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Generation of Astrocyte-specific BEST1 Conditional Knockout Mouse with Reduced Tonic GABA Inhibition in the Brain. 产生星形胶质细胞特异性 BEST1 条件性基因敲除小鼠,降低大脑中的强直性 GABA 抑制。
IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-31 DOI: 10.5607/en24019
Jinhyeong Joo,Ki Jung Kim,Jiwoon Lim,Sun Yeong Choi,Wuhyun Koh,C Justin Lee
Bestrophin-1 (BEST1) is a Ca2+-activated anion channel known for its role in astrocytes. Best1 is permeable to gliotransmitters, including GABA, to contribute to tonic GABA inhibition and modulate synaptic transmission in neighboring neurons. Despite the crucial functions of astrocytic BEST1, there is an absence of genetically engineered cell-type specific conditional mouse models addressing these roles. In this study, we developed an astrocyte-specific BEST1 conditional knock-out (BEST1 aKO) mouse line. Using the embryonic stem cell (ES cell) targeting method, we developed Best1 floxed mice (C57BL/6JCya-Best1em1flox/Cya), which have exon 3, 4, 5, and 6 of Best1 flanked by two loxP sites. By crossing with hGFAP-CreERT2 mice, we generated Best1 floxed/hGFAP-CreERT2 mice, which allowed for the tamoxifen-inducible deletion of Best1 under the human GFAP promoter. We characterized its features across various brain regions, including the striatum, hippocampal dentate gyrus (HpDG), and Parafascicular thalamic nucleus (Pf). Compared to the Cre-negative control, we observed significantly reduced BEST1 protein expression in immunohistochemistry (IHC) and tonic GABA inhibition in patch clamp recordings. The reduction in tonic GABA inhibition was 66.7% in the striatum, 46.4% in the HpDG, and 49.6% in the Pf. Our findings demonstrate that the BEST1 channel in astrocytes significantly contributes to tonic inhibition in the local brain areas. These mice will be valuable for future studies not only on tonic GABA release but also on tonic release of gliotransmitters mediated by astrocytic BEST1.
Bestrophin-1(BEST1)是一种 Ca2+ 激活的阴离子通道,因其在星形胶质细胞中的作用而闻名。Best1 对神经胶质递质(包括 GABA)具有通透性,可促进 GABA 的强直性抑制并调节邻近神经元的突触传递。尽管星形胶质细胞 BEST1 具有重要功能,但目前还没有针对这些功能的基因工程细胞型特异性条件小鼠模型。在这项研究中,我们开发了一种星形胶质细胞特异性 BEST1 条件性基因敲除(BEST1 aKO)小鼠品系。利用胚胎干细胞(ES细胞)靶向方法,我们培育出了Best1 悬浮小鼠(C57BL/6JCya-Best1em1flox/Cya),其Best1的第3、4、5和6外显子两侧有两个loxP位点。通过与 hGFAP-CreERT2 小鼠杂交,我们产生了 Best1 悬浮/hGFAP-CreERT2 小鼠,从而在人类 GFAP 启动子下实现了他莫昔芬诱导的 Best1 基因缺失。我们对其在纹状体、海马齿状回(HpDG)和丘脑副筋膜核(Pf)等多个脑区的特征进行了研究。与Cre阴性对照组相比,我们在免疫组化(IHC)中观察到BEST1蛋白表达明显减少,在膜片钳记录中观察到强直性GABA抑制。在纹状体中,强直 GABA 抑制降低了 66.7%,在 HpDG 中降低了 46.4%,在 Pf 中降低了 49.6%。我们的研究结果表明,星形胶质细胞中的 BEST1 通道对局部脑区的强直性抑制有显著作用。这些小鼠不仅对GABA的强直性释放,而且对星形胶质细胞BEST1介导的神经胶质递质的强直性释放都具有重要的研究价值。
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引用次数: 0
Phosphorylated Tau in the Taste Buds of Alzheimer's Disease Mouse Models. 阿尔茨海默病小鼠模型味蕾中的磷酸化 Tau
IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-31 DOI: 10.5607/en24004
Hyun Ji Kim,Bo Hye Kim,Dong Kyu Kim,Hanbin Kim,Sang-Hyun Choi,Dong-Hoon Kim,Myunghwan Choi,Inhee Mook-Jung,Yong Taek Jeong,Obin Kwon
Numerous systemic diseases manifest with oral symptoms and signs. The molecular diagnosis of Alzheimer's disease (AD), the most prevalent neurodegenerative disease worldwide, currently relies on invasive or expensive methods, emphasizing the imperative for easily accessible biomarkers. In this study, we explored the expression patterns of key proteins implicated in AD pathophysiology within the taste buds of mice. We detected the expression of amyloid precursor protein (APP) and tau protein in the taste buds of normal C57BL/6 mice. Phosphorylated tau was predominantly found in type II and III taste cells, while APP was located in type I taste cells. Remarkably, we observed significantly stronger immunoreactivity to phosphorylated tau in the taste buds of aged AD mouse models compared to age-matched controls. These findings underscore the oral expression of biomarkers associated with AD, highlighting the diagnostic potential of the oral cavity for neurodegenerative diseases.
许多全身性疾病都有口腔症状和体征。阿尔茨海默病(AD)是全球最常见的神经退行性疾病,其分子诊断目前依赖于侵入性或昂贵的方法,这强调了寻找易于获取的生物标志物的必要性。在这项研究中,我们探索了与 AD 病理生理学有关的关键蛋白在小鼠味蕾中的表达模式。我们检测了正常 C57BL/6 小鼠味蕾中淀粉样前体蛋白(APP)和 tau 蛋白的表达。磷酸化 tau 主要存在于 II 型和 III 型味觉细胞中,而 APP 则存在于 I 型味觉细胞中。值得注意的是,与年龄匹配的对照组相比,我们在老年 AD 模型小鼠的味蕾中观察到了明显更强的磷酸化 tau 免疫反应。这些发现强调了口腔中与AD相关的生物标记物的表达,凸显了口腔对神经退行性疾病的诊断潜力。
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引用次数: 0
FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer's Disease. 缺失 FAM19A5 可减轻 Aβ 斑块负担并改善阿尔茨海默病小鼠模型的认知能力。
IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-31 DOI: 10.5607/en24017
Sumi Park, Anu Shahapal, Sangjin Yoo, Hoyun Kwak, Minhyeok Lee, Sang-Myeong Lee, Jong-Ik Hwang, Jae Young Seong

