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Maintenance of neural stem cell regional identity in culture. 培养神经干细胞区域特性的维持。
Pub Date : 2016-05-09 eCollection Date: 2016-01-01 DOI: 10.1080/23262133.2016.1187321
Ryan N Delgado, Changqing Lu, Daniel A Lim

Neural stem cells (NSCs) are distributed throughout the ventricular-subventricular zone (V-SVZ) in the adult mouse brain. NSCs located in spatially distinct regions of the V-SVZ generate different types of olfactory bulb (OB) neurons, and the regional expression of specific transcription factors correlates with these differences in NSC developmental potential. In a recent article, we show that Nkx2.1-expressing embryonic precursors give rise to NKX2.1+ NSCs located in the ventral V-SVZ of adult mice. Here we characterize a V-SVZ monolayer culture system that retains regional gene expression and neurogenic potential of NSCs from the dorsal and ventral V-SVZ. In particular, we find that Nkx2.1-lineage V-SVZ NSCs maintain Nkx2.1 expression through serial passage and can generate new neurons in vitro. Thus, V-SVZ NSCs retain key aspects of their in vivo regional identity in culture, providing new experimental opportunities for understanding how such developmental patterns are established and maintained during development.

神经干细胞(NSCs)分布于成年小鼠大脑的整个脑室-室下区(V-SVZ)。位于V-SVZ空间上不同区域的NSCs产生不同类型的嗅球(OB)神经元,特定转录因子的区域表达与这些差异在NSC发育潜力上的相关性。在最近的一篇文章中,我们发现表达NKX2.1的胚胎前体可以产生位于成年小鼠腹侧V-SVZ的NKX2.1+ NSCs。在这里,我们描述了一个V-SVZ单层培养系统,它保留了来自V-SVZ背侧和腹侧的NSCs的区域基因表达和神经发生潜力。特别是,我们发现Nkx2.1谱系的V-SVZ NSCs通过序列传代维持Nkx2.1的表达,并能在体外产生新的神经元。因此,V-SVZ NSCs在培养中保留了其体内区域身份的关键方面,为理解这种发育模式在发育过程中如何建立和维持提供了新的实验机会。
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引用次数: 7
Adult neural stem cell behavior underlying constitutive and restorative neurogenesis in zebrafish. 斑马鱼成体神经干细胞的行为是构成性和恢复性神经发生的基础。
Pub Date : 2016-05-02 eCollection Date: 2016-01-01 DOI: 10.1080/23262133.2016.1148101
Joana S Barbosa, Jovica Ninkovic

Adult Neural Stem Cells (aNSCs) generate new neurons that integrate into the pre-existing networks in specific locations of the Vertebrate brain. Moreover, aNSCs contribute with new neurons to brain regeneration in some non-mammalian Vertebrates. The similarities and the differences in the cellular and molecular processes governing neurogenesis in the intact and regenerating brain are still to be assessed. Toward this end, we recently established a protocol for non-invasive imaging of aNSC behavior in their niche in vivo in the adult intact and regenerating zebrafish telencephalon. We observed different modes of aNSC division in the intact brain and a novel mode of neurogenesis by direct conversion, which contributes to stem cell depletion with age. After injury, the generation of neurons is increased both by the activation of additional aNSCs and a shift in the division mode of aNSCs, thereby contributing to the successful neuronal regeneration. The cellular behavior we observed opens new questions regarding long-term aNSC maintenance in homeostasis and in regeneration. In this commentary we discuss our data and new questions arising in the context of aNSC behavior, not only in zebrafish but also in other species, including mammals.

