Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Ocular dominance plasticity is easily observed during the critical period in early postnatal life. Chondroitin sulfate (CS) is the most abundant component in extracellular structures called perineuronal nets (PNNs), which surround parvalbumin-expressing interneurons (PV-cells). CS accumulates in PNNs at the critical period, but its function in earlier life is unclear. Here, we show that initiation of ocular dominance plasticity was impaired with reduced CS, using mice lacking a key CS-synthesizing enzyme, CSGalNAcT1. Two-photon in vivo imaging showed a weaker visual response of PV-cells with reduced CS compared to wild-type mice. Plasticity onset was restored by a homeoprotein Otx2, which binds the major CS-proteoglycan aggrecan and promotes its further expression. Continuous CS accumulation together with Otx2 contributed bidirectionally to both onset and offset of plasticity, and was substituted by diazepam, which enhances GABA function. Therefore, CS and Otx2 may act as common inducers of both onset and offset of the critical period by promoting PV-cell function throughout the lifetime.

DOI： 10.1038/s41598-017-04007-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FRONTIERS MEDIA SA  

Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondria' function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as K(v)3.1 had juvenile cortex-specific binding sites, suggesting that Otx2 is involved in regulating fast-spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 (Oxr1), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2 deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast-spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease.

DOI： 10.3389/fnins.2017.00307

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Highly localized neuronal spikes in primate temporal cortex can encode associative memory; however, whether memory formation involves area-wide reorganization of ensemble activity, which often accompanies rhythmicity, or just local microcircuit-level plasticity, remains elusive. Using high-density electrocorticography, we capture local-field potentials spanning the monkey temporal lobes, and show that the visual pair-association (PA) memory is encoded in spatial patterns of theta activity in areas TE, 36, and, partially, in the parahippocampal cortex, but not in the entorhinal cortex. The theta patterns elicited by learned paired associates are distinct between pairs, but similar within pairs. This pattern similarity, emerging through novel PA learning, allows a machine-learning decoder trained on theta patterns elicited by a particular visual item to correctly predict the identity of those elicited by its paired associate. Our results suggest that the formation and sharing of widespread cortical theta patterns via learning-induced reorganization are involved in the mechanisms of associative memory representation.

DOI： 10.1038/ncomms11827

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

During development, cells dynamically move or extend their processes, which are achieved by actin dynamics. In the present study, we paid attention to Coactosin, an actin binding protein, and studied its role in actin dynamics. Coactosin was associated with actin and Capping protein in neural crest cells and N1E-115 neuroblastoma cells. Accumulation of Coactosin to cellular processes and its association with actin filaments prompted us to reveal the effect of Coactosin on cell migration. Coactosin overexpression induced cellular processes in cultured neural crest cells. In contrast, knock-down of Coactosin resulted in disruption of actin polymerization and of neural crest cell migration. Importantly, Coactosin was recruited to lamellipodia and filopodia in response to Rac signaling, and mutated Coactosin that cannot bind to F-actin did not react to Rac signaling, nor support neural crest cell migration. It was also shown that deprivation of Rac signaling from neural crest cells by dominant negative Rac1 (DN-Rac1) interfered with neural crest cell migration, and that co-transfection of DN-Rac1 and Coactosin restored neural crest cell migration. From these results we have concluded that Coactosin functions downstream of Rac signaling and that it is involved in neurite extension and neural crest cell migration by actively participating in actin polymerization. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ydbio.2013.04.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

