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  1. Development of teeth in chick embryos after mouse neural crest transplantations.

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    Mitsiadis, Thimios A; Chéraud, Yvonnick; Sharpe, Paul; Fontaine-Pérus, Josiane

    2003-05-27

    Teeth were lost in birds 70-80 million years ago. Current thinking holds that it is the avian cranial neural crest-derived mesenchyme that has lost odontogenic capacity, whereas the oral epithelium retains the signaling properties required to induce odontogenesis. To investigate the odontogenic capacity of ectomesenchyme, we have used neural tube transplantations from mice to chick embryos to replace the chick neural crest cell populations with mouse neural crest cells. The mouse/chick chimeras obtained show evidence of tooth formation showing that avian oral epithelium is able to induce a nonavian developmental program in mouse neural crest-derived mesenchymal cells.

  2. Development of teeth in chick embryos after mouse neural crest transplantations

    OpenAIRE

    Mitsiadis, Thimios A.; Chéraud, Yvonnick; Sharpe, Paul; Fontaine-Pérus, Josiane

    2003-01-01

    Teeth were lost in birds 70–80 million years ago. Current thinking holds that it is the avian cranial neural crest-derived mesenchyme that has lost odontogenic capacity, whereas the oral epithelium retains the signaling properties required to induce odontogenesis. To investigate the odontogenic capacity of ectomesenchyme, we have used neural tube transplantations from mice to chick embryos to replace the chick neural crest cell populations with mouse neural crest cells. The mouse/chick ...

  3. Two pore channel 2 differentially modulates neural differentiation of mouse embryonic stem cells.

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    Zhe-Hao Zhang

    Full Text Available Nicotinic acid adenine dinucleotide phosphate (NAADP is an endogenous Ca(2+ mobilizing nucleotide presented in various species. NAADP mobilizes Ca(2+ from acidic organelles through two pore channel 2 (TPC2 in many cell types and it has been previously shown that NAADP can potently induce neuronal differentiation in PC12 cells. Here we examined the role of TPC2 signaling in the neural differentiation of mouse embryonic stem (ES cells. We found that the expression of TPC2 was markedly decreased during the initial ES cell entry into neural progenitors, and the levels of TPC2 gradually rebounded during the late stages of neurogenesis. Correspondingly, TPC2 knockdown accelerated mouse ES cell differentiation into neural progenitors but inhibited these neural progenitors from committing to neurons. Overexpression of TPC2, on the other hand, inhibited mouse ES cell from entering the early neural lineage. Interestingly, TPC2 knockdown had no effect on the differentiation of astrocytes and oligodendrocytes of mouse ES cells. Taken together, our data indicate that TPC2 signaling plays a temporal and differential role in modulating the neural lineage entry of mouse ES cells, in that TPC2 signaling inhibits ES cell entry to early neural progenitors, but is required for late neuronal differentiation.

  4. Animal models for studying neural crest development: is the mouse different?

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    Barriga, Elias H; Trainor, Paul A; Bronner, Marianne; Mayor, Roberto

    2015-05-01

    The neural crest is a uniquely vertebrate cell type and has been well studied in a number of model systems. Zebrafish, Xenopus and chick embryos largely show consistent requirements for specific genes in early steps of neural crest development. By contrast, knockouts of homologous genes in the mouse often do not exhibit comparable early neural crest phenotypes. In this Spotlight article, we discuss these species-specific differences, suggest possible explanations for the divergent phenotypes in mouse and urge the community to consider these issues and the need for further research in complementary systems. © 2015. Published by The Company of Biologists Ltd.

  5. Requirement of mouse BCCIP for neural development and progenitor proliferation.

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    Yi-Yuan Huang

    Full Text Available Multiple DNA repair pathways are involved in the orderly development of neural systems at distinct stages. The homologous recombination (HR pathway is required to resolve stalled replication forks and critical for the proliferation of progenitor cells during neural development. BCCIP is a BRCA2 and CDKN1A interacting protein implicated in HR and inhibition of DNA replication stress. In this study, we determined the role of BCCIP in neural development using a conditional BCCIP knock-down mouse model. BCCIP deficiency impaired embryonic and postnatal neural development, causing severe ataxia, cerebral and cerebellar defects, and microcephaly. These development defects are associated with spontaneous DNA damage and subsequent cell death in the proliferative cell populations of the neural system during embryogenesis. With in vitro neural spheroid cultures, BCCIP deficiency impaired neural progenitor's self-renewal capability, and spontaneously activated p53. These data suggest that BCCIP and its anti-replication stress functions are essential for normal neural development by maintaining an orderly proliferation of neural progenitors.

  6. Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects

    NARCIS (Netherlands)

    Korstanje, Ron; Desai, Jigar; Lazar, Gloria; King, Benjamin; Rollins, Jarod; Spurr, Melissa; Joseph, Jamie; Kadambi, Sindhuja; Li, Yang; Cherry, Allison; Matteson, Paul G.; Paigen, Beverly; Millonig, James H.

    Korstanje R, Desai J, Lazar G, King B, Rollins J, Spurr M, Joseph J, Kadambi S, Li Y, Cherry A, Matteson PG, Paigen B, Millonig JH. Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects. Physiol Genomics 35:

  7. Mouse neuroblastoma cell based model and the effect of epileptic events on calcium oscillations and neural spikes

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    Kim, Suhwan; Baek, Juyeong; Jung, Unsang; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

    2013-05-01

    Recently, Mouse neuroblastoma cells are considered as an attractive model for the study of human neurological and prion diseases, and intensively used as a model system in different areas. Among those areas, differentiation of neuro2a (N2A) cells, receptor mediated ion current, and glutamate induced physiological response are actively investigated. The reason for the interest to mouse neuroblastoma N2A cells is that they have a fast growing rate than other cells in neural origin with a few another advantages. This study evaluated the calcium oscillations and neural spikes recording of mouse neuroblastoma N2A cells in an epileptic condition. Based on our observation of neural spikes in mouse N2A cell with our proposed imaging modality, we report that mouse neuroblastoma N2A cells can be an important model related to epileptic activity studies. It is concluded that the mouse neuroblastoma N2A cells produce the epileptic spikes in vitro in the same way as produced by the neurons or the astrocytes. This evidence advocates the increased and strong level of neurotransmitters release by enhancement in free calcium using the 4-aminopyridine which causes the mouse neuroblastoma N2A cells to produce the epileptic spikes and calcium oscillation.

  8. Mouse neuroblastoma cell-based model and the effect of epileptic events on calcium oscillations and neural spikes

    Science.gov (United States)

    Kim, Suhwan; Jung, Unsang; Baek, Juyoung; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

    2013-01-01

    Recently, mouse neuroblastoma cells have been considered as an attractive model for the study of human neurological and prion diseases, and they have been intensively used as a model system in different areas. For example, the differentiation of neuro2a (N2A) cells, receptor-mediated ion current, and glutamate-induced physiological responses have been actively investigated with these cells. These mouse neuroblastoma N2A cells are of interest because they grow faster than other cells of neural origin and have a number of other advantages. The calcium oscillations and neural spikes of mouse neuroblastoma N2A cells in epileptic conditions are evaluated. Based on our observations of neural spikes in these cells with our proposed imaging modality, we reported that they can be an important model in epileptic activity studies. We concluded that mouse neuroblastoma N2A cells produce epileptic spikes in vitro in the same way as those produced by neurons or astrocytes. This evidence suggests that increased levels of neurotransmitter release due to the enhancement of free calcium from 4-aminopyridine causes the mouse neuroblastoma N2A cells to produce epileptic spikes and calcium oscillations.

  9. Decreased neural precursor cell pool in NADPH oxidase 2-deficiency: From mouse brain to neural differentiation of patient derived iPSC

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    Zeynab Nayernia

    2017-10-01

    Full Text Available There is emerging evidence for the involvement of reactive oxygen species (ROS in the regulation of stem cells and cellular differentiation. Absence of the ROS-generating NADPH oxidase NOX2 in chronic granulomatous disease (CGD patients, predominantly manifests as immune deficiency, but has also been associated with decreased cognition. Here, we investigate the role of NOX enzymes in neuronal homeostasis in adult mouse brain and in neural cells derived from human induced pluripotent stem cells (iPSC. High levels of NOX2 were found in mouse adult neurogenic regions. In NOX2-deficient mice, neurogenic regions showed diminished redox modifications, as well as decrease in neuroprecursor numbers and in expression of genes involved in neural differentiation including NES, BDNF and OTX2. iPSC from healthy subjects and patients with CGD were used to study the role of NOX2 in human in vitro neuronal development. Expression of NOX2 was low in undifferentiated iPSC, upregulated upon neural induction, and disappeared during neuronal differentiation. In human neurospheres, NOX2 protein and ROS generation were polarized within the inner cell layer of rosette structures. NOX2 deficiency in CGD-iPSCs resulted in an abnormal neural induction in vitro, as revealed by a reduced expression of neuroprogenitor markers (NES, BDNF, OTX2, NRSF/REST, and a decreased generation of mature neurons. Vector-mediated NOX2 expression in NOX2-deficient iPSCs rescued neurogenesis. Taken together, our study provides novel evidence for a regulatory role of NOX2 during early stages of neurogenesis in mouse and human.

