Biological psychiatry global open science最新文献

英文中文

Integrated Long Noncoding RNA and Messenger RNA Expression Analysis Identifies Molecules Specifically Associated With Resiliency and Susceptibility to Depression and Antidepressant Response 综合长非编码 RNA 和 mRNA 表达分析确定与抑郁症的恢复力和易感性以及抗抑郁药反应特别相关的分子

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2024-07-20 DOI: 10.1016/j.bpsgos.2024.100365

Qingzhong Wang , Huizhen Wang , Yogesh Dwivedi

Background

Depression involves maladaptive processes impairing an individual’s ability to interface with the environment appropriately. Long noncoding RNAs (lncRNAs) are gaining traction for their role in higher-order brain functioning. Recently, we reported that lncRNA coexpression modules may underlie abnormal responses to stress in rats showing depression-like behavior. The current study explored the global expression regulation of lncRNAs and messenger RNAs (mRNAs) in the hippocampus of rats showing susceptibility (learned helplessness [LH]) or resiliency (non-LH) to depression and fluoxetine response to LH (LH+FLX).

Methods

Multiple comparison analysis was performed with an analysis of variance via the aov and summary function in the R platform to identify the differential expression of mRNAs and lncRNAs among LH, non-LH, tested control, and LH+FLX groups. Weighted gene coexpression network analysis was used to identify distinctive modules and pathways associated with each phenotype. A machine learning analysis was conducted to screen the critical target genes. Based on the combined analysis, the regulatory effects of lncRNAs on mRNA expression were explored.

Results

Multiple comparison analyses revealed differentially expressed mRNAs and lncRNAs with each phenotype. Integrated bioinformatics analysis identified novel transcripts, specific modules, and regulatory pairs of mRNA-lncRNA in each phenotype. In addition, the machine learning approach predicted lncRNA-regulated Spp2 and Olr25 genes in developing LH behavior, whereas joint analysis of mRNA-lncRNA pairs identified Mboat7, Lmod1, Il18, and Rfx5 genes in depression-like behavior and Adam6 and Tpra1 in antidepressant response.

Conclusions

The study shows a novel role for lncRNAs in the development of specific depression phenotypes and in identifying newer targets for therapeutic development.

背景抑郁症涉及不适应过程，损害了个体与环境适当互动的能力。长非编码 RNA（lncRNA）在高阶大脑功能中的作用越来越受到关注。最近，我们报道了lncRNA共表达模块可能是大鼠对压力的异常反应的基础，大鼠表现出类似抑郁症的行为。本研究探讨了对抑郁症易感性（习得性无助[LH]）或复原性（非LH）以及氟西汀对LH（LH+FLX）反应的大鼠海马中lncRNA和信使RNA（mRNA）的全局表达调控。方法通过 R 平台中的 aov 和摘要函数进行多重比较分析，以确定 LH 组、非 LH 组、测试对照组和 LH+FLX 组之间 mRNA 和 lncRNA 的差异表达。加权基因共表达网络分析用于识别与每种表型相关的独特模块和通路。通过机器学习分析筛选出关键的靶基因。结果多重对比分析发现了与每种表型相关的不同表达的 mRNA 和 lncRNA。综合生物信息学分析确定了每种表型中的新转录本、特定模块以及 mRNA-lncRNA 的调控对。此外，机器学习方法预测了受 lncRNA 调控的 Spp2 和 Olr25 基因在 LH 行为发展中的作用，而 mRNA-lncRNA 对的联合分析则确定了 Mboat7、Lmod1、Il18 和 Rfx5 基因在抑郁样行为中的作用，以及 Adam6 和 Tpra1 在抗抑郁反应中的作用。

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引用次数: 0

The Impacts of Adolescent Cannabinoid Exposure on Striatal Anxiety- and Depressive-Like Pathophysiology Are Prevented by the Antioxidant N-Acetylcysteine 抗氧化剂 N-乙酰半胱氨酸可预防青少年大麻素暴露对纹状体焦虑和抑郁样病理生理学的影响

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2024-07-20 DOI: 10.1016/j.bpsgos.2024.100361

