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microRNA-125b-5p alleviated CCI-induced neuropathic pain and modulated neuroinflammation via targeting SOX11. microRNA-125b-5p通过靶向SOX11缓解CCI诱导的神经病理性疼痛并调节神经炎症。
IF 1.6 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-09-01 DOI: 10.1002/syn.22306
Liping Wang, Bei Wang, Xia Geng, Xiaona Guo, Tingting Wang, Jingjing Xu, Linkai Jiang, Haining Zhen

Background: Increasing evidence demonstrated the involvement of microRNAs (miRNAs) in the onset and development of neuropathic pain (NP). Exploring the molecular mechanism underlying NP and identifying key molecules could provide potential targets for the therapy of NP. The function and mechanism of miR-125b-5p in regulating NP have been studied, aiming to find a potential therapeutic target for NP.

Methods: NP rat models were established by the chronic constriction injury (CCI) method. The paw withdrawal threshold and paw withdrawal latency were assessed to evaluate the establishment and recovery of rats. Highly aggressive proliferating immortalized (HAPI) micoglia cell, a rat microglia cell line, was treated with lipopolysaccharide (LPS). The M1/M2 polarization and inflammation were evaluated by enzyme-linked immunosorbent assay and western blotting.

Results: Decreasing miR-125b-5p and increasing SOX11 were observed in CCI rats and LPS-induced HAPI cells. Overexpressing miR-125b-5p alleviated mechanical allodynia and thermal hyperalgesia and suppressed inflammation in CCI rats. LPS induced M1 polarization and inflammation of HAPI cells, which was attenuated by miR-125b-5p overexpression. miR-125-5p negatively regulated the expression of SOX11 in CCI rats and LPS-induced HAPI cells. Overexpressing SOX11 reversed the protective effects of miR-125b-5p on mechanical pain in CCI rats and the polarization and inflammation in HAPI cells, which was considered the mechanism underlying miR-125b-5p.

Conclusion: miR-125b-5p showed a protective effect on NP by regulating inflammation and polarization of microglia via negatively modulating SOX11.

背景:越来越多的证据表明,微RNA(miRNA)参与了神经病理性疼痛(NP)的发生和发展。探索神经病理性疼痛的分子机制并确定关键分子可为治疗神经病理性疼痛提供潜在靶点。本研究对miR-125b-5p调控NP的功能和机制进行了研究,旨在寻找NP的潜在治疗靶点:方法:采用慢性收缩损伤(CCI)法建立 NP 大鼠模型。方法:采用慢性收缩性损伤(CCI)方法建立 NP 大鼠模型,评估大鼠爪退缩阈值和爪退缩潜伏期,以评价大鼠的建立和恢复情况。用脂多糖(LPS)处理大鼠小胶质细胞系--高侵袭性增殖永生(HAPI)小胶质细胞。通过酶联免疫吸附试验和免疫印迹法对 M1/M2 极化和炎症进行了评估:结果:在CCI大鼠和LPS诱导的HAPI细胞中观察到miR-125b-5p减少和SOX11增加。过表达 miR-125b-5p 可减轻 CCI 大鼠的机械异感和热痛,并抑制炎症。miR-125b-5p能负向调节SOX11在CCI大鼠和LPS诱导的HAPI细胞中的表达。结论:miR-125b-5p 通过负向调节 SOX11 来调节炎症和小胶质细胞的极化,从而对 NP 起保护作用。
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引用次数: 0
Inhibitory modulation of action potentials in crayfish motor axons by fluoxetine. 氟西汀对小龙虾运动轴突动作电位的抑制性调节。
IF 1.6 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-07-01 DOI: 10.1002/syn.22304
Selene Wang, Si Seng Lam, Anisah Aguilar, Stephanie Anakwe, Katherine Barahona, Hani Haider, Olivia Hunyadi, Kaahini Jain, Derek Kolodziejski, Anindita Lal, Man Li, Frank MacKenzie, John Miller, Oliviero Nardin, Emily Nguyen, Jaii Pappu, Melissa Rodriguez, Jen-Wei Lin

