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Hippocampal SENP3 mediates chronic stress-induced depression-like behaviors by impairing the CREB-BDNF signaling 海马SENP3通过损害CREB-BDNF信号传导介导慢性压力诱导的抑郁样行为
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-31 DOI: 10.1016/j.neuropharm.2024.110203
Zhiwei Gao , Jie Peng , Yi Zhang , Zhuo Chen , Rongrong Song , Ze Song , Qijie Feng , Micona Sun , Haojie Zhu , Xu Lu , Rongrong Yang , Chao Huang
Impaired signaling between cyclic adenosine monophosphate response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus is generally considered to be the cause of depression. The mechanisms underlying the impairment of CREB-BDNF signaling under stress conditions are largely unclear. Small ubiquitin-like modifier (SUMO) specific peptidase 3 (SENP3) is a molecule that can regulate SUMOylation of target proteins related to synaptic plasticity. Its dynamic changes have been reported to be associated with neuronal damage in various models of central nervous disorders such as cerebral ischemia and traumatic brain injury. However, its role in depression is completely unknown. This problem was addressed in the present study. Our results showed that chronic unpredictable stress (CUS) triggered a specific increase in SENP3 expression in the hippocampus of non-stressed mice. Overexpression of SENP3 in the hippocampus of non-stressed mice elicited depression-like behaviors in the tail suspension test, forced swimming test, and sucrose preference test, accompanied by impairment of the CREB-BDNF signaling cascade in the hippocampus. Conversely, genetic silencing of SENP3 in the hippocampus suppressed the development of depression-like behaviors. Furthermore, infusion of SENP3-shRNA into the hippocampus failed to suppress CUS-induced depression-like behaviors when mice received genetic silencing CREB or BDNF in the hippocampus or inhibition of the BDNF receptor by K252a. Taken together, these results suggest that abnormally elevated SENP3 in the hippocampus leads to the development of depression-like behavior by impairing the CREB-BDNF signaling cascade. SENP3 in the hippocampus could be a promising target for the development of new antidepressants.
海马中环磷酸腺苷反应元件结合蛋白(CREB)和脑源性神经营养因子(BDNF)之间的信号传导受损通常被认为是抑郁症的病因。在压力条件下,CREB-BDNF 信号转导受损的机制尚不清楚。小泛素样修饰物(SUMO)特异性肽酶 3(SENP3)是一种可以调节与突触可塑性相关的靶蛋白的 SUMO 化的分子。据报道,在脑缺血和脑外伤等各种中枢神经疾病模型中,其动态变化与神经元损伤有关。然而,它在抑郁症中的作用却完全未知。本研究解决了这一问题。我们的研究结果表明,慢性不可预知应激(CUS)会引发非应激小鼠海马中 SENP3 表达的特异性增加。在非应激小鼠的海马中过表达 SENP3 会在悬尾试验、强迫游泳试验和蔗糖偏好试验中引起抑郁样行为,并伴随着海马中 CREB-BDNF 信号级联的损伤。相反,在海马中基因沉默SENP3可抑制抑郁样行为的发生。此外,当小鼠接受海马CREB或BDNF基因沉默或K252a抑制BDNF受体时,将SENP3-shRNA注入海马也不能抑制CUS诱导的抑郁样行为。综上所述,这些结果表明,海马中异常升高的 SENP3 会损害 CREB-BDNF 信号级联,从而导致抑郁样行为的发生。海马中的 SENP3 可能是开发新型抗抑郁药物的一个有前途的靶点。
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引用次数: 0
Oxytocin alleviates high-fat diet-induced anxiety by decreasing glutamatergic synaptic transmission in the ventral dentate gyrus in adolescent mice 催产素通过减少青春期小鼠腹侧齿状回的谷氨酸能突触传递,缓解高脂饮食诱发的焦虑。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-29 DOI: 10.1016/j.neuropharm.2024.110201
Xi Cao , Qiyuan Wang , Lina Zhang , Huichao Sun , Gang Xu , Xiao Chen , Zhihong Wu , Huibao Liu , Gaole Yuan , Jian Wu , Tao Liu
A high-fat diet (HFD)-induced obesity is associated with mental disorders in adolescence. However, the mechanisms underlying these associations remain unclear. In this study, we hypothesized that synaptic remodeling occurs in the ventral hippocampus (vHP) of obese mice. To investigate this, we established a postnatal model of HFD-induced obesity in mice and observed increased body weight, elevated plasma luteinizing hormone and testosterone levels, premature puberty, and enhanced anxiety-like behavior in male subjects. We also examined the effect of HFD on the c-Fos protein expression in the ventral dentate gyrus (vDG) and explored the influence of intracerebroventricular (i.c.v) oxytocin injections on HFD-induced anxiety. Our results indicated an increase in c-Fos-positive cells in the vDG following HFD consumption. Additionally, we recorded the spontaneous synaptic activity of miniature excitatory postsynaptic currents (mEPSCs) in the vDG. Notably, HFD resulted in an elevated mEPSC frequency without affecting mEPSC amplitude. Subsequently, investigations demonstrated that i.c.v oxytocin injections reversed anxiety-like behavior induced by HFD. Moreover, the application of oxytocin in a bath solution reduced the mEPSC frequency in the vDG. These findings suggest that postnatal HFD intake induces synaptic dysfunction in the vDG, associated with the hyperactivity of vDG neurons, potentially contributing to the anxiety-like behavior in juvenile obesity.
