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Multiple Sclerosis: Glial Cell Diversity in Time and Space 多发性硬化症:胶质细胞在时间和空间的多样性。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-24 DOI: 10.1002/glia.24655
Susanne M. Kooistra, Lucas Schirmer

Multiple sclerosis (MS) is the most prevalent human inflammatory disease of the central nervous system with demyelination and glial scar formation as pathological hallmarks. Glial cells are key drivers of lesion progression in MS with roles in both tissue damage and repair depending on the surrounding microenvironment and the functional state of the individual glial subtype. In this review, we describe recent developments in the context of glial cell diversity in MS summarizing key findings with respect to pathological and maladaptive functions related to disease-associated glial subtypes. A particular focus is on the spatial and temporal dynamics of glial cells including subtypes of microglia, oligodendrocytes, and astrocytes. We contextualize recent high-dimensional findings suggesting that glial cells dynamically change with respect to epigenomic, transcriptomic, and metabolic features across the inflamed rim and during the progression of MS lesions. In summary, detailed knowledge of spatially restricted glial subtype functions is critical for a better understanding of MS pathology and its pathogenesis as well as the development of novel MS therapies targeting specific glial cell types.

多发性硬化症(MS)是最常见的人类中枢神经系统炎症性疾病,以脱髓鞘和神经胶质瘢痕形成为病理标志。神经胶质细胞是MS病变进展的关键驱动因素,其在组织损伤和修复中的作用取决于周围微环境和单个神经胶质亚型的功能状态。在这篇综述中,我们描述了MS中神经胶质细胞多样性的最新进展,总结了与疾病相关的神经胶质亚型相关的病理和不适应功能的关键发现。特别关注的是神经胶质细胞的时空动态,包括小胶质细胞、少突胶质细胞和星形胶质细胞的亚型。我们结合最近的高维研究结果表明,在炎症边缘和MS病变进展过程中,胶质细胞在表观基因组、转录组学和代谢特征方面发生了动态变化。总之,详细了解空间受限的神经胶质亚型功能对于更好地理解MS病理及其发病机制以及开发针对特定神经胶质细胞类型的新型MS疗法至关重要。
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引用次数: 0
Dysregulation of Myelination in Focal Cortical Dysplasia Type II of the Human Frontal Lobe 人类额叶局灶性皮质发育不良II型的髓鞘形成失调。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-24 DOI: 10.1002/glia.24662
Catharina Donkels, Ute Häussler, Susanne Huber, Nina Tiesmeyer, Theo Demerath, Christian Scheiwe, Mukesch J. Shah, Marcel Heers, Horst Urbach, Andreas Schulze-Bonhage, Marco Prinz, Andreas Vlachos, Jürgen Beck, Julia M. Nakagawa, Carola A. Haas

Focal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of intractable epilepsy. FCDs are classified into different subtypes including FCD IIa and IIb, characterized by a blurred gray-white matter boundary or a transmantle sign indicating abnormal white matter myelination. Recently, we have shown that myelination is also compromised in the gray matter of FCD IIa of the temporal lobe. Since myelination is key for brain function, which is imbalanced in epilepsy, in the current study, we investigated myelination in the gray matter of FCD IIa and IIb from the frontal lobe on the morphological, ultrastructural, and transcriptional level. We found that FCD IIa presents with an ordinary radial myelin fiber pattern, but with a reduced thickness of myelin sheaths of 500–1000 nm thick axons in comparison to FCD IIb and with an attenuation of the myelin synthesis machinery. In contrast, FCD IIb showed an irregular and disorganized myelination pattern covering an enlarged area in comparison to FCD IIa and controls and with increased numbers of myelinating oligodendrocytes (OLs). FCD IIb had significantly thicker myelin sheaths of large caliber axons (above 1000 nm) when compared to FCD IIa. Accordingly, FCD IIb showed a significant up-regulation of myelin-associated mRNAs in comparison to FCD IIa and enhanced binding capacities of the transcription factor MYRF to target sites in myelin-associated genes. These data indicate that FCD IIa and IIb are characterized by a differential dysregulation of myelination in the gray matter of the frontal lobe.