  10. In vivo transplantation of enteric neural crest cells into mouse gut; Engraftment, functional integration and long-term safety

    NARCIS (Netherlands)

    J.E. Cooper (Julie E.); C. Mccann; D. Natarajan (Dipa); S. Choudhury; W. Boesmans (Werend); J.-M. Delalande (Jean-Marie); P.V. Berghe (Pieter Vanden); A.J. Burns (Alan); N. Thapar (Nikhil)

    2016-01-01

    textabstractObjectives: Enteric neuropathies are severe gastrointestinal disorders with unsatisfactory outcomes. We aimed to investigate the potential of enteric neural stem cell therapy approaches for such disorders by transplanting mouse enteric neural crest cells (ENCCs) into ganglionic and

  11. Involvement of Atm and Trp53 in neural cell loss due to Terf2 inactivation during mouse brain development.

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    Kim, Jusik; Choi, Inseo; Lee, Youngsoo

    2017-11-01

    Maintenance of genomic integrity is one of the critical features for proper neurodevelopment and inhibition of neurological diseases. The signals from both ATM and ATR to TP53 are well-known mechanisms to remove neural cells with DNA damage during neurogenesis. Here we examined the involvement of Atm and Atr in genomic instability due to Terf2 inactivation during mouse brain development. Selective inactivation of Terf2 in neural progenitors induced apoptosis, resulting in a complete loss of the brain structure. This neural loss was rescued partially in both Atm and Trp53 deficiency, but not in an Atr-deficient background in the mouse. Atm inactivation resulted in incomplete brain structures, whereas p53 deficiency led to the formation of multinucleated giant neural cells and the disruption of the brain structure. These giant neural cells disappeared in Lig4 deficiency. These data demonstrate ATM and TP53 are important for the maintenance of telomere homeostasis and the surveillance of telomere dysfunction during neurogenesis.

  12. Identifying Tmem59 related gene regulatory network of mouse neural stem cell from a compendium of expression profiles

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    Guo Xiuyun

    2011-09-01

    Full Text Available Abstract Background Neural stem cells offer potential treatment for neurodegenerative disorders, such like Alzheimer's disease (AD. While much progress has been made in understanding neural stem cell function, a precise description of the molecular mechanisms regulating neural stem cells is not yet established. This lack of knowledge is a major barrier holding back the discovery of therapeutic uses of neural stem cells. In this paper, the regulatory mechanism of mouse neural stem cell (NSC differentiation by tmem59 is explored on the genome-level. Results We identified regulators of tmem59 during the differentiation of mouse NSCs from a compendium of expression profiles. Based on the microarray experiment, we developed the parallelized SWNI algorithm to reconstruct gene regulatory networks of mouse neural stem cells. From the inferred tmem59 related gene network including 36 genes, pou6f1 was identified to regulate tmem59 significantly and might play an important role in the differentiation of NSCs in mouse brain. There are four pathways shown in the gene network, indicating that tmem59 locates in the downstream of the signalling pathway. The real-time RT-PCR results shown that the over-expression of pou6f1 could significantly up-regulate tmem59 expression in C17.2 NSC line. 16 out of 36 predicted genes in our constructed network have been reported to be AD-related, including Ace, aqp1, arrdc3, cd14, cd59a, cds1, cldn1, cox8b, defb11, folr1, gdi2, mmp3, mgp, myrip, Ripk4, rnd3, and sncg. The localization of tmem59 related genes and functional-related gene groups based on the Gene Ontology (GO annotation was also identified. Conclusions Our findings suggest that the expression of tmem59 is an important factor contributing to AD. The parallelized SWNI algorithm increased the efficiency of network reconstruction significantly. This study enables us to highlight novel genes that may be involved in NSC differentiation and provides a shortcut to

  13. Altered behavior and neural activity in conspecific cagemates co-housed with mouse models of brain disorders.

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    Yang, Hyunwoo; Jung, Seungmoon; Seo, Jinsoo; Khalid, Arshi; Yoo, Jung-Seok; Park, Jihyun; Kim, Soyun; Moon, Jangsup; Lee, Soon-Tae; Jung, Keun-Hwa; Chu, Kon; Lee, Sang Kun; Jeon, Daejong

    2016-09-01

    The psychosocial environment is one of the major contributors of social stress. Family members or caregivers who consistently communicate with individuals with brain disorders are considered at risk for physical and mental health deterioration, possibly leading to mental disorders. However, the underlying neural mechanisms of this phenomenon remain poorly understood. To address this, we developed a social stress paradigm in which a mouse model of epilepsy or depression was housed long-term (>4weeks) with normal conspecifics. We characterized the behavioral phenotypes and electrophysiologically investigated the neural activity of conspecific cagemate mice. The cagemates exhibited deficits in behavioral tasks assessing anxiety, locomotion, learning/memory, and depression-like behavior. Furthermore, they showed severe social impairment in social behavioral tasks involving social interaction or aggression. Strikingly, behavioral dysfunction remained in the cagemates 4weeks following co-housing cessation with the mouse models. In an electrophysiological study, the cagemates showed an increased number of spikes in medial prefrontal cortex (mPFC) neurons. Our results demonstrate that conspecifics co-housed with mouse models of brain disorders develop chronic behavioral dysfunctions, and suggest a possible association between abnormal mPFC neural activity and their behavioral pathogenesis. These findings contribute to the understanding of the psychosocial and psychiatric symptoms frequently present in families or caregivers of patients with brain disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Assessment of the developmental totipotency of neural cells in the cerebral cortex of mouse embryo by nuclear transfer

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    Yamazaki, Yukiko; Makino, Hatsune; Hamaguchi-Hamada, Kayoko; Hamada, Shun; Sugino, Hidehiko; Kawase, Eihachiro; Miyata, Takaki; Ogawa, Masaharu; Yanagimachi, Ryuzo; Yagi, Takeshi

    2001-01-01

    When neural cells were collected from the entire cerebral cortex of developing mouse fetuses (15.5–17.5 days postcoitum) and their nuclei were transferred into enucleated oocytes, 5.5% of the reconstructed oocytes developed into normal offspring. This success rate was the highest among all previous mouse cloning experiments that used somatic cells. Forty-four percent of live embryos at 10.5 days postcoitum were morphologically normal when premature and early-postmitotic neural cells from the ventricular side of the cortex were used. In contrast, the majority (95%) of embryos were morphologically abnormal (including structural abnormalities in the neural tube) when postmitotic-differentiated neurons from the pial side of the cortex were used for cloning. Whereas 4.3% of embryos cloned with ventricular-side cells developed into healthy offspring, only 0.5% of those cloned with differentiated neurons in the pial side did so. These facts seem to suggest that the nuclei of neural cells in advanced stages of differentiation had lost their developmental totipotency. The underlying mechanism for this developmental limitation could be somatic DNA rearrangements in differentiating neural cells. PMID:11698647

  15. Characterization of calcium responses and electrical activity in differentiating mouse neural progenitor cells in vitro

    NARCIS (Netherlands)

    de Groot, Martje W G D M; Dingemans, Milou M L; Rus, Katinka H; de Groot, Aart; Westerink, Remco H S

    In vitro methods for developmental neurotoxicity (DNT) testing have the potential to reduce animal use and increase insight into cellular and molecular mechanisms underlying chemical-induced alterations in the development of functional neuronal networks. Mouse neural progenitor cells (mNPCs)

  16. Deep convolutional neural networks for annotating gene expression patterns in the mouse brain.

    Science.gov (United States)

    Zeng, Tao; Li, Rongjian; Mukkamala, Ravi; Ye, Jieping; Ji, Shuiwang

    2015-05-07

    Profiling gene expression in brain structures at various spatial and temporal scales is essential to understanding how genes regulate the development of brain structures. The Allen Developing Mouse Brain Atlas provides high-resolution 3-D in situ hybridization (ISH) gene expression patterns in multiple developing stages of the mouse brain. Currently, the ISH images are annotated with anatomical terms manually. In this paper, we propose a computational approach to annotate gene expression pattern images in the mouse brain at various structural levels over the course of development. We applied deep convolutional neural network that was trained on a large set of natural images to extract features from the ISH images of developing mouse brain. As a baseline representation, we applied invariant image feature descriptors to capture local statistics from ISH images and used the bag-of-words approach to build image-level representations. Both types of features from multiple ISH image sections of the entire brain were then combined to build 3-D, brain-wide gene expression representations. We employed regularized learning methods for discriminating gene expression patterns in different brain structures. Results show that our approach of using convolutional model as feature extractors achieved superior performance in annotating gene expression patterns at multiple levels of brain structures throughout four developing ages. Overall, we achieved average AUC of 0.894 ± 0.014, as compared with 0.820 ± 0.046 yielded by the bag-of-words approach. Deep convolutional neural network model trained on natural image sets and applied to gene expression pattern annotation tasks yielded superior performance, demonstrating its transfer learning property is applicable to such biological image sets.