Marta De Felice , Hanna J. Szkudlarek , Taygun C. Uzuneser , Mar Rodríguez-Ruiz , Mohammed H. Sarikahya , Mathusha Pusparajah , Juan Pablo Galindo Lazo , Shawn N. Whitehead , Ken K.-C. Yeung , Walter J. Rushlow , Steven R. Laviolette

Background

Exposure to Δ⁹-tetrahydrocannabinol (THC) is an established risk factor for later-life neuropsychiatric vulnerability, including mood- and anxiety-related symptoms. The psychotropic effects of THC on affect and anxiogenic behavioral phenomena are known to target the striatal network, particularly the nucleus accumbens, a neural region linked to mood and anxiety disorder pathophysiology. THC may increase neuroinflammatory responses via the redox system and dysregulate inhibitory and excitatory neural balance in various brain circuits, including the striatum. Thus, interventions that can induce antioxidant effects may counteract the neurodevelopmental impacts of THC exposure.

Methods

In the current study, we used an established preclinical adolescent rat model to examine the impacts of adolescent THC exposure on various behavioral, molecular, and neuronal biomarkers associated with increased mood and anxiety disorder vulnerability. Moreover, we investigated the protective properties of the antioxidant N-acetylcysteine against THC-related pathology.

Results

We demonstrated that adolescent THC exposure induced long-lasting anxiety- and depressive-like phenotypes concomitant with differential neuronal and molecular abnormalities in the two subregions of the nucleus accumbens, the shell and the core. In addition, we report for the first time that N-acetylcysteine can prevent THC-induced accumbal pathophysiology and associated behavioral abnormalities.

Conclusions

The preventive effects of this antioxidant intervention highlight the critical role of redox mechanisms underlying cannabinoid-induced neurodevelopmental pathology and identify a potential intervention strategy for the prevention and/or reversal of these pathophysiological sequelae.

背景接触Δ9-四氢大麻酚（THC）是导致晚年神经精神疾病（包括情绪和焦虑相关症状）的一个既定风险因素。众所周知，四氢大麻酚对情感和焦虑行为现象的精神作用以纹状体网络为目标，尤其是与情绪和焦虑症病理生理学相关的神经区域--伏隔核。四氢大麻酚可能会通过氧化还原系统增加神经炎症反应，并使包括纹状体在内的各种大脑回路中的抑制性和兴奋性神经平衡失调。因此，可诱导抗氧化作用的干预措施可能会抵消暴露于 THC 对神经发育的影响。方法在本研究中，我们使用了一个已建立的临床前青少年大鼠模型，研究青少年暴露于 THC 对与情绪和焦虑症易感性增加相关的各种行为、分子和神经元生物标志物的影响。此外，我们还研究了抗氧化剂 N-乙酰半胱氨酸对四氢大麻酚相关病理学的保护作用。结果我们证明，青少年暴露于四氢大麻酚会诱发长期焦虑和抑郁样表型，同时在伏隔核的两个亚区（外壳和核心）出现不同的神经元和分子异常。结论这种抗氧化剂干预的预防效果突出了氧化还原机制在大麻素诱导的神经发育病理学中的关键作用，并确定了预防和/或逆转这些病理生理后遗症的潜在干预策略。

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引用次数: 0

Computational Modeling Differentiates Learning Rate From Reward Sensitivity Deficits Produced by Early-Life Adversity in a Rodent Touchscreen Probabilistic Reward Task 在啮齿动物触摸屏概率奖励任务中，计算模型能区分学习率和早期生活逆境造成的奖励敏感性缺陷

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2024-07-20 DOI: 10.1016/j.bpsgos.2024.100362

Brian D. Kangas , Yuen-Siang Ang , Annabel K. Short , Tallie Z. Baram , Diego A. Pizzagalli

Background

Exposure to adversity, including unpredictable environments, during early life is associated with neuropsychiatric illness in adulthood. One common factor in this sequela is anhedonia, the loss of responsivity to previously reinforcing stimuli. To accelerate the development of new treatment strategies for anhedonic disorders induced by early-life adversity, animal models have been developed to capture critical features of early-life stress and the behavioral deficits that such stressors induce. We have previously shown that rats exposed to the limited bedding and nesting protocol exhibited blunted reward responsivity in the probabilistic reward task, a touchscreen-based task reverse translated from human studies.