局灶性皮质发育不良(FCDs)是人类新皮质的局部畸形,是难治性癫痫的主要原因。FCD分为不同亚型,包括FCD IIa和IIb,其特征是灰质-白质边界模糊或白质髓鞘形成异常的传递信号。最近,我们发现在颞叶FCD IIa的灰质中,髓鞘形成也受到损害。由于髓鞘形成是大脑功能的关键,在癫痫中是不平衡的,因此在本研究中,我们从形态学、超微结构和转录水平上研究了FCD IIa和IIb灰质中的髓鞘形成。我们发现,FCD IIa呈现出普通的径向髓鞘纤维模式,但与FCD IIb相比,髓鞘厚度减少了500-1000 nm厚的轴突,并且髓鞘合成机制减弱。相比之下,与FCD IIa和对照组相比,FCD IIb表现出不规则和无组织的髓鞘形成模式,覆盖面积扩大,髓鞘形成的少突胶质细胞(OLs)数量增加。与FCD IIa相比,FCD IIb的大口径轴突髓鞘(大于1000 nm)明显变厚。因此,与FCD IIa相比,FCD IIb显示髓磷脂相关mrna的显著上调,并且转录因子MYRF与髓磷脂相关基因靶位的结合能力增强。这些数据表明,FCD IIa和IIb的特征是额叶灰质髓鞘形成的不同失调。
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引用次数: 0
Cover Image, Volume 73, Issue 2
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-21 DOI: 10.1002/glia.24546
Maria Gotkiewicz, Janne Capra, Pasi O. Miettinen, Teemu Natunen, Heikki Tanila

Cover Illustration: 3D IMARIS render of Airyscan confocal z stack image showing the GFP microglia (green) processes diving into the diffuse amyloid plaque shell stained with anti-Aβ antibody D54D2 (red). Activated microglia interacts here with the plaque in two ways: with soma going deep into the plaque, and with thin processes which are intertwined in looser amyloid layers. (See Gotkiewicz, M., et al, https://doi.org/10.1002/glia.24628)

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引用次数: 0
Cover Image, Volume 73, Issue 1 封面图片,第 73 卷第 1 期
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-20 DOI: 10.1002/glia.24544
Maria Gotkiewicz, Janne Capra, Pasi O. Miettinen, Teemu Natunen, Heikki Tanila

Cover Illustration: 3D IMARIS render of Airyscan confocal z stack image showing the GFP microglia (green) processes diving into the diffuse amyloid plaque shell stained with anti-Aβ antibody D54D2 (red). Activated microglia interacts here with the plaque in two ways: with soma going deep into the plaque, and with thin processes which are intertwined in looser amyloid layers. (See Gotkiewicz, M., et al, https://doi.org/10.1002/glia.24628)

封面插图:Airyscan 共聚焦 Z 叠加图像的三维 IMARIS 渲染图,显示 GFP 小胶质细胞(绿色)进程潜入抗 Aβ 抗体 D54D2(红色)染色的弥漫性淀粉样斑块外壳。活化的小胶质细胞在这里以两种方式与斑块相互作用:与深入斑块的体细胞相互作用,以及与交织在较松散淀粉样蛋白层中的细小突触相互作用。(见 Gotkiewicz, M. 等人,https://doi.org/10.1002/glia.24628)
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引用次数: 0
WDR49-Positive Astrocytes Mark Severity of Neurodegeneration in Frontotemporal Lobar Degeneration and Alzheimer's Disease wdr49阳性星形胶质细胞标志着额颞叶变性和阿尔茨海默病神经退行性变的严重程度
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-20 DOI: 10.1002/glia.24663
Ana Rajicic, Lucia A. A. Giannini, Emma Gerrits, Renee van Buuren, Shamiram Melhem, Johan A. Slotman, Annemieke J. M. Rozemuller, Bart J. L. Eggen, John C. van Swieten, Harro Seelaar

