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Alcohol, flexible behavior, and the prefrontal cortex: Functional changes underlying impaired cognitive flexibility 酒精、灵活行为和前额叶皮层:认知灵活性受损背后的功能变化。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110114

Cognitive flexibility enables individuals to alter their behavior in response to changing environmental demands, facilitating optimal behavior in a dynamic world. The inability to do this, called behavioral inflexibility, is a pervasive behavioral phenotype in alcohol use disorder (AUD), driven by disruptions in cognitive flexibility. Research has repeatedly shown that behavioral inflexibility not only results from alcohol exposure across species but can itself be predictive of future drinking. Like many high-level executive functions, flexible behavior requires healthy functioning of the prefrontal cortex (PFC). The scope of this review addresses two primary themes: first, we outline tasks that have been used to investigate flexibility in the context of AUD or AUD models. We characterize these based on the task features and underlying cognitive processes that differentiate them from one another. We highlight the neural basis of flexibility measures, focusing on the PFC, and how acute or chronic alcohol in humans and non-human animal models impacts flexibility. Second, we consolidate findings on the molecular, physiological and functional changes in the PFC elicited by alcohol, that may contribute to cognitive flexibility deficits seen in AUD. Collectively, this approach identifies several key avenues for future research that will facilitate effective treatments to promote flexible behavior in the context of AUD, to reduce the risk of alcohol related harm, and to improve outcomes following AUD.

认知灵活性使个体能够根据不断变化的环境需求改变自己的行为,从而在动态世界中实现最佳行为。无法做到这一点,即所谓的行为缺乏灵活性,是酒精使用障碍(AUD)中普遍存在的行为表型,其驱动因素是认知灵活性的破坏。研究一再表明,行为缺乏灵活性不仅是跨物种酒精暴露的结果,其本身还能预测未来的饮酒情况。与许多高级执行功能一样,灵活的行为需要前额叶皮质(PFC)的健康运作。本综述涉及两个主要主题:首先,我们概述了在 AUD 或 AUD 模型中用于研究灵活性的任务。我们根据这些任务的特征以及区别于其他任务的基本认知过程来描述这些任务。我们强调了灵活性测量的神经基础,重点是前脑功能区,以及人类和非人类动物模型的急性或慢性酒精如何影响灵活性。其次,我们整合了有关酒精引起的前脑功能区分子、生理和功能变化的研究成果,这些变化可能会导致 AUD 中出现的认知灵活性缺陷。总之,这种方法为今后的研究确定了几条关键途径,有助于采取有效的治疗方法,促进 AUD 患者的灵活行为,降低酒精相关伤害的风险,并改善 AUD 后的治疗效果。
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引用次数: 0
Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner 长期富含饱和脂肪的饮食会以性别依赖的方式损害海马学习和记忆过程。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110108

Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.

青少年时期摄入富含饱和脂肪的饮食与海马突触可塑性降低和认知功能受损密切相关。然而,长期摄入这些食物的影响尚未得到研究。在本研究中,我们调查了持续 40 周的富含饱和脂肪(SOLF)饮食对雌雄老年小鼠的以下方面的影响:i)空间学习和记忆;ii)海马突触传递和可塑性;iii)海马基因表达水平。我们的研究结果表明,SOLF 对空间记忆和突触可塑性机制(如长期电位(LTP))有不利影响,并特别下调雄性小鼠的 Gria1 表达。在女性中,SOLF会下调Gria1/2和Grin1/2A/2B谷氨酸受体亚基以及一些促炎性白细胞介素的基因表达。这些发现凸显了在评估高脂饮食对认知和大脑可塑性的长期影响时,考虑性别特异性因素的重要性。
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引用次数: 0
Deguelin inhibits the glioblastoma progression through suppressing CCL2/NFκB signaling pathway Deguelin 通过抑制 CCL2/NFκB 信号通路抑制胶质母细胞瘤的进展。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110109

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM.