FAM19A5, a novel secretory protein highly expressed in the brain, is potentially associated with the progression of Alzheimer's disease (AD). However, its role in the AD pathogenesis remains unclear. Here, we investigated the potential function of FAM19A5 in the context of AD. We generated APP/PS1 mice with partial FAM19A5 deficiency, termed APP/PS1/FAM19A5+/LacZ mice. Compared with control APP/PS1 mice, APP/PS1/FAM19A5+/LacZ mice exhibited significantly lower Aβ plaque density and prolonged the lifespan of the APP/PS1 mice. To further explore the therapeutic potential of targeting FAM19A5, we developed a FAM19A5 antibody. Administration of this antibody to APP/PS1 mice significantly improved their performance in the Y-maze and passive avoidance tests, indicating enhanced cognitive function. This effect was replicated in 5XFAD mice, a model of early-onset AD characterized by rapid Aβ accumulation. Additionally, FAM19A5 antibody treatment in 5XFAD mice led to enhanced exploration of novel objects and increased spontaneous alternation behavior in the novel object recognition and Y-maze tests, respectively, indicating improved cognitive function. These findings suggest that FAM19A5 plays a significant role in AD pathology and that targeting with FAM19A5 antibodies may be a promising therapeutic strategy for AD.

FAM19A5是一种在大脑中高表达的新型分泌蛋白,可能与阿尔茨海默病(AD)的进展有关。然而,它在阿尔茨海默病发病机制中的作用仍不清楚。在此,我们研究了 FAM19A5 在阿尔茨海默病中的潜在功能。我们培育了部分缺乏FAM19A5的APP/PS1小鼠,称为APP/PS1/FAM19A5+/LacZ小鼠。与对照组APP/PS1小鼠相比,APP/PS1/FAM19A5+/LacZ小鼠的Aβ斑块密度显著降低,并延长了APP/PS1小鼠的寿命。为了进一步探索靶向 FAM19A5 的治疗潜力,我们开发了一种 FAM19A5 抗体。给APP/PS1小鼠注射该抗体后,它们在Y迷宫和被动回避测试中的表现明显改善,表明认知功能增强。这种效果在5XFAD小鼠中得到了复制,5XFAD是一种以Aβ快速积累为特征的早发性AD模型。此外,对5XFAD小鼠进行FAM19A5抗体治疗后,小鼠对新物体的探索能力增强,在新物体识别和Y迷宫测试中的自发交替行为增加,这表明小鼠的认知功能得到了改善。这些研究结果表明,FAM19A5在AD病理学中起着重要作用,用FAM19A5抗体靶向治疗AD可能是一种很有前景的治疗策略。
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引用次数: 0
Modulation of Brain-derived Neurotrophic Factor Expression by Physical Exercise in Reserpine-induced Pain-depression Dyad in Mice. 体育锻炼对小鼠肾上腺素诱发的疼痛-抑郁二联症中脑源性神经营养因子表达的调节作用
IF 2.4 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-08-31 DOI: 10.5607/en24014
Dong-Wook Kang,Sheu-Ran Choi,Hyunjin Shin,Hyeryeong Lee,Jaehong Park,Miae Lee,Miok Bae,Hyun-Woo Kim