成体神经干细胞(aNSCs)产生新的神经元,整合到脊椎动物大脑特定位置的预先存在的网络中。此外,在一些非哺乳动物的脊椎动物中,aNSCs对大脑再生有新的神经元贡献。在完整和再生的大脑中,控制神经发生的细胞和分子过程的异同仍有待评估。为此,我们最近建立了一种无创成像方案,用于在成年完整和再生的斑马鱼端脑的体内生态位中观察aNSC的行为。我们在完整的大脑中观察到不同的aNSC分裂模式,以及一种通过直接转化的新神经发生模式,这种模式有助于干细胞随着年龄的增长而耗损。损伤后,通过激活额外的aNSCs和改变aNSCs的分裂模式来增加神经元的生成,从而有助于成功的神经元再生。我们观察到的细胞行为打开了关于长期内稳态和再生中aNSC维持的新问题。在这篇评论中,我们讨论了我们的数据和在斑马鱼以及包括哺乳动物在内的其他物种的aNSC行为背景下出现的新问题。
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引用次数: 23
Mcidas and GemC1/Lynkeas specify embryonic radial glial cells. Mcidas和GemC1/Lynkeas指定胚胎放射状胶质细胞。
Pub Date : 2016-04-27 eCollection Date: 2016-01-01 DOI: 10.1080/23262133.2016.1172747
Christina Kyrousi, Maria-Eleni Lalioti, Eleni Skavatsou, Zoi Lygerou, Stavros Taraviras

Ependymal cells are multiciliated cells located in the wall of the lateral ventricles of the adult mammalian brain and are key components of the subependymal zone niche, where adult neural stem cells reside. Through the movement of their motile cilia, ependymal cells control the cerebrospinal fluid flow within the ventricular system from which they receive secreted molecules and morphogens controlling self-renewal and differentiation decisions of adult neural stem cells. Multiciliated ependymal cells become fully differentiated at postnatal stages however they are specified during mid to late embryogenesis from a population of radial glial cells. Here we discuss recent findings suggesting that 2 novel molecules, Mcidas and GemC1/Lynkeas are key players on radial glial specification to ependymal cells. Both proteins were initially described as cell cycle regulators revealing sequence similarity to Geminin. They are expressed in radial glial cells committed to the ependymal cell lineage during embryogenesis, while overexpression and knock down experiments showed that are sufficient and necessary for ependymal cell generation. We propose that Mcidas and GemC1/Lynkeas are key components of the molecular cascade that promotes radial glial cells fate commitment toward multiciliated ependymal cell lineage operating upstream of c-Myb and FoxJ1.

室管膜细胞是位于成年哺乳动物脑侧脑室壁上的多纤毛细胞,是成体神经干细胞所在的室管膜下区生态位的关键组成部分。室管膜细胞通过其运动纤毛的运动控制脑室系统内的脑脊液流动,并从中获得控制成体神经干细胞自我更新和分化决定的分泌分子和形态因子。多纤毛室管膜细胞在出生后完全分化,但它们是在胚胎发生中后期从放射状胶质细胞群体中分化出来的。在这里,我们讨论了最近的研究结果,表明两种新分子Mcidas和GemC1/Lynkeas是室管膜细胞径向胶质特化的关键分子。这两种蛋白最初被描述为细胞周期调节因子,揭示了与gemini的序列相似性。它们在胚胎发生过程中在室管膜细胞谱系的放射状胶质细胞中表达,而过表达和敲除实验表明,它们是室管膜细胞生成的充分和必要条件。我们认为Mcidas和GemC1/Lynkeas是分子级联的关键组成部分,该分子级联促进放射状胶质细胞向c-Myb和FoxJ1上游的多管室膜细胞谱系的命运承诺。
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引用次数: 12
Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network. 支持平衡的大脑:目标来源的FGF信号调节成熟海马网络中的兴奋/抑制性张力和成人神经发生。
Pub Date : 2016-04-12 eCollection Date: 2016-01-01 DOI: 10.1080/23262133.2016.1168504
Ania Dabrowski, Hisashi Umemori

Brain development involves multiple levels of molecular coordination in forming a functional nervous system. The hippocampus is a brain area that is important for memory formation and spatial reasoning. During early postnatal development of the hippocampal circuit, Fibroblast growth factor 22 (FGF22) and FGF7 act to establish a balance of excitatory and inhibitory tone. Both FGFs are secreted from CA3 dendrites, acting on excitatory or inhibitory axon terminals formed onto CA3 dendrites, respectively. Mechanistically, FGF22 utilizes FGFR2b and FGFR1b to induce synaptic vesicle recruitment within axons of dentate granule cells (DGCs), and FGF7 utilizes FGFR2b to induce synaptic vesicle recruitment within interneuron axons. FGF signaling eventually induces gene expression in the presynaptic neurons; however, the effects of FGF22-induced gene expression within DGCs and FGF7-induced gene expression within interneurons in the context of a developing hippocampal circuit have yet to be explored. Here, we propose one hypothetical mechanism of FGF22-induced gene expression in controlling adult neurogenesis.