多形性胶质母细胞瘤(GBM)是最常见的原发性颅内肿瘤,具有侵袭性强、预后差的特点。非洲豆科植物Mundulea sericea树皮中的一种成分Deguelin对某些肿瘤具有抗增殖作用,但Deguelin对GBM的抑制作用和机制仍不甚明了。首先,我们发现鹿角菜苷通过使细胞周期停滞在 G2/M 期并诱导细胞凋亡来降低 GBM 细胞的活力。其次,deguelin抑制了GBM细胞的迁移。接着,RNA-seq分析发现,CCL2(编码一种重要的趋化因子CCL2)在deguelin处理的GBM细胞中显著下调。据报道,CCL2通过NFκB信号通路促进GBM细胞的活力和迁移,抑制GBM细胞的凋亡,并调节GBM肿瘤微环境(TME),从而促进GBM的进展。此外,我们还发现CCL2可以挽救deguelin通过NFκB信号通路对GBM细胞的抗抑制作用。最后,我们建立了颅内同种异位 GBM 模型,发现 deguelin 可抑制肿瘤生长,通过抑制 CCL2/NFκB 促进免疫抑制 TME 并抑制体内 GBM 的血管生成。综上所述,这些结果表明,deguelin可通过抑制CCL2/NFκB途径发挥抗GBM作用,这可能为治疗GBM提供了一种新策略。
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引用次数: 0
MSK1 is required for the experience- and ampakine-dependent enhancement of spatial reference memory and reversal learning and for the induction of Arc and BDNF MSK1是经验和安巴碱依赖性增强空间参照记忆和逆转学习的必要条件。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-10 DOI: 10.1016/j.neuropharm.2024.110110
There is considerable interest in the development of nootropics, pharmacological agents that can improve cognition across a range of both cognitive modalities and cognitive disabilities. One class of cognitive enhancers, the ampakines, has attracted particular attention by virtue of improving cognition associated with animal models of neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as in age-related cognitive impairment. Ampakines elevate CNS levels of BDNF, and it is through this elevation that their beneficial actions are believed to occur. However, what transduces the elevation of BDNF into long-lasting cognitive enhancement is not known. We have previously shown that MSK1, by virtue of its ability to regulate gene transcription, converts the elevation of BDNF associated with environmental enrichment into molecular, synaptic, cognitive and genomic adaptations that underlie enrichment-induced enhanced synaptic plasticity and learning and memory, a property that MSK1 retains across the lifespan. To establish whether MSK1 similarly converts ampakine-induced elevations of BDNF into cognitive enhancement we tested an ampakine (CX929) in male WT mice and in male mice in which the kinase activity of MSK1 was inactivated. We found that MSK1 is required for the ampakine-dependent improvement in spatial reference memory and cognitive flexibility, and for the elevations of BDNF and the plasticity-related protein Arc associated with ampakines and experience. These observations implicate MSK1 as a key enabler of the beneficial effects of ampakines on cognitive function, and furthermore identify MSK1 as a hub for BDNF-elevating nootropic strategies.
人们对能改善各种认知模式和认知障碍的药理制剂--促智剂的开发产生了浓厚的兴趣。其中一类认知增强剂--安非他酮类药物--因能改善与神经发育、神经退行性和精神疾病动物模型相关的认知能力,以及与年龄相关的认知障碍,而引起了人们的特别关注。安帕金类药物能提高中枢神经系统的 BDNF 水平,人们认为正是通过这种提高,安帕金类药物才发挥了有益的作用。然而,是什么将 BDNF 的升高转化为持久的认知能力增强尚不清楚。我们之前已经证明,MSK1 凭借其调控基因转录的能力,将与环境富集相关的 BDNF 升高转化为分子、突触、认知和基因组适应性,这些适应性是富集诱导的突触可塑性增强以及学习和记忆增强的基础,MSK1 的这一特性在人的一生中都会保持。为了确定 MSK1 是否同样能将安帕金诱导的 BDNF 升高转化为认知增强,我们在雄性 WT 小鼠和 MSK1 激酶活性发生突变的雄性小鼠体内测试了安帕金(CX929)。我们发现,安非他明依赖性地改善空间参照记忆和认知灵活性,以及与安非他明和经验相关的 BDNF 和可塑性相关蛋白 Arc 的升高,都需要 MSK1。这些观察结果表明,MSK1是安非他明类药物对认知功能产生有益影响的关键因素,并进一步确定了MSK1是提高BDNF的促智策略的枢纽。
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引用次数: 0
Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-d-aspartate receptors Zelquistinel 作用于细胞外结合域,调节 N-甲基-D-天冬氨酸受体的细胞内钙失活。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-06 DOI: 10.1016/j.neuropharm.2024.110100

Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca2+ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca2+-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.