Pain accompanied by depressive symptoms is a common reason for seeking medical assistance, and many chronic pain patients experience comorbid depression. The brain-derived neurotrophic factor (BDNF) is a well-known neurotrophin expressed throughout the nervous system, playing a crucial role in neuronal growth and neuroplasticity. This study aimed to examine the effects of exercise on BDNF expression in the nervous system and reserpine (RSP)-induced pain-depression dyad. RSP (1 mg/kg) was subcutaneously administered once daily for three days in mice. The exercise was performed using a rota-rod tester for seven consecutive days following RSP administration. Pain responses were evaluated using von Frey filaments, and depression-like behaviors were assessed through forced swimming and open field tests. Immunofluorescence staining was performed to examine the changes in BDNF expression in the dorsal root ganglion (DRG), spinal cord, and hippocampus. Administration of RSP reduced mechanical paw withdrawal threshold, increased immobility time in the forced swimming test, and decreased movement in the open field test. The immunoreactivity of BDNF was increased in the DRG and spinal dorsal regions, and decreased in the hippocampus after RSP administration. Physical exercise significantly reduced the RSP-induced mechanical hypersensitivity and depression-like behaviors. In addition, exercise suppressed not only the increased expression of BDNF in the DRG and spinal dorsal regions but also the decreased expression of BDNF in the hippocampus induced by RSP administration. These findings suggest that repetitive exercise could serve as an effective and non-invasive treatment option for individuals experiencing both pain and depression by modulating BDNF expression.
伴有抑郁症状的疼痛是寻求医疗帮助的常见原因,许多慢性疼痛患者会合并抑郁症。脑源性神经营养因子(BDNF)是一种众所周知的神经营养素,在整个神经系统中均有表达,在神经元生长和神经可塑性中起着至关重要的作用。本研究旨在探讨运动对神经系统和利舍平(RSP)诱导的疼痛-抑郁二联症中 BDNF 表达的影响。小鼠皮下注射雷舍平(1 毫克/千克),每天一次,连续三天。给药后连续七天使用罗塔杆测试仪进行锻炼。使用 von Frey 灯丝评估疼痛反应,并通过强迫游泳和开阔地测试评估抑郁样行为。免疫荧光染色检查了背根神经节(DRG)、脊髓和海马中 BDNF 表达的变化。给予 RSP 会降低机械爪抽出阈值,增加强迫游泳试验中的静止时间,并减少开阔地试验中的运动。服用RSP后,DRG和脊髓背侧区的BDNF免疫活性增加,海马区的BDNF免疫活性降低。体育锻炼能明显减轻 RSP 引起的机械过敏和抑郁样行为。此外,运动不仅抑制了RSP诱导的DRG和脊髓背区BDNF表达的增加,还抑制了RSP诱导的海马区BDNF表达的减少。这些研究结果表明,通过调节 BDNF 的表达,重复运动可作为一种有效的非侵入性治疗方法,用于治疗疼痛和抑郁患者。
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引用次数: 0
Changes in Retinal Structure and Function in Mice Exposed to Flickering Blue Light: Electroretinographic and Optical Coherence Tomographic Analyses. 暴露于闪烁蓝光的小鼠视网膜结构和功能的变化:视网膜电图和光学相干断层扫描分析。
IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-06-30 DOI: 10.5607/en24011
Yan Zhang, Sun-Sook Paik, In-Beom Kim