大脑发育涉及多个层次的分子协调,形成一个功能性的神经系统。海马体是大脑中一个对记忆形成和空间推理很重要的区域。在出生后早期海马回路发育过程中,成纤维细胞生长因子22 (FGF22)和FGF7的作用是建立兴奋性和抑制性张力的平衡。这两种fgf都是从CA3树突分泌的,分别作用于CA3树突上形成的兴奋性或抑制性轴突终端。机制上,FGF22利用FGFR2b和FGFR1b诱导齿状颗粒细胞(DGCs)轴突内的突触囊泡募集,FGF7利用FGFR2b诱导神经元间轴突内的突触囊泡募集。FGF信号最终诱导突触前神经元的基因表达;然而,fgf22诱导的DGCs内基因表达和fgf7诱导的中间神经元内基因表达在海马回路发育背景下的影响尚待探讨。在这里,我们提出了一种假设的fgf22诱导基因表达控制成人神经发生的机制。
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引用次数: 4
Coordinating progenitor cell cycle exit and differentiation in the developing vertebrate retina. 发育中的脊椎动物视网膜中协调祖细胞周期的退出和分化。
Pub Date : 2016-04-11 eCollection Date: 2016-01-01 DOI: 10.1080/23262133.2016.1161697
Amanda Miles, Vincent Tropepe

The proper development of the vertebrate retina relies heavily on producing the correct number and type of differentiated retinal cell types. To achieve this, proliferating retinal progenitor cells (RPCs) must exit the cell cycle at an appropriate time and correctly express a subset of differentiation markers that help specify retinal cell fate. Homeobox genes, which encode a family of transcription factors, have been accredited to both these processes, implicated in the transcriptional regulation of important cell cycle components, such as cyclins and cyclin-dependent kinases, and proneural genes. This dual regulation of homeobox genes allows these factors to help co-ordinate the transition from the proliferating RPC to postmitotic, differentiated cell. However, understanding the exact molecular targets of these factors remains a challenging task. This commentary highlights the current knowledge we have about how these factors regulate cell cycle progression and differentiation, with particular emphasis on a recent discovery from our lab demonstrating an antagonistic relationship between Vsx2 and Dmbx1 to control RPC proliferation. Future studies should aim to further understand the direct transcriptional targets of these genes, additional co-factors/interacting proteins and the possible recruitment of epigenetic machinery by these homeobox genes.

脊椎动物视网膜的正常发育在很大程度上依赖于产生正确数量和类型的分化视网膜细胞类型。为了实现这一目标,增殖的视网膜祖细胞(RPCs)必须在适当的时间退出细胞周期,并正确表达一组有助于确定视网膜细胞命运的分化标记。同源盒基因编码一个转录因子家族,已被证实参与这两个过程,涉及重要细胞周期成分的转录调控,如细胞周期蛋白和细胞周期蛋白依赖性激酶,以及原基因。这种同源盒基因的双重调控允许这些因子帮助协调从增殖的RPC到有丝分裂后分化的细胞的转变。然而,了解这些因子的确切分子靶点仍然是一项具有挑战性的任务。这篇评论强调了我们目前关于这些因子如何调节细胞周期进程和分化的知识,特别强调了我们实验室最近发现的Vsx2和Dmbx1之间的拮抗关系,以控制RPC增殖。未来的研究应旨在进一步了解这些基因的直接转录靶点、其他辅助因子/相互作用蛋白以及这些同源盒基因可能募集的表观遗传机制。
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引用次数: 11
Cannabinoid receptor signaling induces proliferation but not neurogenesis in the mouse olfactory epithelium. 大麻素受体信号传导诱导小鼠嗅上皮细胞增殖,但不诱导神经发生。
Pub Date : 2016-01-13 eCollection Date: 2016-01-01 DOI: 10.1080/23262133.2015.1118177
Chelsea R Hutch, Colleen C Hegg