The goal of this report is to explore how K2P channels modulate axonal excitability by using the crayfish ventral superficial flexor preparation. This preparation allows for simultaneous recording of motor nerve extracellular action potentials (eAP) and intracellular excitatory junctional potential (EJP) from a muscle fiber. Previous pharmacological studies have demonstrated the presence of K2P-like channels in crayfish. Fluoxetine (50 µM) was used to block K2P channels in this study. The blocker caused a gradual decline, and eventually complete block, of motor axon action potentials. At an intermediate stage of the block, when the peak-to-peak amplitude of eAP decreased to ∼60%-80% of the control value, the amplitude of the initial positive component of eAP declined at a faster rate than that of the negative peak representing sodium influx. Furthermore, the second positive peak following this sodium influx, which corresponds to the after-hyperpolarizing phase of intracellularly recorded action potentials (iAP), became larger during the intermediate stage of eAP block. Finally, EJP recorded simultaneously with eAP showed no change in amplitude, but did show a significant increase in synaptic delay. These changes in eAP shape and EJP delay are interpreted as the consequence of depolarized resting membrane potential after K2P channel block. In addition to providing insights to possible functions of K2P channels in unmyelinated axons, results presented here also serve as an example of how changes in eAP shape contain information that can be used to infer alterations in intracellular events. This type of eAP-iAP cross-inference is valuable for gaining mechanistic insights here and may also be applicable to other model systems.

本报告旨在利用小龙虾腹侧浅屈肌制备方法,探讨 K2P 通道如何调节轴突兴奋性。这种制备方法可同时记录来自肌纤维的运动神经胞外动作电位(eAP)和胞内兴奋交界电位(EJP)。之前的药理学研究已经证明了小龙虾体内存在 K2P 样通道。本研究使用氟西汀(50 µM)阻断 K2P 通道。阻断剂导致运动轴突动作电位逐渐下降,最终完全阻断。在阻滞的中间阶段,当 eAP 的峰-峰振幅下降到对照值的∼60%-80% 时,eAP 初始正分量的振幅下降速度快于代表钠流入的负峰值。此外,钠流入后的第二个正峰值(对应于细胞内记录的动作电位(iAP)的超极化后阶段)在 eAP 阻滞的中间阶段变得更大。最后,与 eAP 同时记录的 EJP 在振幅上没有变化,但在突触延迟上有显著增加。eAP 形状和 EJP 延迟的这些变化被解释为 K2P 通道阻滞后静息膜电位去极化的结果。除了深入了解 K2P 通道在无髓鞘轴突中可能发挥的功能外,本文介绍的结果还可作为一个实例,说明 eAP 形状的变化所包含的信息可用于推断细胞内事件的改变。这种 eAP-iAP 交叉推论对于深入了解这里的机理很有价值,也可能适用于其他模型系统。
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引用次数: 0
Correction to "Inhibitory modulation of action potentials in crayfish motor axons by fluoxetine". 对 "氟西汀对小龙虾运动轴突动作电位的抑制性调节 "的更正。
IF 1.6 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-07-01 DOI: 10.1002/syn.22305
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引用次数: 0
Exploring miR-21 as a key regulator in two distinct approaches of bone marrow stromal cells differentiation into Schwann-like cells. 探索 miR-21 作为骨髓基质细胞分化成施万样细胞的两种不同方法中的关键调节因子。
IF 1.6 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-05-01 DOI: 10.1002/syn.22293
Yu-Mei Liu, He-Ying Wang, Cai-Hong Wei, Jun-Ping Li, Ying Wang, Wen-Zhi Ma, Hua Jia