高脂饮食(HFD)导致的肥胖与青少年精神障碍有关。然而,这些关联的机制仍不清楚。在本研究中,我们假设肥胖小鼠的腹侧海马(vHP)发生了突触重塑。为了研究这一点,我们建立了一个高氟酸膳食诱导的小鼠产后肥胖模型,并观察到雄性受试者体重增加、血浆黄体生成素和睾酮水平升高、青春期提前以及焦虑样行为增强。我们还研究了高密度脂蛋白胆固醇对腹侧齿状回(vDG)c-Fos蛋白表达的影响,并探讨了脑室内注射催产素对高密度脂蛋白胆固醇诱发焦虑的影响。我们的研究结果表明,摄入高氟酸后,vDG 中的 c-Fos 阳性细胞有所增加。此外,我们还记录了vDG中微型兴奋性突触后电流(mEPSCs)的自发突触活动。值得注意的是,HFD 导致 mEPSC 频率升高,但不影响 mEPSC 振幅。随后的研究表明,静脉注射催产素可逆转高频分解诱导的焦虑样行为。此外,在浴液中注射催产素还能降低vDG中的mEPSC频率。这些研究结果表明,出生后摄入高氟酸诱导vDG突触功能障碍,与vDG神经元的过度活跃有关,可能导致青少年肥胖症中的焦虑样行为。
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引用次数: 0
Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice 多巴胺D3受体通过调节小鼠脑核中miR-29c的表达介导天然和甲基苯丙胺奖励
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-28 DOI: 10.1016/j.neuropharm.2024.110200
Rui Wang , Li Zhu , Yunting Fan , Huiqing Du , Wei Han , Fanglin Guan , Yingjie Zhu , Tong Ni , Teng Chen
The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.
多巴胺 D3 受体(D3R)主要局限于脑核(NAc),参与调节自然和药物奖赏;然而,相关过程的分子机制仍不清楚。早先的研究报道了在NAc中表达的D3R和miR-29c同时影响甲基苯丙胺(METH)诱导的奖赏行为和小胶质细胞活化,暗示了在奖赏处理过程中的调节作用。在此,我们对雄性D3R基因敲除小鼠和野生型小鼠的整个NAc进行了病毒操作介导的D3R/miR-29c过表达和抑制,以研究这种潜在的关系。我们使用蔗糖偏好评分、METH 诱导的运动敏化和 METH 诱导的条件性位置偏好测试评估了对奖赏刺激的行为反应。总体而言,我们观察到 D3R 缺陷小鼠对蔗糖和 METH 的行为反应明显降低,同时 NAc 中 miR-29c 的表达下调。D3R缺陷小鼠对这些奖赏刺激的反应减弱主要源于GSK3β活性的降低以及随后NAc中miR-29c的下调。NAc中的小胶质细胞活化介导了D3R-miR-29c缺陷对蔗糖和METH奖赏效应的影响。药物抑制小胶质细胞的活性可以挽救在NAc中缺乏D3R-miR-29c的小鼠的反应减弱。总之,本研究揭示了小鼠NAc中D3R通过miR-29c调节自然奖赏和药物奖赏的机制,突出了NAc D3R-miR-29c通路作为奖赏关键调节因子的作用,并为NAc D3R-miR-29c在编码奖赏体验中的作用提供了新的见解。
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引用次数: 0
Neuroprotection by 4R-cembranoid against Gulf War Illness-related Chemicals is mediated by ERK, PI3K, and CaMKII pathways 4R-cembranoid 对海湾战争相关化学物质的神经保护作用由 ERK、PI3K 和 CaMKII 途径介导。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-22 DOI: 10.1016/j.neuropharm.2024.110199
Sorangely Vázquez Alicia , Félix G. Rivera-Moctezuma , José L. Marrero Valentín , Dinely Pérez , Eduardo L. Tosado-Rodríguez , Abiel Roche Lima , Pedro A. Ferchmin , Nadezhda Sabeva
Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a Kv7 channel agonist).