The harmful effects of blue light on the retina and health issues attributed to flickering light have been researched extensively. However, reports on the effects of flickering blue light at a frequency in the visible range on the retina are limited. This study aimed to non-invasively investigate the structural and functional changes in mice retinas following exposure to flickering blue light. BALB/c mice were subjected to non-flickering and flickering blue light, and changes in the retinal function and structure were assessed using electroretinography (ERG) and spectral-domain optical coherence tomography (SD-OCT), respectively. Retinal damage progression was monitored on days 3, 7, 14, and 42 following light exposure. Significant reductions in scotopic and photopic ERG responses were observed on day 3 (p<0.05). On day 7, the non-flickering and flickering groups demonstrated different functional changes: the flickering group showed further ERG response reduction, while the non-flickering group showed no reduction or slight improvement that was statistically insignificant (p>0.05). A similar trend lasted by day 14. On day 42, however, the difference between the non-flickering and flickering groups was significant, which was corroborated by the normalized amplitudes at 0, 0.5, and 1 log cd s/m2 (p<0.05). Quantitative and qualitative SD-OCT assays revealed more severe and progressive retinal damage in the flickering group throughout the study. Flickering blue light causes more persistent and severe retinal damage than non-flickering blue light and may be a risk factor for retinal degeneration even at frequencies as low as 20 Hz.

关于蓝光对视网膜的有害影响以及闪烁光引起的健康问题,已经进行了广泛的研究。然而,关于频率在可见光范围内的闪烁蓝光对视网膜的影响的报道却很有限。本研究旨在对小鼠视网膜暴露于闪烁蓝光后的结构和功能变化进行非侵入性研究。将 BALB/c 小鼠置于非闪烁蓝光和闪烁蓝光下,分别使用视网膜电图(ERG)和光谱域光学相干断层扫描(SD-OCT)评估视网膜功能和结构的变化。在光照射后的第 3、7、14 和 42 天,监测视网膜损伤的进展情况。在第 3 天,观察到散光和光视 ERG 反应显著降低(p0.05)。类似的趋势持续到第 14 天。然而,在第 42 天,非闪烁组和闪烁组之间的差异显著,这在 0、0.5 和 1 log cd s/m2 的归一化振幅上得到了证实(p.05)。
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引用次数: 0
Egocentric 3D Skeleton Learning in a Deep Neural Network Encodes Obese-like Motion Representations. 在深度神经网络中进行以自我为中心的三维骨架学习,可编码类似肥胖的运动表象。
IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-06-30 DOI: 10.5607/en24008
Jea Kwon, Moonsun Sa, Hyewon Kim, Yejin Seong, C Justin Lee

Obesity is a growing health concern, mainly caused by poor dietary habits. Yet, accurately tracking the diet and food intake of individuals with obesity is challenging. Although 3D motion capture technology is becoming increasingly important in healthcare, its potential for detecting early signs of obesity has not been fully explored. In this research, we used a deep LSTM network trained with individual identity (identity-trained deep LSTM network) to analyze 3D time-series skeleton data from mouse models with diet-induced obesity. First, we analyzed the data from two different viewpoints: allocentric and egocentric. Second, we trained various deep recurrent networks (e.g., RNN, GRU, LSTM) to predict the identity. Lastly, we tested whether these models effectively encode obese-like motion representations by training a support vector classifier with the latent features from the last layer. Our experimental results indicate that the optimal performance is achieved when utilizing an identity-trained deep LSTM network in conjunction with an egocentric viewpoint. This approach suggests a new way to use deep learning to spot health risks in mouse models of obesity and should be useful for detecting early signs of obesity in humans.