The differentiation of bone marrow stromal cells (BMSCs) into Schwann-like cells (SCLCs) has the potential to promote the structural and functional restoration of injured axons. However, the optimal induction protocol and its underlying mechanisms remain unclear. This study aimed to compare the effectiveness of different induction protocols in promoting the differentiation of rat BMSCs into SCLCs and to explore their potential mechanisms. BMSCs were induced using two distinct methods: a composite factor induction approach (Protocol-1) and a conditioned culture medium induction approach (Protocol-2). The expression of Schwann cells (SCs) marker proteins and neurotrophic factors (NTFs) in the differentiated cells was assessed. Cell proliferation and apoptosis were also measured. During induction, changes in miR-21 and Sprouty RTK signaling antagonist 2 (SPRY2) mRNA were analyzed. Following the transfection of BMSCs with miR-21 agomir or miR-21 antagomir, induction was carried out using both protocols, and the expression of SPRY2, ERK1/2, and SCs marker proteins was examined. The results revealed that NTFs expression was higher in Protocol-1, whereas SCs marker proteins expression did not significantly differ between the two groups. Compared to Protocol-1, Protocol-2 exhibited enhanced cell proliferation and fewer apoptotic and necrotic cells. Both protocols showed a negative correlation between miR-21 and SPRY2 expression throughout the induction stages. After induction, the miR-21 agomir group exhibited reduced SPRY2 expression, increased ERK1/2 expression, and significantly elevated expression of SCs marker proteins. This study demonstrates that Protocol-1 yields higher NTFs expression, whereas Protocol-2 results in stronger SCLCs proliferation. Upregulating miR-21 suppresses SPRY2 expression, activates the ERK1/2 signaling pathway, and promotes BMSC differentiation into SCLCs.

将骨髓基质细胞(BMSCs)分化成施万样细胞(SCLCs)有可能促进损伤轴突的结构和功能恢复。然而,最佳诱导方案及其内在机制仍不清楚。本研究旨在比较不同诱导方案在促进大鼠BMSCs分化为SCLCs方面的有效性,并探索其潜在机制。BMSCs 采用两种不同的方法进行诱导:复合因子诱导法(方案-1)和条件培养基诱导法(方案-2)。对分化细胞中许旺细胞(SCs)标记蛋白和神经营养因子(NTFs)的表达进行了评估。此外还测定了细胞增殖和凋亡。在诱导过程中,分析了 miR-21 和 Sprouty RTK 信号拮抗剂 2 (SPRY2) mRNA 的变化。用 miR-21 agomir 或 miR-21 antagomir 转染 BMSCs 后,使用两种方案进行诱导,并检测 SPRY2、ERK1/2 和 SCs 标记蛋白的表达。结果显示,"方案-1 "中 NTFs 的表达量更高,而 SCs 标记蛋白的表达量在两组之间没有显著差异。与方案-1相比,方案-2的细胞增殖增强,凋亡和坏死细胞减少。在整个诱导阶段,两种方案的 miR-21 和 SPRY2 表达均呈负相关。诱导后,miR-21 激动剂组的 SPRY2 表达减少,ERK1/2 表达增加,SCs 标记蛋白表达显著升高。这项研究表明,方案-1能产生更高的NTFs表达,而方案-2则会导致更强的SCLCs增殖。上调 miR-21 可抑制 SPRY2 的表达,激活 ERK1/2 信号通路,促进 BMSC 分化为 SCLCs。
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引用次数: 0
Time of day does not impact spinal serotonin levels in humans. 一天中的任何时间都不会影响人体脊髓血清素的水平。
IF 1.6 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-05-01 DOI: 10.1002/syn.22291
Sharath Kumar Anand, Raj S Lavadi, Benjamin R Johnston, Joshua I Chalif, James M Scanlon, Weiwen Wang, Nitin Agarwal, David K Hamilton, Daryl P Fields, Clinton W Van't Land

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

脊髓血清素可使衰弱性瘫痪患者的神经运动功能得到恢复(即可塑性)。虽然依赖血清素的脊髓可塑性存在日间波动,但在人类中,这种波动是由于脊髓血清素水平的动态变化还是下游信号转导过程所致,目前尚不清楚。本研究的主要目的是确定人类脊髓血清素水平是否存在日间变化。为了评估这一点,研究人员在七名成年人体内放置了鞘内引流管,并在昼间(5:00 至 07:00)和夜间(17:00 至 19:00)收集脑脊液(CSF)。采用高效液相色谱-质谱法对脑脊液血清素水平进行定量分析,并通过单变量分析进行比较。从 7 名成年患者中采集了 21 份不同的 CSF 样本:9 份在昼间采集,12 份在夜间采集。昼间脑脊液样本显示血清素平均水平为 216.6 ± $pm $ 67.7 nM。夜间CSF样本显示血清素平均水平为206.7 ± $ pm $ 75.8 nM。昼间和夜间 CSF 血清素水平没有明显差异(p = .762)。在这一小批脊柱健康的成年人中,昼夜脊髓血清素水平没有差异。这些观察结果排除了脊髓血清素水平是血清素依赖性脊髓可塑性表达的日间波动的病因。
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引用次数: 0
Role of M4 -receptor cholinergic signaling in direct pathway striatal projection neurons during dopamine depletion. 多巴胺耗竭时 M4 - 受体胆碱能信号在直接通路纹状体投射神经元中的作用
IF 1.6 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-03-01 DOI: 10.1002/syn.22287
V H Avilés‐Rosas, E A Rendón‐Ochoa, T Hernández-Flores, M Flores-León, C Arias, E Galarraga, J Bargas

