泛覆盖该区域，这就强调了精细绘图方法的必要性。此外，表观遗传学糖皮质激素暴露得分与童年虐待、孕产妇精神障碍和妊娠并发症有关，从而突出了糖皮质激素信号在早期逆境的表观遗传学后果中的作用。这些结果强调了在DNA甲基化的定向评估中评估细胞类型异质性的必要性，并显示了除童年虐待（如糖皮质激素暴露）以外的暴露的影响。

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引用次数: 0

Interaction between corticotropin-releasing factor, orexin, and dynorphin in the infralimbic cortex may mediate exacerbated alcohol-seeking behavior 下边缘皮层的促肾上腺皮质激素释放因子、奥曲肽和达诺啡素之间的相互作用可能是加剧酗酒行为的介导因素

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-11-01 DOI: 10.1016/j.ynstr.2024.100695

Francisco J. Flores-Ramirez , Jessica M. Illenberger , Rémi Martin-Fardon

A major challenge for the treatment of alcohol use disorder (AUD) is relapse to alcohol use, even after protracted periods of self-imposed abstinence. Stress significantly contributes to the chronic relapsing nature of AUD, given its long-lasting ability to elicit intense craving and precipitate relapse. As individuals transition to alcohol dependence, compensatory allostatic mechanisms result in insults to hypothalamic-pituitary-adrenal axis function, mediated by corticotropin-releasing factor (CRF), which is subsequently hypothesized to alter brain reward pathways, influence affect, elicit craving, and ultimately perpetuate problematic drinking and relapse vulnerability. Orexin (OX; also called hypocretin) plays a well-established role in regulating diverse physiological processes, including stress, and has been shown to interact with CRF. Interestingly, most hypothalamic cells that express Ox mRNA also express Pdyn mRNA. Both dynorphin and OX are located in the same synaptic vesicles, and they are co-released. The infralimbic cortex (IL) of the medial prefrontal cortex (mPFC) has emerged as being directly involved in the compulsive nature of alcohol consumption during dependence. The IL is a CRF-rich region that receives OX projections from the hypothalamus and where OX receptor mRNA has been detected. Although not thoroughly understood, anatomical and behavioral pharmacology data suggest that CRF, OX, and dynorphin may interact, particularly in the IL, and that functional interactions between these three systems in the IL may be critical for the etiology and pervasiveness of compulsive alcohol seeking in dependent subjects that may render them vulnerable to relapse. The present review presents evidence of the role of the IL in AUD and discusses functional interactions between CRF, OX, and dynorphin in this structure and how they are related to exacerbated alcohol drinking and seeking.

酒精使用障碍（AUD）治疗面临的一个主要挑战是酒精使用的复发，即使在长期自我戒酒之后也是如此。压力是导致 AUD 长期复发的重要原因，因为压力能够长期引发强烈的渴求并促使复发。当个体过渡到酒精依赖时，代偿性异位机制会导致下丘脑-垂体-肾上腺轴功能受到损伤，并由促肾上腺皮质激素释放因子（CRF）介导。促肾上腺皮质激素（OX，又称视网膜下视素）在调节包括压力在内的各种生理过程中发挥着公认的作用，并已被证明能与 CRF 相互作用。有趣的是，大多数表达 Ox mRNA 的下丘脑细胞也表达 Pdyn mRNA。达吗啡和 OX 位于相同的突触小泡中，并且它们会共同释放。内侧前额叶皮层（mPFC）的下边缘皮层（IL）已被认为直接参与了酒精依赖期的强迫性饮酒。内侧前额叶皮层是一个富含 CRF 的区域，可接收来自下丘脑的 OX 投射，在该区域已检测到 OX 受体 mRNA。尽管还不十分清楚，但解剖学和行为药理学数据表明，CRF、OX 和达因吗啡可能会相互作用，尤其是在 IL 中，而且 IL 中这三个系统之间的功能性相互作用可能对依赖性受试者强迫性饮酒的病因和普遍性至关重要，这可能使他们容易复发。本综述提供了IL在AUD中作用的证据，并讨论了CRF、OX和达因吗啡在该结构中的功能性相互作用，以及它们与酒精饮酒和酒精寻求的加剧之间的关系。

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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

Neurobiology of Stress

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

Neurobiology of Stress

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

Neurobiology of Stress

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

Neurobiology of Stress

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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引用次数: 0

Intra-BLA alteration of interneurons’ modulation of activity in rats, reveals a dissociation between effects on anxiety symptoms and extinction learning 大鼠神经元间活动调节的 BLA 内改变揭示了对焦虑症状和消退学习的不同影响