肥胖是一个日益令人担忧的健康问题,其主要原因是不良的饮食习惯。然而,准确跟踪肥胖症患者的饮食和食物摄入量却具有挑战性。虽然三维运动捕捉技术在医疗保健领域的重要性日益凸显,但其在检测肥胖症早期症状方面的潜力尚未得到充分挖掘。在这项研究中,我们使用以个体身份进行训练的深度 LSTM 网络(身份训练深度 LSTM 网络)来分析节食诱发肥胖小鼠模型的三维时间序列骨骼数据。首先,我们从两个不同的视角对数据进行了分析:分配中心视角和自我中心视角。其次,我们训练了各种深度递归网络(如 RNN、GRU、LSTM)来预测身份。最后,我们利用最后一层的潜在特征训练支持向量分类器,测试这些模型是否能有效地编码类似肥胖的运动表征。我们的实验结果表明,当利用身份训练的深度 LSTM 网络与自我中心视角相结合时,可以获得最佳性能。这种方法为利用深度学习发现小鼠肥胖模型中的健康风险提供了一种新方法,并可用于检测人类肥胖的早期迹象。
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引用次数: 0
The Effects of Acute Stress on Evoked-cortical Connectivity through Wide-field Optical Mapping of Neural and Hemodynamic Signals. 通过对神经和血液动力学信号的宽视场光学绘图研究急性应激对诱发皮层连接性的影响
IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-06-30 DOI: 10.5607/en23009
Hayeon Kim, Haebin Jeong, Jiyoung Lee, Jaeseung Yei, Minah Suh

A single exposure to stress can induce functional changes in neurons, potentially leading to acute stress disorder or post-traumatic stress disorder. In this study, we used in vivo wide-field optical mapping to simultaneously measure neural calcium signals and hemodynamic responses over the whole cortical area. We found that cortical mapping to whisker stimuli was altered under acute stress conditions. In particular, callosal projections in the anterior cortex (primary/secondary motor, somatosensory forelimb cortex) relative to barrel field (S1BF) of somatosensory cortex were weakened. On the contrary, the projections in posterior cortex relative to S1BF were mostly unchanged or were only occasionally strengthened. In addition, changes in intra-cortical connection were opposite to those in inter-cortical connection. Thus, the S1BF connections to the anterior cortex were strengthened while those to the posterior cortex were weakened. This suggests that the well-known barrel cortex projection route was enhanced. In summary, our in vivo wide-field optical mapping study indicates that a single acute stress can impact whole-brain networks, affecting both neural and hemodynamic responses.

单次暴露于应激可诱发神经元的功能变化,从而可能导致急性应激障碍或创伤后应激障碍。在这项研究中,我们利用体内宽视场光学映射同时测量了整个皮层区域的神经钙信号和血液动力学反应。我们发现,在急性应激条件下,大脑皮层对胡须刺激的映射发生了改变。特别是,相对于躯体感觉皮层的桶状场(S1BF),前部皮层(初级/次级运动、躯体感觉前肢皮层)的胼胝体投射减弱了。相反,后部皮层相对于 S1BF 的投射大部分保持不变或偶尔增强。此外,皮层内连接的变化与皮层间连接的变化相反。因此,S1BF 与前部皮层的连接加强了,而与后部皮层的连接却减弱了。这表明,众所周知的桶状皮层投射路线得到了加强。总之,我们的活体广域光学绘图研究表明,一次急性应激可影响整个大脑网络,同时影响神经和血液动力学反应。
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引用次数: 0
Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model. 耳廓迷走神经刺激对啮齿动物模型中奥沙利铂诱发的外周神经病理性疼痛的镇痛效果
IF 1.8 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-06-30 DOI: 10.5607/en24012
In Seon Baek, Seunghwan Choi, Heera Yoon, Geehoon Chung, Sun Kwang Kim

Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α1-, α2-, or β-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the β-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS. These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through β-adrenergic receptor activation.

