Progress in Neuro-Psychopharmacology & Biological Psychiatry最新文献_第6页

Enriched and deficient omega-3 PUFA exposure from gestation to adulthood modulates anxiety-related behavior and stress- and neuroplasticity-related brain gene expression in mice 在小鼠中，从妊娠期到成年期，omega-3多聚脂肪酸的丰富和缺乏会调节与焦虑相关的行为以及与压力和神经可塑性相关的大脑基因表达

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-09 DOI: 10.1016/j.pnpbp.2025.111581

Santiago Bianconi , Verónica I. Cantarelli , Juan E. Robledo Almonacid , Emilio Zingerling , Diego M. Weigandt , María del Carmen Baez , Marina F. Ponzio , Michael J. Williams , Helgi B. Schiöth , María E. Santillán , Graciela Stutz , Valeria P. Carlini

Omega-3 polyunsaturated fatty acids (PUFAs) are essential for brain development and function, affecting inflammation, neurotransmission, and neuroplasticity. These nutrients are associated with benefits in managing stress, sleep disorders, anxiety, and mild cognitive impairment. This study investigated the effects of chronic exposure to varying omega-3 PUFA levels, from gestation to adulthood, on behavioral and molecular aspects related to memory, anxiety, and depression in male mice. Dams received one of three diets: Control (soybean oil, 7 %), omega-3 Deficient (sunflower oil, 7 %), or omega-3 Enriched (4.2 % cod liver oil +2.8 % soybean oil). After weaning, the offspring continued on their respective diets until adulthood. The omega-3 Deficient diet led to increased locomotor activity, anxiety-like behavior, and a trend toward greater immobility time in the tail suspension test. It also upregulated the expression of Avp and its receptor Avpr1b within the hypothalamic-pituitary axis, suggesting a potential mechanistic link between omega-3 deficiency and mood disorders. In contrast, the Enriched group exhibited reduced locomotor activity and anxiolytic-like behavior in the elevated plus maze. At the molecular level, the Deficient diet downregulated Grin1, while the Enriched diet upregulated Creb1 in the hippocampus, providing insight into how omega-3 PUFAs influence cognitive processes. Chronic insufficient omega-3 consumption throughout development and adulthood may negatively affect anxiety- and depression-related responses, while high omega-3 intake may play a protective role in anxiety regulation. These findings deepen our understanding of the role of omega-3 PUFAs in affective and cognitive regulation, highlighting the significance of balanced intake to support mental health.

Omega-3多不饱和脂肪酸（PUFAs）对大脑发育和功能至关重要，影响炎症、神经传递和神经可塑性。这些营养物质有助于缓解压力、睡眠障碍、焦虑和轻度认知障碍。本研究调查了从妊娠期到成年期长期暴露于不同omega-3 PUFA水平对雄性小鼠记忆、焦虑和抑郁相关的行为和分子方面的影响。饲喂三种饲料中的一种：对照组（大豆油，7%）、缺乏欧米茄-3（葵花籽油，7%）或富含欧米茄-3（4.2%鱼肝油+ 2.8%大豆油）。断奶后，后代继续各自的饮食，直到成年。缺乏omega-3的饮食导致运动活动增加，焦虑样行为，并且在尾部悬挂测试中有更长的静止时间的趋势。它还上调了下丘脑-垂体轴中Avp及其受体Avpr1b的表达，表明omega-3缺乏与情绪障碍之间存在潜在的机制联系。相反，富集组在高加迷宫中表现出运动活动减少和焦虑样行为。在分子水平上，缺乏饮食组下调了Grin1，而强化饮食组上调了海马体中的Creb1，这为我们了解omega-3 PUFAs如何影响认知过程提供了线索。在整个发育和成年期间，长期摄入omega-3不足可能会对焦虑和抑郁相关反应产生负面影响，而高摄入omega-3可能在焦虑调节中发挥保护作用。这些发现加深了我们对omega-3 PUFAs在情感和认知调节中的作用的理解，强调了平衡摄入对支持心理健康的重要性。

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引用次数: 0

Population pharmacokinetic analysis for simultaneous fit of clozapine and norclozapine concentrations in adult psychiatric patients 成人精神病患者氯氮平和去氯氮平同时服用的人群药动学分析

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-09 DOI: 10.1016/j.pnpbp.2025.111583

Bojana Panić , Vera Lukić , Katarina Vučićević , Branislava Miljković , Srđan Milovanović , Marija Jovanović

Background

Clozapine (CLZ) exhibits a high potential for pharmacokinetic interactions due to its extensive and complex metabolism. Additionally, several patient-related factors contribute to the pharmacokinetic variability, making treatment optimization even more challenging. The goal of this study was to develop a parent-metabolite population pharmacokinetic model for CLZ and its primary metabolite norclozapine (NCLZ) and to evaluate sources of variability in a real-world clinical setting.