Methods

To test the quantitative limits of this translational platform, we examined the ability of Bayesian computational modeling and probability analyses identical to those optimized in previous human studies to quantify the putative mechanisms that underlie these deficits with precision. Specifically, 2 parameters that have been shown to independently contribute to probabilistic reward task outcomes in patient populations, reward sensitivity and learning rate, were extracted, as were trial-by-trial probability analyses of choices as a function of the preceding trial.

Results

Significant deficits in reward sensitivity, but not learning rate, contributed to the anhedonic phenotypes in rats exposed to early-life adversity.

Conclusions

The current findings confirm and extend the translational value of these rodent models by verifying the effectiveness of computational modeling in distinguishing independent features of reward sensitivity and learning rate that complement the probabilistic reward task’s signal detection end points. Together, these metrics serve to objectively quantify reinforcement learning deficits associated with anhedonic phenotypes.

背景早年遭遇逆境，包括不可预测的环境，与成年后的神经精神疾病有关。这种后遗症的一个共同因素是失乐症，即对以前具有强化作用的刺激失去反应能力。为了加快开发新的治疗策略来治疗早年逆境引起的失认症，人们开发了动物模型来捕捉早年生活压力的关键特征以及这种压力诱发的行为缺陷。为了测试这一转化平台的定量限制，我们检验了贝叶斯计算建模和概率分析的能力，它们与之前人类研究中优化的方法相同，能够精确地量化导致这些缺陷的假定机制。结果奖赏敏感性的显著缺陷（而非学习率）导致了暴露于早期生活逆境中的大鼠的厌食表型。结论目前的研究结果证实了计算建模在区分奖赏敏感性和学习率的独立特征方面的有效性，这些特征补充了概率奖赏任务的信号检测终点，从而证实并扩展了这些啮齿类动物模型的转化价值。这些指标共同作用，客观地量化了与失认症表型相关的强化学习缺陷。

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引用次数: 0

Multiparametric Assays Capture Sex- and Environment-Dependent Modifiers of Behavioral Phenotypes in Autism Mouse Models 多参数测定捕捉自闭症小鼠模型行为表型的性别和环境依赖性修饰因子

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2024-07-20 DOI: 10.1016/j.bpsgos.2024.100366

Lucas Wahl, Arun Karim, Amy R. Hassett, Max van der Doe, Stephanie Dijkhuizen, Aleksandra Badura

Background

Current phenotyping approaches for murine autism models often focus on one selected behavioral feature, making the translation onto a spectrum of autistic characteristics in humans challenging. Furthermore, sex and environmental factors are rarely considered. Here, we aimed to capture the full spectrum of behavioral manifestations in 3 autism mouse models to develop a “behavioral fingerprint” that takes environmental and sex influences under consideration.

Methods

To this end, we employed a wide range of classical standardized behavioral tests and 2 multiparametric behavioral assays—the Live Mouse Tracker and Motion Sequencing—on male and female Shank2, Tsc1, and Purkinje cell–specific Tsc1 mutant mice raised in standard or enriched environments. Our aim was to integrate our high dimensional data into one single platform to classify differences in all experimental groups along dimensions with maximum discriminative power.

Results

Multiparametric behavioral assays enabled a more accurate classification of experimental groups than classical tests, and dimensionality reduction analysis demonstrated significant additional gains in classification accuracy, highlighting the presence of sex, environmental, and genotype differences in our experimental groups.

Conclusions

Together, our results provide a complete phenotypic description of all tested groups, suggesting that multiparametric assays can capture the entire spectrum of the heterogeneous phenotype in autism mouse models.