Stinels是一类新型的N-甲基-D-天冬氨酸谷氨酸受体(NMDAR)正异构调节剂。我们在表达重组 NMDARs 的 HEK 293 细胞中探索了 Stinel zelquistinel (ZEL) 的作用机制和 NR2 亚型特异性。ZEL 能有效增强 NR2A(EC50=9.9 ± 0.5 nM)和含 NR2C(EC50=9.7 ± 0.6 nM)的 NMDAR 电流,对 NR2B-NMDAR 的上限增强更大(EC50=35.0 ± 0.7 nM),而对含 NR2D 的 NMDAR 无影响。在表达含 NR2A 和 NR2C 的 NMDAR 的细胞中,ZEL 表现出倒 U 型的剂量-反应关系,低浓度增强,高浓度抑制 NMDAR 电流。细胞外施用 ZEL 可通过延长 NMDAR 电流来增强 NMDAR 受体的活性。用快速螯合剂 BAPTA 取代慢速 Ca2+ 细胞内螯合剂 EGTA 可阻断 ZEL 对 NMDAR 的增效作用,这表明 ZEL 对细胞内 Ca2+ - 钙调素依赖性失活 (CDI) 起作用。与这一作用机制相一致的是,去除 NR1 细胞内的 C 端,或在细胞内注入钙调蛋白阻断肽,都会阻断 ZEL 对 NMDAR 电流的增效作用。与此相反,BAPTA 并不能阻止大剂量抑制电流,这表明这种效应具有不同的作用机制。这些数据表明,ZEL 是一种新型的正性异构调节剂,它能在细胞外结合,并通过独特的长程机制降低 NMDAR CDI,从而增强 NMDAR 电流。NMDAR 在长期、依赖活动的突触可塑性、学习、记忆和认知中发挥着关键作用,这表明 CDI 失调可能是抑郁症、精神分裂症等精神疾病的诱因,而 Stinel 类药物可以通过降低依赖活动的 CDI 来恢复突触可塑性。
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引用次数: 0
Chronic ethanol exposure produces long-lasting, subregion-specific physiological adaptations in RMTg-projecting mPFC neurons 慢性乙醇暴露会在 RMTg 投射的 mPFC 神经元中产生持久的、亚区域特异性的生理适应。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-06 DOI: 10.1016/j.neuropharm.2024.110098

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) that are thought to facilitate maladaptive behaviors that interfere with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is functionally altered by chronic ethanol exposure. Our recent work identified dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7–10 days following ethanol exposure. CIE exposure significantly increased intrinsic excitability as well as spontaneous excitatory and inhibitory postsynaptic currents (sE/IPSCs) in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE exposure also increased the frequency of sEPSCs in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol exposure.

长期接触乙醇会在内侧前额叶皮层(mPFC)中产生神经适应,从而促进不良行为的发生,影响酒精使用障碍的康复。尽管有证据表明,不同的皮质-皮质下投射在行为中发挥着不同的作用,但很少有研究在回路水平上研究慢性乙醇的生理效应。喙内侧被盖核(RMTg)会因长期接触乙醇而发生功能性改变。我们最近的研究发现了从 mPFC 到 RMTg 的密集输入,但慢性乙醇暴露对该回路的影响尚不清楚。在本研究中,我们检测了慢性乙醇暴露后投射到 RMTg 的前边缘(PL)和下边缘(IL)mPFC 神经元的生理变化。我们向成年雄性 Long-Evans 大鼠的 RMTg 注射了荧光反向珠,并使用为期 14 天的慢性间歇性乙醇(CIE)蒸汽暴露范例使其产生依赖性。乙醇暴露7-10天后,对荧光标记(RMTg投射)和未标记(未定义投射)的第5层锥体神经元进行全细胞膜片钳电生理记录。在RMTg投射的IL神经元中,CIE暴露明显增加了其内在兴奋性以及自发兴奋性和抑制性突触后电流(sE/IPSCs)。相比之下,在RMTg投射的PL神经元中没有观察到兴奋性的持久变化,尽管在投射未定义的PL神经元中观察到了CIE诱导的兴奋性降低。CIE暴露还增加了RMTg投射的PL神经元的sEPSCs频率。这些数据揭示了慢性乙醇暴露后 mPFC 中新的亚区域和回路特异性神经适应,并揭示了 IL mPFC-RMTg 投射在慢性乙醇暴露的长期影响下具有独特的脆弱性。
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引用次数: 0
Early protein restriction in rats induces anhedonia in adult offspring: A key role of BDNF-TrkB signaling in the nucleus accumbens shell 大鼠早期蛋白质限制诱导成年后代产生失认症:BDNF-TrkB 信号在核团外壳中的关键作用。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-08-05 DOI: 10.1016/j.neuropharm.2024.110099