A subpopulation of astrocytes expressing WD Repeat Domain 49 (WDR49) was recently identified in frontotemporal lobar degeneration (FTLD) with GRN pathogenic variants. This is the first study to investigate their expression and relation to pathology in other FTLD subtypes and Alzheimer's disease (AD). In a postmortem cohort of TDP-43 proteinopathies (12 GRN, 11 C9orf72, 9 sporadic TDP-43), tauopathies (13 MAPT, 8 sporadic tau), 10 AD, and four controls, immunohistochemistry and immunofluorescence were performed for WDR49 and pathological inclusions on frontal, temporal, and occipital cortical sections. WDR49-positive cell counts (adjusted per mm2) were examined and related to digitally quantified percentage areas of TDP-43/tau pathology and semiquantitative scores of neurodegeneration. Quantitative colocalization analysis of WDR49 and pathological inclusions was done. WDR49-positive astrocytes were present across FTLD subtypes and AD in the brain parenchyma and (peri-)vascular space, with distinct morphological patterns, and were particularly enriched in gray matter. In controls, sporadic WDR49-positive cells were found enveloping vessels. WDR49-positive astrocytes were most abundant in the frontal cortex (FC) of GRN cases and temporal cortex in GRN, AD, and sporadic primary tauopathy. In the occipital cortex, only a few cells were found across groups. WDR49-positive astrocyte counts positively correlated with the severity of neurodegeneration and TDP-43 pathology but not tauopathy. Furthermore, in frontotemporal cortices, WDR49 partly colocalized with TDP-43 (14%–21%) and tau (31%–45%). In conclusion, WDR49 is a marker for a subset of astrocytes with different morphologies across FTLD and AD, reflecting the severity of neurodegeneration. These astrocytes may become activated in neurodegeneration in response to pathological damage and migrate from the vessel wall to the parenchyma.

最近在具有GRN致病变异的额颞叶变性(FTLD)中发现了一个表达WD重复结构域49 (WDR49)的星形胶质细胞亚群。这是第一个研究它们在其他FTLD亚型和阿尔茨海默病(AD)中的表达及其病理关系的研究。在TDP-43蛋白病变(12例GRN, 11例C9orf72, 9例散发性TDP-43), tau病变(13例MAPT, 8例散发性tau), 10例AD和4例对照组的死后队列中,对WDR49和额部、颞部和枕部皮质切片的病理包膜进行免疫组织化学和免疫荧光检测。检测wdr49阳性细胞计数(每mm2调整),并将其与数字量化的TDP-43/tau病理百分比面积和神经退行性变的半定量评分相关。定量共定位分析WDR49和病理包涵体。wdr49阳性星形胶质细胞存在于FTLD亚型和AD的脑实质和(周围)血管间隙中,具有不同的形态模式,尤其在灰质中富集。在对照组中,发现零星的wdr49阳性细胞包裹着血管。wdr49阳性星形胶质细胞在GRN患者的额叶皮质(FC)和GRN、AD和散发性原发性牛头病患者的颞叶皮质中最为丰富。在枕叶皮层,只有少数细胞在各组间被发现。wdr49阳性星形胶质细胞计数与神经退行性变和TDP-43病理的严重程度呈正相关,但与tau病变无关。此外,在额颞叶皮层中,WDR49与TDP-43(14%-21%)和tau(31%-45%)部分共定位。总之,WDR49是FTLD和AD中具有不同形态的星形胶质细胞亚群的标志物,反映了神经退行性变的严重程度。这些星形胶质细胞可能在神经退行性变中因病理损伤而被激活,并从血管壁迁移到实质。
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引用次数: 0
Axonal Selectivity of Myelination by Single Oligodendrocytes Established During Development in Mouse Cerebellar White Matter 小鼠小脑白质发育过程中形成的单个少突胶质细胞髓鞘化的轴突选择性
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1002/glia.24660
Batpurev Battulga, Yasuyuki Osanai, Reiji Yamazaki, Yoshiaki Shinohara, Nobuhiko Ohno

Myelin formation by oligodendrocytes regulates the conduction velocity and functional integrity of neuronal axons. While individual oligodendrocytes form myelin sheaths around multiple axons and control the functions of neural circuits where the axons are involved, it remains unclear if oligodendrocytes selectively form myelin sheaths around specific subtypes of axons. Using the combination of rabies virus-mediated single oligodendrocyte labeling and immunostaining with tissue clearing, we revealed that approximately half of the oligodendrocytes preferentially myelinate axons originating from Purkinje cells in the white matter of adult mouse cerebella. The preference for Purkinje cell axons was more pronounced during development when the process of myelination within cerebellar white matter was initiated; over 90% of oligodendrocytes preferentially myelinated Purkinje cell axons. Preferential myelination of Purkinje cell axons was further confirmed by immuno-electron microscopy and transgenic mice that label early-born oligodendrocytes. Transgenic mice that label oligodendrocytes differentiated at the early development showed that early-born oligodendrocytes preferentially myelinate Purkinje cell axons in the matured cerebellar white matter. In contrast, transgenic mice that label oligodendrocytes differentiated after the peak of cerebellar myelination showed that the later-differentiated oligodendrocytes dominantly myelinated non-Purkinje cell axons. These results demonstrate that a significant proportion of oligodendrocytes preferentially myelinate functionally distinct axons in the cerebellar white matter, and the axonal preference of myelination by individual oligodendrocytes is established depending on the timing of their differentiation during development. Our data provide the evidence that there is a critical time window of myelination that a specific subtype of axons are dominantly myelinated by the oligodendrocytes.