  17. The effect of interferon-β on mouse neural progenitor cell survival and differentiation

    International Nuclear Information System (INIS)

    Hirsch, Marek; Knight, Julia; Tobita, Mari; Soltys, John; Panitch, Hillel; Mao-Draayer, Yang

    2009-01-01

    Interferon-β (IFN-β) is a mainstay therapy for relapse-remitting multiple sclerosis (MS). However, the direct effects of IFN-β on the central nervous system (CNS) are not well understood. To determine whether IFN-β has direct neuroprotective effects on CNS cells, we treated adult mouse neural progenitor cells (NPCs) in vitro with IFN-β and examined the effects on proliferation, apoptosis, and differentiation. We found that mouse NPCs express high levels of IFNα/β receptor (IFNAR). In response to IFN-β treatment, no effect was observed on differentiation or proliferation. However, IFN-β treated mouse NPCs demonstrated decreased apoptosis upon growth factor withdrawal. Pathway-specific polymerase chain reaction (PCR) arrays demonstrated that IFN-β treatment upregulated the STAT 1 and 2 signaling pathway, as well as GFRA2, NOD1, Caspases 1 and 12, and TNFSF10. These results suggest that IFN-β can directly affect NPC survival, possibly playing a neuroprotective role in the CNS by modulating neurotrophic factors.

  18. The effect of interferon-{beta} on mouse neural progenitor cell survival and differentiation

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    Hirsch, Marek [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States); Knight, Julia [Neuroscience Department, University of Vermont College of Medicine, Burlington, VT (United States); Tobita, Mari; Soltys, John; Panitch, Hillel [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States); Mao-Draayer, Yang, E-mail: yang.mao-draayer@vtmednet.org [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States)

    2009-10-16

    Interferon-{beta} (IFN-{beta}) is a mainstay therapy for relapse-remitting multiple sclerosis (MS). However, the direct effects of IFN-{beta} on the central nervous system (CNS) are not well understood. To determine whether IFN-{beta} has direct neuroprotective effects on CNS cells, we treated adult mouse neural progenitor cells (NPCs) in vitro with IFN-{beta} and examined the effects on proliferation, apoptosis, and differentiation. We found that mouse NPCs express high levels of IFN{alpha}/{beta} receptor (IFNAR). In response to IFN-{beta} treatment, no effect was observed on differentiation or proliferation. However, IFN-{beta} treated mouse NPCs demonstrated decreased apoptosis upon growth factor withdrawal. Pathway-specific polymerase chain reaction (PCR) arrays demonstrated that IFN-{beta} treatment upregulated the STAT 1 and 2 signaling pathway, as well as GFRA2, NOD1, Caspases 1 and 12, and TNFSF10. These results suggest that IFN-{beta} can directly affect NPC survival, possibly playing a neuroprotective role in the CNS by modulating neurotrophic factors.

  19. Isolation and characterization of neural stem cells from dystrophic mdx mouse

    International Nuclear Information System (INIS)

    Annese, Tiziana; Corsi, Patrizia; Ruggieri, Simona; Tamma, Roberto; Marinaccio, Christian; Picocci, Sabrina; Errede, Mariella; Specchia, Giorgina; De Luca, Annamaria; Frassanito, Maria Antonia; Desantis, Vanessa; Vacca, Angelo; Ribatti, Domenico; Nico, Beatrice

    2016-01-01

    The blood-brain barrier (BBB) is altered in mdx mouse, an animal model to study Duchenne muscular dystrophy (DMD). Our previous work demonstrated that perivascular glial endfeet control the selective exchanges between blood and neuropil as well as the BBB development and integrity; the alterations of dystrophin and dystrophin-associated protein complex (DAPs) in the glial cells of mdx mouse, parallel damages of the BBB and increase in vascular permeability. The aim of this study was to improve our knowledge about brain cellular components in the mdx mouse through the isolation, for the first time, of the adult neural stem cells (ANSCs). We characterized them by FACS, electron microscopy, confocal immunofluorescence microscopy, Real Time-PCR and western blotting, and we studied the expression of the DAPs aquaporin-4 (AQP4), potassium channel Kir4.1, α- and β-dystroglycan (αDG, βDG), α-syntrophin (αSyn), and short dystrophin isoform Dp71 proteins. The results showed that the mdx ANSCs expressed CD133 and Nestin receptor as the control ones, but showed a reduction in Notch receptor and altered cell proliferation with an increment in the apoptotic nuclei. Ultrastructurally, they appeared 50% size reduced compared to control ones, with a few cytoplasmic organelles. Moreover, the mdx ANSCs are devoid in full length dystrophin 427, and they expressed post-transcriptional reduction in the Dp71 in parallel with the ubiquitin proteasome activation, and decrement of DAPs proteins which appeared diffused in the cytoplasm and not polarized on the stem cells plasmamembrane, as prevalently observed in the controls. Overall, these results indicate that structural and molecular alterations affect the neural stem cells in the dystrophic brain, whose increased apoptosis and reduced Dp71 and DAPs proteins expression, together with loss in Dp427 dystrophin, could be responsible of the altered mdx glial maintenance and differentiation and consequent failure in the vessels barrier

  20. Isolation and characterization of neural stem cells from dystrophic mdx mouse

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    Annese, Tiziana [Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Corsi, Patrizia [Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Physiology, University of Bari Medical School, Bari (Italy); Ruggieri, Simona; Tamma, Roberto; Marinaccio, Christian [Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Picocci, Sabrina [Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Physiology, University of Bari Medical School, Bari (Italy); Errede, Mariella [Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); Specchia, Giorgina [Department of Emergency and Transplantation, Section of Hematology, University of Bari Medical School, Bari (Italy); De Luca, Annamaria [Department of Bioscience, Biotechnology and Pharmacological Sciences, Section of Pharmacology, University of Bari (Italy); Frassanito, Maria Antonia; Desantis, Vanessa; Vacca, Angelo [Department of Internal Medicine and Oncology, University of Bari Medical School, Bari (Italy); Ribatti, Domenico, E-mail: domenico.ribatti@uniba.it [Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy); National Cancer Institute “Giovanni Paolo II”, Bari (Italy); Nico, Beatrice, E-mail: beatrice.nico@uniba.it [Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari (Italy)

    2016-05-01

    The blood-brain barrier (BBB) is altered in mdx mouse, an animal model to study Duchenne muscular dystrophy (DMD). Our previous work demonstrated that perivascular glial endfeet control the selective exchanges between blood and neuropil as well as the BBB development and integrity; the alterations of dystrophin and dystrophin-associated protein complex (DAPs) in the glial cells of mdx mouse, parallel damages of the BBB and increase in vascular permeability. The aim of this study was to improve our knowledge about brain cellular components in the mdx mouse through the isolation, for the first time, of the adult neural stem cells (ANSCs). We characterized them by FACS, electron microscopy, confocal immunofluorescence microscopy, Real Time-PCR and western blotting, and we studied the expression of the DAPs aquaporin-4 (AQP4), potassium channel Kir4.1, α- and β-dystroglycan (αDG, βDG), α-syntrophin (αSyn), and short dystrophin isoform Dp71 proteins. The results showed that the mdx ANSCs expressed CD133 and Nestin receptor as the control ones, but showed a reduction in Notch receptor and altered cell proliferation with an increment in the apoptotic nuclei. Ultrastructurally, they appeared 50% size reduced compared to control ones, with a few cytoplasmic organelles. Moreover, the mdx ANSCs are devoid in full length dystrophin 427, and they expressed post-transcriptional reduction in the Dp71 in parallel with the ubiquitin proteasome activation, and decrement of DAPs proteins which appeared diffused in the cytoplasm and not polarized on the stem cells plasmamembrane, as prevalently observed in the controls. Overall, these results indicate that structural and molecular alterations affect the neural stem cells in the dystrophic brain, whose increased apoptosis and reduced Dp71 and DAPs proteins expression, together with loss in Dp427 dystrophin, could be responsible of the altered mdx glial maintenance and differentiation and consequent failure in the vessels barrier