Clinical evidence suggests that early malnutrition promotes symptoms related to psychiatric disorders later in life. Nevertheless, the molecular mechanisms underpinning nutritional injury induce depression remains unknown. The purpose of the present study was to evaluate whether perinatal protein restriction increases vulnerability to developing depressive-like behavior in adulthood by focusing on anhedonia, a core symptom of depression. To this, male adult Wistar rats submitted to a protein restriction schedule at perinatal age (PR-rats), were subjected to the sucrose preference test (SPT), the novel object recognition test (NORT), the forced swim test (FST), and the elevated plus maze (EPM), and compared to animals fed with a normoprotein diet. To investigate neurobiological substrates linked to early protein undernutrition-facilitated depressive-like behavior, we assessed the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the nucleus accumbens (NAc), and evaluated the reversal of anhedonic-like behavior by infusing ANA-12. We found that early malnutrition decreased sucrose preference, impaired performance in the NORT and increased immobility time in the FST. Furthermore, perinatal protein-restriction-induced anhedonia correlated with increased BDNF and p-TrkB protein levels in the NAc, a core structure in the reward circuit linked with anhedonia. Finally, bilateral infusion of the TrkB antagonist ANA-12 into the NAc shell ameliorated a reduced sucrose preference in the PR-rats.

Altogether, these findings revealed that protein restriction during pregnancy and lactation facilitates depressive-like behavior later in life and may increase the risk of developing anhedonia by altering BDNF-TrkB in the NAc shell.

临床证据表明,早期营养不良会诱发日后与精神障碍有关的症状。然而,营养损伤诱发抑郁症的分子机制仍然未知。本研究的目的是通过关注抑郁症的核心症状--失乐症,评估围产期蛋白质限制是否会增加成年后出现抑郁样行为的脆弱性。为此,研究人员对围产期限制蛋白质摄入的雄性成年 Wistar 大鼠(PR-rats)进行了蔗糖偏好试验(SPT)、新物体识别试验(NORT)、强迫游泳试验(FST)和高架加迷宫试验(EPM),并将其与正常蛋白质饮食喂养的动物进行了比较。为了研究与早期蛋白质营养不良促进抑郁样行为相关的神经生物学底物,我们评估了脑源性神经营养因子(BDNF)及其受体TrkB在纳氏核(NAc)中的水平,并通过注入ANA-12评估了厌食样行为的逆转情况。我们发现,早期营养不良会降低蔗糖偏好,损害NORT的表现,增加FST的不动时间。此外,围产期蛋白质限制诱发的失神与 NAc 中 BDNF 和 p-TrkB 蛋白水平的升高有关,而 NAc 是奖赏回路中与失神有关的核心结构。最后,将TrkB拮抗剂ANA-12双侧注入NAc外壳可改善PR大鼠对蔗糖偏好的降低。总之,这些研究结果表明,妊娠期和哺乳期的蛋白质限制会促进日后的抑郁样行为,并可能通过改变NAc外壳中的BDNF-TrkB而增加患失张力症的风险。
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引用次数: 0
Sex-dependent changes in AMPAR expression and Na, K-ATPase activity in the cerebellum and hippocampus of α-Klotho-Hypomorphic mice α-Klotho-Hypomorphic小鼠小脑和海马中AMPAR表达和Na、K-ATP酶活性的性别依赖性变化
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-07-31 DOI: 10.1016/j.neuropharm.2024.110097