Methods

Data from routine therapeutic drug monitoring (TDM) of 126 adult in- and out-patients with psychiatric disorders were used for the analysis. A nonlinear mixed-effects modeling approach was applied for data analysis to simultaneously fit CLZ and NCLZ concentrations.

Results

A one-compartment model for the drug with an additional compartment for NCLZ was used to fit the concentration-time data. The population pharmacokinetic value of oral clearance for CLZ (CL/F) for a typical patient (female, non-smoker) was 26.4 L/h. Male sex and positive smoking status were associated with an increase in CL/F of 25.9 % and 29.2 %, respectively. The estimated value of metabolite clearance (CL_m/F) for a typical patient was 29.6 L/h, while male sex and valproic acid (VPA) use were associated with its increases for 45.1 % and 95.5 %, respectively.

Conclusion

The developed population pharmacokinetic model describes the simultaneous disposition of CLZ and NCLZ in adult psychiatric patients, accounting for impact of patient and co-therapy factors. In addition to the well-established effects of sex and smoking status on CLZ pharmacokinetics, the model characterizes the significant impact of VPA co-therapy, primarily on NCLZ disposition.

氯氮平（CLZ）由于其广泛而复杂的代谢而表现出很高的药代动力学相互作用潜力。此外，一些患者相关因素会导致药代动力学变异性，使治疗优化更具挑战性。本研究的目的是建立CLZ及其主要代谢物去氯氮平（NCLZ）的亲本代谢物群体药代动力学模型，并评估真实临床环境中变异性的来源。方法对126例成人精神障碍门诊患者的常规药物监测数据进行分析。采用非线性混合效应建模方法进行数据分析，同时拟合CLZ和NCLZ浓度。结果采用药物单室模型和NCLZ加室模型拟合浓度-时间数据。典型患者（女性，非吸烟者）口服CLZ清除率（CL/F）的人群药代动力学值为26.4 L/h。男性和吸烟阳性与CL/F分别增加25.9%和29.2%相关。典型患者代谢物清除率（CLm/F）的估计值为29.6 L/h，而男性和丙戊酸（VPA）的使用分别与其增加45.1%和95.5%相关。结论建立的人群药代动力学模型描述了成人精神病患者CLZ和NCLZ的同时处置，考虑了患者和共同治疗因素的影响。除了性别和吸烟状况对CLZ药代动力学的既定影响外，该模型还描述了VPA联合治疗的显著影响，主要是对NCLZ处置的影响。

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引用次数: 0

Corticosterone regulates the balance between freezing and rearing in defensive responses to predator threat 在面对捕食者威胁的防御反应中，皮质酮调节冻结和饲养之间的平衡。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-08 DOI: 10.1016/j.pnpbp.2025.111579

J.L. Baumbach , C.Y.Y. Mui , A.M. Leonetti , L.J. Martin

The hormonal stress response critically shapes how animals respond to threats. We examined how corticosterone (CORT) synthesis modulates defensive behaviors in mice exposed to the synthetic predator odor 2,4,5-trimethylthiazoline (TMT). Pharmacological inhibition of CORT synthesis using metyrapone reduced freezing and increased rearing during TMT exposure, without impairing threat recognition—evidenced by robust conditioned place aversion and context-specific freezing. We also found that freezing increased upon repeated TMT exposure, but this effect was blunted when CORT synthesis was blocked during the initial encounter. Furthermore, stress priming via restraint or footshock replicated the effects of prior TMT exposure, enhancing freezing and suppressing rearing. These findings suggest that while recognition of TMT's aversiveness remains intact without CORT, this hormone is essential for determining the qualitative and temporal dynamics of defensive responses. Our results reveal a key role for CORT in shaping behavioral flexibility during threat perception.

荷尔蒙应激反应决定了动物对威胁的反应。我们研究了皮质酮（CORT）合成如何调节暴露于捕食者气味2,4,5-三甲基噻唑啉（TMT）的小鼠的防御行为。在TMT暴露期间，使用甲替拉酮对CORT合成进行药物抑制可以减少冷冻和增加饲养，而不会损害威胁识别——这一点可以通过强大的条件性场所厌恶和情境特异性冷冻来证明。我们还发现，CORT与恐惧敏化有关：在反复接触TMT后，冻结会增加，但当CORT合成在初次接触时被阻断时，这种影响会减弱。此外，通过抑制或足部刺激的应激启动复制了先前TMT暴露的效果，增强了冻结并抑制了饲养。这些发现表明，尽管在没有CORT的情况下，对TMT厌恶的识别仍然是完整的，但这种激素对于确定防御反应的定性和时间动态至关重要。我们的研究结果揭示了CORT在威胁感知过程中塑造行为灵活性的关键作用。