To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 h, cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against GWI.
海湾战争病(GWI)一直与暴露于吡啶斯的明(PB)、N,N-二乙基间甲苯胺(DEET)、氯菊酯(PER)和痕量沙林有关。这项研究发现,二异丙基氟磷酸酯(DFP,沙林替代物)和与 GWI 相关的化学物质会减少大鼠海马切片中功能活跃神经元的数量。这些发现证实了 GWI 神经毒剂与 N-甲基-D-天门冬氨酸(NMDA)介导的兴奋毒性之间的联系,而 Edelfosine(一种磷脂酶 Cβ (PLCβ3) 抑制剂)和 Flupirtine(一种 KCNQ/M (Kv7) 通道激动剂)能成功逆转这种毒性。4R-cembranoid(4R)是一种以神经保护特性著称的烟碱α7乙酰胆碱酯酶受体(α7AChR)调节剂,为了测试它是否能使海马神经元从谷氨酸诱导的神经毒性中恢复过来,我们用 DFP 暴露大鼠海马切片 10 分钟,然后用 4R 处理 60 分钟。我们研究了 LY294002、PD98059 和 KN-62 预孵育后的 4R 神经保护机制。抑制磷脂酰肌醇 3-激酶(PI3K)、丝裂原活化蛋白激酶激酶(MEK1/2)和钙/钙调蛋白依赖性蛋白激酶(CaMKII)会减弱 4R 对 DFP 诱导的神经毒性的保护作用。在不同的实验中,用 DFP 和 4R 分别孵育 1 小时后,制备细胞提取物,对磷酸化-Akt、磷酸化-GSK3β、磷酸化的细胞外信号调节激酶(ERK)1/2、CaMKII 和 cAMP 反应元件结合蛋白(CREB)进行 Western 印迹。我们的结果表明,DFP 通过去磷酸化诱导神经元功能障碍,而 4R 则恢复 Akt、GSK3、ERK1/2、CREB 和 CaMKII 的磷酸化。此外,我们的蛋白质组学分析还支持这样一种观点,即 4R 可激活与增强神经元信号传导、突触可塑性和抑制细胞凋亡有关的其他信号通路,从而促进细胞存活以对抗 DFP,这为开发针对 GWI 的治疗方法提供了生物标志物。
{"title":"Neuroprotection by 4R-cembranoid against Gulf War Illness-related Chemicals is mediated by ERK, PI3K, and CaMKII pathways","authors":"Sorangely Vázquez Alicia ,&nbsp;Félix G. Rivera-Moctezuma ,&nbsp;José L. Marrero Valentín ,&nbsp;Dinely Pérez ,&nbsp;Eduardo L. Tosado-Rodríguez ,&nbsp;Abiel Roche Lima ,&nbsp;Pedro A. Ferchmin ,&nbsp;Nadezhda Sabeva","doi":"10.1016/j.neuropharm.2024.110199","DOIUrl":"10.1016/j.neuropharm.2024.110199","url":null,"abstract":"<div><div>Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a Kv7 channel agonist).</div><div>To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 h, cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against <span>GWI</span>.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"264 ","pages":"Article 110199"},"PeriodicalIF":4.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504839","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
Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring 大麻二酚可部分缓解成年后代因母体肥胖而产生的行为、神经炎症和内源性大麻素功能障碍。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-22 DOI: 10.1016/j.neuropharm.2024.110196
Fernanda da Silva Rodrigues , Jeferson Jantsch , Gabriel de Farias Fraga , Victor Silva Dias , Camila Pereira Medeiros , Fernanda Wickert , Nadja Schroder , Marcia Giovernardi , Renata Padilha Guedes
Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females. These findings underscore the persistent influence of maternal obesity on the offspring's health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.
