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Ketamine Prevents Inflammation-Induced Reduction of Human Hippocampal Neurogenesis via Inhibiting the Production of Neurotoxic Metabolites of the Kynurenine Pathway. 氯胺酮通过抑制神经毒性代谢产物犬尿氨酸途径的产生,防止炎症诱导的人类海马神经发生减少。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae041
Gargi Mandal, Madeline Kirkpatrick, Silvia Alboni, Nicole Mariani, Carmine M Pariante, Alessandra Borsini

Background: Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway in our well-established in vitro model of depression in a dish.

Methods: We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine's impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/mL) or IL-6 (50 pg/mL), alone or in combination with ketamine enantiomers arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM) or antidepressants sertraline (1 mM) or venlafaxine (1 mM).

Results: Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b- and IL-6-induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b-induced production of IL-2 and IL-13 by R-ketamine and of IL-1b-induced tumor necrosis factor-alpha by S-ketamine. Likewise, R-ketamine inhibited IL-6-induced production of IL-13, whereas S-ketamine inhibited IL-6-induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b-induced increases in indoleamine 2,3-dioxygenase expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6-induced kynurenine pathway activation.

Conclusions: Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties; however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine's antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalized therapeutic approaches for patients suffering from depression.

背景:了解氯胺酮的确切机制对于复制其快速抗抑郁效果而不诱发精神拟态变化至关重要。在此,我们将在已建立的体外抑郁模型中,探讨氯胺酮对映体的抗抑郁样作用是否通过防止细胞因子诱导的海马神经发生减少和神经毒性犬尿氨酸通路的激活而得到强调:我们使用胎儿海马祖细胞系(HPC0A07/03C)来研究氯胺酮对细胞因子诱导的体外神经发生减少的影响。用白细胞介素1β(IL-1b)(10纳克/毫升)或IL-6(50皮克/毫升)处理细胞,单独或与氯胺酮对映体、氯胺酮(R-氯胺酮,400毫微克)或氯胺酮(S-氯胺酮,400毫微克)或抗抑郁药舍曲林(1毫摩尔)或文拉法辛(1毫摩尔)联合使用:与抗抑郁药的作用相似,两种氯胺酮对映体都能防止IL-1b和IL-6诱导的神经发生减少和细胞凋亡增加。R-氯胺酮抑制了IL-1b诱导的IL-2和IL-13的产生,S-氯胺酮抑制了IL-1b诱导的肿瘤坏死因子-α(TNF-a)的产生。同样,R-氯胺酮能抑制 IL-6 诱导的 IL-13 的产生,而 S-氯胺酮则能抑制 IL-6 诱导的 IL-1b 和 IL-8。此外,R-和S-氯胺酮都能阻止IL-1b诱导的吲哚胺2,3-二氧化酶(IDO)表达的增加以及犬尿氨酸的产生,而犬尿氨酸反过来又能介导IL-1b对神经发生和细胞凋亡的不利影响。相比之下,R-和S-氯胺酮都不能阻止IL-6诱导的犬尿氨酸通路激活:结论:研究结果表明,R-和S-氯胺酮具有促进神经发生和抗炎的特性,但这仅在IL-1b的情况下通过抑制犬尿氨酸通路来实现。总之,这项研究加深了我们对氯胺酮在不同炎症表型下的抗抑郁作用机制的了解,最终将为抑郁症患者开发出更有效的个性化治疗方法。
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引用次数: 0
Evidence for the Contribution of the miR-206/BDNF Pathway in the Pathophysiology of Depression. miR-206/BDNF 通路在抑郁症病理生理学中的作用证据
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae039
Ya-Bin Zheng, Xiang Jin