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引用次数: 0

Broad transcriptomic effects of Egr1 knockdown in the mouse nucleus accumbens core and its role in cocaine locomotor sensitization 小鼠伏隔核Egr1敲低的广泛转录组效应及其在可卡因运动致敏中的作用。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-06 DOI: 10.1016/j.pnpbp.2025.111574

Yuki Nakamura , Mélody Labarchède , Tiago Mendes , Yukari Nakamura , Sophie Longueville , Giulia Albertini , Lucile Marion-Poll , Louise-Laure Mariani , Denis Hervé , Anne Roumier , Jean-Antoine Girault

Immediate early genes are widely used markers of neuronal activation, but their function in neurons is not well understood. We focused on the role of Egr1 in the nucleus accumbens core (NAc-c) in the long-lasting behavioral effects of cocaine, using an AAV expressing short hairpin RNA (Egr1-shRNA). Egr1 knockdown did not alter acute cocaine locomotor effects or conditioned place preference. In contrast, shEgr1 markedly decreased the locomotor sensitization induced by repeated cocaine administration. Because EGR1 is a transcription factor, we explored the transcriptomic alterations using RNAseq completed by RT-qPCR and protein studies. Egr1 knockdown modified the expression of numerous genes. Analysis of the upregulated genes revealed indirect activation of astrocytes and microglia evidenced by immunohistofluorescence, but shEgr1-induced dampening of cocaine sensitization was unaffected by minocycline, a microglia inhibitor. Proteasome genes were upregulated by shEgr1, possibly contributing to its functional consequences. Downregulated genes included potential EGR1 targets and comprised many genes characteristic of striatal neurons, including those coding signaling proteins (DARPP-32, CDK5 activator p35), glutamate ionotropic (NMDA NR1/2B, AMPA GluA1–3) and metabotropic (mGluR1/5) receptors, and postsynaptic proteins (PSD-95). We confirmed these alterations at the protein level and found decreased cocaine-induced phospho-Ser845-GluA1. Thus our study shows the broad transcriptional consequences of silencing Egr1 in neurons. It provides a mechanism by which Egr1 knockdown in the NAc-c can alter cocaine-induced locomotor sensitization, through downregulation of many genes including key components of glutamate neurotransmission. This broad role of EGR1 in regulating transcription provides clues about its function and role in learning, memory, and synaptic plasticity.

即时早期基因是广泛使用的神经元激活标记，但其在神经元中的功能尚不清楚。我们利用表达短发夹RNA （Egr1- shrna）的AAV，研究了伏隔核（nac -）中Egr1在可卡因长期行为效应中的作用。Egr1敲除不改变急性可卡因运动效应或条件位置偏好。相反，shEgr1显著降低了重复给药引起的运动致敏。由于EGR1是一种转录因子，我们利用RT-qPCR和蛋白质研究完成的RNAseq来探索转录组学改变。Egr1敲低修饰了许多基因的表达。对上调基因的分析显示，免疫组织荧光证实了星形胶质细胞和小胶质细胞的间接激活，但小胶质细胞抑制剂米诺环素不影响shegr1诱导的可卡因致敏抑制。蛋白酶体基因被shEgr1上调，可能有助于其功能后果。下调的基因包括潜在的EGR1靶点，包括纹状体神经元的许多特征基因，包括编码信号蛋白（DARPP-32， CDK5激活因子p35），谷氨酸嗜离子性（NMDA n1 / 2b, AMPA GluA1-3）和代谢（mGluR1/5）受体和突触后蛋白（PSD-95）。我们在蛋白水平上证实了这些改变，并发现可卡因诱导的磷酸化ser845 - glua1减少。因此，我们的研究显示了在神经元中沉默Egr1的广泛转录后果。它提供了一种机制，通过下调包括谷氨酸神经传递关键成分在内的许多基因，nac中的Egr1敲低可以改变可卡因诱导的运动敏化。EGR1在调节转录中的广泛作用为其在学习、记忆和突触可塑性中的功能和作用提供了线索。

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引用次数: 0

NMDA glutamate receptor polymorphisms modulate antipsychotic-induced hyperprolactinemia in schizophrenia NMDA谷氨酸受体多态性调节精神分裂症抗精神病药诱导的高催乳素血症

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-05 DOI: 10.1016/j.pnpbp.2025.111569

