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Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use. Metabotropic glutamatergic receptor 5 作为创伤与吸食大麻交汇的潜在生物标志物。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae044
Emily R Weiss, Margaret T Davis, Ruth H Asch, Deepak Cyril D'Souza, Ryan Cool, Irina Esterlis

Background: Metabotropic glutamate receptor 5 (mGlu5) dysregulation has been implicated in the pathophysiology of trauma-related psychopathology, and there are direct interactions between the endocannabinoid and glutamatergic systems. However, relationships between cannabis use (CU) and mGlu5 have not been directly investigated in trauma-related psychopathology.

Methods: Using positron emission tomography with [18F]FPEB, we examined relationships between CU status and mGlu5 availability in vivo in a cross-diagnostic sample of individuals with trauma-related psychopathology (n = 55). Specifically, we tested whether mGlu5 availability in frontolimbic regions of interest (ROIs; dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, hippocampus) differed as a function of CU status.

Results: Past-year CU (n = 22) was associated with 18.62%-19.12% higher mGlu5 availability in frontal and 14.24%-16.55% higher mGlu5 in limbic ROIs relative to participants with no recent CU. Similarly, past-month or monthly CU (n = 16) was associated with higher mGlu5 availability in frontal (18.05%-20.62%) and limbic (15.53%-16.83%) ROIs. mGlu5 availability in the orbitofrontal cortex and amygdala was negatively associated with depressive symptoms in the past-year CU group. In both CU groups, exploratory analyses showed negative correlations between mGlu5 availability and sadness across all ROIs and with perceptions of worthlessness and past failures (r's = -.47 to .66, P's = .006-.033) in the ventromedial prefrontal cortex. Participants with CU reported lower mean depressive symptoms (P's = .006-.037) relative to those without CU.

Conclusions: These findings have substantial implications for our understanding of interactions between CU and glutamatergic neurotransmission in trauma-related psychopathology, underscoring the need for treatment development efforts to consider the effects of CU in this population.

背景:代谢谷氨酸受体 5(mGlu5)失调被认为与创伤相关精神病理学的病理生理学有关,而且内源性大麻素与谷氨酸能系统之间存在直接的相互作用。然而,在创伤相关精神病理学中,大麻使用(CU)与 mGlu5 之间的关系尚未得到直接研究:方法:我们使用[18F]FPEB正电子发射断层扫描(PET),在创伤相关精神病理学交叉诊断样本(N = 55)中研究了CU状态与体内mGlu5可用性之间的关系。具体来说,我们测试了前边缘感兴趣区(ROIs;dlPFC、OFC、vmPFC、杏仁核、海马)的mGlu5可用性是否随CU状态而变化:与近期没有CU的参与者相比,过去一年的CU(n = 22)与额叶和边缘ROI的mGlu5可用性分别高出18.97%-19.12%和14.24%-16.55%有关。同样,过去一个月/每月的 CU(n = 16)与额叶(18.05-20.62%)和边缘(15.53-16.83%)ROI 中较高的 mGlu5 可用性相关。在两个CU组中,探索性分析表明,在所有ROI中,mGlu5可用性与悲伤情绪呈负相关,在vmPFC中,mGlu5可用性与无价值感和过去的失败呈负相关(r's = -.46-.66,p's = .006-.033)。与没有CU的参与者相比,有CU的参与者报告的抑郁症状平均值较低(p's = .019-.031):这些发现对我们理解 CU 与谷氨酸能神经递质之间在创伤相关精神病理学中的相互作用具有重要意义,并强调了在制定治疗方案时需要考虑 CU 对这一人群的影响。
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引用次数: 0
Dissociable Roles of the mPFC-to-VTA Pathway in the Control of Impulsive Action and Risk-Related Decision-Making in Roman High- and Low-Avoidance Rats. mPFC-VTA通路在控制罗马高回避和低回避大鼠冲动行为和风险决策中的不同作用
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae034
Ginna Urueña-Méndez, Chloé Arrondeau, Florian Marchessaux, Raphaël Goutaudier, Nathalie Ginovart

Background: Impulsive action and risk-related decision-making (RDM) are associated with various psychiatric disorders, including drug abuse. Both behavioral traits have also been linked to reduced frontocortical activity and alterations in dopamine function in the ventral tegmental area (VTA). However, despite direct projections from the medial prefrontal cortex (mPFC) to the VTA, the specific role of the mPFC-to-VTA pathway in controlling impulsive action and RDM remains unexplored.