Direct pathway striatal projection neurons (dSPNs) are characterized by the expression of dopamine (DA) class 1 receptors (D1 R), as well as cholinergic muscarinic M1 and M4 receptors (M1 R, M4 R). D1 R enhances neuronal firing through phosphorylation of voltage-gate calcium channels (CaV 1 Ca2+ channels) activating Gs proteins and protein kinase A (PKA). Concurrently, PKA suppresses phosphatase PP-1 through DARPP-32, thus extending this facilitatory modulation. M1 R also influences Ca2+ channels in SPNs through Gq proteins and protein kinase C. However, the signaling mechanisms of M4 R in dSPNs are less understood. Two pathways are attributed to M4 R: an inhibitory one through Gi/o proteins, and a facilitatory one via the cyclin Cdk5. Our study reveals that a previously observed facilitatory modulation via CaV 1 Ca2+ channels is linked to the Cdk5 pathway in dSPNs. This result could be significant in treating parkinsonism. Therefore, we questioned whether this effect persists post DA-depletion in experimental parkinsonism. Our findings indicate that in such conditions, M4 R activation leads to a decrease in Ca2+ current and an increased M4 R protein level, contrasting with the control response. Nevertheless, parkinsonian and control actions are inhibited by the Cdk5 inhibitor roscovitine, suggesting Cdk5's role in both conditions. Cdk5 may activate PP-1 via PKA inhibition in DA depletion. Indeed, we found that inhibiting PP-1 restores control M4 R actions, implying that PP-1 is overly active via M4 Rs in DA-depleted condition. These insights contribute to understanding how DA-depletion alters modulatory signaling in striatal neurons. Additional working hypotheses are discussed.

直接通路纹状体投射神经元(dSPNs)的特征是表达多巴胺(DA)1 类受体(D1 R)以及胆碱能毒蕈碱 M1 和 M4 受体(M1 R、M4 R)。D1 R 通过磷酸化电压门钙通道(CaV 1 Ca2+ 通道)激活 Gs 蛋白和蛋白激酶 A(PKA)来增强神经元的发射。同时,PKA 通过 DARPP-32 抑制磷酸酶 PP-1,从而扩大了这种促进性调节作用。M1 R 还通过 Gq 蛋白和蛋白激酶 C 影响 SPN 中的 Ca2+ 通道。M4 R有两种途径:通过Gi/o蛋白的抑制性途径和通过细胞周期蛋白Cdk5的促进性途径。我们的研究发现,之前观察到的通过 CaV 1 Ca2+ 通道的促进性调节与 dSPNs 中的 Cdk5 途径有关。这一结果可能对治疗帕金森病具有重要意义。因此,我们质疑这种效应在实验性帕金森病的 DA 缺失后是否持续存在。我们的研究结果表明,在这种情况下,M4 R 的激活会导致 Ca2+ 电流的减少和 M4 R 蛋白水平的增加,这与对照组的反应形成鲜明对比。然而,Cdk5抑制剂roscovitine抑制了帕金森症和对照组的反应,这表明Cdk5在这两种情况下都发挥作用。Cdk5可能会在DA耗竭时通过抑制PKA激活PP-1。事实上,我们发现抑制 PP-1 可以恢复 M4 R 的控制作用,这意味着在 DA 缺失的情况下,PP-1 通过 M4 Rs 过度活跃。这些见解有助于理解DA耗竭如何改变纹状体神经元的调节信号。本文还讨论了其他工作假设。
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引用次数: 0
Gender-related variation expressions of neuroplastin TRAF6, GluA1, GABA(A) receptor, and PMCA in cortex, hippocampus, and brainstem in an experimental epilepsy model. 实验性癫痫模型中大脑皮层、海马和脑干中神经弹性蛋白TRAF6、GluA1、GABA(A)受体和PMCA的表达与性别有关。
IF 2.3 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-03-01 DOI: 10.1002/syn.22289
Züleyha Doğanyiğit, Aslı Okan, Seher Yılmaz, A Cihangir Uğuz, Enes Akyüz