Depression is a complex disorder with substantial impacts on individual health and has major public health implications. Depression results from complex interactions between genetic and environmental factors. Epigenetic mechanisms, including DNA methylation, microRNAs (miRNAs), and histone modifications, can produce heritable phenotypic changes without a change in DNA sequence and recently were proven to mediate lasting increases in the risk of depression following exposure to adverse life events. Of these, miRNAs are gaining attention for their role in the pathogenesis of many stress-associated mental disorders, including depression. One such miRNA is microRNA-206 (miR-206), which is a critical candidate for increasing the susceptibility to stress. Although miR-206 is thought to be a typical muscle-specific miRNA, it is expressed throughout the brain, particularly in the hippocampus and prefrontal cortex. Until now, only a few studies have been conducted on rodents to understand the role of miR-206 in stress-related abnormalities in neurogenesis. However, the precise underlying molecular mechanism of miR-206-mediated depression-like behaviors remains largely unknown. Here, we reviewed recent advances in the field of biomedical and clinical research on the role of miR-206 in the pathogenesis of depression from studies using different tissues and various experimental designs and described how abnormalities in miR-206 expression in these tissues can affect neuronal functions. Moreover, we focused on studies investigating the brain-derived neurotrophic factor (BDNF) as a functional target of miR-206, where miR-206 has been implicated in the pathogenesis of depression by suppressing the expression of the BDNF. In summary, these studies confirm the existence of a tight correlation between the pathogenesis of depression and the miR-206/BDNF pathway.

抑郁症是一种复杂的疾病,对个人健康有重大影响,对公共卫生也有重大影响。抑郁症是遗传因素和环境因素复杂相互作用的结果。表观遗传机制,包括 DNA 甲基化(DNAm)、microRNAs(miRNAs)和组蛋白修饰,可以在不改变 DNA 序列的情况下产生可遗传的表型变化,最近已被证实可在暴露于不良生活事件后介导抑郁症风险的持续增加。其中,miRNA 在包括抑郁症在内的许多与压力相关的精神疾病的发病机制中的作用日益受到关注。其中一种 miRNA 是 microRNA-206 (miR-206),它是增加压力易感性的关键候选因子。尽管 miR-206 被认为是一种典型的肌肉特异性 miRNA,但它在整个大脑中都有表达,尤其是在海马体和前额叶皮质(PFC)中。迄今为止,只有少数针对啮齿类动物的研究了解了它在与压力相关的神经发生异常中的作用。然而,miR-206 介导抑郁样行为的确切潜在分子机制在很大程度上仍不为人所知。在此,我们回顾了生物医学和临床研究领域关于 miR-206 在抑郁症发病机制中作用的最新进展,这些研究采用了不同的组织和不同的实验设计,并描述了 miR-206 在这些组织中的表达异常如何影响神经元功能。此外,我们还重点研究了将脑源性神经营养因子(BDNF)作为 miR-206 功能靶点的研究,在这些研究中,miR-206 通过抑制 BDNF 的表达被认为与抑郁症的发病机制有关。总之,这些研究证实了抑郁症的发病机制与 miR-206/BDNF 通路之间存在密切的相关性。
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引用次数: 0
GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine's Rapid-Acting Effects in Mice. 小鼠成体颗粒细胞上的 GluN2B 可调节(R,S)-氯胺酮的速效作用。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-01 DOI: 10.1093/ijnp/pyae036
Nicholas E Bulthuis, Josephine C McGowan, Liliana R Ladner, Christina T LaGamma, Sean C Lim, Claire X Shubeck, Rebecca A Brachman, Ezra Sydnor, Ina P Pavlova, Dong-Oh Seo, Michael R Drew, Christine A Denny

Background: Standard antidepressant treatments often take weeks to reach efficacy and are ineffective for many patients. (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be a rapid-acting antidepressant and to decrease depressive symptoms within hours of administration. While previous studies have shown the importance of the GluN2B subunit of the NMDA receptor on interneurons in the medial prefrontal cortex, no study to our knowledge has investigated the influence of GluN2B-expressing adult-born granule cells.

Methods: Here, we examined whether (R,S)-ketamine's efficacy depends on adult-born hippocampal neurons using a genetic strategy to selectively ablate the GluN2B subunit of the NMDA receptor from Nestin+ cells in male and female mice, tested across an array of standard behavioral assays.