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-17 DOI: 10.1016/j.ynstr.2024.100681

Rinki Saha , Lisa-Sophie Wüstner , Darpan Chakraborty , Rachel Anunu , Silvia Mandel , Joyeeta Dutta Hazra , Martin Kriebel , Hansjuergen Volkmer , Hanoch Kaphzan , Gal Richter-Levin

The basolateral amygdala (BLA) is a dynamic brain region involved in emotional experiences and subject to long-term plasticity. The BLA also modulates activity, plasticity, and related behaviors associated with other brain regions, including the mPFC and hippocampus. Accordingly, intra-BLA plasticity can be expected to alter both BLA-dependent behaviors and behaviors mediated by other brain regions. Lasting intra-BLA plasticity may be considered a form of metaplasticity, since it will affect subsequent plasticity and response to challenges later on. Activity within the BLA is tightly modulated by GABAergic interneurons, and thus inducing lasting alteration of GABAergic modulation of principal neurons may have an impactful metaplastic effect on BLA functioning. Previously, we demonstrated that intra-BLA knockdown (KD) of neurofascin (NF) reduced GABAergic synapses exclusively at the axon initial segment (AIS). Here, by reducing the expression of the tyrosine kinase receptor ephrin A7 (EphA7), we selectively impaired the modulatory function of a different subpopulation of interneurons, specifically targeting the soma and proximal dendrites of principal neurons. This perturbation induced an expected reduction in the spontaneous inhibitory synaptic input and an increase in the excitatory spontaneous synaptic activity, most probably due to the reduction of inhibitory tone. Moreover, this increased synaptic activity was followed by a reduction in intrinsic excitability. While intra-BLA NF-KD resulted in impaired extinction learning, without increased symptoms of anxiety, intra-BLA reduction of EphA7 expression resulted in increased symptoms of anxiety, as measured in the elevated plus maze, but without affecting fear conditioning or extinction learning. These results confirm the role of the BLA and intra-BLA metaplasticity in stress-induced increased anxiety symptoms and in impaired fear extinction learning but reveals a difference in intra-BLA mechanisms involved. The results also confirm the contribution of GABAergic interneurons to these effects but indicate selective roles for different subpopulations of intra-BLA interneurons.

杏仁基底外侧（BLA）是一个动态脑区，参与情绪体验并具有长期可塑性。基底外侧杏仁核还能调节其他脑区的活动、可塑性和相关行为，包括前脑皮质和海马。因此，BLA内部的可塑性可望改变依赖于BLA的行为和由其他脑区介导的行为。BLA内的持久可塑性可被视为一种元可塑性，因为它将影响以后的可塑性和对挑战的反应。BLA内的活动受到GABA能中间神经元的严格调控，因此诱导持久改变GABA能对主要神经元的调控可能会对BLA的功能产生影响。此前，我们曾证实，在BLA内敲除（KD）神经瀑蛋白（NF）会减少GABA能突触，而这种突触只出现在轴突起始节段（AIS）。在这里，通过减少酪氨酸激酶受体ephrin A7（EphA7）的表达，我们选择性地损害了不同亚群中间神经元的调节功能，特别是针对主神经元的体节和近端树突。这种扰动引起了自发抑制性突触输入的预期减少和兴奋性自发突触活动的增加，这很可能是由于抑制张力的降低。此外，突触活动增加后，内在兴奋性也随之降低。BLA内的NF-KD会导致消减学习受损，但不会增加焦虑症状，而BLA内减少EphA7的表达会导致焦虑症状增加，这是在高架加迷宫中测得的结果，但不会影响恐惧条件反射或消减学习。这些结果证实了BLA和BLA内变态反应在应激诱导的焦虑症状加重和恐惧消退学习受损中的作用，但揭示了BLA内机制的不同。这些结果还证实了GABA能中间神经元对这些效应的贡献，但表明了BLA内中间神经元不同亚群的选择性作用。

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引用次数: 0

Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation – Relevance to psychiatric and neurodevelopmental illness, and implications for treatment 社会隔离诱发慢性压力后大鼠前额叶皮层的转录组分析--与精神病和神经发育疾病的相关性以及对治疗的影响

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-17 DOI: 10.1016/j.ynstr.2024.100679

Jen-Yin Goh , Patricia Rueda , Joy Taylor , Alex Rathbone , Daniel Scott , Christopher J. Langmead , Kevin C.F. Fone , Gregory D. Stewart , Madeleine V. King

Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22–24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (Hrh3, Snca and Sod1) and agonists or activators for products of six of these down-regulated DEGs (Chrm4, Klf2, Lrrk2, Nr4a1, Nr4a3 and Prkca). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to Hrh3, Sod1, Chrm4, Lrrk2, Nr4a1 and Prkca were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.