Olga Yu. Fedorenko , Evgeniya G. Poltavskaya , Elena G. Kornetova , Maxim B. Freidin , Anna V. Bocharova , Anastasiya S. Boiko , Vadim A. Stepanov , Nikolay A. Bokhan , Svetlana A. Ivanova , Kuzma Strelnikov

Dopamine receptor inhibition underlies both the therapeutic and adverse effects of antipsychotics, but the mechanisms modulating these effects in patients with schizophrenia remain incompletely understood. Hyperprolactinemia (HPRL), a direct consequence of D2 dopamine receptor blockade, provides a unique clinical model to investigate how genetic variation in glutamatergic signaling influences the downstream effects of dopaminergic disruption. We hypothesized that polymorphisms in GRIN2A and GRIN2B, encoding NMDA glutamate receptor subunits, modify the neuroendocrine consequences of dopamine receptor inhibition. By studying antipsychotic-induced HPRL, we aimed to demonstrate that NMDA receptor genetic variants shape the functional outcomes of dopaminergic perturbation.

In a cross-sectional analysis of 536 schizophrenia patients, we measured prolactin levels—a sensitive biomarker of D2 receptor inhibition—and genotyped 23 GRIN2A/GRIN2B variants. Logistic regression assessed gene-drug relationships while controlling for clinical covariates.

NMDA receptor genetic variation significantly influenced susceptibility to HPRL, with distinct effects observed between antipsychotic classes with the highest effect for the typical antipsychotics, which are D2 dopamine receptor antagonists. This demonstrates that glutamatergic genotypes predict interindividual variability in the neuroendocrine response to dopamine receptor blockade.

These results provide the first clinical evidence in support of the hypothesis that NMDA receptor polymorphisms modulate the effects of dopaminergic inhibition in schizophrenia. Beyond HPRL, this dopamine-glutamate relationships paradigm may extend to other clinical outcomes of antipsychotic treatment, including therapeutic response and neurological side effects. Our findings underscore the importance of glutamatergic pathways in determining the functional consequences of dopamine receptor targeting.

多巴胺受体抑制是抗精神病药物治疗和不良反应的基础，但在精神分裂症患者中调节这些作用的机制仍不完全清楚。高泌乳素血症（HPRL）是D2多巴胺受体阻断的直接后果，为研究谷氨酸信号的遗传变异如何影响多巴胺能破坏的下游效应提供了一个独特的临床模型。我们假设编码NMDA谷氨酸受体亚基的GRIN2A和GRIN2B的多态性改变了多巴胺受体抑制的神经内分泌后果。通过研究抗精神病药诱导的HPRL，我们旨在证明NMDA受体遗传变异影响多巴胺能扰动的功能结果。在对536名精神分裂症患者的横断面分析中，我们测量了催乳素水平（D2受体抑制的敏感生物标志物），并对23种GRIN2A/GRIN2B变体进行了基因分型。在控制临床协变量的同时，逻辑回归评估了基因与药物的关系。NMDA受体遗传变异显著影响对HPRL的易感性，在抗精神病药物类别之间观察到明显的影响，典型的抗精神病药物D2多巴胺受体拮抗剂效果最高。这表明谷氨酸能基因型预测神经内分泌对多巴胺受体阻断反应的个体间变异性。这些结果为NMDA受体多态性调节精神分裂症中多巴胺能抑制作用的假设提供了第一个临床证据。除了HPRL，这种多巴胺-谷氨酸关系范例可能扩展到抗精神病药物治疗的其他临床结果，包括治疗反应和神经系统副作用。我们的发现强调了谷氨酸能通路在确定多巴胺受体靶向的功能后果中的重要性。