The olfactory epithelium actively generates neurons through adulthood, and this neurogenesis is tightly regulated by multiple factors that are not fully defined. Here, we examined the role of cannabinoids in the regulation of neurogenesis in the mouse olfactory epithelium. In vivo proliferation and cell lineage studies were performed in mice (C57BL/6 and cannabinoid type 1 and 2 receptor deficient strains) treated with cannabinoids directly (WIN 55,212-2 or 2-arachidonylglycerol ether) or indirectly via inhibition of cannabinoid hydrolytic enzymes. Cannabinoids increased proliferation in neonatal and adult mice, and had no effect on proliferation in cannabinoid type 1 and 2 receptor deficient adult mice. Pretreatment with the cannabinoid type1 receptor antagonist AM251 decreased cannabinoid-induced proliferation in adult mice. Despite a cannabinoid-induced increase in proliferation, there was no change in newly generated neurons or non-neuronal cells 16 d post-treatment. However, cannabinoid administration increased apoptotic cell death at 72 hours post-treatment and by 16 d the level of apoptosis dropped to control levels. Thus, cannabinoids induce proliferation, but do not induce neurogenesis nor non-neuronal cell generation. Cannabinoid receptor signaling may regulate the balance of progenitor cell survival and proliferation in adult mouse olfactory epithelium.

嗅觉上皮在成年期积极产生神经元,这种神经发生受到多种因素的严格调节,这些因素尚未完全确定。在这里,我们研究了大麻素在调节小鼠嗅上皮神经发生中的作用。在小鼠(C57BL/6和大麻素1型和2型受体缺陷菌株)中,通过大麻素直接(WIN 55,212-2或2-花生四烯基甘油醚)或通过抑制大麻素水解酶间接处理,进行了体内增殖和细胞谱系研究。大麻素增加了新生小鼠和成年小鼠的增殖,而对大麻素1型和2型受体缺乏的成年小鼠的增殖没有影响。大麻素1型受体拮抗剂AM251预处理可降低大麻素诱导的成年小鼠增殖。尽管大麻素诱导增殖增加,但在处理16天后,新生成的神经元或非神经元细胞没有变化。然而,给药后72小时,大麻素增加了凋亡细胞的死亡,到16 d,凋亡水平下降到对照水平。因此,大麻素诱导增殖,但不诱导神经发生或非神经元细胞的产生。大麻素受体信号可能调节成年小鼠嗅上皮祖细胞存活和增殖的平衡。
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引用次数: 12
Can manipulation of differentiation conditions eliminate proliferative cells from a population of ES cell-derived forebrain cells? 操纵分化条件能否消除胚胎干细胞来源的前脑细胞群中的增殖细胞?
Pub Date : 2016-01-11 eCollection Date: 2016-01-01 DOI: 10.1080/23262133.2015.1127311
Sophie V Precious, Claire M Kelly, Nicholas D Allen, Anne E Rosser

There is preliminary evidence that implantation of primary fetal striatal cells provides functional benefit in patients with Huntington's disease, a neurodegenerative condition resulting in loss of medium-sized spiny neurons (MSN) of the striatum. Scarcity of primary fetal tissue means it is important to identify a renewable source of cells from which to derive donor MSNs. Embryonic stem (ES) cells, which predominantly default to telencephalic-like precursors in chemically defined medium (CDM), offer a potentially inexhaustible supply of cells capable of generating the desired neurons. Using an ES cell line, with the forebrain marker FoxG1 tagged to the LacZ reporter, we assessed effects of known developmental factors on the yield of forebrain-like precursor cells in CDM suspension culture. Addition of FGF2, but not DKK1, increased the proportion of FoxG1-expressing cells at day 8 of neural induction. Oct4 was expressed at day 8, but was undetectable by day 16. Differentiation of day 16 precursors generated GABA-expressing neurons, with few DARPP32 positive MSNs. Transplantation of day 8 precursor cells into quinolinic acid-lesioned striata resulted in generation of teratomas. However, transplantation of day 16 precursors yielded grafts expressing neuronal markers including NeuN, calbindin and parvalbumin, but no DARPP32 6 weeks post-transplantation. Manipulation of fate of ES cells requires optimization of both concentration and timing of addition of factors to culture systems to generate the desired phenotypes. Furthermore, we highlight the value of increasing the precursor phase of ES cell suspension culture when directing differentiation toward forebrain fate, so as to dramatically reduce the risk of teratoma formation.