癌症化疗通常会引发患者的周围神经病变,导致四肢神经性疼痛。以往的研究探索了各种神经刺激方法来缓解化疗引起的周围神经病变(CIPN),但无创耳部迷走神经刺激(aVNS)的有效性仍不确定。本研究旨在探讨无创迷走神经刺激对缓解 CIPN 疼痛的疗效。为诱导实验动物出现 CIPN,给大鼠腹腔注射奥沙利铂(6 毫克/千克)。分别使用 von Frey 试验和丙酮试验评估神经病理性疼痛的代表性症状--机械异感和冷异感。CIPN 动物被随机分配到各组,并接受不同频率(2、20 或 100 Hz)的 aVNS(5 V,方波)治疗 20 分钟。结果显示,20 Hz aVNS 的镇痛效果最明显,而 2 Hz 或 100 Hz aVNS 的镇痛效果较弱。免疫组化分析表明,与假治疗相比,接受 aVNS 治疗的 CIPN 大鼠脑部神经节(LC)中的 c-Fos 表达增加。为了阐明涉及肾上腺素能递减通路的镇痛机制,在 20 Hz aVNS 之前给脊髓注射了 α1-、α2- 或 β-肾上腺素能受体拮抗剂。只有β肾上腺素能受体拮抗剂普萘洛尔能阻断aVNS的镇痛作用。这些研究结果表明,20 Hz aVNS 可通过激活 β 肾上腺素能受体有效缓解 CIPN 疼痛。
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引用次数: 0
NKCC1 in Neonatal Cochlear Support Cells Reloads Ions Necessary for Cochlear Spontaneous Activity. 新生儿耳蜗支持细胞中的 NKCC1 重载耳蜗自发活动所需的离子
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-04-30 DOI: 10.5607/en24003
Kwon-Woo Kang, Kushal Sharma, Shi-Hyun Park, Jae Kwang Lee, Justin C Lee, Eunyoung Yi

In the auditory system, the spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from inner supporting cells (ISCs). This ATP release sets off a cascade, activating purinergic autoreceptors, opening of Ca2+-activated Cl- channel TMEM16A, Cl- efflux and osmotic cell shrinkage. Then, the shrunken ISCs efficiently regain their original volume, suggesting the existence of mechanisms for refilling Cland K+, priming them for subsequent activity. This study explores the potential involvement of NKCCs (Na+-K+-Cl- cotransporters) and KCCs (K+-Cl- cotransporters) in ISC spontaneous activity, considering their capability to transport both Cl- and K+ ions across the cell membrane. Employing a combination of immunohistochemistry, pharmacological interventions, and shRNA experiment, we unveiled the pivotal role of NKCC1 in cochlear spontaneous activity. Immunohistochemistry revealed robust NKCC1 expression in ISCs, persisting until the 2nd postnatal week. Intriguingly, we observed a developmental shift in NKCC1 expression from ISCs to synaptophysin-positive efferent terminals at postnatal day 18, hinting at its potential involvement in modulating synaptic transmission during the post-hearing period. Experiments using bumetanide, a well-known NKCC inhibitor, supported the functional significance of NKCC1 in ISC spontaneous activity. Bumetanide significantly reduced the frequency of spontaneous extracellular potentials (sEP) and spontaneous optical changes (sOCs) in ISCs. NKCC1-shRNA experiments conducted in cultured cochlear tissues further supported these findings, demonstrating a substantial decrease in event frequency and area. Taken together, we revealed the role of NKCC1 in shaping the ISC spontaneous activity that govern auditory pathway development.