Specific transfer of (orthodenticle homeobox 2) Otx2 homeoprotein into GABAergic interneurons expressing parvalbumin (PV) is necessary and sufficient to open, then close, a critical period (CP) of plasticity in the developing mouse visual cortex. The accumulation of endogenous Otx2 in PV cells suggests the presence of specific Otx2 binding sites. Here, we find that perineuronal nets (PNNs) on the surfaces of PV cells permit the specific, constitutive capture of Otx2. We identify a 15 aa domain containing an arginine-lysine doublet(RK peptide) within Otx2, bearing prototypic traits of a glycosaminoglycan (GAG) binding sequence that mediates Otx2 binding to PNNs, and specifically to chondroitin sulfate D and E, with high affinity. Accordingly, PNN hydrolysis by chondroitinase ABC reduces the amount of endogenous Otx2 in PV cells. Direct infusion of RK peptide similarly disrupts endogenous Otx2 localization to PV cells, reduces PV and PNN expression, and reopens plasticity in adult mice. The closure of one eye during this transient window reduces cortical acuity and is specific to the RK motif, as an Alanine-Alanine variant or a scrambled peptide fails to reactivate plasticity. Conversely, this transient reopening of plasticity in the adult restores binocular vision in amblyopic mice. Thus, one function of PNNs is to facilitate the persistent internalization of Otx2 by PV cells to maintain CP closure. The pharmacological use of the Otx2 GAG binding domain offers a novel, potent therapeutic tool with which to restore cortical plasticity in the mature brain.

DOI： 10.1523/JNEUROSCI.0394-12.2012

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Language：English   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

The shaping of neuronal circuits is essential during postnatal brain development. A window of neuronal remodeling by sensory experience typically occurs during a unique time in early life. The many types of behavior and perception, like human language, birdsong, hearing and vision are refined by experience during these distinct 'critical periods'. The onset of critical periods for vision is delayed in animals that remain in complete darkness from birth. It is then predicted that a 'messenger' within the visual pathway signals the amount of sensory experience that has occurred. Our recent results indicate that Otx2 homeoprotein, an essential morphogen for embryonic head formation, is reused later in life as this 'messenger' for critical period plasticity. The homeoprotein is stimulated by visual experience to propagate into the visual cortex, where it is internalized by GABAergic interneurons, especially Parvalbumin-positive cells (PV-cells). Otx2 promotes the maturation of PV-cells, consequently activating critical period onset in the visual cortex. Here, we discuss recent data that are beginning to illuminate the physiological function of non-cell autonomous homeoproteins, as well as the restriction of their transfer to PV-cells in vivo.

DOI： 10.1111/j.1440-169X.2009.01093.x

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Japan  

An essential approach to understanding the mechanisms of development is to alter a gene function/expression. In vivo electroporation has been adapted as one such technique (Muramatsu et al., 1997). It is a very useful tool to achieve a gain- and loss-of-function (by using RNAi or morpholinos) of a gene of interest (Funahashi et al., 1999
Fukuchi-Shimogori and Grove, 2001
Kos et al., 2001
Katahira and Nakamura, 2003
Sugiyama and Nakamura, 2003). The technique has allowed the altering of gene expression temporally and spatially. Pulse-labeling technique is an approach to manipulate a specific cell population temporally, depending on its birthday, as this chapter describes. This technique is more advantageous over the BrdU application, as it can reveal cell lineage
it also has the ability to manipulate a gain- and loss-of-function into specific precursor cells (Tabata and Nakajima, 2001
Sugiyama and Nakamura, 2003
Huber et al., 2008). In spatial terms, widespread gene transfer by electroporation has provided an efficient way to unveil a new gene function on a given tissue (Nakamura and Funahashi, 2001). On the other hand, the spatial precision of gene transfer also has been addressed as each individual cell responds differently to gene expression. Thus, there has been increasing efforts to improve electrodes and create new techniques such as single-cell electroporation (Haas et al., 2001
Kitamura et al., 2008). © 2009 Springer Japan.