有初步证据表明,原代胎儿纹状体细胞的植入对亨廷顿氏病(一种神经退行性疾病,导致纹状体中等大小的棘神经元(MSN)丢失)患者的功能有益。原代胎儿组织的稀缺性意味着确定可再生细胞来源以获得供体msn非常重要。胚胎干细胞(ES)在化学定义介质(CDM)中主要默认为端脑样前体,提供了潜在的取之不尽的细胞供应,能够产生所需的神经元。我们使用一种ES细胞系,将前脑标记物FoxG1标记在LacZ报告基因上,评估了已知发育因素对CDM悬浮培养中前脑样前体细胞产量的影响。在神经诱导的第8天,添加FGF2而不添加DKK1增加了foxg1表达细胞的比例。Oct4在第8天表达,但在第16天无法检测到。第16天的前体分化产生表达gaba的神经元,很少有DARPP32阳性的msn。将第8天的前体细胞移植到喹啉酸损伤的纹状体中导致畸胎瘤的产生。然而,移植第16天的前体产生的移植物表达神经元标志物包括NeuN, calbindin和parvalbumin,但在移植后6周没有DARPP32。操纵胚胎干细胞的命运需要在培养系统中优化添加因子的浓度和时间,以产生所需的表型。此外,我们强调了增加胚胎干细胞悬浮培养的前体细胞在引导分化走向前脑命运时的价值,从而显著降低畸胎瘤形成的风险。
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引用次数: 2
Prenatal deletion of DNA methyltransferase 1 in neural stem cells impairs neurogenesis and causes anxiety-like behavior in adulthood 神经干细胞中DNA甲基转移酶1的产前缺失会损害神经发生并导致成年期的焦虑样行为
Pub Date : 2016-01-01 DOI: 10.1080/23262133.2016.1232679
Hirofumi Noguchi, Ayaka Kimura, Naoya Murao, M. Namihira, K. Nakashima
ABSTRACT Despite recent advances in our understanding of epigenetic regulation of central nervous system development, little is known regarding the effects of epigenetic dysregulation on neurogenesis and brain function in adulthood. In the present study, we show that prenatal deletion of DNA methyltransferase 1 (Dnmt1) in neural stem cells results in impaired neurogenesis as well as increases in inflammatory features (e.g., elevated glial fibrillary acidic protein [GFAP] expression in astrocytes and increased numbers of microglia) in the adult mouse brain. Moreover, these mice exhibited anxiety-like behavior during an open-field test. These findings suggest that Dnmt1 plays a critical role in regulating neurogenesis and behavior in the developing brain and into adulthood.
尽管最近我们对中枢神经系统发育的表观遗传调控的理解取得了进展,但对于表观遗传失调对成年期神经发生和脑功能的影响知之甚少。在本研究中,我们发现神经干细胞中DNA甲基转移酶1 (Dnmt1)的产前缺失会导致成年小鼠大脑中神经发生受损以及炎症特征增加(例如,星形胶质细胞中胶质纤维酸性蛋白[GFAP]表达升高和小胶质细胞数量增加)。此外,这些小鼠在野外测试中表现出焦虑样行为。这些发现表明,Dnmt1在调节发育中的大脑和成年期的神经发生和行为方面起着关键作用。
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引用次数: 10
USP9X deletion elevates the density of oligodendrocytes within the postnatal dentate gyrus USP9X缺失会增加出生后齿状回内少突胶质细胞的密度
Pub Date : 2016-01-01 DOI: 10.1080/23262133.2016.1235524
Sabrina Oishi, Oressia H. Zalucki, Susitha Premarathne, S. Wood, M. Piper
ABSTRACT Neural stem cells (NSCs) within the adult hippocampal dentate gyrus reside in the subgranular zone (SGZ). A dynamic network of signaling mechanisms controls the balance between the maintenance of NSC identity, and their subsequent differentiation into dentate granule neurons. Recently, the ubiquitin-specific protease 9 X-linked (USP9X) was shown to be important for hippocampal morphogenesis, as mice lacking this gene exhibited a higher proportion of proliferating NSCs, yet a decrease in