Methods: We used positron emission tomography with [18F]-fluorodeoxyglucose to evaluate brain metabolic activity in Roman high- (RHA) and low-avoidance (RLA) rats, which exhibit innate differences in impulsive action and RDM. Notably, we used a viral-based double dissociation chemogenetic strategy to isolate, for the first time to our knowledge, the role of the mPFC-to-VTA pathway in controlling these behaviors. We selectively activated the mPFC-to-VTA pathway in RHA rats and inhibited it in RLA rats, assessing the effects on impulsive action and RDM in the rat gambling task.

Results: Our results showed that RHA rats displayed higher impulsive action, less optimal decision-making, and lower cortical activity than RLA rats at baseline. Chemogenetic activation of the mPFC-to-VTA pathway reduced impulsive action in RHA rats, whereas chemogenetic inhibition had the opposite effect in RLA rats. However, these manipulations did not affect RDM. Thus, by specifically targeting the mPFC-to-VTA pathway in a phenotype-dependent way, we reverted innate patterns of impulsive action but not RDM.

Conclusion: Our findings suggest a dissociable role of the mPFC-to-VTA pathway in impulsive action and RDM, highlighting its potential as a target for investigating impulsivity-related disorders.

背景:冲动行为和风险相关决策(RDM)与包括药物滥用在内的各种精神疾病有关。然而,尽管内侧前额叶皮层(mPFC)直接投射到 VTA,但 mPFC 到 VTA 通路在控制冲动行为和 RDM 方面的具体作用仍有待探索:方法:我们使用[18F]-氟脱氧葡萄糖正电子发射断层扫描评估了罗马高回避大鼠(RHA)和低回避大鼠(RLA)的大脑代谢活动,这两种大鼠在冲动行为和RDM方面表现出先天性差异。值得注意的是,我们使用了基于病毒的双重解离化学遗传学策略,首次分离出了 mPFC 到 VTA 通路在控制这些行为中的作用。我们选择性地激活了RHA大鼠的mPFC-VTA通路,抑制了RLA大鼠的mPFC-VTA通路,评估了其对大鼠赌博任务中冲动行为和RDM的影响:结果表明,与基线时的RLA大鼠相比,RHA大鼠表现出更高的冲动行为、更低的最优决策能力和更低的皮质活动。化学基因激活 mPFC 至 VTA 通路可减少 RHA 大鼠的冲动行为,而化学基因抑制则对 RLA 大鼠产生相反的效果。然而,这些操作并不影响冲动性行为障碍。因此,通过以表型依赖的方式特异性地靶向 mPFC 到 VTA 通路,我们恢复了冲动行为的先天模式,但没有恢复 RDM:我们的研究结果表明,mPFC-VTA通路在冲动行为和RDM中扮演着不同的角色,突出了其作为研究冲动相关疾病靶点的潜力。
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引用次数: 0
Smoking-Related Increases in Alcohol Outcomes and Preliminary Evidence for the Protective Effect of a Functional Nicotine Receptor Gene (CHRNA5) Variant on Alcohol Consumption in Individuals Without Alcohol Use Disorder. 与吸烟有关的酒精结果增加,以及功能性尼古丁受体基因(CHRNA5)变异对无酒精使用障碍者酒精消费的保护作用的初步证据。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae035
Shyamala K Venkatesh, Bethany L Stangl, Jia Yan, Natalia A Quijano Cardé, Elliot A Stein, Nancy Diazgranados, Melanie L Schwandt, Hui Sun, Reza Momenan, David Goldman, Mariella De Biasi, Vijay A Ramchandani

Background: Alcohol and nicotine interact with the nicotinic acetylcholine receptor system to alter reward-related responses, thereby contributing to the co-use and misuse of these drugs. A missense polymorphism rs16969968 (G>A) in the CHRNA5 gene has shown a strong association with nicotine-related phenotypes. However, less is known about the impact of this variant on alcohol-related phenotypes.