Epileptic seizures are seen as a result of changing excitability balance depending on the deterioration in synaptic plasticity in the brain. Neuroplastin, and its related molecules which are known to play a role in synaptic plasticity, neurotransmitter activities that provide balance of excitability and, different neurological diseases, have not been studied before in epilepsy. In this study, a total of 34 Sprague-Dawley male and female rats, 2 months old, weighing 250-300 g were used. The epilepsy model in rats was made via pentylenetetrazole (PTZ). After the completion of the experimental procedure, the brain tissue of the rats were taken and the histopathological changes in the hippocampus and cortex parts and the brain stem were investigated, as well as the immunoreactivity of the proteins related to the immunohistochemical methods. As a result of the histopathological evaluation, it was determined that neuron degeneration and the number of dilated blood vessels in the hippocampus, frontal cortex, and brain stem were higher in the PTZ status epilepticus (SE) groups than in the control groups. It was observed that neuroplastin and related proteins TNF receptor-associated factor 6 (TRAF6), Gamma amino butyric acid type A receptors [(GABA(A)], and plasma membrane Ca2+ ATPase (PMCA) protein immunoreactivity levels increased especially in the male hippocampus, and only AMPA receptor subunit type 1 (GluA1) immunoreactivity decreased, unlike other proteins. We believe this may be caused by a problem in the mechanisms regulating the interaction of neuroplastin and GluA1 and may cause problems in synaptic plasticity in the experimental epilepsy model. It may be useful to elucidate this mechanism and target GluA1 when determining treatment strategies.