Results: We report that in male mice, GluN2B expression on 6-week-old adult-born neurons is necessary for (R,S)-ketamine's effects on behavioral despair in the forced swim test and on hyponeophagia in the novelty suppressed feeding paradigm, as well on fear behavior following contextual fear conditioning. In female mice, GluN2B expression is necessary for effects on hyponeophagia in novelty suppressed feeding. These effects were not replicated when ablating GluN2B from 2-week-old adult-born neurons. We also find that ablating neurogenesis increases fear expression in contextual fear conditioning, which is buffered by (R,S)-ketamine administration.

Conclusions: In line with previous studies, these results suggest that 6-week-old adult-born hippocampal neurons expressing GluN2B partially modulate (R,S)-ketamine's rapid-acting effects. Future work targeting these 6-week-old adult-born neurons may prove beneficial for increasing the efficacy of (R,S)-ketamine.

背景:标准的抗抑郁治疗通常需要数周时间才能见效,对许多患者无效。(N-甲基-D-天冬氨酸(NMDA)拮抗剂--(R,S)-氯胺酮已被证明是一种速效抗抑郁剂,可在用药后数小时内减轻抑郁症状。以往的研究表明,NMDA 受体(NMDAR)的 GluN2B 亚基对内侧前额叶皮层(mPFC)的中间神经元非常重要,但还没有研究调查过表达 GluN2B 的成体颗粒细胞(abGCs)的影响。方法:在此,我们采用一种遗传策略,选择性地消减雄性和雌性小鼠 Nestin+ 细胞中的 NMDAR GluN2B 亚基,并通过一系列标准行为测定进行了测试,从而研究了(R,S)-氯胺酮的药效是否取决于这些成体海马神经元:我们报告说,在雄性小鼠中,(R,S)-氯胺酮对强迫游泳试验(FST)中的行为绝望和新奇性抑制摄食(NSF)范例中的食欲减退以及情境恐惧条件反射(CFC)后的恐惧行为的影响需要6周大的成体神经元上的GluN2B表达。在雌性小鼠中,GluN2B的表达是影响NSF食欲减退的必要条件。在消减 2 周大的成体神经元中的 GluN2B 时,这些效应并没有得到复制。我们还发现,消减神经发生会增加 CFC 中的恐惧表达,而服用(R,S)-氯胺酮可以缓冲恐惧表达:与之前的研究一致,这些结果表明,表达 GluN2B 的 6 周龄成体海马神经元部分调节了(R,S)-氯胺酮的速效作用。未来针对这些6周大的成神经元开展的工作可能会被证明有利于提高(R,S)-氯胺酮的疗效。
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引用次数: 0
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。
{"title":"Metabotropic Glutamate Receptor 5 as a Potential Biomarker of the Intersection of Trauma and Cannabis Use.","authors":"Emily R Weiss, Margaret T Davis, Ruth H Asch, Deepak Cyril D'Souza, Ryan Cool, Irina Esterlis","doi":"10.1093/ijnp/pyae044","DOIUrl":"10.1093/ijnp/pyae044","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346271","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
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。
{"title":"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.","authors":"Ginna Urueña-Méndez, Chloé Arrondeau, Florian Marchessaux, Raphaël Goutaudier, Nathalie Ginovart","doi":"10.1093/ijnp/pyae034","DOIUrl":"10.1093/ijnp/pyae034","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999852","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
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。
{"title":"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.","authors":"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","doi":"10.1093/ijnp/pyae035","DOIUrl":"10.1093/ijnp/pyae035","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107200","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
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。
{"title":"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.","authors":"Ya-Mei Bai, Mu-Hong Chen, Ju-Wei Hsu, Hsiang-Hsuan Huang, Jia-Shyun Jeng, Shih-Jen Tsai","doi":"10.1093/ijnp/pyae043","DOIUrl":"10.1093/ijnp/pyae043","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Discussion: </strong>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.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11450626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142286424","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
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
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International Journal of Neuropsychopharmacology
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