Methods: We assessed the main and interactive effect of smoking and rs16969968 polymorphism on alcohol consumption using the Alcohol Use Disorders Identification Test (AUDIT), Timeline Follow Back (TLFB), and Lifetime Drinking History (LDH) in 980 healthy adults without alcohol use disorder. We further examined the effect of the rs16969968 polymorphism on acute alcohol consumption using a free-access i.v. alcohol self-administration (IV-ASA) human laboratory paradigm in a subset of 153 nonsmoking participants. Subjective alcohol responses, alcohol sensitivity, and expectancy measures were compared between genotype groups (GG; AA/AG).

Results: We observed a significant association of smoking with AUDIT, TLFB, and LDH measures across genotype groups, with smokers showing higher scores compared with nonsmokers. Additionally, we found an association between genotype and TLFB-total drinks in the IV-ASA subset, with the GG group showing higher scores than AA/AG group. Relatedly, the alcohol negative expectancy score was significantly lower in the GG group than the AA/AG group.

Conclusions: Our findings underscore the association of smoking with alcohol measures. We found preliminary evidence for the protective effect of the functional CHRNA5 polymorphism on alcohol consumption and its association with increased negative alcohol expectancies, which highlights the substantial heterogeneity in alcohol responses.

背景:酒精和尼古丁与烟碱乙酰胆碱受体系统相互作用,改变与奖赏相关的反应,从而导致这些药物的共同使用和滥用。CHRNA5 基因中的一个错义多态性 rs16969968 (G>A) 与尼古丁相关表型有密切联系。然而,人们对这一变异对酒精相关表型的影响知之甚少:我们使用酒精使用障碍鉴定测试(AUDIT)、时间线回溯(TLFB)和终生饮酒史(LDH)评估了吸烟和 rs16969968 多态性对 980 名无酒精使用障碍的健康成年人饮酒的主要影响和交互影响。我们还进一步研究了 rs16969968 多态性对急性酒精消费的影响,在 153 名非吸烟者中采用了自由静脉注射酒精自我给药(IV-ASA)人体实验室范式。比较了不同基因型组(GG;AA/AG)的主观酒精反应、酒精敏感性和期望值:结果:我们观察到,在不同基因型组中,吸烟与 AUDIT、TLFB 和 LDH 的测量结果有明显的关联,吸烟者的得分高于不吸烟者。此外,我们还发现在 IV-ASA 亚组中,基因型与 TLFB-总饮酒量之间存在关联,GG 组的得分高于 AA/AG 组。与此相关的是,GG 组的酒精负期望值得分明显低于 AA/AG 组:我们的研究结果强调了吸烟与酒精测量之间的联系。我们发现了功能性 CHRNA5 多态性对酒精消费的保护作用及其与酒精负期望值增加相关的初步证据,这凸显了酒精反应的巨大异质性。
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引用次数: 0
Distinct Effects of Major Affective Disorder Diagnoses and Suicidal Symptom Severity on Inhibitory Control Function and Proinflammatory Cytokines: Single-Site Analysis of 800 Adolescents and Adults. 重度情感障碍诊断和自杀症状严重程度对抑制控制功能和促炎细胞因子的不同影响:对 800 名青少年和成年人的单点分析。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae043
Ya-Mei Bai, Mu-Hong Chen, Ju-Wei Hsu, Hsiang-Hsuan Huang, Jia-Shyun Jeng, Shih-Jen Tsai

Background: Inhibitory control function and proinflammatory cytokines play a role in the pathomechanisms underlying major affective disorders and suicidal behavior. However, the distinct or interactive effects of major affective disorders and suicidal symptom severity on inhibitory control function and proinflammatory cytokines remain unclear.

Methods: This study included 287 patients with bipolar disorder, 344 with major depressive disorder, and 169 healthy controls. We categorized the participants into 3 groups based on Montgomery-Åsberg Depression Rating Scale (MADRS) item 10 (suicidal symptoms) score: 0, 2 or 3, and ≥4. The participants completed the go/no-go task and the measurements for C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) levels.

Results: Errors in the go/no-go task were associated with suicidality (P = .040), regardless of the severity of suicidal symptoms and diagnosis. An elevated CRP level was especially associated with a Montgomery-Åsberg Depression Rating Scale item 10 score ≥4 (P = .001). An increased TNF-α level could distinguish bipolar disorder from major depressive disorder (P < .001).