{"title":"NMDA glutamate receptor polymorphisms modulate antipsychotic-induced hyperprolactinemia in schizophrenia","authors":"Olga Yu. Fedorenko , Evgeniya G. Poltavskaya , Elena G. Kornetova , Maxim B. Freidin , Anna V. Bocharova , Anastasiya S. Boiko , Vadim A. Stepanov , Nikolay A. Bokhan , Svetlana A. Ivanova , Kuzma Strelnikov","doi":"10.1016/j.pnpbp.2025.111569","DOIUrl":"10.1016/j.pnpbp.2025.111569","url":null,"abstract":"<div><div>Dopamine receptor inhibition underlies both the therapeutic and adverse effects of antipsychotics, but the mechanisms modulating these effects in patients with schizophrenia remain incompletely understood. Hyperprolactinemia (HPRL), a direct consequence of D2 dopamine receptor blockade, provides a unique clinical model to investigate how genetic variation in glutamatergic signaling influences the downstream effects of dopaminergic disruption. We hypothesized that polymorphisms in <em>GRIN2A</em> and <em>GRIN2B</em>, encoding NMDA glutamate receptor subunits, modify the neuroendocrine consequences of dopamine receptor inhibition. By studying antipsychotic-induced HPRL, we aimed to demonstrate that NMDA receptor genetic variants shape the functional outcomes of dopaminergic perturbation.</div><div>In a cross-sectional analysis of 536 schizophrenia patients, we measured prolactin levels—a sensitive biomarker of D2 receptor inhibition—and genotyped 23 <em>GRIN2A</em>/<em>GRIN2B</em> variants. Logistic regression assessed gene-drug relationships while controlling for clinical covariates.</div><div>NMDA receptor genetic variation significantly influenced susceptibility to HPRL, with distinct effects observed between antipsychotic classes with the highest effect for the typical antipsychotics, which are D2 dopamine receptor antagonists. This demonstrates that glutamatergic genotypes predict interindividual variability in the neuroendocrine response to dopamine receptor blockade.</div><div>These results provide the first clinical evidence in support of the hypothesis that NMDA receptor polymorphisms modulate the effects of dopaminergic inhibition in schizophrenia. Beyond HPRL, this dopamine-glutamate relationships paradigm may extend to other clinical outcomes of antipsychotic treatment, including therapeutic response and neurological side effects. Our findings underscore the importance of glutamatergic pathways in determining the functional consequences of dopamine receptor targeting.</div></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":"143 ","pages":"Article 111569"},"PeriodicalIF":3.9,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145684522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unraveling the altered trajectories of cerebellar gray matter volume in attention-deficit/hyperactivity disorder 揭示了注意缺陷/多动障碍患者小脑灰质体积的改变轨迹

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-04 DOI: 10.1016/j.pnpbp.2025.111577

Shuting Li , Leilei Ma , Yanpei Wang

Increasing evidence implicates atypical cerebellar development in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, the trajectories of cerebellar subregions from childhood into adulthood—and the impact of ADHD on those trajectories—remain unclear.

We analyzed the publicly available ADHD-200 dataset, comprising 871 participants aged 7.09–20.90 years (325 with ADHD, 546 typically developing [TD] controls). High-resolution T1-weighted images were processed with the automated CERES segmentation pipeline to obtain absolute gray matter volumes for the whole cerebellum and 12 lobular subdivisions (lobules I–VI, VIIB, VIIIA, VIIIB, IX–X, and crus I–II). Relative volume is also employed in this study, which refers to the relative proportion of absolute volume to intracranial volume. Age-related change was modeled with linear regression models that included diagnosis-by-age interactions. For absolute volume, a significant age-by-diagnosis interaction was observed in the right lobule I–II and bilateral lobule X. Follow-up analyses revealed that, compared with TD individuals, those with ADHD exhibited a steeper age-related increase in gray matter volume in these regions, indicating smaller volumes at younger ages and a more pronounced age-associated rise across the observed age range. For relative volume, significant age-by-diagnosis interaction effects were found in the bilateral lobule IV and bilateral crus II. Follow-up analyses indicated that both ADHD and TD individuals showed age-related decreases in gray matter volume; however, this decline was more pronounced in the ADHD group. Taken together, the divergent age-related patterns of absolute and relative gray matter volume suggest that overall intracranial volume expansion may lag behind cerebellar growth in ADHD, such that the relative cerebellar differences are proportionally less marked than the global brain differences.

These findings unravel normative and ADHD developmental trajectories of cerebellar gray matter volume from childhood through adulthood and provide a neuroanatomical framework for optimizing the cerebellum-focused prevention and intervention strategies in ADHD.

越来越多的证据表明，非典型小脑发育在注意缺陷/多动障碍（ADHD）的病理生理中起作用。然而，小脑亚区从童年到成年的轨迹——以及多动症对这些轨迹的影响——仍然不清楚。我们分析了公开可用的ADHD-200数据集，包括871名年龄在7.09-20.90岁之间的参与者（325名患有ADHD， 546名典型发展[TD]对照组）。采用自动化CERES分割管道对高分辨率t1加权图像进行处理，获得整个小脑和12个小叶细分（小叶I-VI、VIIB、viia、VIIB、IX-X和小腿I-II）的绝对灰质体积。本研究还采用了相对体积，即绝对体积与颅内体积的相对比例。年龄相关的变化用线性回归模型建模，其中包括年龄诊断的相互作用。对于绝对体积，在右侧小叶I-II和双侧小叶x中观察到显著的年龄与诊断的相互作用。随访分析显示，与TD个体相比，ADHD患者在这些区域表现出更急剧的年龄相关的灰质体积增加，这表明在年轻时体积较小，并且在观察的年龄范围内年龄相关的增加更为明显。对于相对体积，在双侧小叶IV和双侧小腿II中发现了显著的年龄诊断相互作用效应。随访分析表明，ADHD和TD患者的灰质体积均表现出与年龄相关的减少；然而，这种下降在多动症组更为明显。综上所述，绝对灰质体积和相对灰质体积的不同年龄相关模式表明，ADHD患者的整体颅内体积扩张可能落后于小脑的生长，因此小脑的相对差异在比例上不如整体大脑的差异那么显著。这些发现揭示了从儿童期到成年期小脑灰质体积的规范性和ADHD发展轨迹，并为优化小脑为重点的ADHD预防和干预策略提供了神经解剖学框架。