众所周知,母亲肥胖会增加后代患焦虑症、抑郁症、精神分裂症和自闭症谱系障碍等精神疾病的风险。虽然预防措施已得到充分证实,但在损害已经形成后,解决损害问题的实用方法却很有限。我们最近证明了母体肥胖和大麻二酚(CBD)治疗对青春期神经炎症和外周代谢紊乱的相互影响,但众所周知,这两个因素往往在整个生命过程中都会发生变化。因此,我们在此研究了大麻二酚缓解肥胖母鼠成年后代这些变化的潜力。雌性 Wistar 大鼠在交配前、妊娠期和哺乳期喂食食堂饮食 12 周。后代从出生后第 70 天开始连续 3 周服用 CBD(50 毫克/千克)。行为测试评估了焦虑样表现和社交行为,同时评估了下丘脑、前额叶皮质(PFC)和海马的神经炎症和内源性大麻素标记物,以及血浆中的生化概况。CBD治疗减轻了母体肥胖引起的焦虑样和社交行为改变,恢复了后代下丘脑、前额叶皮质和海马中加剧的星形胶质细胞和小胶质细胞标记物,以及前额叶皮质中的内源性大麻素水平,并存在明显的性别差异。此外,CBD还能降低雌性血浆葡萄糖和脂多糖(LPS)的浓度。这些研究结果强调了母体肥胖对后代健康的持续影响,包括代谢异常和行为障碍,以及内源性大麻素系统在整个生命周期中介导这些结果的作用。
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引用次数: 0
Mild forced exercise in young mice prevents anergia induced by dopamine depletion in late adulthood: Relation to CDNF and DARPP-32 phosphorylation patterns in nucleus accumbens 年轻小鼠的轻度强迫运动可防止成年晚期多巴胺耗竭引起的兴奋:与核团中 CDNF 和 DARPP-32 磷酸化模式的关系
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-21 DOI: 10.1016/j.neuropharm.2024.110197
Régulo Olivares-García , Laura López-Cruz , Carla Carratalá-Ros , Paula Matas-Navarro , John D. Salamone , Mercè Correa
Mesolimbic dopamine (DA) plays a critical role in behavioral activation and exertion of effort in motivated behaviors. DA antagonism and depletion in nucleus accumbens (Nacb) induces anergia in effort-based decision-making tasks. Exercise improves motor function in Parkinson's disease (PD). However, the beneficial effects of physical exercise on anergia, a symptom present in many psychiatric and neurological pathologies needs to be studied. During 9 weeks, young CD1 male mice were trained to run at a moderate speed in automatically turning running wheels (RW) (forced exercise group) or locked in static RWs (control group) in 1 h daily sessions. Both groups were tested in a 3-choice-T-maze task developed for the assessment of preference between active (RW) vs. sedentary reinforcers, and vulnerability to DA depletion-induced anergia was studied after tetrabenazine administration (TBZ; VMAT-2 blocker). Exercise did not change spontaneous preferences, did not affect body weight, plasma corticosterone levels or measures of anxiety, but it increased the cerebral DA neurotrophic factor (CDNF) in Nacb core, suggesting a neuroprotective effect in this nucleus. After TBZ administration, only the non-trained group showed a shift in relative preferences from active to sedentary options, reducing time running but increasing consumption of pellets, thus showing a typical anergic but not anhedonic effect. Moreover, only in the non-trained group, phosphorylation of DARPP-32(Thr34) increased after TBZ administration. These results are the first to show that mild forced exercise carried out from a young age to adulthood could act on Nacb-related functions, and prevent the anergia-inducing effects of DA depletion.