Discussion: Our study indicated the distinct effects of major affective disorder diagnosis and suicide symptom severity on inhibitory control function and CRP and TNF-α levels. Importantly, individuals with the poorest inhibitory control function and highest CRP levels had more severe suicidal symptoms.

背景:抑制控制功能和促炎细胞因子在重性情感障碍和自杀行为的病理机制中起着一定作用。然而,重性情感障碍和自杀症状严重程度对抑制控制功能和促炎细胞因子的不同影响或交互影响仍不清楚:这项研究包括 287 名双相情感障碍患者、344 名重度抑郁障碍患者和 169 名健康对照者。我们根据蒙哥马利-阿斯伯格抑郁量表(MADRS)第10项(自杀症状)的得分将参与者分为三组:0分、2分或3分以及≥4分。参与者完成了去/不去任务,并测量了C反应蛋白(CRP)和肿瘤坏死因子-α(TNF-α)的水平:结果:无论自杀症状和诊断的严重程度如何,去/不去任务中的错误都与自杀有关(p = .040)。CRP水平的升高与MADRS第10项得分≥4尤其相关(p = 0.001)。TNF-α水平的升高可将双相情感障碍与重度抑郁障碍区分开来(p < .001):我们的研究表明,重度情感障碍诊断和自杀症状严重程度对抑制控制功能、CRP和TNF-α水平有不同的影响。重要的是,抑制控制功能最差、CRP水平最高的个体具有更严重的自杀症状。
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引用次数: 0
Decreased Brain pH Correlated With Progression of Alzheimer Disease Neuropathology: A Systematic Review and Meta-Analyses of Postmortem Studies. 大脑 pH 值降低与阿尔茨海默氏症神经病理学进展的相关性:尸检研究的系统回顾和荟萃分析。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae047
Hideo Hagihara, Tsuyoshi Miyakawa

Background: Altered brain energy metabolism is implicated in Alzheimer disease (AD). Limited and conflicting studies on brain pH changes, indicative of metabolic alterations associated with neural activity, warrant a comprehensive investigation into their relevance in this neurodegenerative condition. Furthermore, the relationship between these pH changes and established AD neuropathological evaluations, such as Braak staging, remains unexplored.

Methods: We conducted quantitative meta-analyses on postmortem brain and cerebrospinal fluid pH in patients with AD and non-AD controls using publicly available demographic data. We collected raw pH data from studies in the NCBI GEO, PubMed, and Google Scholar databases.

Results: Our analysis of 20 datasets (723 patient samples and 524 control samples) using a random-effects model showed a significant decrease in brain and cerebrospinal fluid pH in patients compared with controls (Hedges' g = -0.57, P < .0001). This decrease remained significant after considering postmortem interval, age at death, and sex. Notably, pH levels were negatively correlated with Braak stage, indicated by the random-effects model of correlation coefficients from 15 datasets (292 patient samples and 159 control samples) (adjusted r = -0.26, P < .0001). Furthermore, brain pH enhanced the discriminative power of the APOEε4 allele, the most prevalent risk gene for AD, in distinguishing patients from controls in a meta-analysis of 4 combined datasets (95 patient samples and 87 control samples).

Conclusions: The significant decrease in brain pH in AD underlines its potential role in disease progression and diagnosis. This decrease, potentially reflecting neural hyperexcitation, could enhance our understanding of neurodegenerative pathology and aid in developing diagnostic strategies.