neuronal numbers, within the postnatal dentate gyrus. Here we reveal that Usp9x-deficiency results in the upregulation of numerous oligodendrocytic and myelin-associated genes within the postnatal hippocampus. Moreover, cell counts reveal a significant increase in oligodendrocyte precursor cells and mature oligodendrocytes per unit volume of the mutant dentate gyrus. Collectively, these findings indicate that USP9X may regulate NSC lineage determination within the postnatal SGZ.
成人海马齿状回内的神经干细胞(NSCs)位于亚颗粒区(SGZ)。一个动态的信号机制网络控制着NSC身份维持和随后向齿状颗粒神经元分化之间的平衡。最近,泛素特异性蛋白酶9x -linked (USP9X)被证明对海马形态发生很重要,因为缺乏该基因的小鼠在出生后齿状回中表现出更高比例的增殖性NSCs,但神经元数量减少。在这里,我们揭示了usp9x缺乏导致出生后海马中许多少突胶质细胞和髓磷脂相关基因的上调。此外,细胞计数显示突变体齿状回单位体积的少突胶质细胞前体细胞和成熟少突胶质细胞显著增加。总的来说,这些发现表明USP9X可能调节出生后SGZ内的NSC谱系决定。
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引用次数: 6
Zebrafish embryos as in vivo test tubes to unravel cell-specific mechanisms of neurogenesis during neurodevelopment and in diseases 斑马鱼胚胎作为体内试管,揭示神经发育和疾病中神经发生的细胞特异性机制
Pub Date : 2016-01-01 DOI: 10.1080/23262133.2016.1232678
É. Samarut
ABSTRACT Zebrafish has become a model of choice for developmental studies in particular for studying neural development and related mechanisms involved in diseases. Indeed, zebrafish provides a fast, handy and accurate model to perform functional genomics on a gene or network of genes of interest. Recently, we successfully purified neural stem cells (NSCs) by fluorescence-activated cell sorting (FACS) from whole embryos in order to analyze cell-specific transcriptomic effects by RNA sequencing. As a result, our work sheds light on signaling pathways that are more likely to be involved in our morpholino-induced neurogenesis phenotype. This cell purification strategy brings zebrafish to a higher level since it now allows one to investigate cell-specific effects of a genetic condition of interest (knockout, knock-down, gain-of-function etc.) at the genomic, transcriptomic and proteomic levels in a genuine in vivo context. With this new potential, there is no doubt that zebrafish will be of a major model with which to unravel complex underlying molecular mechanisms of neurological disorders such as epilepsy, autism spectrum disorders and schizophrenia.
斑马鱼已经成为发育研究的首选模型,特别是在研究神经发育和疾病相关机制方面。事实上,斑马鱼提供了一个快速、方便和准确的模型来对感兴趣的基因或基因网络进行功能基因组学。最近,我们成功地利用荧光激活细胞分选(FACS)从全胚胎中纯化神经干细胞(NSCs),以便通过RNA测序分析细胞特异性转录组效应。因此,我们的工作揭示了更有可能参与我们的morpholino诱导的神经发生表型的信号通路。这种细胞纯化策略将斑马鱼提升到了一个更高的水平,因为它现在允许人们在真正的体内环境中,在基因组、转录组和蛋白质组水平上研究感兴趣的遗传条件(敲除、敲除、功能获得等)的细胞特异性效应。有了这种新的潜力,毫无疑问,斑马鱼将成为揭示癫痫、自闭症谱系障碍和精神分裂症等神经系统疾病复杂的潜在分子机制的主要模型。
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引用次数: 2
期刊
Neurogenesis (Austin, Tex.)
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