在听觉系统中,耳蜗内毛细胞(IHC)的自发活动是由内支持细胞(ISC)释放的 ATP 启动的。ATP 的释放会引发一系列连锁反应,包括激活嘌呤能自受体、打开 Ca2+ 激活的 Cl- 通道 TMEM16A、Cl- 外流和渗透性细胞收缩。然后,萎缩的 ISC 会有效地恢复其原有体积,这表明存在重新填充 Cland K+ 的机制,从而为其后续活动做好准备。考虑到NKCCs(Na+-K+-Cl-共转运体)和KCCs(K+-Cl-共转运体)具有跨细胞膜转运Cl-和K+离子的能力,本研究探讨了它们参与ISC自发活动的可能性。通过免疫组化、药物干预和 shRNA 实验,我们揭示了 NKCC1 在耳蜗自发活动中的关键作用。免疫组化显示,NKCC1在ISC中的表达很强,一直持续到出生后第2周。耐人寻味的是,我们观察到 NKCC1 的表达在发育过程中发生了转变,即在出生后第 18 天从 ISC 转移到突触素阳性的传出末梢,这表明它可能参与了听觉后时期突触传递的调节。使用著名的 NKCC 抑制剂布美他尼进行的实验证实了 NKCC1 在 ISC 自发活动中的重要功能。布美他尼显著降低了 ISC 的自发胞外电位(sEP)和自发光学变化(sOC)的频率。在培养的耳蜗组织中进行的 NKCC1-shRNA 实验进一步证实了这些发现,证明了事件频率和面积的大幅减少。综上所述,我们揭示了 NKCC1 在影响听觉通路发育的 ISC 自发活动中的作用。
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引用次数: 0
Sensory Stimulation-dependent Npas4 Expression in the Olfactory Bulb during Early Postnatal Development. 出生后早期发育过程中嗅球中依赖于感觉刺激的 Npas4 表达
IF 2.4 4区 医学 Q1 Medicine Pub Date : 2024-04-30 DOI: 10.5607/en23037
Oh-Hoon Kwon, Jiyun Choe, Dokyeong Kim, Sunghwan Kim, Cheil Moon

The development of the olfactory system is influenced by sensory inputs, and it maintains neuronal generation and plasticity throughout the lifespan. The olfactory bulb contains a higher proportion of interneurons than other brain regions, particularly during the early postnatal period of neurogenesis. Although the relationship between sensory stimulation and olfactory bulb development during the postnatal period has been well studied, the molecular mechanisms have yet to be identified. In this study, we used western blotting and immunohistochemistry to analyze the expression of the transcription factor Npas4, a neuron-specific immediate-early gene that acts as a developmental regulator in many brain regions. We found that Npas4 is highly expressed in olfactory bulb interneurons during the early postnatal stages and gradually decreases toward the late postnatal stages. Npas4 expression was observed in all olfactory bulb layers, including the rostral migratory stream, where newborn neurons are generated and migrate to the olfactory bulb. Under sensory deprivation, the olfactory bulb size and the number of olfactory bulb interneurons were reduced. Furthermore, Npas4 expression and the expression of putative Npas4 downstream molecules were decreased. Collectively, these findings indicate that Npas4 expression induced by sensory input plays a role in the formation of neural circuits with excitatory mitral/tufted cells by regulating the survival of olfactory bulb interneurons during the early stages of postnatal development.

嗅觉系统的发育受到感官输入的影响,并在整个生命周期中保持神经元的生成和可塑性。与其他脑区相比,嗅球含有较高比例的中间神经元,尤其是在出生后早期的神经发生期。尽管对出生后时期感觉刺激与嗅球发育之间的关系已有深入研究,但其分子机制仍有待确定。在这项研究中,我们利用 Western 印迹和免疫组化技术分析了转录因子 Npas4 的表达,Npas4 是一种神经元特异性的即刻早期基因,在许多脑区起着发育调控作用。我们发现,Npas4在出生后早期的嗅球中间神经元中高度表达,并在出生后晚期逐渐减少。Npas4在嗅球各层均有表达,包括喙迁徙流,新生神经元在此产生并迁徙至嗅球。在感觉剥夺的情况下,嗅球的大小和嗅球中间神经元的数量都会减少。此外,Npas4 的表达和推定的 Npas4 下游分子的表达也减少了。总之,这些研究结果表明,在出生后发育的早期阶段,由感觉输入诱导的Npas4表达通过调节嗅球中间神经元的存活,在具有兴奋性丝裂细胞/簇细胞的神经环路的形成过程中发挥作用。
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Experimental Neurobiology
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