  1. Bitter taste stimuli induce differential neural codes in mouse brain.

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    David M Wilson

    Full Text Available A growing literature suggests taste stimuli commonly classified as "bitter" induce heterogeneous neural and perceptual responses. Here, the central processing of bitter stimuli was studied in mice with genetically controlled bitter taste profiles. Using these mice removed genetic heterogeneity as a factor influencing gustatory neural codes for bitter stimuli. Electrophysiological activity (spikes was recorded from single neurons in the nucleus tractus solitarius during oral delivery of taste solutions (26 total, including concentration series of the bitter tastants quinine, denatonium benzoate, cycloheximide, and sucrose octaacetate (SOA, presented to the whole mouth for 5 s. Seventy-nine neurons were sampled; in many cases multiple cells (2 to 5 were recorded from a mouse. Results showed bitter stimuli induced variable gustatory activity. For example, although some neurons responded robustly to quinine and cycloheximide, others displayed concentration-dependent activity (p<0.05 to quinine but not cycloheximide. Differential activity to bitter stimuli was observed across multiple neurons recorded from one animal in several mice. Across all cells, quinine and denatonium induced correlated spatial responses that differed (p<0.05 from those to cycloheximide and SOA. Modeling spatiotemporal neural ensemble activity revealed responses to quinine/denatonium and cycloheximide/SOA diverged during only an early, at least 1 s wide period of the taste response. Our findings highlight how temporal features of sensory processing contribute differences among bitter taste codes and build on data suggesting heterogeneity among "bitter" stimuli, data that challenge a strict monoguesia model for the bitter quality.

  2. Cocaine- and amphetamine-regulated transcript promotes the differentiation of mouse bone marrow-derived mesenchymal stem cells into neural cells

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    Jin Jiali; Chen Zhibin; Zhang Meijuan; Huang Danqing; Liu Zhuo; Huang Siyuan; Zhang Zhuo; Wang Zhongyuan; Chen Lei; Chen Ling; Xu Yun

    2011-01-01

    Abstract Background Neural tissue has limited potential to self-renew after neurological damage. Cell therapy using BM-MSCs (bone marrow mesenchymal stromal cells) seems like a promising approach for the treatment of neurological diseases. However, the neural differentiation of stem cells influenced by massive factors and interactions is not well studied at present. Results In this work, we isolated and identified MSCs from mouse bone marrow. Co-cultured with CART (0.4 nM) for six days, BM-MS...

  3. Intraocular Injection of ES Cell-Derived Neural Progenitors Improve Visual Function in Retinal Ganglion Cell-Depleted Mouse Models

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    Mundackal S. Divya

    2017-09-01

    Full Text Available Retinal ganglion cell (RGC transplantation is a promising strategy to restore visual function resulting from irreversible RGC degeneration occurring in glaucoma or inherited optic neuropathies. We previously demonstrated FGF2 induced differentiation of mouse embryonic stem cells (ESC to RGC lineage, capable of retinal ganglion cell layer (GCL integration upon transplantation. Here, we evaluated possible improvement of visual function by transplantation of ES cell derived neural progenitors in RGC depleted glaucoma mice models. ESC derived neural progenitors (ES-NP were transplanted into N-Methyl-D-Aspartate (NMDA injected, RGC-ablated mouse models and a pre-clinical glaucoma mouse model (DBA/2J having sustained higher intra ocular pressure (IOP. Visual acuity and functional integration was evaluated by behavioral experiments and immunohistochemistry, respectively. GFP-expressing ES-NPs transplanted in NMDA-injected RGC-depleted mice differentiated into RGC lineage and possibly integrating into GCL. An improvement in visual acuity was observed after 2 months of transplantation, when compared to the pre-transplantation values. Expression of c-Fos in the transplanted cells, upon light induction, further suggests functional integration into the host retinal circuitry. However, the transplanted cells did not send axonal projections into optic nerve. Transplantation experiments in DBA/2J mouse showed no significant improvement in visual functions, possibly due to both host and transplanted retinal cell death which could be due to an inherent high IOP. We showed that, ES NPs transplanted into the retina of RGC-ablated mouse models could survive, differentiate to RGC lineage, and possibly integrate into GCL to improve visual function. However, for the survival of transplanted cells in glaucoma, strategies to control the IOP are warranted.

  4. Induced Neural Stem Cells Achieve Long-Term Survival and Functional Integration in the Adult Mouse Brain

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    Kathrin Hemmer

    2014-09-01

    Full Text Available Differentiated cells can be converted directly into multipotent neural stem cells (i.e., induced neural stem cells [iNSCs]. iNSCs offer an attractive alternative to induced pluripotent stem cell (iPSC technology with regard to regenerative therapies. Here, we show an in vivo long-term analysis of transplanted iNSCs in the adult mouse brain. iNSCs showed sound in vivo long-term survival rates without graft overgrowths. The cells displayed a neural multilineage potential with a clear bias toward astrocytes and a permanent downregulation of progenitor and cell-cycle markers, indicating that iNSCs are not predisposed to tumor formation. Furthermore, the formation of synaptic connections as well as neuronal and glial electrophysiological properties demonstrated that differentiated iNSCs migrated, functionally integrated, and interacted with the existing neuronal circuitry. We conclude that iNSC long-term transplantation is a safe procedure; moreover, it might represent an interesting tool for future personalized regenerative applications.

  5. In Vivo Transplantation of Enteric Neural Crest Cells into Mouse Gut; Engraftment, Functional Integration and Long-Term Safety.

    Directory of Open Access Journals (Sweden)

    Julie E Cooper

    Full Text Available Enteric neuropathies are severe gastrointestinal disorders with unsatisfactory outcomes. We aimed to investigate the potential of enteric neural stem cell therapy approaches for such disorders by transplanting mouse enteric neural crest cells (ENCCs into ganglionic and aganglionic mouse gut in vivo and analysing functional integration and long-term safety.Neurospheres generated from yellow fluorescent protein (YFP expressing ENCCs selected from postnatal Wnt1-cre;R26R-YFP/YFP murine gut were transplanted into ganglionic hindgut of wild-type littermates or aganglionic hindgut of Ednrbtm1Ywa mice (lacking functional endothelin receptor type-B. Intestines were then assessed for ENCC integration and differentiation using immunohistochemistry, cell function using calcium imaging, and long-term safety using PCR to detect off-target YFP expression.YFP+ ENCCs engrafted, proliferated and differentiated into enteric neurons and glia within recipient ganglionic gut. Transplanted cells and their projections spread along the endogenous myenteric plexus to form branching networks. Electrical point stimulation of endogenous nerve fibres resulted in calcium transients (F/F0 = 1.16 ± 0.01;43 cells, n = 6 in YFP+ transplanted ENCCs (abolished with TTX. Long-term follow-up (24 months showed transplanted ENCCs did not give rise to tumours or spread to other organs (PCR negative in extraintestinal sites. In aganglionic gut ENCCs similarly spread and differentiated to form neuronal and glial networks with projections closely associated with endogenous neural networks of the transition zone.Transplanted ENCCs successfully engrafted into recipient ganglionic and aganglionic gut showing appropriate spread, localisation and, importantly, functional integration without any long-term safety issues. This study provides key support for the development and use of enteric neural stem cell therapies.

  6. Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain.

    Science.gov (United States)

    Matthes, Michaela; Preusse, Martin; Zhang, Jingzhong; Schechter, Julia; Mayer, Daniela; Lentes, Bernd; Theis, Fabian; Prakash, Nilima; Wurst, Wolfgang; Trümbach, Dietrich

    2014-01-01

    The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior-posterior, dorsal-ventral and medial- lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson's disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input. http://mouseidgenes.helmholtz-muenchen.de. © The Author(s) 2014. Published by Oxford University Press.