背景:大脑能量代谢的改变与阿尔茨海默病(AD)有关。大脑 pH 值的变化表明与神经活动相关的新陈代谢发生了改变,但有关大脑 pH 值变化的研究有限且相互矛盾,因此有必要对其与这种神经退行性疾病的相关性进行全面调查。此外,这些 pH 值变化与既定的 AD 神经病理学评估(如 Braak 分期)之间的关系仍未得到探讨:我们利用公开的人口统计学数据,对AD患者和非AD对照者死后大脑和脑脊液pH值进行了定量荟萃分析。我们从 NCBI GEO、PubMed 和 Google Scholar 数据库中的研究中收集了原始 pH 值数据:我们使用随机效应模型对 20 个数据集(723 个患者样本和 524 个对照组样本)进行了分析,结果显示,与对照组相比,患者大脑和脑脊液 pH 值显著下降(Hedges' g = -0.57,p < 0.0001)。在考虑了死后间隔时间、死亡年龄和性别因素后,这一下降仍然明显。值得注意的是,pH值与Braak分期呈负相关,15个数据集(292个患者样本和159个对照样本)的相关系数的随机效应模型表明了这一点(调整后的r = -0.26,p < 0.0001)。此外,在对四个综合数据集(95个患者样本和87个对照样本)的荟萃分析中,脑pH值增强了APOEε4等位基因(AD最常见的风险基因)在区分患者和对照组方面的鉴别力:结论:AD患者大脑pH值的显著下降突显了其在疾病进展和诊断中的潜在作用。这一下降可能反映了神经过度兴奋,可增进我们对神经退行性病理的了解,并有助于制定诊断策略。
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引用次数: 0
Differential impact of adolescent or adult stress on behavior and cortical parvalbumin interneurons and perineuronal nets in male and female mice 青春期或成年期应激对雌雄小鼠行为、皮层副视蛋白中间神经元和神经元周围网的不同影响
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-13 DOI: 10.1093/ijnp/pyae042
Thamyris Santos-Silva, Beatriz Kinchin Souza, Débora Akemi Endo Colodete, Lara Ramos Campos, Thaís Santos Almeida Lima¹, Francisco S Guimarães, Felipe V Gomes
Background Stress has become a prevalent public health concern, contributing to the rising prevalence of psychiatric disorders. Understanding stress impact considering critical variables, such as age, sex, and individual differences, is of utmost importance for developing effective intervention strategies. Methods Stress effects (daily footshocks for ten days) during adolescence (postnatal day, PND31–40) and adulthood (PND65–74) were investigated on behavioral outcomes and parvalbumin (PV)-expressing GABAergic interneurons and their associated perineuronal nets (PNNs) in the prefrontal cortex (PFC) of male and female mice five weeks post-stress. Results In adulthood, adolescent stress induced behavioral alterations in male mice, including anxiety-like behaviors, social deficits, cognitive impairments, and altered dopamine system responsivity. Applying integrated behavioral z-score analysis, we identified sex-specific differences in response to adolescent stress, with males displaying greater vulnerability than females. Furthermore, adolescent-stressed male mice showed a decrease PV+ and PNN+ cell numbers and PV+/PNN+ colocalization, while in females, adolescent stress reduced prefrontal PV+/PNN+ colocalization in the PFC. Further analysis identified distinct behavioral clusters, with certain females demonstrating resilience to adolescent stress-induced deficits in sociability and PV+ cell number. Adult stress in male and female mice did not cause long-lasting changes in behavior and PV+ and PNN+ cell number. Conclusion Our findings indicate that the timing of stress, sex and individual variabilities seem to be determinants for the development of behavioral changes associated with psychiatric disorders, particularly in male mice during adolescence.
背景 压力已成为一个普遍的公共健康问题,导致精神疾病的发病率不断上升。考虑到年龄、性别和个体差异等关键变量,了解压力的影响对于制定有效的干预策略至关重要。方法 研究了青春期(出生后31-40天,PND31-40)和成年期(PND65-74)应激对行为结果和雌雄小鼠应激后五周前额叶皮层(PFC)中表达GABA能的副神经元(PV)及其相关神经元周围网(PNN)的影响。结果 成年后,青春期应激会诱发雄性小鼠的行为改变,包括焦虑样行为、社交障碍、认知障碍和多巴胺系统反应性改变。通过综合行为Z-分数分析,我们发现了雄性小鼠对青春期应激反应的性别差异,雄性小鼠比雌性小鼠更容易受到青春期应激的影响。此外,青春期应激雄性小鼠的PV+和PNN+细胞数量以及PV+/PNN+共定位均有所减少,而雌性小鼠的青春期应激则减少了前额叶PFC中的PV+/PNN+共定位。进一步的分析发现了不同的行为集群,某些雌性小鼠对青春期应激诱导的交际能力和PV+细胞数量缺陷表现出恢复力。雄性和雌性小鼠的成年应激不会导致行为以及 PV+ 和 PNN+ 细胞数量的长期变化。结论 我们的研究结果表明,应激的时间、性别和个体差异似乎是与精神障碍相关的行为变化发展的决定因素,尤其是在青春期的雄性小鼠中。
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引用次数: 0
Investigating the Impact of IL-6 and CXCL8 on Neurodegeneration and Cognitive Decline in Alzheimer's Disease. 研究 IL-6 和 CXCL8 对阿尔茨海默病神经变性和认知能力下降的影响
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1093/ijnp/pyae038
Dongdong Jin, Min Zhang, Lei Shi, Hengfang Liu