背景目前对小鼠自闭症模型进行表型的方法通常只关注一种选定的行为特征，这使得将其转化为人类自闭症特征谱系具有挑战性。此外，性别和环境因素也很少被考虑在内。为此，我们采用了一系列经典的标准化行为测试和两种多参数行为测定--活体小鼠追踪器和运动序列测定--在标准或富集环境中饲养的雌雄Shank2、Tsc1和浦肯野细胞特异性Tsc1突变小鼠。我们的目的是将高维数据整合到一个单一的平台上，以最大的鉴别力对所有实验组的差异进行分类。结果与传统测试相比，多参数行为测定能对实验组进行更准确的分类，降维分析表明分类准确性有了显著提高，突出了实验组中存在的性别、环境和基因型差异。结论我们的研究结果为所有测试组提供了完整的表型描述，表明多参数测定可以捕捉自闭症小鼠模型异质性表型的整个谱系。

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引用次数: 0

Effects of Cohabitation on Neurodevelopmental Outcomes in Rats Discordant for Neonatal Exposure to Sevoflurane 同居对七氟烷新生儿暴露不一致大鼠神经发育结果的影响

IF 4 Q2 NEUROSCIENCES

Biological psychiatry global open science

Pub Date : 2024-07-15 DOI: 10.1016/j.bpsgos.2024.100359

Ling-Sha Ju , Timothy Morey , Nikolaus Gravenstein , Barry Setlow , Christoph N. Seubert , Anatoly E. Martynyuk

Background

Having a sibling with autism spectrum disorder is a risk factor for autism spectrum disorder. We used a rat model in which the general anesthetic sevoflurane (SEVO) induces autism spectrum disorder–like neurodevelopmental abnormalities to test whether they can be transmitted via cohabitation.

Methods

Male rat pups from several litters were mixed and randomized to 3 new litter types: SEVO-exposed (SEVO), SEVO-unexposed (control), and equal numbers of SEVO-exposed and SEVO-unexposed (MIXED). After weaning, rats in experiment 1 were housed with littermates in SEVO, control, and MIXED (MIXED-exposed and MIXED-unexposed) pairs. In experiment 2, MIXED-exposed and MIXED-unexposed rats were paired with an unfamiliar naïve cagemate. Corticosterone levels, gene expression, central inflammatory markers (experiment 1), and behavior and corticosterone levels (experiment 2) were assessed in adulthood.

Results

In experiment 1, compared with control rats, SEVO rats exhibited abnormalities in the hypothalamic-pituitary-adrenal axis, inflammatory markers, oxytocin, arginine vasopressin, and DNA methylation systems. Almost all these measures in MIXED-exposed and MIXED-unexposed rats were statistically indistinguishable from and similar to those in SEVO or control rats, with most measures in MIXED rats being similar to those in SEVO rats. Experiment 2 showed that pairing with unfamiliar, naïve rats after weaning caused MIXED-unexposed and MIXED-exposed rats’ behavior to be no different from that of control and SEVO rats, respectively; however, the 2 groups of MIXED rats also did not differ from each other.

Conclusions

These findings suggest that neurodevelopmental abnormalities can be transmitted to otherwise healthy individuals through interactions during cohabitation; however, subsequent pairing with unfamiliar, naïve cohabitants may weaken this interaction effect.

背景有一个患有自闭症谱系障碍的兄弟姐妹是自闭症谱系障碍的一个危险因素。我们使用了一种大鼠模型，在该模型中，全身麻醉剂七氟醚（SEVO）会诱发类似自闭症谱系障碍的神经发育异常，以检验这些异常是否会通过同居传播：暴露于SEVO的大鼠（SEVO）、未暴露于SEVO的大鼠（对照组）以及同等数量的暴露于SEVO和未暴露于SEVO的大鼠（MIXED）。断奶后，实验 1 中的大鼠分别与 SEVO、对照组和 MIXED（暴露于 MIXED 和未暴露于 MIXED）配对的同窝鼠一起饲养。在实验 2 中，暴露于 MIXED 和未暴露于 MIXED 的大鼠与陌生的天真笼友配对。结果在实验 1 中，与对照组大鼠相比，SEVO 大鼠在下丘脑-垂体-肾上腺轴、炎症标记物、催产素、精氨酸加压素和 DNA 甲基化系统中表现出异常。在统计上，暴露于 MIXED 和未暴露于 MIXED 的大鼠的几乎所有这些指标都与 SEVO 或对照组大鼠的无差别且相似，MIXED 大鼠的大多数指标与 SEVO 大鼠相似。实验 2 显示，断奶后与不熟悉的天真大鼠配对会导致 MIXED 未暴露大鼠和 MIXED 暴露大鼠的行为分别与对照组大鼠和 SEVO 大鼠的行为没有差异；但是，两组 MIXED 大鼠之间也没有差异。