  7. A spontaneous and novel Pax3 mutant mouse that models Waardenburg syndrome and neural tube defects.

    Science.gov (United States)

    Ohnishi, Tetsuo; Miura, Ikuo; Ohba, Hisako; Shimamoto, Chie; Iwayama, Yoshimi; Wakana, Shigeharu; Yoshikawa, Takeo

    2017-04-05

    Genes responsible for reduced pigmentation phenotypes in rodents are associated with human developmental defects, such as Waardenburg syndrome, where patients display congenital deafness along with various abnormalities mostly related to neural crest development deficiency. In this study, we identified a spontaneous mutant mouse line Rwa, which displays variable white spots on mouse bellies and white digits and tail, on a C57BL/6N genetic background. Curly tail and spina bifida were also observed, although at a lower penetrance. These phenotypes were dominantly inherited by offspring. We searched for the genetic mechanism of the observed phenotypes. We harnessed a rapid mouse gene mapping system newly developed in our laboratories to identify a responsible gene. We detected a region within chromosome 1 as a probable locus for the causal mutation. Dense mapping using interval markers narrowed the locus down to a 670-kbp region, containing four genes including Pax3, a gene known to be implicated in the types I and III Waardenburg syndrome. Extensive mutation screening of Pax3 detected an 841-bp deletion, spanning the promoter region and intron 1 of the gene. The defective allele of Pax3, named Pax3 Rwa , lacked the first coding exon and co-segregated perfectly with the phenotypes, confirming its causal nature. The genetic background of Rwa mice is almost identical to that of inbred C57BL/6N. These results highlight Pax3 Rwa mice as a beneficial tool for analyzing biological processes involving Pax3, in particular the development and migration of neural crest cells and melanocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Fgf8-related secondary organizers exert different polarizing planar instructions along the mouse anterior neural tube.

    Science.gov (United States)

    Crespo-Enriquez, Ivan; Partanen, Juha; Martinez, Salvador; Echevarria, Diego

    2012-01-01

    Early brain patterning depends on proper arrangement of positional information. This information is given by gradients of secreted signaling molecules (morphogens) detected by individual cells within the responding tissue, leading to specific fate decisions. Here we report that the morphogen FGF8 exerts initially a differential signal activity along the E9.5 mouse neural tube. We demonstrate that this polarizing activity codes by RAS-regulated ERK1/2 signaling and depends on the topographical location of the secondary organizers: the isthmic organizer (IsO) and the anterior neural ridge (anr) but not on zona limitans intrathalamica (zli). Our results suggest that Sprouty2, a negative modulator of RAS/ERK pathway, is important for regulating Fgf8 morphogenetic signal activity by controlling Fgf8-induced signaling pathways and positional information during early brain development.

  9. Highly efficient methods to obtain homogeneous dorsal neural progenitor cells from human and mouse embryonic stem cells and induced pluripotent stem cells.

    Science.gov (United States)

    Zhang, Meixiang; Ngo, Justine; Pirozzi, Filomena; Sun, Ying-Pu; Wynshaw-Boris, Anthony

    2018-03-15

    Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been widely used to generate cellular models harboring specific disease-related genotypes. Of particular importance are ESC and iPSC applications capable of producing dorsal telencephalic neural progenitor cells (NPCs) that are representative of the cerebral cortex and overcome the challenges of maintaining a homogeneous population of cortical progenitors over several passages in vitro. While previous studies were able to derive NPCs from pluripotent cell types, the fraction of dorsal NPCs in this population is small and decreases over several passages. Here, we present three protocols that are highly efficient in differentiating mouse and human ESCs, as well as human iPSCs, into a homogeneous and stable population of dorsal NPCs. These protocols will be useful for modeling cerebral cortical neurological and neurodegenerative disorders in both mouse and human as well as for high-throughput drug screening for therapeutic development. We optimized three different strategies for generating dorsal telencephalic NPCs from mouse and human pluripotent cell types through single or double inhibition of bone morphogenetic protein (BMP) and/or SMAD pathways. Mouse and human pluripotent cells were aggregated to form embryoid bodies in suspension and were treated with dorsomorphin alone (BMP inhibition) or combined with SB431542 (double BMP/SMAD inhibition) during neural induction. Neural rosettes were then selected from plated embryoid bodies to purify the population of dorsal NPCs. We tested the expression of key dorsal NPC markers as well as nonectodermal markers to confirm the efficiency of our three methods in comparison to published and commercial protocols. Single and double inhibition of BMP and/or SMAD during neural induction led to the efficient differentiation of dorsal NPCs, based on the high percentage of PAX6-positive cells and the NPC gene expression profile. There were no statistically

  10. Induced neural stem cells achieve long-term survival and functional integration in the adult mouse brain.

    Science.gov (United States)

    Hemmer, Kathrin; Zhang, Mingyue; van Wüllen, Thea; Sakalem, Marna; Tapia, Natalia; Baumuratov, Aidos; Kaltschmidt, Christian; Kaltschmidt, Barbara; Schöler, Hans R; Zhang, Weiqi; Schwamborn, Jens C

    2014-09-09

    Differentiated cells can be converted directly into multipotent neural stem cells (i.e., induced neural stem cells [iNSCs]). iNSCs offer an attractive alternative to induced pluripotent stem cell (iPSC) technology with regard to regenerative therapies. Here, we show an in vivo long-term analysis of transplanted iNSCs in the adult mouse brain. iNSCs showed sound in vivo long-term survival rates without graft overgrowths. The cells displayed a neural multilineage potential with a clear bias toward astrocytes and a permanent downregulation of progenitor and cell-cycle markers, indicating that iNSCs are not predisposed to tumor formation. Furthermore, the formation of synaptic connections as well as neuronal and glial electrophysiological properties demonstrated that differentiated iNSCs migrated, functionally integrated, and interacted with the existing neuronal circuitry. We conclude that iNSC long-term transplantation is a safe procedure; moreover, it might represent an interesting tool for future personalized regenerative applications. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Soman poisoning increases neural progenitor proliferation and induces long-term glial activation in mouse brain

    International Nuclear Information System (INIS)

    Collombet, Jean-Marc; Four, Elise; Bernabe, Denis; Masqueliez, Catherine; Burckhart, Marie-France; Baille, Valerie; Baubichon, Dominique; Lallement, Guy

    2005-01-01

    To date, only short-term glial reaction has been extensively studied following soman or other warfare neurotoxicant poisoning. In a context of cell therapy by neural progenitor engraftment to repair brain damage, the long-term effect of soman on glial reaction and neural progenitor division was analyzed in the present study. The effect of soman poisoning was estimated in mouse brains at various times ranging from 1 to 90 days post-poisoning. Using immunochemistry and dye staining techniques (hemalun-eosin staining), the number of degenerating neurons, the number of dividing neural progenitors, and microglial, astroglial or oligodendroglial cell activation were studied. Soman poisoning led to rapid and massive (post-soman day 1) death of mature neurons as assessed by hemalun-eosin staining. Following this acute poisoning phase, a weak toxicity effect on mature neurons was still observed for a period of 1 month after poisoning. A massive short-termed microgliosis peaked on day 3 post-poisoning. Delayed astrogliosis was observed from 3 to 90 days after soman poisoning, contributing to glial scar formation. On the other hand, oligodendroglial cells or their precursors were practically unaffected by soman poisoning. Interestingly, neural progenitors located in the subgranular zone of the dentate gyrus (SGZ) or in the subventricular zone (SVZ) of the brain survived soman poisoning. Furthermore, soman poisoning significantly increased neural progenitor proliferation in both SGZ and SVZ brain areas on post-soman day 3 or day 8, respectively. This increased proliferation rate was detected up to 1 month after poisoning

  12. Neural differentiation of mouse embryonic stem cells as a tool to assess developmental neurotoxicity in vitro.

    Science.gov (United States)

    Visan, Anke; Hayess, Katrin; Sittner, Dana; Pohl, Elena E; Riebeling, Christian; Slawik, Birgitta; Gulich, Konrad; Oelgeschläger, Michael; Luch, Andreas; Seiler, Andrea E M

    2012-10-01

    Mouse embryonic stem cells (mESCs) represent an attractive cellular system for in vitro studies in developmental biology as well as toxicology because of their potential to differentiate into all fetal cell lineages. The present study aims to establish an in vitro system for developmental neurotoxicity testing employing mESCs. We developed a robust and reproducible protocol for fast and efficient differentiation of the mESC line D3 into neural cells, optimized with regard to chemical testing. Morphological examination and immunocytochemical staining confirmed the presence of different neural cell types, including neural progenitors, neurons, astrocytes, oligodendrocytes, and radial glial cells. Neurons derived from D3 cells expressed the synaptic proteins PSD95 and synaptophysin, and the neurotransmitters serotonin and γ-aminobutyric acid. Calcium ion imaging revealed the presence of functionally active glutamate and dopamine receptors. In addition, flow cytometry analysis of the neuron-specific marker protein MAP2 on day 12 after induction of differentiation demonstrated a concentration dependent effect of the neurodevelopmental toxicants methylmercury chloride, chlorpyrifos, and lead acetate on neuronal differentiation. The current study shows that D3 mESCs differentiate efficiently into neural cells involving a neurosphere-like state and that this system is suitable to detect adverse effects of neurodevelopmental toxicants. Therefore, we propose that the protocol for differentiation of mESCs into neural cells described here could constitute one component of an in vitro testing strategy for developmental neurotoxicity. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure