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引用次数: 0

Circulating levels of gut hormones in anorexia nervosa before and after short-term weight restoration 短期体重恢复前后神经性厌食症患者肠道激素循环水平的变化。

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-04 DOI: 10.1016/j.pnpbp.2025.111576

Theresa Kolb , Louisa Licht , Friederike I. Tam , Evelina M. Stender , Michaela Ohme , Alessandra Borsini , Stefan Ehrlich , Nikolaos Perakakis

Gastrointestinal hormones such as glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), glucagon, and glicentin are important regulators of appetite and glucose homeostasis. While agonists of GLP-1 and GIP receptors are approved treatments for type 2 diabetes and obesity, their role in anorexia nervosa (AN) remains largely unknown.

In this study, we measured fasting serum levels of GLP-1, GIP, glucagon, and glicentin in 80 female patients with AN before (acAN-T1) and after short-term weight restoration (acAN-T2) compared to 80 age-matched female healthy controls (HC).

GIP levels were higher (42.9%) in acAN-T1 than in HC, while GLP-1, glicentin, and glucagon showed no group differences. Additionally, acAN-T1 patients exhibited lower fasting glucose (-8.4%) and insulin (-42.6%) levels than HC. In acAN-T2, GIP, GLP-1, and glicentin levels decreased (-30.4%, -9.7%, −15.7 %, respectively), with only GIP normalizing. Glucose and insulin levels increased (4.5% and 41.4%, respectively), although they remained lower than in HC.

Importantly, changes in GIP levels after short-term weight restoration negatively correlated (r = -0.279) with changes in glucose levels. Furthermore, GIP levels in acAN-T1 were positively associated with disordered eating and depressive symptoms, independent of BMI-SDS.

These results reveal that GIP shows a distinct pattern of dysregulation and normalization in AN and link GIP levels to both glucose metabolism and symptom severity in AN. Thus, our findings support the rationale for investigating GIP receptor-targeted therapies in AN.

胃肠激素如胰高血糖素样肽-1 （GLP-1）、胃抑制肽（GIP）、胰高血糖素和胰甘肽素是食欲和葡萄糖稳态的重要调节因子。虽然GLP-1和GIP受体激动剂已被批准用于治疗2型糖尿病和肥胖症，但它们在神经性厌食症（AN）中的作用仍不清楚。在这项研究中，我们测量了80名女性AN患者在（acAN-T1）和短期体重恢复（acAN-T2）之前和之后的空腹血清GLP-1、GIP、胰高血糖素和glicentin水平，并与80名年龄匹配的女性健康对照组（HC）进行了比较。acAN-T1组的GIP水平高于HC组（42.9% %），而GLP-1、glicentin和胰高血糖素组间差异无统计学意义。此外，与HC相比，acAN-T1患者的空腹血糖（-8.4 %）和胰岛素（-42.6 %）水平更低。在acAN-T2中，GIP、GLP-1和glicentin水平下降（分别为-30.4 %、-9.7 %、- 15.7 %），只有GIP恢复正常。葡萄糖和胰岛素水平升高（分别为4.5% %和41.4% %），但仍低于HC组。重要的是，短期体重恢复后GIP水平的变化与血糖水平的变化呈负相关（r = -0.279）。此外，acAN-T1中的GIP水平与饮食失调和抑郁症状呈正相关，独立于BMI-SDS。这些结果表明，GIP在AN中表现出明显的失调和正常化模式，并将GIP水平与AN的糖代谢和症状严重程度联系起来。因此，我们的研究结果支持研究GIP受体靶向治疗AN的基本原理。

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引用次数: 0

More insights into disruption and decoupling of individual metabolic connectomes in Parkinson's disease 更多关于帕金森病中个体代谢连接体的破坏和解耦的见解

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-04 DOI: 10.1016/j.pnpbp.2025.111578

Song'an Shang , Daixin Li , Jun Yao , Weikai Li , Zhendong Guo , Xiang Lv , Lanlan Chen , Jie Shi , Yu-Chen Chen , Jing Ye

Purpose

Metabolic disturbances are hallmark pathological features of Parkinson's disease (PD) and can be noninvasively captured by arterial spin labeling (ASL). However, the metabolic pattern of disconnections beyond regional alterations remains scarcely documented. We aimed to comprehensively investigate metabolic impairments in PD at the individual network scale by utilizing abundant hemodynamic metrics.