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily affecting the elderly, characterized by severe cognitive impairment and memory loss. Emerging evidence suggests that neuroinflammation plays a significant role in AD pathogenesis, with cytokines like interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL8) contributing to the disease progression.

Methods: We utilized GEO datasets to identify IL-6 and CXCL8 as pivotal inflammatory markers in AD. In vitro experiments were conducted using SK-N-BE(2)-M17 and THP-1 cell lines treated with IL-6 and CXCL8 to model AD. Additionally, in vivo tests on Amyloid Precursor Protein/Presenilin 1 (APP/PS1) AD mouse models were performed to assess the impact of these cytokines on cognitive functions and brain pathology.

Results: The results indicated a significant decrease in cell viability, increased apoptosis, and elevated inflammatory factor secretion following IL-6 and CXCL8 treatment in vitro. In vivo, AD mouse models treated with these cytokines exhibited exacerbated emotional distress, decreased social interaction, impaired cognitive functions, and increased amyloid protein deposition in neural tissues.

Conclusions: The study highlights the detrimental effects of IL-6 and CXCL8 on neuronal health and cognitive functions in AD. These findings suggest that targeting these cytokines could offer potential therapeutic interventions for improving patient outcomes in Alzheimer's disease.

背景:阿尔茨海默病(AD)是一种主要影响老年人的进行性神经退行性疾病,其特征是严重的认知障碍和记忆丧失。新的证据表明,神经炎症在阿尔茨海默病的发病机制中起着重要作用,白细胞介素-6(IL-6)和C-X-C motif趋化因子配体8(CXCL8)等细胞因子有助于疾病的进展:我们利用 GEO 数据集确定了 IL-6 和 CXCL8 作为 AD 的关键炎症标记物。体外实验使用经IL-6和CXCL8处理的SK-N-BE(2)-M17和THP-1细胞系来模拟AD。此外,还对淀粉样前体蛋白/Presenilin 1(APP/PS1)AD小鼠模型进行了体内试验,以评估这些细胞因子对认知功能和大脑病理学的影响:结果表明,体外处理 IL-6 和 CXCL8 后,细胞活力明显降低,凋亡增加,炎症因子分泌增加。在体内,用这些细胞因子处理的AD小鼠模型表现出情绪困扰加剧、社会交往减少、认知功能受损以及神经组织中淀粉样蛋白沉积增加:该研究强调了IL-6和CXCL8对AD患者神经元健康和认知功能的不利影响。这些研究结果表明,针对这些细胞因子可提供潜在的治疗干预,改善阿尔茨海默病患者的预后。
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引用次数: 0
GluN2A: A Promising Target for Developing Novel Antidepressants. GluN2A:开发新型抗抑郁药物的前景看好的靶点。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-01 DOI: 10.1093/ijnp/pyae037
Gang Wang, Wang Qi, Qiu-Hua Liu, Wei Guan

Background: Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems regarding mental health care. It is now well established that N-methyl D-aspartate receptor (NMDAR) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS), and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated.

Methods: We reviewed several past studies to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression.

Results: These evidence suggests that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods.

Conclusions: Specific inhibition of the GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.