DOI： 10.1007/978-4-431-09427-2_12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Neural circuits are shaped by experience in early postnatal life. Distinct GABAergic connections within visual cortex determine the timing of the critical period for rewiring ocular dominance to establish visual acuity. We find that maturation of the parvalbumin (PV)-cell network that controls plasticity onset is regulated by a selective re-expression of the embryonic Otx2 homeoprotein. Visual experience promoted the accumulation of non-cell-autonomous Otx2 in PV-cells, and cortical infusion of exogenous Otx2 accelerated both PV-cell development and critical period timing. Conversely, conditional removal of Otx2 from non-PV cells or from the visual pathway abolished plasticity. Thus, the experience-dependent transfer of a homeoprotein may establish the physiological milieu for postnatal plasticity of a neural circuit.

DOI： 10.1016/j.cell.2008.05.054

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

The mes-metencephalic boundary (isthmus) works as an organizer for the tectum, and the organizing molecule may be Fgf8. The region where Otx2, En1, and Pax2 are expressed overlappingly may differentiate into the mesencephalon. The di-mesencephalic and mes-metencephalic boundaries are determined by repressive interaction of Pax6 and En1/Pax2 and of Otx2 and Gbx2, respectively. The optic tectum is a visual center in lower vertebrates. The tectum and the retina should be regionalized and be positionally specialized for the proper retinotopic projection. Gradient of En2 plays a crucial role in rostrocaudal polarity formation of the tectum. En2 confers caudal characteristics of the retina by inducing ephrinA2 and A5, which are the repellant molecules for the growth cones of temporal retinal ganglion cells. Grg4 antagonizes the isthmus-related genes, and is involved in the formation of di-mesencephalic boundary and tectal polarity formation at an early phase of development. Then, Grg4 plays a role in tectal laminar formation by controlling the migration pathway. Migration pathway of tectal postmitotic cells changes after E5. The late migratory cells split the early migratory neurons to form laminae h-j of SGFS. Grg4 is expressed in the ventricular layer after E5, and forces postmitotic cells to follow the late migratory pathway, though retinal fibers terminate at laminae a-f of SGFS. Misexpression of Grg4 disrupts the lamina g, and in such tecta retinal arbors invade deep into the tectal layer, indicating that lamina g is a nonpermissive lamina for the retinal arbors. (C) 2004 Wiley Periodicals, Inc.

DOI： 10.1002/neu.10339

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：COMPANY OF BIOLOGISTS LTD  

Mature chick optic tecta consist of 16 laminae and receive retinal fiber projections in a precise retinotopic manner. Retinal axons arborize in laminae a-f of the SGFS, but do not cross the border between lamina f and g. In order to elucidate molecular mechanisms of tectal laminar formation, we first looked at the migration of tectal postmitotic cells. We found that the migration pattern of postmitotic cells changes around E5 and that late migratory cells intervened laminae that were formed by early migratory cells. The coincident appearance of Grg4 expression in the tectal ventricular layer and the change in migration pattern suggested an important role for Grg4. 451 Clonal misexpression of Grg4 resulted in cells migrating to laminae h-j of the SGFS. Massive misexpression of Grg4 resulted in disruption of laminae that were formed by early migratory cells, in particular lamina g of the SGFS. Application of Grg4 morpholino antisense oligonucleotide or the misexpression of a dominant-negative form of Grg4 exerted the opposite effect. We concluded that Grg4 may direct tectal postmitotic cells to follow a late migratory pathway.

DOI： 10.1242/dev.00232

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC  

Alar plate of chick mesencephalon differentiates into the optic tectum. It has been shown that factors expressed in the mes-metencephalic boundary induce the tectum and give positional specificity. Chick Grg4 is expressed at first in the anterior neural fold. The expression localizes from the posterior diencephalon to the mesencephalon by stage 10. To investigate the function of Grg4 in mesencephalic development, Grg4 overexpression was carried out by in ovo electroporation. After Grg4 overexpression, expression of En-2, Pax5, Fgf8, and EphrinA2 was repressed, and Pax6 was upregulated in the mesencephalic region. Grg4 overexpression caused the morphological change; mesencephalic swelling became smaller and the di-mesencephalic boundary shifted posteriorly, that is, the anterior limit of tectum shifted posteriorly. Importantly, cotransfection of Grg4 with Pax5 canceled the tectum-inducing activity of Pax5. These results suggest that Grg4 works as an antagonist against tectum-organizing activity. It was also shown that transfected N-terminal domains of Grg4 induced En-2 expression. Since N-terminal domains were transported to the nucleus in the neuroepithelium, they could act as dominant negative for endogenous Grg4. These results indicate that Grg4 has repressing activity against the organizing molecules and suggest that Grg4 plays important roles in formation of anterior tectal boundary and polarity. (C) 2000 Academic Press.