Aging is characterized by a functional decline in several physiological systems. α-Klotho-hypomorphic mice (Kl−/−) exhibit accelerated aging and cognitive decline. We evaluated whether male and female α-Klotho-hypomorphic mice show changes in the expression of synaptic proteins, N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, postsynaptic density protein 95 (PSD-95), synaptophysin and synapsin, and the activity of Na+, K+-ATPase (NaK) isoforms in the cerebellum and hippocampus. In this study, we demonstrated that in the cerebellum, Kl−/− male mice have reduced expression of GluA1 (AMPA) compared to wild-type (Kl+/+) males and Kl−/− females. Also, Kl−/− male and female mice show reduced ɑ2/ɑ3-NaK and Mg2+-ATPase activities in the cerebellum, respectively, and sex-based differences in NaK and Mg2+-ATPase activities in both the regions. Our findings suggest that α-Klotho could influence the expression of AMPAR and the activity of NaK isoforms in the cerebellum in a sex-dependent manner, and these changes may contribute, in part, to cognitive decline.

衰老的特征是多个生理系统的功能衰退。α-Klotho-hypomorphic小鼠(Kl-/-)表现出加速衰老和认知能力下降。我们评估了雌雄α-Klotho-hypomorphic小鼠的突触蛋白、N-甲基-D-天冬氨酸受体(NMDAR)和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)亚基的表达是否发生了变化、突触后密度蛋白 95(PSD-95)、突触蛋白和突触素,以及小脑和海马中 Na+、K+-ATPase(NaK)同工酶的活性。本研究表明,在小脑中,与野生型(Kl+/+)雄性小鼠和Kl-/-雌性小鼠相比,Kl-/-雄性小鼠的GluA1(AMPA)表达量减少。此外,Kl-/-雄性和雌性小鼠小脑中的ɑ2/ɑ3-NaK和Mg2+-ATPase活性也分别降低,而且这两个区域的NaK和Mg2+-ATPase活性也存在性别差异。我们的研究结果表明,α-Klotho可能以性别依赖的方式影响小脑中AMPAR的表达和NaK同工酶的活性,而这些变化可能是认知能力下降的部分原因。
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引用次数: 0
Anti-inflammatory and anti-apoptotic activity of synaptamide improves the morphological state of neurons in traumatic brain injury 突触酰胺的抗炎和抗凋亡活性可改善脑外伤神经元的形态状态。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-07-31 DOI: 10.1016/j.neuropharm.2024.110094

Traumatic brain injuries (TBI) of varying severity are becoming more frequent all over the world. The process of neuroinflammation, in which macrophages and microglia are key players, underlies all types of brain damage. The present study focuses on evaluating the therapeutic potential of N-docosahexaenoylethanolamine (DHEA, synaptamide), which is an endogenous metabolite of docosahexaenoic acid in traumatic brain injury. Previously, several in vitro and in vivo models have shown significant anti-neuroinflammatory and synaptogenic activity of synaptamide. The results of the present study show that synaptamide by subcutaneous administration (10 mg/kg/day, 7 days) exerts anti-inflammatory and anti-apoptotic effects in the thalamus and cerebral cortex of experimental animals (male C57BL/6 mice). Were analyzed the dynamics of changes in the activity of Iba-1- and CD68-positive microglia/macrophages, the level of production of pro-inflammatory cytokines (IL1β, IL6, TNFα) and pro-apoptotic proteins (Bad, Bax), the expression of pro- and anti-inflammatory markers (CD68, CD206, arg-1). ATF3 transcription factor distribution and neuronal state in the thalamus and cerebral cortex of animals with craniotomy, traumatic brain injury, and therapy are quantitatively assessed. The obtained data showed that synaptamide: (1) has no effect on the total pool of microglia/macrophages; (2) inhibits the activity of pro-inflammatory microglia/macrophages and cytokines they produce; (3) increases the expression of CD206 but not arg-1; (4) has anti-apoptotic effect and (5) improves the morphological state of neurons. The results obtained confirm the high therapeutic potential of synaptamide in the therapy of traumatic brain injury.