中叶多巴胺(DA)在动机行为的行为激活和努力中起着关键作用。多巴胺拮抗剂(DA)的拮抗作用和凹凸核(Nacb)的耗竭可诱导努力决策任务中的无动力状态。运动能改善帕金森病(PD)患者的运动功能。然而,体育锻炼对许多精神和神经疾病症状中存在的能动性的有益影响还有待研究。在为期9周的时间里,年轻的CD1雄性小鼠接受训练,以中等速度在自动转动的跑步轮(RW)中奔跑(强迫运动组)或锁定在静态RW中(对照组),每天训练1小时。这两组小鼠都接受了一项 3 选 T 迷宫任务的测试,该任务是为评估小鼠对主动强化物(RW)和静止强化物的偏好而开发的,并研究了小鼠在服用四苯嗪(TBZ;VMAT-2 阻断剂)后对 DA 耗竭诱发的兴奋的脆弱性。运动并不改变自发偏好,也不影响体重、血浆皮质酮水平或焦虑测量,但它增加了Nacb核的脑DA神经营养因子(CDNF),表明对该核有神经保护作用。给药 TBZ 后,只有未训练组的相对偏好从活动选项转向静坐选项,减少了跑步时间,但增加了颗粒食物的消耗量,从而显示出典型的能动效应,但不是失乐效应。此外,只有在非训练组中,服用 TBZ 后 DARPP-32(Thr34)的磷酸化增加。这些结果首次表明,从幼年到成年期进行的轻度强迫运动可对Nacb相关功能产生作用,并防止DA耗竭的兴奋诱导效应。
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引用次数: 0
QRFP and GPR103 in the paraventricular nucleus play a role in chronic stress-induced depressive-like symptomatology by enhancing the hypothalamic-pituitary-adrenal axis 室旁核中的 QRFP 和 GPR103 通过增强下丘脑-垂体-肾上腺轴,在慢性压力诱发的抑郁样症状中发挥作用。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-21 DOI: 10.1016/j.neuropharm.2024.110198
Yan-Mei Chen , Jie Huang , Hua Fan , Wei-Yu Li , Tian-Shun Shi , Jie Zhao , Cheng-Niu Wang , Wei-Jia Chen , Bao-Lun Zhu , Jun-Jie Qian , Wei Guan , Bo Jiang
Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for depression neurobiology. As the latest member of the RFamide peptide family in mammals, pyroglutamylated RFamide peptide (QRFP) is closely implicated in neuroendocrine maintenance by activating G-protein-coupled receptor 103 (GPR103). We hypothesized that QRFP and GPR103 might contribute to chronic stress-induced depression by promoting corticotropin-releasing hormone (CRH) release from neurons in the paraventricular nucleus (PVN), and various methods were employed in this study, with male C57BL/6J mice adopted as the experimental subjects. Chronic stress induced not only depression-like behaviors but also significant enhancement in QRFP and GPR103 in the PVN. Genetic overexpression of QRFP/GPR103 and stereotactic infusion of QRFP-26/QRFP-43 peptide in the PVN all mimicked chronic stress that induced various depression-like phenotypes in naïve mice, and this was mediated by promoting CRH biosynthesis and HPA activity. In contrast, genetic knockdown of QRFP/GPR103 in the PVN produced notable antidepressant-like effects in mice exposed to chronic stress. Furthermore, genetic knockout of QRFP also protected against chronic stress in mice. In addition, both the C-terminal biological region of QRFP and the downstream PKA/PKC-CREB signaling coupled to GPR103 stimulation underlie the role of QRFP and GPR103 in depression. Collectively, QRFP and GPR103 in PVN neurons could be viable targets for novel antidepressants.