    Directory of Open Access Journals (Sweden)

    Keith S. K. Fong

    2016-05-01

    Full Text Available Genetic variations affecting neural tube closure along the head result in malformations of the face and brain. Neural tube defects (NTDs are among the most common birth defects in humans. We previously reported a mouse mutant called tuft that arose spontaneously in our wild-type 3H1 colony. Adult tuft mice present midline craniofacial malformations with or without an anterior cephalocele. In addition, affected embryos presented neural tube closure defects resulting in insufficient closure of the anterior neuropore or exencephaly. Here, through whole-genome sequencing, we identified a nonsense mutation in the Tet1 gene, which encodes a methylcytosine dioxygenase (TET1, co-segregating with the tuft phenotype. This mutation resulted in premature termination that disrupts the catalytic domain that is involved in the demethylation of cytosine. We detected a significant loss of TET enzyme activity in the heads of tuft embryos that were homozygous for the mutation and had NTDs. RNA-Seq transcriptome analysis indicated that multiple gene pathways associated with neural tube closure were dysregulated in tuft embryo heads. Among them, the expressions of Cecr2, Epha7 and Grhl2 were significantly reduced in some embryos presenting neural tube closure defects, whereas one or more components of the non-canonical WNT signaling pathway mediating planar cell polarity and convergent extension were affected in others. We further show that the recombinant mutant TET1 protein was capable of entering the nucleus and affected the expression of endogenous Grhl2 in IMCD-3 (inner medullary collecting duct cells. These results indicate that TET1 is an epigenetic determinant for regulating genes that are crucial to closure of the anterior neural tube and its mutation has implications to craniofacial development, as presented by the tuft mouse.

  14. Runoff Modelling in Urban Storm Drainage by Neural Networks

    DEFF Research Database (Denmark)

    Rasmussen, Michael R.; Brorsen, Michael; Schaarup-Jensen, Kjeld

    1995-01-01

    A neural network is used to simulate folw and water levels in a sewer system. The calibration of th neural network is based on a few measured events and the network is validated against measureed events as well as flow simulated with the MOUSE model (Lindberg and Joergensen, 1986). The neural...... network is used to compute flow or water level at selected points in the sewer system, and to forecast the flow from a small residential area. The main advantages of the neural network are the build-in self calibration procedure and high speed performance, but the neural network cannot be used to extract...... knowledge of the runoff process. The neural network was found to simulate 150 times faster than e.g. the MOUSE model....

  15. The effect of hydrostatic pressure on staurosporine-induced neural differentiation in mouse bone marrow‑derived mesenchymal stem cells.

    Science.gov (United States)

    Javanmard, F; Azadbakht, M; Pourmoradi, M

    2016-01-01

    In this study, the role of hydrostatic pressure on staurosporine-induced neural differentiation in mouse bone marrow mesenchymal stem cells were investigated. The cells were cultured in treatment medium containing 100 nM of staurosporine for 4 hours; then the cells were affected by hydrostatic pressure (0, 25,50, 100 mmHg). The percentage of cell viability by trypan blue staining and the percentage of cell death by Hoechst/PI differential staining were assessed. We obtained the total neurite length. Expression of β-tubulin III and GFAP (Glial fibrillary acidic protein) proteins were also analyzed by immunocytochemistry. The percentage of cell viability in treatments decreased relative to the increase in hydrostatic pressure and time (p Keywords: bone marrow mesenchymal stem cell, hydrostatic pressure, immunocytochemistry, neural differentiation, neurite length, cell differentiation.

  16. Induction of neural stem cell-like cells (NSCLCs) from mouse astrocytes by Bmi1

    International Nuclear Information System (INIS)

    Moon, Jai-Hee; Yoon, Byung Sun; Kim, Bona; Park, Gyuman; Jung, Hye-Youn; Maeng, Isaac; Jun, Eun Kyoung; Yoo, Seung Jun; Kim, Aeree; Oh, Sejong; Whang, Kwang Youn; Kim, Hyunggee; Kim, Dong-Wook; Kim, Ki Dong; You, Seungkwon

    2008-01-01

    Recently, Bmi1 was shown to control the proliferation and self-renewal of neural stem cells (NSCs). In this study, we demonstrated the induction of NSC-like cells (NSCLCs) from mouse astrocytes by Bmi1 under NSC culture conditions. These NSCLCs exhibited the morphology and growth properties of NSCs, and expressed NSC marker genes, including nestin, CD133, and Sox2. In vitro differentiation of NSCLCs resulted in differentiated cell populations containing astrocytes, neurons, and oligodendrocytes. Following treatment with histone deacetylase inhibitors (trichostatin A and valproic acid), the potential of NSCLCs for proliferation, dedifferentiation, and self-renewal was significantly inhibited. Our data indicate that multipotent NSCLCs can be generated directly from astrocytes by the addition of Bmi1

  17. Neural induction with neurogenin 1 enhances the therapeutic potential of mesenchymal stem cells in an amyotrophic lateral sclerosis mouse model.

    Science.gov (United States)

    Chan-Il, Choi; Young-Don, Lee; Heejaung, Kim; Kim, Seung Hyun; Suh-Kim, Haeyoung; Kim, Sung-Soo

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized by progressive dysfunction and degeneration of motor neurons in the central nervous system (CNS). In the absence of effective drug treatments for ALS, stem cell treatment has emerged as a candidate therapy for this disease. To date, however, there is no consensus protocol that stipulates stem cell types, transplantation timing, or frequency. Using an ALS mouse model carrying a high copy number of a mutant human superoxide dismutase-1 (SOD1)(G93A) transgene, we investigated the effect of neural induction on the innate therapeutic potential of mesenchymal stem cells (MSCs) in relation to preclinical transplantation parameters. In our study, the expression of monocyte chemoattractant protein-1 (MCP-1) was elevated in the ALS mouse spinal cord. Neural induction of MSCs with neurogenin 1 (Ngn1) upregulated the expression level of the MCP-1 receptor, CCR2, and enhanced the migration activity toward MCP-1 in vitro. Ngn1-expressing MSCs (MSCs-Ngn1) showed a corresponding increase in tropism to the CNS after systemic transplantation in ALS mice. Notably, MSCs-Ngn1 delayed disease onset if transplanted during preonset ages,whereas unprocessed MSCs failed to do so. If transplanted near the onset ages, a single treatment with MSCs-Ngn1 was sufficient to enhance motor functions during the symptomatic period (15–17 weeks), whereas unprocessed MSCs required repeated transplantation to achieve similar levels of motor function improvement. Our data indicate that systemically transplanted MSCs-Ngn1 can migrate to the CNS and exert beneficial effects on host neural cells for an extended period of time through paracrine functions, suggesting a potential benefit of neural induction of transplanted MSCs in long-term treatment of ALS.

  18. Cocaine- and amphetamine-regulated transcript promotes the differentiation of mouse bone marrow-derived mesenchymal stem cells into neural cells

    Directory of Open Access Journals (Sweden)

    Jin Jiali

    2011-07-01

    Full Text Available Abstract Background Neural tissue has limited potential to self-renew after neurological damage. Cell therapy using BM-MSCs (bone marrow mesenchymal stromal cells seems like a promising approach for the treatment of neurological diseases. However, the neural differentiation of stem cells influenced by massive factors and interactions is not well studied at present. Results In this work, we isolated and identified MSCs from mouse bone marrow. Co-cultured with CART (0.4 nM for six days, BM-MSCs were differentiated into neuron-like cells by the observation of optical microscopy. Immunofluorescence demonstrated that the differentiated BM-MSCs expressed neural specific markers including MAP-2, Nestin, NeuN and GFAP. In addition, NeuN positive cells could co-localize with TH or ChAT by double-labled immunofluorescence and Nissl bodies were found in several differentiated cells by Nissl stain. Furthermore, BDNF and NGF were increased by CART using RT-PCR. Conclusion This study demonstrated that CART could promote the differentiation of BM-MSCs into neural cells through increasing neurofactors, including BNDF and NGF. Combined application of CART and BM-MSCs may be a promising cell-based therapy for neurological diseases.

  19. MRI visualization of endogenous neural progenitor cell migration along the RMS in the adult mouse brain

    DEFF Research Database (Denmark)

    Vreys, Ruth; Vande Velde, Greetje; Krylychkina, Olga

    2010-01-01

    The adult rodent brain contains neural progenitor cells (NPCs), generated in the subventricular zone (SVZ), which migrate along the rostral migratory stream (RMS) towards the olfactory bulb (OB) where they differentiate into neurons. The aim of this study was to visualize endogenous NPC migration...... by a longitudinal MRI study and validated with histology. Here, we visualized endogenous NPC migration in the mouse brain by in vivo MRI and demonstrated accumulation of MPIO-labeled NPCs in the OB over time with ex vivo MRI. Furthermore, we investigated the influence of in situ injection of MPIOs on adult...