世界各地不同程度的创伤性脑损伤(TBI)越来越频繁。神经炎症过程是所有类型脑损伤的基础,而巨噬细胞和小胶质细胞是其中的关键角色。本研究的重点是评估 N-二十二碳六烯醇胺(DHEA,突触酰胺)的治疗潜力,它是二十二碳六烯酸在创伤性脑损伤中的内源性代谢产物。此前,一些体外和体内模型显示,突触酰胺具有显著的抗神经炎症和突触生成活性。本研究结果表明,皮下注射突触酰胺(10 毫克/千克/天,7 天)对实验动物(雄性 C57BL/6 小鼠)的丘脑和大脑皮层具有抗炎和抗凋亡作用。分析了 Iba-1 和 CD68 阳性小胶质细胞/巨噬细胞活性的动态变化、促炎细胞因子(IL1β、IL6、TNFα)和促凋亡蛋白(Bad、Bax)的产生水平、促炎和抗炎标记物(CD68、CD206、arg-1)的表达。定量评估了开颅手术、脑外伤和治疗动物丘脑和大脑皮层中 ATF3 转录因子的分布和神经元状态。所得数据显示,突触酰胺:(1)对小胶质细胞/巨噬细胞的总量没有影响;(2)抑制促炎性小胶质细胞/巨噬细胞的活性及其产生的细胞因子;(3)增加 CD206 的表达,但不增加 arg-1;(4)具有抗凋亡作用;(5)改善神经元的形态状态。这些结果证实了突触酰胺在治疗脑外伤方面的巨大潜力。
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引用次数: 0
Prolactin mitigates chronic stress-induced maladaptive behaviors and physiology in ovariectomized female rats 催乳素可减轻卵巢切除雌性大鼠慢性应激诱发的适应不良行为和生理机能
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-07-30 DOI: 10.1016/j.neuropharm.2024.110095

Stress is a major risk factor for several neuropsychiatric disorders in women, including postpartum depression. During the postpartum period, diminished ovarian hormone secretion increases susceptibility to developing depressive symptoms. Pleiotropic peptide hormones, like prolactin, are markedly released during lactation and suppress hypothalamic-pituitary-adrenal axis responses in women and acute stress-induced behavioral responses in female rodents. However, the effects of prolactin on chronic stress-induced maladaptive behaviors remain unclear. Here, we used chronic variable stress to induce maladaptive physiology in ovariectomized female rats and concurrently administered prolactin to assess its effects on several depression-relevant behavioral, endocrine, and neural characteristics. We found that chronic stress increased sucrose anhedonia and passive coping in saline-treated, but not prolactin-treated rats. Prolactin treatment did not alter stress-induced thigmotaxis, corticosterone (CORT) concentrations, hippocampal cell activation or survival. However, prolactin treatment reduced basal CORT concentrations and increased dopaminergic cells in the ventral tegmental area. Further, prolactin-treated rats had reduced microglial activation in the ventral hippocampus following chronic stress exposure. Together, these data suggest prolactin mitigates chronic stress-induced maladaptive behaviors and physiology in hypogonadal females. Moreover, these findings imply neuroendocrine-immune mechanisms by which peptide hormones confer stress resilience during periods of low ovarian hormone secretion.

压力是女性患上多种神经精神疾病(包括产后抑郁症)的主要风险因素。在产后期间,卵巢激素分泌减少会增加抑郁症状的易感性。催乳素等多肽激素在哺乳期会显著释放,并抑制女性的下丘脑-垂体-肾上腺轴反应和雌性啮齿动物的急性应激诱发行为反应。然而,催乳素对慢性应激诱导的适应不良行为的影响仍不清楚。在这里,我们利用慢性可变应激诱导卵巢切除雌性大鼠的适应不良生理,并同时施用催乳素来评估其对几种抑郁相关行为、内分泌和神经特征的影响。我们发现,在生理盐水处理的大鼠中,慢性压力会增加蔗糖失乐症和被动应对,而催乳素处理的大鼠则不会。催乳素处理不会改变应激诱导的滞后性、皮质酮(CORT)浓度、海马细胞活化或存活率。然而,催乳素治疗降低了基础 CORT 浓度,并增加了腹侧被盖区的多巴胺能细胞。此外,经催乳素处理的大鼠在慢性应激暴露后,腹侧海马的小胶质细胞活化减少。这些数据表明,催乳素可减轻慢性应激诱发的性腺功能低下雌性大鼠的适应不良行为和生理机能。此外,这些发现还暗示了肽类激素在卵巢激素分泌不足期间赋予应激复原力的神经内分泌-免疫机制。
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Neuropharmacology
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