慢性应激期间下丘脑-垂体-肾上腺(HPA)轴的过度活跃对抑郁神经生物学至关重要。作为哺乳动物RF酰胺肽家族的最新成员,焦谷氨酰化RF酰胺肽(QRFP)通过激活G蛋白偶联受体103(GPR103)与神经内分泌的维持密切相关。我们假设QRFP和GPR103可能通过促进脑室旁核(PVN)神经元释放促肾上腺皮质激素释放激素(CRH)而导致慢性应激诱导的抑郁症,本研究采用了多种方法,以雄性C57BL/6J小鼠为实验对象。慢性应激不仅会诱发类似抑郁的行为,还会显著增强PVN中的QRFP和GPR103。基因过表达QRFP/GPR103和立体定向灌注QRFP-26/QRFP-43肽到PVN中都能模拟慢性应激,诱导天真小鼠出现各种抑郁样表型,而这是通过促进CRH的生物合成和HPA活性介导的。与此相反,在PVN中基因敲除QRFP/GPR103会对暴露于慢性应激的小鼠产生明显的抗抑郁样效应。此外,基因敲除 QRFP 还能保护小鼠免受慢性压力的影响。此外,QRFP 的 C 端生物区和与 GPR103 刺激耦合的下游 PKA/PKC-CREB 信号都是 QRFP 和 GPR103 在抑郁症中发挥作用的基础。总而言之,PVN神经元中的QRFP和GPR103可能是新型抗抑郁药物的可行靶点。
{"title":"QRFP and GPR103 in the paraventricular nucleus play a role in chronic stress-induced depressive-like symptomatology by enhancing the hypothalamic-pituitary-adrenal axis","authors":"Yan-Mei Chen ,&nbsp;Jie Huang ,&nbsp;Hua Fan ,&nbsp;Wei-Yu Li ,&nbsp;Tian-Shun Shi ,&nbsp;Jie Zhao ,&nbsp;Cheng-Niu Wang ,&nbsp;Wei-Jia Chen ,&nbsp;Bao-Lun Zhu ,&nbsp;Jun-Jie Qian ,&nbsp;Wei Guan ,&nbsp;Bo Jiang","doi":"10.1016/j.neuropharm.2024.110198","DOIUrl":"10.1016/j.neuropharm.2024.110198","url":null,"abstract":"<div><div>Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for depression neurobiology. As the latest member of the RFamide peptide family in mammals, pyroglutamylated RFamide peptide (QRFP) is closely implicated in neuroendocrine maintenance by activating G-protein-coupled receptor 103 (GPR103). We hypothesized that QRFP and GPR103 might contribute to chronic stress-induced depression by promoting corticotropin-releasing hormone (CRH) release from neurons in the paraventricular nucleus (PVN), and various methods were employed in this study, with male C57BL/6J mice adopted as the experimental subjects. Chronic stress induced not only depression-like behaviors but also significant enhancement in QRFP and GPR103 in the PVN. Genetic overexpression of QRFP/GPR103 and stereotactic infusion of QRFP-26/QRFP-43 peptide in the PVN all mimicked chronic stress that induced various depression-like phenotypes in naïve mice, and this was mediated by promoting CRH biosynthesis and HPA activity. In contrast, genetic knockdown of QRFP/GPR103 in the PVN produced notable antidepressant-like effects in mice exposed to chronic stress. Furthermore, genetic knockout of QRFP also protected against chronic stress in mice. In addition, both the C-terminal biological region of QRFP and the downstream PKA/PKC-CREB signaling coupled to GPR103 stimulation underlie the role of QRFP and GPR103 in depression. Collectively, QRFP and GPR103 in PVN neurons could be viable targets for novel antidepressants.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110198"},"PeriodicalIF":4.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504840","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
Prelimbic cortex perineuronal net expression and social behavior: Impact of adolescent intermittent ethanol exposure 前边缘皮层神经元网络表达与社交行为:青少年间歇性接触乙醇的影响
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-20 DOI: 10.1016/j.neuropharm.2024.110195
Trevor T. Towner, Harper J. Coleman, Matthew A. Goyden, Andrew S. Vore, Kimberly M. Papastrat, Elena I. Varlinskaya, David F. Werner
Adolescent intermittent ethanol (AIE) exposure in rats leads to social deficits. Parvalbumin (PV) expressing fast-spiking interneurons in the prelimbic cortex (PrL) contribute to social behavior, and perineuronal nets (PNNs) within the PrL preferentially encompass and regulate PV interneurons. AIE exposure increases PNNs, but it is unknown if this upregulation contributes to AIE-induced social impairments. The current study was designed to determine the effect of AIE exposure on PNN expression in the PrL and to assess whether PNN dysregulation contributes to social deficits elicited by AIE. cFos-LacZ male and female rats were exposed every other day to tap water or ethanol (4 g/kg, 25% w/v) via intragastric gavage between postnatal day (P) 25–45. We evaluated neuronal activation by β-galactosidase expression and PNN levels either at the end of the exposure regimen on P45 and/or in adulthood on P70. In addition, we used Chondroitinase ABC (ChABC) to deplete PNNs following adolescent exposure (P48) and allowed for PNN restoration before social testing in adulthhod. AIE exposure increased PNN expression in the PrL of adult males, but decreased PNNs immediately following AIE. Vesicular glutamate transporter 2 (vGlut2) and vesicular GABA transporter (vGat) near PNNs were downregulated only in AIE-exposed females. Gene expression of PNN components was largely unaffected by AIE exposure. Removal and reestablishment of PrL PNNs by ChABC led to upregulation of PNNs and social impairments in males, regardless of adolescent exposure. These data suggest that AIE exposure in males upregulates PrL PNNs that likely contribute to social impairments induced by AIE.