DOI： 10.1006/dbio.2000.9643

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Otx2 is expressed in the mesencephalon and prosencephalon, and Gbx2 is expressed in the rhombencephalon around stage 10. Loss-of-function studies of these genes in mice have revealed that Otx2 is indispensable for the development of the anterior brain segment, and that Gbx2 is required for the development of the isthmus. We carried out gain-of-function experiments of these genes in chick embryos with a newly developed gene transfer system, in ovo electroporation. When Otx2 was ectopically expressed caudally beyond the midbrain-hindbrain boundary (MHB), the alar plate of the metencephalon differentiated into the optic tectum instead of differentiating into the cerebellum. On the other hand, when Gbx2 was ectopically expressed at the mesencephalon, the caudal limit of the tectum shifted rostrally. We looked at the effects of misexpression on the isthmus- and tectum-related molecules. Otx2 and Gbx2 interacted to repress each other's expression. Ectopic Otx2 and Gbx2 repressed endogenous expression of Fgf8 in the isthmus, but induced Fgf8 expression at the interface between Otx2 and Gbx2 expression. Thus, it is suggested that interaction between Otx2 and Gbx2 determines the site of Fgf8 expression and the posterior limit of the tectum. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0925-4773(99)00262-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

In the early chick embryo, the dorsal-ventral (DV) boundary organizes the apical ectodermal ridge (AER) structure in the limb bud field. Here it is reported that Engrailed-1 (En-l), a homolog of the Drosophila segment polarity gene engrailed expressed in the ventral limb ectoderm, participates in AER formation at the DV boundary of the limb bud. Restricted ectopic expression of En-1 in the dorsal side of the limb bud by transplantation of En-1-overexpressing ectoderm induces ectopic AER at the boundary of En-1-positive and -negative cells. The results suggest that En-1 is involved in AER formation at the DV boundary of the limb bud.

DOI： 10.1046/j.1440-169X.1998.t01-2-00007.x

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En-1, En-2 and Wnt-1 are proposed to be essential signals for the development of the optic tectum in chick embryos. Drosophila engrailed and wingless, homologs of En (En-1 and En-2) and Wnt-1, respectively, have been shown to crossregulate each other. In the present paper, it is reported that crossregulation between En-2 and Wnt-1 is preserved in the development of the chick optic tectum. When En-2 is overexpressed by the replication competent retroviral vector, Wnt-1 is expressed ectopically at the dorsal midline of the diencephalon. When Wnt-1 is introduced extrinsically either by ectopic transplantation of mesencephalon, or by implantation of Wnt-1 producing cells, En-2 is induced ectopically at the dorsal midline of the tel-diencephalic border. Thus, ectopic expression of En-2 and Wnt-1 leads to crossregulation of each other in the chick brain. As diencephalon transdifferentiates into the optic tectum by an appropriate signal, the crossregulation of En-2 and Wnt-1 in the diencephalon may mimic the relationship required for early development in the tectum.

DOI： 10.1046/j.1440-169X.1998.00005.x

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：金原一郎記念医学医療振興財団  

DOI： 10.11477/mf.2425902265

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Language：Japanese   Publisher：(株)中外医学社  

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Language：Japanese   Publisher：東北大学加齢医学研究所  

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