癫痫发作是大脑突触可塑性恶化导致兴奋性平衡发生变化的结果。众所周知,神经弹性蛋白及其相关分子在突触可塑性、提供兴奋性平衡的神经递质活动以及不同的神经系统疾病中发挥着作用,但这些分子在癫痫中的作用还没有被研究过。在这项研究中,共使用了 34 只 Sprague-Dawley 雄性和雌性大鼠,鼠龄 2 个月,体重 250-300 克。大鼠癫痫模型是通过戊四唑(PTZ)制作的。实验过程结束后,取大鼠脑组织,研究海马、皮层和脑干的组织病理学变化,以及与免疫组化方法相关的蛋白质的免疫反应性。组织病理学评估结果表明,与对照组相比,PTZ 癫痫状态(SE)组海马、额叶皮层和脑干的神经元变性和血管扩张数量更多。我们观察到,神经弹性蛋白和相关蛋白 TNF 受体相关因子 6(TRAF6)、γ 氨基丁酸 A 型受体[(GABA(A)]和质膜 Ca2+ ATPase(PMCA)蛋白免疫反应水平升高,尤其是在男性海马中,只有 AMPA 受体亚基 1 型(GluA1)免疫反应降低,而其他蛋白则不同。我们认为,这可能是神经细胞蛋白和 GluA1 相互作用的调节机制出现了问题,并可能导致实验性癫痫模型的突触可塑性出现问题。在确定治疗策略时,阐明这一机制并以 GluA1 为靶点可能会有所帮助。
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引用次数: 0
Liproxstatin-1 alleviates ferroptosis in sevoflurane anesthesia-induced cognitive deficits of aged mice: The role oxidative stress 脂氧司他丁-1能缓解七氟醚麻醉诱导的老年小鼠认知缺陷中的铁蛋白沉积:氧化应激的作用
IF 2.3 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-01-15 DOI: 10.1002/syn.22286
Shunyuan Li, Yingle Chen, Yingmei Wang, Xianmei Zhong, Xiaoquan Yu, Zhenming Kang, Yangyi Li
In this study, we aimed to validate the hypothesis that the interplay between sevoflurane, oxidative stress and ferroptosis is crucial for the pathogenesis of sevoflurane-induced cognitive impairment in aged individuals. The mice with sevoflurane-induced cognitive impairment were used to explore the effects of sevoflurane on oxidative stress, iron homeostasis, and cognitive function in aged mice. Iron content and oxidative stress markers were analyzed in hippocampal tissue homogenates using specific assays. Additionally, the levels of iron death-related markers (Fth1 and Gpx4) were assessed by real-time PCR and Western blotting. Morris Water Maze and novel object recognition (NOR) tests were conducted to evaluate cognitive function. Sevoflurane exposure in aged mice resulted in a significant increase in iron overloading in the hippocampus, followed by a subsequent stabilization. Oxidative stress levels were elevated in the hippocampal tissue of sevoflurane-exposed mice, and a significant correlation was observed between iron death and oxidative stress. Liproxstatin-1, a ferroptosis inhibitor, effectively ameliorated the decline in memory and learning abilities induced by sevoflurane anesthesia. Liproxstatin-1 treatment reduced iron overload and oxidative stress in the hippocampal tissue of aged mice. The expression of Fth1 and Gpx4, iron death-related markers, was downregulated following Liproxstatin-1 intervention. Our findings suggest that sevoflurane anesthesia disrupts iron homeostasis, leading to increased oxidative stress and cognitive impairment in aged mice. These results highlight the potential of targeting iron-mediated processes to mitigate sevoflurane-induced cognitive impairment in the aging population.
在本研究中,我们的目的是验证七氟醚、氧化应激和铁变态反应之间的相互作用对于七氟醚诱导的老年认知障碍的发病机制至关重要这一假设。研究人员利用七氟烷诱导的认知障碍小鼠来探讨七氟烷对氧化应激、铁稳态和老年小鼠认知功能的影响。使用特定的检测方法分析了海马组织匀浆中的铁含量和氧化应激标记物。此外,还通过实时 PCR 和 Western 印迹技术评估了铁死亡相关标记物(Fth1 和 Gpx4)的水平。还进行了莫里斯水迷宫和新物体识别(NOR)测试以评估认知功能。七氟醚暴露导致老年小鼠海马铁超载显著增加,随后趋于稳定。暴露于七氟烷的小鼠海马组织中的氧化应激水平升高,并观察到铁死亡与氧化应激之间存在显著的相关性。脂氧司他丁-1是一种铁氧化抑制剂,它能有效改善七氟醚麻醉引起的记忆力和学习能力下降。脂氧司他丁-1能减轻老年小鼠海马组织的铁超载和氧化应激。脂联素-1干预后,铁死亡相关标志物Fth1和Gpx4的表达下调。我们的研究结果表明,七氟醚麻醉会破坏铁的稳态,导致氧化应激增加和老年小鼠认知功能受损。这些结果凸显了针对铁介导的过程减轻七氟醚诱导的老龄人群认知功能损害的潜力。
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引用次数: 0
α7 nicotinic acetylcholine receptors induce long-term synaptic enhancement in the dorsal but not ventral hippocampus α7烟碱乙酰胆碱受体诱导海马背侧而非腹侧的长期突触增强
IF 2.3 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-01-08 DOI: 10.1002/syn.22285
Giota Tsotsokou, Vasiliki Kouri, Costas Papatheodoropoulos
Agents that positively modulate the activity of α7nAChRs are used as cognitive enhancers and for the treatment of hippocampus-dependent functional decline. However, it is not known whether the expression and the effects of α7nAChRs apply to the entire longitudinal axis of the hippocampus equally. Given that cholinergic system-involving hippocampal functions are not equally distributed along the hippocampus, we comparatively examined the expression and the effects of α7nAChRs on excitatory synaptic transmission between the dorsal and the ventral hippocampal slices from adult rats. We found that α7nAChRs are equally expressed in the CA1 field of the two segments of the hippocampus. However, activation of α7nAChRs by their highly selective agonist PNU 282987 induced a gradually developing increase in field excitatory postsynaptic potential only in the dorsal hippocampus. This long-term potentiation was not reversed upon application of nonselective nicotinic receptor antagonist mecamylamine, but the induction of potentiation was prevented by prior blockade of α7nAChRs by their antagonist MG 624. In contrast to the long-term synaptic plasticity, we found that α7nAChRs did not modulate short-term synaptic plasticity in either the dorsal or the ventral hippocampus. These results may have implications for the role that α7nAChRs play in specifically modulating functions that depend on the normal function of the dorsal hippocampus. We propose that hippocampal functions that rely on a direct α7 nAChR-mediated persistent enhancement of glutamatergic synaptic transmission are preferably supported by dorsal but not ventral hippocampal synapses.
积极调节α7nAChRs活性的药物被用作认知增强剂和治疗海马依赖性功能衰退的药物。然而,α7nAChRs 的表达和作用是否同样适用于海马的整个纵轴尚不清楚。鉴于胆碱能系统参与的海马功能在海马上的分布并不均等,我们比较研究了α7nAChRs在成年大鼠海马背侧和腹侧切片之间兴奋性突触传递的表达和影响。我们发现,α7nAChRs在海马两个区段的CA1区域中表达相同。然而,α7nAChRs的高选择性激动剂PNU 282987激活α7nAChRs后,仅在海马背侧引起场兴奋突触后电位逐渐升高。使用非选择性烟碱受体拮抗剂麦卡米拉明不会逆转这种长期电位,但事先用α7nAChRs拮抗剂MG 624阻断α7nAChRs可阻止电位的诱导。与长期突触可塑性相反,我们发现α7nAChRs并不调节海马背侧或腹侧的短期突触可塑性。这些结果可能对α7nAChRs在特异性调节依赖于背侧海马正常功能的功能方面所起的作用有影响。我们认为,依赖于α7 nAChR直接介导的持续增强谷氨酸能突触传递的海马功能最好由背侧海马突触而非腹侧海马突触来支持。
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引用次数: 0
Gating small conductance calcium-activated potassium channels in the thalamic reticular nucleus. 门控小电导钙激活丘脑网状核中的钾通道。
IF 2.3 4区 医学 Q4 NEUROSCIENCES Pub Date : 2024-01-01 Epub Date: 2023-10-14 DOI: 10.1002/syn.22283
Ágata Silván, Kristi Anne Kohlmeier, Kjartan Frisch Herrik, Charlotte Hougaard