少突胶质细胞髓磷脂的形成调节神经轴突的传导速度和功能完整性。虽然单个少突胶质细胞在多个轴突周围形成髓鞘并控制涉及轴突的神经回路的功能,但尚不清楚少突胶质细胞是否选择性地在特定亚型轴突周围形成髓鞘。利用狂犬病毒介导的单个少突胶质细胞标记和组织清除免疫染色相结合的方法,我们发现大约一半的少突胶质细胞优先于髓鞘化成年小鼠小脑白质中源自浦肯野细胞的轴突。在发育过程中,当小脑白质髓鞘形成过程开始时,浦肯野细胞轴突的偏好更为明显;超过90%的少突胶质细胞优先有髓鞘的浦肯野细胞轴突。免疫电镜和标记早期出生的少突胶质细胞的转基因小鼠进一步证实了浦肯野细胞轴突的优先髓鞘形成。标记在发育早期分化的少突胶质细胞的转基因小鼠表明,早期出生的少突胶质细胞优先在成熟的小脑白质中形成浦肯野细胞轴突。相比之下,标记少突胶质细胞的转基因小鼠在小脑髓鞘形成高峰后分化,发现后期分化的少突胶质细胞主要有髓鞘形成非浦肯野细胞轴突。这些结果表明,在小脑白质中,有相当比例的少突胶质细胞优先向功能不同的轴突形成髓鞘,并且单个少突胶质细胞对轴突形成髓鞘的偏好取决于它们在发育过程中分化的时间。我们的数据提供的证据表明,有一个关键的时间窗口的髓鞘形成,一个特定亚型的轴突主要是由少突细胞髓鞘形成。
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引用次数: 0
Lipids: Emerging Players of Microglial Biology 脂质:小胶质细胞生物学的新角色
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1002/glia.24654
Priya Prakash, Caitlin E. Randolph, Katherine A. Walker, Gaurav Chopra

Lipids are small molecule immunomodulators that play critical roles in maintaining cellular health and function. Microglia, the resident immune cells of the central nervous system, regulate lipid metabolism both in the extracellular environment and within intracellular compartments through various mechanisms. For instance, glycerophospholipids and fatty acids interact with protein receptors on the microglial surface, such as the Triggering Receptor Expressed on Myeloid Cells 2, influencing cellular functions like phagocytosis and migration. Moreover, cholesterol is essential not only for microglial survival but, along with other lipids such as fatty acids, is crucial for the formation, function, and accumulation of lipid droplets, which modulate microglial activity in inflammatory diseases. Other lipids, including acylcarnitines and ceramides, participate in various signaling pathways within microglia. Despite the complexity of the microglial lipidome, only a few studies have investigated the effects of specific lipid classes on microglial biology. In this review, we focus on major lipid classes and their roles in modulating microglial function. We also discuss novel analytical techniques for characterizing the microglial lipidome and highlight gaps in current knowledge, suggesting new directions for future research on microglial lipid biology.