  20. Neural population-level memory traces in the mouse hippocampus.

    Science.gov (United States)

    Chen, Guifen; Wang, L Phillip; Tsien, Joe Z

    2009-12-16

    One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.

  1. Neural population-level memory traces in the mouse hippocampus.

    Directory of Open Access Journals (Sweden)

    Guifen Chen

    2009-12-01

    Full Text Available One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.

  2. DGCR8 Promotes Neural Progenitor Expansion and Represses Neurogenesis in the Mouse Embryonic Neocortex

    Directory of Open Access Journals (Sweden)

    Nadin Hoffmann

    2018-04-01

    Full Text Available DGCR8 and DROSHA are the minimal functional core of the Microprocessor complex essential for biogenesis of canonical microRNAs and for the processing of other RNAs. Conditional deletion of Dgcr8 and Drosha in the murine telencephalon indicated that these proteins exert crucial functions in corticogenesis. The identification of mechanisms of DGCR8- or DROSHA-dependent regulation of gene expression in conditional knockout mice are often complicated by massive apoptosis. Here, to investigate DGCR8 functions on amplification/differentiation of neural progenitors cells (NPCs in corticogenesis, we overexpress Dgcr8 in the mouse telencephalon, by in utero electroporation (IUEp. We find that DGCR8 promotes the expansion of NPC pools and represses neurogenesis, in absence of apoptosis, thus overcoming the usual limitations of Dgcr8 knockout-based approach. Interestingly, DGCR8 selectively promotes basal progenitor amplification at later developmental stages, entailing intriguing implications for neocortical expansion in evolution. Finally, despite a 3- to 5-fold increase of DGCR8 level in the mouse telencephalon, the composition, target preference and function of the DROSHA-dependent Microprocessor complex remain unaltered. Thus, we propose that DGCR8-dependent modulation of gene expression in corticogenesis is more complex than previously known, and possibly DROSHA-independent.

  3. Abnormal neural precursor cell regulation in the early postnatal Fragile X mouse hippocampus.

    Science.gov (United States)

    Sourial, Mary; Doering, Laurie C

    2017-07-01

    The regulation of neural precursor cells (NPCs) is indispensable for a properly functioning brain. Abnormalities in NPC proliferation, differentiation, survival, or integration have been linked to various neurological diseases including Fragile X syndrome. Yet, no studies have examined NPCs from the early postnatal Fragile X mouse hippocampus despite the importance of this developmental time point, which marks the highest expression level of FMRP, the protein missing in Fragile X, in the rodent hippocampus and is when hippocampal NPCs have migrated to the dentate gyrus (DG) to give rise to lifelong neurogenesis. In this study, we examined NPCs from the early postnatal hippocampus and DG of Fragile X mice (Fmr1-KO). Immunocytochemistry on neurospheres showed increased Nestin expression and decreased Ki67 expression, which collectively indicated aberrant NPC biology. Intriguingly, flow cytometric analysis of the expression of the antigens CD15, CD24, CD133, GLAST, and PSA-NCAM showed a decreased proportion of neural stem cells (GLAST + CD15 + CD133 + ) and an increased proportion of neuroblasts (PSA-NCAM + CD15 + ) in the DG of P7 Fmr1-KO mice. This was mirrored by lower expression levels of Nestin and the mitotic marker phospho-histone H3 in vivo in the P9 hippocampus, as well as a decreased proportion of cells in the G 2 /M phases of the P7 DG. Thus, the absence of FMRP leads to fewer actively cycling NPCs, coinciding with a decrease in neural stem cells and an increase in neuroblasts. Together, these results show the importance of FMRP in the developing hippocampal formation and suggest abnormalities in cell cycle regulation in Fragile X. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  4. Culture of Mouse Neural Stem Cell Precursors

    OpenAIRE

    Currle, D. Spencer; Hu, Jia Sheng; Kolski-Andreaco, Aaron; Monuki, Edwin S.

    2007-01-01

    Primary neural stem cell cultures are useful for studying the mechanisms underlying central nervous system development. Stem cell research will increase our understanding of the nervous system and may allow us to develop treatments for currently incurable brain diseases and injuries. In addition, stem cells should be used for stem cell research aimed at the detailed study of mechanisms of neural differentiation and transdifferentiation and the genetic and environmental signals that direct the...

  5. Proposal of a model of mammalian neural induction

    Science.gov (United States)

    Levine, Ariel J.; Brivanlou, Ali H.

    2009-01-01

    How does the vertebrate embryo make a nervous system? This complex question has been at the center of developmental biology for many years. The earliest step in this process – the induction of neural tissue – is intimately linked to patterning of the entire early embryo, and the molecular and embryological basis these processes are beginning to emerge. Here, we analyze classic and cutting-edge findings on neural induction in the mouse. We find that data from genetics, tissue explants, tissue grafting, and molecular marker expression support a coherent framework for mammalian neural induction. In this model, the gastrula organizer of the mouse embryo inhibits BMP signaling to allow neural tissue to form as a default fate – in the absence of instructive signals. The first neural tissue induced is anterior and subsequent neural tissue is posteriorized to form the midbrain, hindbrain, and spinal cord. The anterior visceral endoderm protects the pre-specified anterior neural fate from similar posteriorization, allowing formation of forebrain. This model is very similar to the default model of neural induction in the frog, thus bridging the evolutionary gap between amphibians and mammals. PMID:17585896

  6. Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Brault

    2016-08-01

    Full Text Available The recent Zika outbreak in South America and French Polynesia was associated with an epidemic of microcephaly, a disease characterized by a reduced size of the cerebral cortex. Other members of the Flavivirus genus, including West Nile virus (WNV, can cause encephalitis but were not demonstrated to cause microcephaly. It remains unclear whether Zika virus (ZIKV and other flaviviruses may infect different cell populations in the developing neocortex and lead to distinct developmental defects. Here, we describe an assay to infect mouse E15 embryonic brain slices with ZIKV, WNV and dengue virus serotype 4 (DENV-4. We show that this tissue is able to support viral replication of ZIKV and WNV, but not DENV-4. Cell fate analysis reveals a remarkable tropism of ZIKV infection for neural stem cells. Closely related WNV displays a very different tropism of infection, with a bias towards neurons. We further show that ZIKV infection, but not WNV infection, impairs cell cycle progression of neural stem cells. Both viruses inhibited apoptosis at early stages of infection. This work establishes a powerful comparative approach to identify ZIKV-specific alterations in the developing neocortex and reveals specific preferential infection of neural stem cells by ZIKV.

  7. DNA methyltransferase 3b is dispensable for mouse neural crest development.

    Directory of Open Access Journals (Sweden)

    Bridget T Jacques-Fricke

    Full Text Available The neural crest is a population of multipotent cells that migrates extensively throughout vertebrate embryos to form diverse structures. Mice mutant for the de novo DNA methyltransferase DNMT3b exhibit defects in two neural crest derivatives, the craniofacial skeleton and cardiac ventricular septum, suggesting that DNMT3b activity is necessary for neural crest development. Nevertheless, the requirement for DNMT3b specifically in neural crest cells, as opposed to interacting cell types, has not been determined. Using a conditional DNMT3b allele crossed to the neural crest cre drivers Wnt1-cre and Sox10-cre, neural crest DNMT3b mutants were generated. In both neural crest-specific and fully DNMT3b-mutant embryos, cranial neural crest cells exhibited only subtle migration defects, with increased numbers of dispersed cells trailing organized streams in the head. In spite of this, the resulting cranial ganglia, craniofacial skeleton, and heart developed normally when neural crest cells lacked DNMT3b. This indicates that DNTM3b is not necessary in cranial neural crest cells for their development. We conclude that defects in neural crest derivatives in DNMT3b mutant mice reflect a requirement for DNMT3b in lineages such as the branchial arch mesendoderm or the cardiac mesoderm that interact with neural crest cells during formation of these structures.

  8. Role of SDF1/CXCR4 Interaction in Experimental Hemiplegic Models with Neural Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Noboru Suzuki

    2012-02-01

    Full Text Available Much attention has been focused on neural cell transplantation because of its promising clinical applications. We have reported that embryonic stem (ES cell derived neural stem/progenitor cell transplantation significantly improved motor functions in a hemiplegic mouse model. It is important to understand the molecular mechanisms governing neural regeneration of the damaged motor cortex after the transplantation. Recent investigations disclosed that chemokines participated in the regulation of migration and maturation of neural cell grafts. In this review, we summarize the involvement of inflammatory chemokines including stromal cell derived factor 1 (SDF1 in neural regeneration after ES cell derived neural stem/progenitor cell transplantation in mouse stroke models.