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Biological psychiatry global open science

Pub Date : 2024-07-01 DOI: 10.1016/S2667-1743(24)00062-4

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Guide for Authors 作者指南

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Biological psychiatry global open science

Pub Date : 2024-07-01 DOI: 10.1016/S2667-1743(24)00064-8

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Biological psychiatry global open science

Pub Date : 2024-07-01 DOI: 10.1016/S2667-1743(24)00061-2

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Targeting the Hippocampus in the Context of Trauma 在创伤背景下瞄准海马体

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Biological psychiatry global open science

Pub Date : 2024-07-01 DOI: 10.1016/j.bpsgos.2024.100335

Sanne J.H. van Rooij

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Misperceiving Momentum: Computational Mechanisms of Biased Striatal Reward Prediction Errors in Bipolar Disorder 误解动量：双相情感障碍患者纹状体奖励预测偏差的计算机制

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Biological psychiatry global open science

Pub Date : 2024-07-01 DOI: 10.1016/j.bpsgos.2024.100330

Hestia Moningka , Liam Mason

Background

Dysregulated reward processing and mood instability are core features of bipolar disorder that have largely been considered separately, with contradictory findings. We sought to test a mechanistic account that emphasizes an excessive tendency in bipolar disorder to enter recursive cycles in which reward perception is biased by signals that the environment may be changing for the better or worse.

Methods

Participants completed a probabilistic reward task with functional magnetic resonance imaging. Using an influential computational model, we ascertained whether participants with bipolar disorder (n = 21) showed greater striatal tracking of momentum-biased reward prediction errors (RPEs) than matched control participants (n = 21). We conducted psychophysiological interaction analyses to quantify the degree to which each group modulated functional connectivity between the ventral striatum and left anterior insula in response to fluctuations in momentum.

Results

In participants with bipolar disorder, but not control participants, the momentum-biased RPE model accounted for significant additional variance in striatal activity beyond a standard model of veridical RPEs. Compared with control participants, participants with bipolar disorder exhibited lower insular-striatal functional connectivity modulated by momentum-biased RPEs, an effect that was more pronounced as a function of current manic symptoms.

Conclusions

Consistent with existing theory, we found evidence that bipolar disorder is associated with a tendency for momentum to excessively bias striatal tracking of RPEs. We identified impaired insular-striatal connectivity as a possible locus for this propensity. We argue that computational psychiatric approaches that examine momentary shifts in reward and mood dynamics have strong potential for yielding new mechanistic insights and intervention targets.

背景奖赏处理失调和情绪不稳定是躁郁症的核心特征，人们大多将其分开考虑，但得出的结论却相互矛盾。我们试图检验一种机理解释，这种解释强调双相情感障碍患者过度倾向于进入递归循环，在这种循环中，奖赏感知会受到环境好坏变化信号的影响。利用一个有影响力的计算模型，我们确定了患有双相情感障碍的参与者（n = 21）是否比匹配的对照组参与者（n = 21）表现出更强的纹状体追踪动量偏倚奖赏预测错误（RPE）的能力。我们进行了心理生理学交互作用分析，以量化各组在多大程度上调节了腹侧纹状体和左侧前脑岛之间的功能连接，从而对动量波动做出反应。结果在双相情感障碍参与者（而非对照组参与者）中，动量偏倚 RPE 模型在真实 RPE 的标准模型之外解释了纹状体活动的显著额外差异。与对照组参与者相比，双相情感障碍参与者在动量偏倚 RPE 的调节下表现出较低的岛叶-纹状体功能连接性，这种效应在当前躁狂症状的作用下更为明显。结论与现有理论一致，我们发现双相情感障碍与动量过度偏倚纹状体 RPE 跟踪的倾向有关。我们发现岛叶-纹状体连通性受损可能是导致这种倾向的原因之一。我们认为，研究奖赏和情绪动态瞬时变化的计算精神病学方法极有可能产生新的机理认识和干预目标。

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