脂质是一种小分子免疫调节剂,在维持细胞健康和功能方面发挥着至关重要的作用。小胶质细胞是中枢神经系统的常驻免疫细胞,它们通过各种机制调节细胞外环境和细胞内区室的脂质代谢。例如,甘油磷脂和脂肪酸与小胶质细胞表面的蛋白受体(如髓样细胞上表达的触发受体 2)相互作用,影响吞噬和迁移等细胞功能。此外,胆固醇不仅对小胶质细胞的存活至关重要,而且与脂肪酸等其他脂质一起,对脂滴的形成、功能和积聚也至关重要,而脂滴会在炎症性疾病中调节小胶质细胞的活动。包括酰基肉碱和神经酰胺在内的其他脂质参与了小胶质细胞内的各种信号通路。尽管小胶质细胞脂质体非常复杂,但只有少数研究调查了特定脂质类别对小胶质细胞生物学的影响。在本综述中,我们将重点讨论主要脂质类别及其在调节小胶质细胞功能方面的作用。我们还讨论了表征小胶质细胞脂质体的新型分析技术,并强调了当前知识中的空白,为未来小胶质细胞脂质生物学研究提出了新的方向。
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引用次数: 0
Alzheimer's Disease Risk Gene SORL1 Promotes Receptiveness of Human Microglia to Pro-Inflammatory Stimuli 阿尔茨海默病风险基因SORL1促进人类小胶质细胞对促炎刺激的接受性
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-17 DOI: 10.1002/glia.24659
Peter Lund Ovesen, Kristian Juul-Madsen, Narasimha S. Telugu, Vanessa Schmidt, Silke Frahm, Helena Radbruch, Emma Louise Louth, Anders Rosendal Korshøj, Frank L. Heppner, Sebastian Diecke, Helmut Kettenmann, Thomas E. Willnow

Sorting protein-related receptor containing class A repeats (SORLA) is an intracellular trafficking receptor encoded by the Alzheimer's disease (AD) gene SORL1 (sortilin-related receptor 1). Recent findings argue that altered expression in microglia may underlie the genome-wide risk of AD seen with some SORL1 gene variants, however, the functional significance of the receptor in microglia remains poorly explained. Using unbiased omics and targeted functional analyses in iPSC-based human microglia, we identified a crucial role for SORLA in sensitizing microglia to pro-inflammatory stimuli. We show that SORLA acts as a sorting factor for the pattern recognition receptor CD14, directing CD14 exposure on the cell surface and priming microglia to stimulation by pro-inflammatory factors. Loss of SORLA in gene-targeted microglia impairs proper CD14 sorting and blunts pro-inflammatory responses. Our studies indicate an important role for SORLA in shaping the inflammatory brain milieu, a biological process important to local immune responses in AD.

含有A类重复序列的分选蛋白相关受体(SORLA)是一种由阿尔茨海默病(AD)基因SORL1 (sortilin相关受体1)编码的细胞内转运受体。最近的研究结果认为,小胶质细胞中表达改变可能是一些SORL1基因变异导致AD全基因组风险的基础,然而,该受体在小胶质细胞中的功能意义仍未得到充分解释。通过对基于ipsc的人类小胶质细胞进行无偏组学和靶向功能分析,我们确定了SORLA在使小胶质细胞对促炎刺激敏感方面的关键作用。我们发现SORLA作为模式识别受体CD14的分选因子,引导CD14暴露在细胞表面,并启动促炎因子对小胶质细胞的刺激。SORLA在基因靶向小胶质细胞中的缺失会损害CD14的正确分选并减弱促炎反应。我们的研究表明SORLA在形成炎症性脑环境中发挥重要作用,这是一个对AD局部免疫反应很重要的生物学过程。
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引用次数: 0
Multi Layered Omics Approaches Reveal Glia Specific Alterations in Alzheimer's Disease: A Systematic Review and Future Prospects 多层组学方法揭示阿尔茨海默病中胶质细胞特异性改变:系统回顾和未来展望。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-09 DOI: 10.1002/glia.24652
Özkan İş, Yuhao Min, Xue Wang, Stephanie R. Oatman, Ann Abraham Daniel, Nilüfer Ertekin-Taner

Alzheimer's disease (AD) is the most common neurodegenerative dementia with multi-layered complexity in its molecular etiology. Multiple omics-based approaches, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and lipidomics are enabling researchers to dissect this molecular complexity, and to uncover a plethora of alterations yielding insights into the pathophysiology of this disease. These approaches reveal multi-omics alterations essentially in all cell types of the brain, including glia. In this systematic review, we screen the literature for human studies implementing any omics approach within the last 10 years, to discover AD-associated molecular perturbations in brain glial cells. The findings from over 200 AD-related studies are reviewed under four different glial cell categories: microglia, oligodendrocytes, astrocytes and brain vascular cells. Under each category, we summarize the shared and unique molecular alterations identified in glial cells through complementary omics approaches. We discuss the implications of these findings for the development, progression and ultimately treatment of this complex disease as well as directions for future omics studies in glia cells.