Methods

The multi-delay (m-ASL) was employed to obtain corrected cerebral blood flow (CBF), arterial cerebral blood volume and arterial transit time from groups of PD patients and healthy controls (HCs). For the comparison or cross-modality analysis, the uncorrected CBF and grey matter volume were also acquired via the ASL approach with single post-labeling delay (s-ASL) and T1 sequences, respectively. Metabolic similarity network (MSN) based on perfusion data and structural similarity network (SSN) were constructed for each individual, followed by analyses of connectivity, topology, classification and coupling.

Results

Metabolic similarity networks in patients with PD belong to small-world connectomes but exhibit decreased global integration and local segregation at the global level. The impairments in nodal centralities, modular architectures and connectivity strengths were diverse among MSNs. m-ASL improved the diagnostic efficiency of CBF-MSN by the CBF correction and further optimized the classification performance via the integration of all MSNs. Decoupling of SSN-MSN presented pathologically increased coefficients within subnetworks, deriving from altered metabolic and structural connectivity.

Conclusion

Our study revealed the complex metabolic disconnections and SSN–MSN decoupling that underlie the complicated neurodegenerative process in PD, highlighting the clinical implications of m-ASL for comprehensive investigations of the metabolic pattern of disconnection syndromes.

代谢紊乱是帕金森病（PD）的标志性病理特征，可以通过动脉自旋标记（ASL）无创捕捉。然而，除了区域变化之外，断连的代谢模式几乎没有记录。我们旨在利用丰富的血流动力学指标，在个体网络尺度上全面研究帕金森病的代谢损伤。方法采用多延时法（m-ASL）测定PD患者组和健康对照（hc）的校正脑血流量（CBF）、动脉脑血容量和动脉运输时间。为了进行比较或交叉模态分析，还分别通过单标记后延迟（s-ASL）和T1序列的ASL方法获得未校正的脑血流和灰质体积。基于灌注数据构建个体代谢相似网络（MSN）和结构相似网络（SSN），并进行连通性、拓扑、分类和耦合分析。结果PD患者的代谢相似网络属于小世界连接体，但在整体水平上表现出整体整合和局部分离的减少。节点中心性、模块化架构和连接强度的损害在不同的msn中是不同的。m-ASL通过CBF校正提高了CBF- msn的诊断效率，并通过整合所有msn进一步优化了分类性能。由于代谢和结构连通性的改变，sns - msn的解耦在子网内表现出病理性的系数增加。结论我们的研究揭示了PD复杂的神经退行性过程背后的复杂代谢断开和SSN-MSN解耦合，强调了m-ASL在全面研究断开综合征代谢模式方面的临床意义。

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引用次数: 0

Agomelatine normalizes region-specific, diurnal mGluR5 dysregulation in a chronic mild stress rat model of depression 阿戈美拉汀在慢性轻度应激大鼠抑郁症模型中使区域特异性、每日mGluR5失调正常化

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-03 DOI: 10.1016/j.pnpbp.2025.111572

Celine Knudsen , Majken B. Thomsen , Kristoffer Højgaard , Sofie L. Christiansen , Ove Wiborg , Heidi K. Müller , Anne M. Landau , Betina Elfving

Desynchronization of circadian rhythms is a hallmark of major depressive disorder (MDD). Agomelatine is an atypical antidepressant that acts as a melatonin receptor agonist and serotonin receptor antagonist. It has shown efficacy in alleviating symptoms of MDD with a favorable side effect profile. In the brain, agomelatine also modulates the glutamatergic system and in the present study, we investigated the effects of chronic mild stress (CMS) and agomelatine treatment on metabotropic glutamate receptor 5 (mGluR5) and synaptic vesicle glycoprotein 2 A (SV2A) binding in the medial prefrontal cortex (mPFC) and hippocampus (HP) in postmortem brain tissue derived from male rats using autoradiography. To account for diurnal influences, assessments were conducted at two time points: light-on (ZT6) and light-off (ZT18). The sucrose consumption test classified animals into four groups: Control, anhedonic-like, agomelatine responders, and non-responders.

CMS increased mGluR5 binding in the prelimbic cortex of the mPFC during the light-on phase, an effect that was normalized by agomelatine treatment in responder rats. Agomelatine also reduced mGluR5 binding in the infralimbic cortex of the mPFC. No changes in mGluR5 binding were detected during the light-off phase or in the HP at either time point. Presynaptic density, assessed by SV2A levels, remained unchanged across all groups and time points.