背景:抑郁症是一种异质性疾病,发病率和致残率都很高,给精神卫生保健带来了严重问题。目前,N-甲基-D-天冬氨酸受体(NMDARs)调节剂作为治疗抑郁症的潜在疗法正受到越来越多的关注,但人们对其作用机制的了解却相对较少。NMDARs 是谷氨酸门控离子通道,在中枢神经系统(CNS)中普遍表达,已被证明在兴奋性突触传递中发挥关键作用。神经元中功能性 NMDARs 的主要 Glu2N 亚基 GluN2A 参与了中枢神经系统的各种生理过程,并与焦虑、抑郁和精神分裂症等疾病相关。然而,GluN2A 在抑郁症病理生理学中的作用尚未阐明:方法:为了更好地了解 GluN2A 在抑郁症中的功能,我们回顾了过去的一些研究。此外,我们还总结了基于 GluN2A 表达调控的抑郁症发病机制,尤其是它与神经炎症和神经发生的相互作用,这一点已受到了相当多的关注,并与抑郁症的发病高度相关:这些证据表明,GluN2A 的过度表达会损害突触的结构和功能可塑性,从而导致抑郁症的发生。因此,这些知识对于利用药理学和分子方法开发针对 GluN2A 亚基的选择性拮抗剂至关重要:结论:特异性抑制 GluN2A NMDAR 亚基对慢性应激诱导的抑郁样行为有抵抗作用,使其成为开发新型抗抑郁药物的有前途的靶点。
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引用次数: 0
Catecholaminergic Modulation of Metacontrol Is Reflected by Changes in Aperiodic EEG Activity. 周期性脑电图活动的变化反映了儿茶酚胺能对代谢控制的调节作用
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 DOI: 10.1093/ijnp/pyae033
Yang Gao, Veit Roessner, Ann-Kathrin Stock, Moritz Mückschel, Lorenza Colzato, Bernhard Hommel, Christian Beste

Background: "Metacontrol" describes the ability to maintain an optimal balance between cognitive control styles that are either more persistent or more flexible. Recent studies have shown a link between metacontrol and aperiodic EEG patterns. The present study aimed to gain more insight into the neurobiological underpinnings of metacontrol by using methylphenidate (MPH), a compound known to increase postsynaptic catecholamine levels and modulate cortical noise.

Methods: In a double-blind, randomized, placebo-controlled study design, we investigated the effect of MPH (0.5 mg/kg) on aperiodic EEG activity during a flanker task in a sample of n = 25 neurotypical adults. To quantify cortical noise, we employed the fitting oscillations and one over f algorithm.

Results: Compared with placebo, MPH increased the aperiodic exponent, suggesting that it reduces cortical noise in 2 ways. First, it did so in a state-like fashion, as the main effect of the drug was visible and significant in both pre-trial and within-trial periods. Second, the electrode-specific analyses showed that the drug also affects specific processes by dampening the downregulation of noise in conditions requiring more control.

Conclusions: Our findings suggest that the aperiodic exponent provides a neural marker of metacontrol states and changes therein. Further, we propose that the effectiveness of medications targeting catecholaminergic signaling can be evaluated by studying changes of cortical noise, fostering the idea of using the quantification of cortical noise as an indicator in pharmacological treatment.