青春期大鼠间歇性接触乙醇(AIE)会导致社交障碍。前边缘皮层(PrL)中表达快速尖峰中间神经元的副发光素(PV)有助于社会行为,而PrL中的神经元周围网(PNN)优先包含并调节PV中间神经元。暴露于 AIE 会增加 PNNs,但这种上调是否会导致 AIE 引起的社交障碍尚不清楚。本研究旨在确定 AIE 暴露对 PrL 中 PNN 表达的影响,并评估 PNN 失调是否会导致 AIE 引起的社交障碍。在出生后第 25-45 天期间,cFos-LacZ 雄性和雌性大鼠每隔一天通过胃内灌胃暴露于自来水或乙醇(4 克/千克,25% w/v)。我们通过β-半乳糖苷酶的表达和PNN水平来评估神经元的活化情况,评估时间为P45接触方案结束时和/或P70成年时。此外,我们还使用软骨素酶ABC(ChABC)来消耗青少年期(P48)暴露后的PNN,并允许在成年期社会测试前恢复PNN。AIE暴露增加了成年雄性PrL中PNN的表达,但在AIE暴露后立即减少了PNN。PNN附近的谷氨酸转运体2(vGlut2)和GABA转运体(vGat)仅在暴露于AIE的雌性中下调。PNN成分的基因表达基本不受AIE暴露的影响。ChABC 清除和重建 PrL PNNs 会导致雄性 PNNs 上调和社交障碍,与青春期暴露无关。这些数据表明,男性暴露于AIE会上调PrL PNNs,而PrL PNNs很可能会导致AIE诱发的社交障碍。
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引用次数: 0
Inhibition of matrix metalloproteinases to reduce blood brain barrier disruption and haemorrhagic transformation in ischaemic stroke: Go broad or go narrow? 抑制基质金属蛋白酶,减少缺血性中风的血脑屏障破坏和出血转化:走宽还是走窄?
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-16 DOI: 10.1016/j.neuropharm.2024.110192
Hala Kawa , Zubair Ahmed , Arshad Majid , Ruoli Chen
Ischaemic stroke characterises impulsive cerebral-region hypoxia due to deep intracerebral arteriole blockage, often accompanied by permanent cerebral infarction and cognitive impairment. Thrombolysis with recombinant tissue plasminogen activator (rtPA) and thrombectomy remain the only guidance-approved therapies. However, emerging data draws clear links between such therapies and haemorrhage transformation, which occur when cerebral vasculature is damaged during ischaemia/reperfusion. Studies have shown that matrix metalloproteinases (MMPs) play a significant role in haemorrhage transformation, by depleting the extracellular matrix (ECM) and disrupting the blood brain barrier (BBB). Inhibitors of MMPs may be used to prevent ischaemic stroke patients from BBB disruption and haemorrhage transformation, particularly for those receiving rtPA treatment. Preclinical studies found that inhibition of MMPs with agents or in knock out mice, effectively reduced BBB disruption and infarct volume, leading to improved ischaemic stroke outcomes. At present, MMP inhibition is not an approved therapy for stroke patients. There remain concerns about timing, dosing, duration of MMP inhibition and selection of either broad spectrum or specific MMP inhibitors for stroke patients. This review aims to summarize current knowledge on MMP inhibition in ischaemic stroke and explore whether a broad spectrum or a specific MMP inhibitor should be used for ischaemic stroke patient treatment. It is crucial to inhibit MMP activities early and sufficiently to ensure BBB intact during ischaemia and reperfusion, but also to reduce side effects of MMP inhibitors to minimum. Recent advance in stroke therapy by thrombectomy could aid in such treatment with intra-arterially delivery of MMP inhibitors (and/or antioxidants).