These findings reveal significant region-specific and diurnal alterations in mGluR5, emphasizing the role of time-of-day dependent timing in regulating mGluR5 and its association with depressive-like behaviors. Furthermore, the selective normalization of mGluR5 by agomelatine in responders reinforces its potential as a targeted therapeutic approach for MDD.

昼夜节律的不同步是重度抑郁症（MDD）的一个标志。阿戈美拉汀是一种非典型抗抑郁药，作为褪黑激素受体激动剂和血清素受体拮抗剂。它已显示出缓解重度抑郁症症状的疗效，并具有良好的副作用。在大脑中，阿戈美拉汀也调节谷氨酸能系统，在本研究中，我们研究了慢性轻度应激（CMS）和阿戈美拉汀治疗对雄性大鼠死后脑组织中内侧前额叶皮层（mPFC）和海马（HP）中代谢性谷氨酸受体5 （mGluR5）和突触囊泡糖蛋白2a （SV2A）结合的影响。为了考虑昼夜影响，在两个时间点进行评估：开灯（ZT6）和熄灯（ZT18）。蔗糖消耗试验将动物分为四组：对照组、快感缺乏症、阿戈美拉汀应答者和无应答者。在光照阶段，CMS增加了mPFC前边缘皮层的mGluR5结合，在有反应的大鼠中，阿戈美拉汀治疗使这种效果正常化。阿戈美拉汀也降低了mGluR5在mPFC边缘下皮层的结合。mGluR5结合在熄灯期和HP中均未检测到变化。通过SV2A水平评估的突触前密度在所有组和时间点保持不变。这些发现揭示了mGluR5显著的区域特异性和昼夜变化，强调了在调节mGluR5及其与抑郁样行为的关联中，时间依赖的作用。此外，阿戈美拉汀对mGluR5的选择性正常化增强了其作为重度抑郁症靶向治疗方法的潜力。

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引用次数: 0

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Progress in Neuro-Psychopharmacology & Biological Psychiatry

Pub Date : 2025-12-03 DOI: 10.1016/j.pnpbp.2025.111571

Paweł Krukow , Natalia Kopiś-Posiej , Víctor Gutiérrez-de Pablo , Víctor Rodríguez-González , Carlos Gómez , Jesús Poza

Childhood adversity is considered a risk factor for neurocognitive development impairments in adulthood, although research evidence for this notion is rather inconclusive. This study aimed to examine the effects of childhood trauma on rudimentary cognitive processes and their neurophysiological underpinnings in non-clinical samples of young adults. Two groups were formed based on scores from the Childhood Trauma Questionnaire: a high early trauma group (high-ACE) and a low early trauma group (low-ACE). All participants performed two versions of the choice reaction time (RT) task, while their brain activity was recorded via electroencephalography (EEG) to reconstruct global network dynamics in response to displayed stimuli. Results indicated that the high-ACE group exhibited greater RTs intra-individual variability and altered functional connectivity (FC) dynamics compared to the low-ACE group, particularly in the short foreperiod block. Performance inconsistency indexes and FC strength values were significantly correlated in the high-ACE group (p < 0.05, Spearman's correlation, FDR-corrected). Our findings showed that adults with higher early trauma exposure demonstrate reduced network flexibility and difficulties in connectivity resource allocation, which is quantified by means of delayed and less dynamic FC responses following stimulus presentation. This study contributes to the understanding of how childhood adversities alter brain functional repertoire and basic cognitive mechanisms, including those that process non-affective stimuli.

童年的逆境被认为是成年后神经认知发育障碍的风险因素，尽管这一观点的研究证据相当不确定。本研究旨在研究儿童创伤对基本认知过程的影响及其在年轻人非临床样本中的神经生理基础。根据儿童创伤问卷得分分为两组：早期创伤高组（高ace）和早期创伤低组（低ace）。所有参与者都完成了两个版本的选择反应时间（RT）任务，同时通过脑电图（EEG）记录他们的大脑活动，以重建对显示刺激的全球网络动态反应。结果表明，与低ace组相比，高ace组表现出更大的RTs个体内变异性和改变的功能连接（FC）动力学，特别是在短前期阻滞。高ace组表现不一致指标与FC强度值显著相关（p < 0.05， Spearman相关，经fdr校正）。我们的研究结果表明，早期创伤暴露较高的成年人表现出较低的网络灵活性和连接资源分配困难，这可以通过刺激呈现后延迟和较低动态的FC反应来量化。这项研究有助于理解童年逆境如何改变大脑功能和基本认知机制，包括那些处理非情感刺激的机制。

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引用次数: 0