背景介绍"元控制 "描述的是在更持久或更灵活的认知控制方式之间保持最佳平衡的能力。最近的研究表明,元控制与非周期性脑电图模式之间存在联系。哌醋甲酯(MPH)是一种已知能提高突触后儿茶酚胺水平并调节皮层噪声的化合物,本研究旨在通过使用哌醋甲酯进一步了解元控制的神经生物学基础:在一项双盲、随机、安慰剂对照研究设计中,我们调查了哌醋甲酯(0.5 mg/kg)对神经畸形成人(n = 25)在侧翼任务中的非周期性脑电图活动的影响。为了量化皮层噪声,我们采用了 FOOOF(拟合振荡和一过 F)算法:与安慰剂相比,MPH 增加了非周期性指数,这表明它通过两种方式减少了皮质噪声:首先,它以一种类似状态的方式降低了噪声,因为药物的主效应在试验前和试验内都是明显和显著的。其次,针对特定电极的分析表明,在需要更多控制的条件下,药物还能抑制噪声的下调,从而影响特定过程:我们的研究结果表明,非周期性指数是元控制状态及其变化的神经标记。此外,我们还提出,可以通过研究皮质噪声的变化来评估针对儿茶酚胺能信号传导的药物的有效性;这也促进了将皮质噪声的量化作为药物治疗指标的想法。
{"title":"Catecholaminergic Modulation of Metacontrol Is Reflected by Changes in Aperiodic EEG Activity.","authors":"Yang Gao, Veit Roessner, Ann-Kathrin Stock, Moritz Mückschel, Lorenza Colzato, Bernhard Hommel, Christian Beste","doi":"10.1093/ijnp/pyae033","DOIUrl":"10.1093/ijnp/pyae033","url":null,"abstract":"<p><strong>Background: </strong>\"Metacontrol\" describes the ability to maintain an optimal balance between cognitive control styles that are either more persistent or more flexible. Recent studies have shown a link between metacontrol and aperiodic EEG patterns. The present study aimed to gain more insight into the neurobiological underpinnings of metacontrol by using methylphenidate (MPH), a compound known to increase postsynaptic catecholamine levels and modulate cortical noise.</p><p><strong>Methods: </strong>In a double-blind, randomized, placebo-controlled study design, we investigated the effect of MPH (0.5 mg/kg) on aperiodic EEG activity during a flanker task in a sample of n = 25 neurotypical adults. To quantify cortical noise, we employed the fitting oscillations and one over f algorithm.</p><p><strong>Results: </strong>Compared with placebo, MPH increased the aperiodic exponent, suggesting that it reduces cortical noise in 2 ways. First, it did so in a state-like fashion, as the main effect of the drug was visible and significant in both pre-trial and within-trial periods. Second, the electrode-specific analyses showed that the drug also affects specific processes by dampening the downregulation of noise in conditions requiring more control.</p><p><strong>Conclusions: </strong>Our findings suggest that the aperiodic exponent provides a neural marker of metacontrol states and changes therein. Further, we propose that the effectiveness of medications targeting catecholaminergic signaling can be evaluated by studying changes of cortical noise, fostering the idea of using the quantification of cortical noise as an indicator in pharmacological treatment.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Brain mGlu5 Is Linked to Cognition and Cigarette Smoking but Does Not Differ From Control in Early Abstinence From Chronic Methamphetamine Use. 大脑 mGlu5 与认知和吸烟有关,但在长期吸食甲基苯丙胺的早期戒断中与对照组没有差异。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-01 DOI: 10.1093/ijnp/pyae031
Megan N McClintick, Robert M Kessler, Mark A Mandelkern, Tarannom Mahmoudie, Daicia C Allen, Hilary Lachoff, Jean-Baptiste F Pochon, Dara G Ghahremani, Judah B Farahi, Edwin Partiai, Robert A Casillas, Larissa J Mooney, Andy C Dean, Edythe D London

Background: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance.

Methods: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested.

Results: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus.

Conclusion: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

背景:I组代谢谷氨酸受体亚型五(mGlu5)与动物甲基苯丙胺暴露和人类认知有关。由于甲基苯丙胺使用障碍(MUD)患者表现出认知缺陷,我们评估了MUD患者和对照组的mGlu5,并测试了其与认知表现的关联:正电子发射断层扫描测量了 mGlu5 的放射性示踪剂 [18F]FPEB 在 MUD 患者(戒断甲基苯丙胺至少两周,n = 14)和对照组(n = 14)大脑中的总分布容积(VT)。研究人员还进行了吸毒史问卷调查以及言语学习、空间工作记忆和执行功能测试。测试了 VT 与甲基苯丙胺使用、烟草使用和认知能力的关联:结果:MUD 参与者在整体或区域 VT 方面与对照组没有差异,甲基苯丙胺使用情况与 VT 没有相关性。与吸烟者相比,不吸烟者的VT明显高于吸烟者(主效应,p = 0.0041)。与对照组相比,MUD 参与者在雷伊听觉言语学习任务(RAVLT)和 Stroop 测试(分别为 p = 0.08 和 p = 0.13)上表现出不明显的弱点,效应大小为中等到较大,而在 SCAP 上的表现则明显低于对照组(p = 0.015)。在各组中,RAVLT表现与背外侧前额叶皮层(DLPFC)和额上回的VT相关:结论:禁欲 MUD 患者的大脑中没有 mGlu5 下调的证据,但 dlPFC 中的 VT 与言语学习相关,这表明针对 mGlu5 的药物可能会改善认知能力。
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引用次数: 0
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International Journal of Neuropsychopharmacology
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