阿尔茨海默病(AD)是最常见的神经退行性痴呆,其分子病因具有多层复杂性。多种基于组学的方法,如基因组学、表观基因组学、转录组学、蛋白质组学、代谢组学和脂质组学,使研究人员能够剖析这种分子复杂性,并揭示大量的改变,从而深入了解这种疾病的病理生理学。这些方法揭示了大脑所有细胞类型的多组学改变,包括神经胶质细胞。在这篇系统综述中,我们筛选了近10年来实施任何组学方法的人类研究文献,以发现ad在脑胶质细胞中的相关分子扰动。本文从小胶质细胞、少突胶质细胞、星形胶质细胞和脑血管细胞四种不同的胶质细胞类别中综述了200多项与ad相关的研究结果。在每个类别下,我们总结了通过互补组学方法在胶质细胞中发现的共享和独特的分子改变。我们讨论了这些发现对这种复杂疾病的发展、进展和最终治疗的意义,以及未来神经胶质细胞组学研究的方向。
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引用次数: 0
Potassium Release From the Habenular Astrocytes Induces Depressive-Like Behaviors in Mice 小鼠缰状星形胶质细胞释放钾诱导抑郁样行为。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-29 DOI: 10.1002/glia.24647
Hidenori Aizawa, Miho Matsumata, Laura Ayaka Noguera Oishi, Fumie Nishimura, Deepa Kamath Kasaragod, Xintong Yao, Wanqin Tan, Tomomi Aida, Kohichi Tanaka

The habenula has been implicated in psychiatric disorders such as depression, primarily because of its role in the modulation of the dopaminergic and serotonergic systems, which play a role in the pathophysiology of these disorders. Despite growing evidence supporting the role of the habenula in behavioral regulation, the process by which neural cells develop in the habenula remains elusive. Since the habenular anlage is found in the prosomere 2 domain expressing transcription factor Dbx1 in mouse embryos, we hypothesized that the Dbx1-expressing prosomere domain is a source of astrocytes that modulate neuronal activity in the habenula. To address this, we examined the cell lineage generated from Dbx1-expressing cells in male mice using tamoxifen-inducible Cre recombinase under the control of the Dbx1 promoter. Perinatal induction of Cre activity labeled cells migrating radially from the ventricular zone to the pial side of the habenular anlage, and eventually showed astrocyte-like morphology with expression of the marker protein, S100β, for mature astrocytes in the habenula of the adult mouse. Photostimulation of astrocytes expressing ChR2 released potassium ions into the extracellular space, which in turn excited the neurons with an increased firing rate in the lateral habenula. Finally, photostimulation of habenular astrocytes exacerbated depression-like phenotypes with reduced locomotor activity, exaggerated despair behavior and impaired sucrose preference in open-field, tail suspension and sucrose preference tests, respectively. These results indicated that the Dbx1-expressing perinatal domain generated astrocytes that modulated neuronal activity via the regulation of extracellular potassium levels.

habenula与抑郁症等精神疾病有关,主要是因为它在多巴胺能和血清素能系统的调节中起作用,而多巴胺能和血清素能系统在这些疾病的病理生理学中起作用。尽管越来越多的证据支持缰带在行为调节中的作用,但缰带中神经细胞发育的过程仍然难以捉摸。由于在小鼠胚胎中,在表达转录因子Dbx1的prosomer 2结构域中发现了habenular样本,因此我们假设表达Dbx1的prosomer结构域是调节habenula神经元活动的星形胶质细胞的来源。为了解决这个问题,我们在Dbx1启动子的控制下,使用他莫昔芬诱导的Cre重组酶检测了表达Dbx1的雄性小鼠细胞的细胞系。围产期感应Cre活动标记细胞的迁移从心室区径向的软膜的一侧habenular原基,并最终显示astrocyte-like形态学标记蛋白的表达,S100β,成熟的星形胶质细胞在成年小鼠的系带。光刺激表达ChR2的星形胶质细胞将钾离子释放到细胞外空间,进而刺激神经元,增加外侧缰核的放电率。最后,光刺激缰状星形胶质细胞加重了抑郁样表型,在野外、悬尾和蔗糖偏好试验中分别表现为运动活动减少、绝望行为加剧和蔗糖偏好受损。这些结果表明,表达dbx1的围产期结构域产生的星形胶质细胞通过调节细胞外钾水平来调节神经元活动。
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引用次数: 0
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