社会隔离是导致精神疾病的一个既定风险因素，随着SARS-CoV-2的传播，这一问题日益受到关注。我们利用 RNA 测序（RNA-Seq）技术对隔离饲养大鼠前额叶皮层（PFC）的转录组变化进行了无偏见的评估。为了深入了解这种操作对研究人类疾病的意义，我们将差异表达基因（DEGs）和富集的生物功能与精神疾病和神经发育疾病患者的死后额叶皮层组织数据集进行了比较。16只雄性Sprague-Dawley大鼠从出生后第22-24天断奶到收集额叶皮质组织进行RNA-Seq分析（第64-66天）期间，每4只一组或单独饲养。我们在分离物中共鉴定出 183 个 DEGs，其中 128 个与压力相关精神疾病和/或具有社交缺陷的神经发育状况患者的 PFC 组织中的 DEGs 一致。71个编码蛋白被基因-药物相互作用数据库归类为可药用蛋白。有趣的是，其中三个上调 DEGs（Hrh3、Snca 和 Sod1）的产物有拮抗剂或抑制剂，六个下调 DEGs（Chrm4、Klf2、Lrrk2、Nr4a1、Nr4a3 和 Prkca）的产物有激动剂或激活剂。其中一些已经进行了临床前和临床评估，其余的可能需要进行研究。通过定量反转录聚合酶链反应 (qRT-PCR)，Hrh3、Sod1、Chrm4、Lrrk2、Nr4a1 和 Prkca 的变化在十六只雄性 Sprague-Dawley 大鼠的独立队列中得到了复制。我们的研究结果支持继续使用断奶后隔离饲养来研究应激相关疾病的神经生物学并评估治疗目标。

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引用次数: 0

Cholecystokinin-expressing interneurons mediated inhibitory transmission and plasticity in basolateral amygdala modulate stress-induced anxiety-like behaviors in mice 胆囊收缩素表达的中间神经元介导的杏仁核基底外侧抑制性传导和可塑性调节小鼠应激诱发的焦虑样行为

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-16 DOI: 10.1016/j.ynstr.2024.100680

Wei Fang , Xi Chen , Jufang He

The basolateral amygdala (BLA) hyperactivity has been implicated in the pathophysiology of anxiety disorders. We recently found that enhancing inhibitory transmission in BLA by chemo-genetic activation of local interneurons (INs) can reduce stress-induced anxiety-like behaviors in mice. Cholecystokinin interneurons (CCK-INs) are a major part of INs in BLA. It remains unknown whether CCK-INs modulated inhibition in BLA can mediate anxiety. In the present study, we found that BLA CCK-INs project extensively to most local excitatory neurons. Activating these CCK-INs using chemo-genetics and optogenetics can both effectively suppress electrical-induced neuronal activity within the BLA. Additionally, we observed that direct and sustained activation of CCK-INs within the BLA via chemo-genetics can mitigate stress-induced anxiety-like behaviors in mice and reduce stress-induced hyperactivity within the BLA itself. Furthermore, augmenting inhibitory plasticity within the BLA through a brief, 10-min high-frequency laser stimulation (HFLS) of CCK-INs also reduce stress-induced anxiety-like behaviors in mice. Collectively, these findings underscore the pivotal role of BLA CCK-IN-mediated inhibitory transmission and plasticity in modulating anxiety.

杏仁基底外侧（BLA）的过度活跃与焦虑症的病理生理学有关。我们最近发现，通过化学基因激活局部中间神经元（INs）来增强杏仁基底外侧的抑制性传导，可以减少小鼠由压力诱发的焦虑样行为。胆囊收缩素中间神经元（CCK-INs）是BLA中INs的主要组成部分。CCK-INs调节BLA中的抑制作用是否能介导焦虑仍是一个未知数。在本研究中，我们发现 BLA CCK-INs 广泛投射到大多数局部兴奋性神经元。利用化学遗传学和光遗传学激活这些 CCK-INs 都能有效抑制 BLA 内电诱导的神经元活动。此外，我们还观察到，通过化学遗传学直接、持续地激活 BLA 内的 CCK-INs 可以减轻应激诱导的小鼠焦虑样行为，并降低应激诱导的 BLA 自身的过度活跃性。此外，通过对CCK-INs进行10分钟的短暂高频激光刺激（HFLS）来增强BLA内的抑制可塑性，也能减少小鼠应激诱发的焦虑样行为。总之，这些发现强调了BLA CCK-IN介导的抑制性传递和可塑性在调节焦虑中的关键作用。

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引用次数: 0