Small conductance calcium-activated potassium (SK) channels are well-known regulators of neuronal excitability. In the thalamic hub, SK2 channels act as pacemakers of thalamic reticular neurons, which play a key role in the thalamocortical circuit. Several disease-linked genes are highly enriched in these neurons, including genes known to be associated with schizophrenia and attentional disorders, which could affect neuronal firing. The present study assessed the effect of pharmacological modulation of SK channels in the firing pattern and intrinsic properties of thalamic reticular neurons by performing whole cell patch clamp recordings in brain slices. Two SK positive allosteric modulators and one negative allosteric modulator were used: CyPPA, NS309, and NS8593, respectively. By acting on the burst afterhyperpolarization (AHP), negative modulation of SK channels resulted in increased action potential (AP) firing, increased burst duration, and decreased intervals between bursts. Conversely, both CyPPA and NS309 increased the afterburst AHP, prolonging the interburst interval, which additionally resulted in reduced AP firing in the case of NS309. Alterations in SK channel activity would be expected to alter functioning of thalamocortical circuits. Targeting SK channels could be promising in treating disorders involving thalamic reticular dysfunction such as psychiatric and neurodevelopmental disorders.

小电导钙激活钾(SK)通道是众所周知的神经元兴奋性调节因子。在丘脑中枢,SK2通道充当丘脑网状神经元的起搏器,在丘脑皮质回路中发挥关键作用。一些与疾病相关的基因在这些神经元中高度富集,包括已知与精神分裂症和注意力障碍有关的基因,这些基因可能会影响神经元的放电。本研究通过在脑切片中进行全细胞膜片钳记录,评估了SK通道的药理学调节对丘脑网状神经元放电模式和内在特性的影响。使用两种SK阳性变构调节剂和一种阴性变构调节剂:分别为CyPPA、NS309和NS8593。通过作用于突发后超极化(AHP),SK信道的负调制导致动作电位(AP)发射增加,突发持续时间增加,突发间隔缩短。相反,CyPPA和NS309都增加了后爆发AHP,延长了爆发间隔,这还导致NS309的AP发射减少。SK通道活性的改变有望改变丘脑皮质回路的功能。靶向SK通道可能有希望治疗涉及丘脑网状功能障碍的疾病,如精神和神经发育障碍。
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Synapse
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