缺血性脑卒中是由于大脑内深层动脉阻塞导致的脑区缺氧,通常伴有永久性脑梗塞和认知障碍。目前,重组组织浆细胞酶原激活剂(rtPA)溶栓疗法和血栓切除术仍是唯一获得指南批准的疗法。然而,新出现的数据表明,这些疗法与脑血管在缺血/再灌注过程中受损时发生的出血转化之间存在明显联系。研究表明,基质金属蛋白酶(MMPs)通过消耗细胞外基质(ECM)和破坏血脑屏障(BBB),在出血转化中发挥着重要作用。MMPs 抑制剂可用于防止缺血性中风患者的 BBB 被破坏和出血转化,尤其是那些接受 rtPA 治疗的患者。临床前研究发现,用药物或基因敲除小鼠抑制 MMPs 可有效减少 BBB 破坏和梗死体积,从而改善缺血性中风的预后。目前,MMP 抑制疗法尚未被批准用于中风患者。对于中风患者使用 MMP 抑制剂的时机、剂量、持续时间以及广谱或特异性 MMP 抑制剂的选择等问题仍存在疑虑。本综述旨在总结缺血性脑卒中 MMP 抑制的现有知识,并探讨缺血性脑卒中患者的治疗应使用广谱还是特异性 MMP 抑制剂。在缺血和再灌注期间及早充分抑制 MMP 活性以确保 BBB 的完整性至关重要,同时也要将 MMP 抑制剂的副作用降至最低。通过血栓切除术治疗中风的最新进展可以通过动脉内输送 MMP 抑制剂(和/或抗氧化剂)来帮助这种治疗。
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引用次数: 0
A bibliometric analysis of research on empathy for pain 对疼痛移情研究的文献计量分析。
IF 4.6 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-10-16 DOI: 10.1016/j.neuropharm.2024.110193
Teng He , Siqi Yang , Changmao Zhu , Bingyuan Zhang , Qi Zhang , Yawei Ji , Yuanyuan Wang , Riyue Jiang
Empathy for pain encompasses the processes of perceiving, understanding, and responding to the pain of others, playing a crucial role in social interaction and individual development. The increasing interest in this field has led to a surge in related publications; however, the overall quantity and quality of these works remain uncertain. To address this issue, we conducted a bibliometric analysis of research on empathy for pain. Our study meticulously examined 479 publications to provide a comprehensive analysis of bibliographic elements such as annual publication trends, authorship, country of origin, institutional affiliations, journals, and keywords. Our findings indicate that, although there has been a rise in research on empathy for pain in recent years, the volume remains insufficient and is predominantly concentrated in a few countries, authors, and institutions. Additionally, current research mainly focuses on four primary areas: perception, pain, empathy, and emotion. We assert that future research will likely explore the relationship between EEG measurements and empathy for pain to determine if such measurements can effectively quantify empathy, thereby enhancing clinical management.
对疼痛的移情包括感知、理解和回应他人疼痛的过程,在社会交往和个人发展中起着至关重要的作用。人们对这一领域的兴趣与日俱增,导致相关出版物激增;然而,这些作品的总体数量和质量仍不确定。为了解决这个问题,我们对有关疼痛移情的研究进行了文献计量分析。我们的研究细致地检查了 479 篇出版物,对书目要素(如年度出版趋势、作者、原籍国、所属机构、期刊和关键词)进行了全面分析。我们的研究结果表明,尽管近年来对疼痛移情的研究有所上升,但数量仍然不足,而且主要集中在少数国家、作者和机构。此外,目前的研究主要集中在四个主要领域:感知、疼痛、移情和情感。我们认为,未来的研究将可能探索脑电图测量与疼痛共鸣之间的关系,以确定此类测量是否能有效量化共鸣,从而加强临床管理。
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引用次数: 0
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Neuropharmacology
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