  9. Regenerative therapy for vestibular disorders using human induced pluripotent stem cells (iPSCs): neural differentiation of human iPSC-derived neural stem cells after in vitro transplantation into mouse vestibular epithelia.

    Science.gov (United States)

    Taura, Akiko; Nakashima, Noriyuki; Ohnishi, Hiroe; Nakagawa, Takayuki; Funabiki, Kazuo; Ito, Juichi; Omori, Koichi

    2016-10-01

    Vestibular ganglion cells, which convey sense of motion from vestibular hair cells to the brainstem, are known to degenerate with aging and after vestibular neuritis. Thus, regeneration of vestibular ganglion cells is important to aid in the recovery of balance for associated disorders. The present study derived hNSCs from induced pluripotent stem cells (iPSCs) and transplanted these cells into mouse utricle tissues. After a 7-day co-culture period, histological and electrophysiological examinations of transplanted hNSCs were performed. Injected hNSC-derived cells produced elongated axon-like structures within the utricle tissue that made contact with vestibular hair cells. A proportion of hNSC-derived cells showed spontaneous firing activities, similar to those observed in cultured mouse vestibular ganglion cells. However, hNSC-derived cells around the mouse utricle persisted as immature neurons or occasionally differentiated into putative astrocytes. Moreover, electrophysiological examination showed hNSC-derived cells around utricles did not exhibit any obvious spontaneous firing activities. Injected human neural stem cells (hNSCs) showed signs of morphological maturation including reconnection to denervated hair cells and partial physiological maturation, suggesting hNSC-derived cells possibly differentiated into neurons.

  10. Long Noncoding RNA-1604 Orchestrates Neural Differentiation through the miR-200c/ZEB Axis.

    Science.gov (United States)

    Weng, Rong; Lu, Chenqi; Liu, Xiaoqin; Li, Guoping; Lan, Yuanyuan; Qiao, Jing; Bai, Mingliang; Wang, Zhaojie; Guo, Xudong; Ye, Dan; Jiapaer, Zeyidan; Yang, Yiwei; Xia, Chenliang; Wang, Guiying; Kang, Jiuhong

    2018-03-01

    Clarifying the regulatory mechanisms of embryonic stem cell (ESC) neural differentiation is helpful not only for understanding neural development but also for obtaining high-quality neural progenitor cells required by stem cell therapy of neurodegenerative diseases. Here, we found that long noncoding RNA 1604 (lncRNA-1604) was highly expressed in cytoplasm during neural differentiation, and knockdown of lncRNA-1604 significantly repressed neural differentiation of mouse ESCs both in vitro and in vivo. Bioinformatics prediction and mechanistic analysis revealed that lncRNA-1604 functioned as a novel competing endogenous RNA of miR-200c and regulated the core transcription factors ZEB1 and ZEB2 during neural differentiation. Furthermore, we also demonstrated the critical role of miR-200c and ZEB1/2 in mouse neural differentiation. Either introduction of miR-200c sponge or overexpression of ZEB1/2 significantly reversed the lncRNA-1604 knockdown-induced repression of mouse ESC neural differentiation. Collectively, these findings not only identified a previously unknown role of lncRNA-1604 and ZEB1/2 but also elucidated a new regulatory lncRNA-1604/miR-200c/ZEB axis in neural differentiation. Stem Cells 2018;36:325-336. © 2017 AlphaMed Press.

  11. Spatial integration in mouse primary visual cortex

    OpenAIRE

    Vaiceliunaite, Agne; Erisken, Sinem; Franzen, Florian; Katzner, Steffen; Busse, Laura

    2013-01-01

    Responses of many neurons in primary visual cortex (V1) are suppressed by stimuli exceeding the classical receptive field (RF), an important property that might underlie the computation of visual saliency. Traditionally, it has proven difficult to disentangle the underlying neural circuits, including feedforward, horizontal intracortical, and feedback connectivity. Since circuit-level analysis is particularly feasible in the mouse, we asked whether neural signatures of spatial integration in ...

  12. Spatial integration in mouse primary visual cortex.

    Science.gov (United States)

    Vaiceliunaite, Agne; Erisken, Sinem; Franzen, Florian; Katzner, Steffen; Busse, Laura

    2013-08-01

    Responses of many neurons in primary visual cortex (V1) are suppressed by stimuli exceeding the classical receptive field (RF), an important property that might underlie the computation of visual saliency. Traditionally, it has proven difficult to disentangle the underlying neural circuits, including feedforward, horizontal intracortical, and feedback connectivity. Since circuit-level analysis is particularly feasible in the mouse, we asked whether neural signatures of spatial integration in mouse V1 are similar to those of higher-order mammals and investigated the role of parvalbumin-expressing (PV+) inhibitory interneurons. Analogous to what is known from primates and carnivores, we demonstrate that, in awake mice, surround suppression is present in the majority of V1 neurons and is strongest in superficial cortical layers. Anesthesia with isoflurane-urethane, however, profoundly affects spatial integration: it reduces the laminar dependency, decreases overall suppression strength, and alters the temporal dynamics of responses. We show that these effects of brain state can be parsimoniously explained by assuming that anesthesia affects contrast normalization. Hence, the full impact of suppressive influences in mouse V1 cannot be studied under anesthesia with isoflurane-urethane. To assess the neural circuits of spatial integration, we targeted PV+ interneurons using optogenetics. Optogenetic depolarization of PV+ interneurons was associated with increased RF size and decreased suppression in the recorded population, similar to effects of lowering stimulus contrast, suggesting that PV+ interneurons contribute to spatial integration by affecting overall stimulus drive. We conclude that the mouse is a promising model for circuit-level mechanisms of spatial integration, which relies on the combined activity of different types of inhibitory interneurons.

  13. Single-site neural tube closure in human embryos revisited.

    Science.gov (United States)

    de Bakker, Bernadette S; Driessen, Stan; Boukens, Bastiaan J D; van den Hoff, Maurice J B; Oostra, Roelof-Jan

    2017-10-01

    Since the multi-site closure theory was first proposed in 1991 as explanation for the preferential localizations of neural tube defects, the closure of the neural tube has been debated. Although the multi-site closure theory is much cited in clinical literature, single-site closure is most apparent in literature concerning embryology. Inspired by Victor Hamburgers (1900-2001) statement that "our real teacher has been and still is the embryo, who is, incidentally, the only teacher who is always right", we decided to critically review both theories of neural tube closure. To verify the theories of closure, we studied serial histological sections of 10 mouse embryos between 8.5 and 9.5 days of gestation and 18 human embryos of the Carnegie collection between Carnegie stage 9 (19-21 days) and 13 (28-32 days). Neural tube closure was histologically defined by the neuroepithelial remodeling of the two adjoining neural fold tips in the midline. We did not observe multiple fusion sites in neither mouse nor human embryos. A meta-analysis of case reports on neural tube defects showed that defects can occur at any level of the neural axis. Our data indicate that the human neural tube fuses at a single site and, therefore, we propose to reinstate the single-site closure theory for neural tube closure. We showed that neural tube defects are not restricted to a specific location, thereby refuting the reasoning underlying the multi-site closure theory. Clin. Anat. 30:988-999, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  14. Brain-Derived Neurotrophic Factor Loaded PS80 PBCA Nanocarrier for In Vitro Neural Differentiation of Mouse Induced Pluripotent Stem Cells

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    Chiu-Yen Chung

    2017-03-01

    Full Text Available Brain derived neurotrophic factor (BDNF can induce neural differentiation in stem cells and has the potential for repair of the nervous system. In this study, a polysorbate 80-coated polybutylcyanoacrylate nanocarrier (PS80 PBCA NC was constructed to deliver plasmid DNAs (pDNAs containing BDNF gene attached to a hypoxia-responsive element (HRE-cmvBDNF. The hypoxia-sensing mechanism of BDNF expression and inductiveness of the nano-formulation on mouse induced pluripotent stem cells (iPSCs to differentiate into neurons following hypoxia was tested in vitro with immunofluorescent staining and Western blotting. The HRE-cmvBDNF appeared to adsorb onto the surface of PS80 PBCA NC, with a resultant mean diameter of 92.6 ± 1.0 nm and zeta potential of −14.1 ± 1.1 mV. HIF-1α level in iPSCs was significantly higher in hypoxia, which resulted in a 51% greater BDNF expression when transfected with PS80 PBCA NC/HRE-cmvBDNF than those without hypoxia. TrkB and phospho-Akt were also elevated which correlated with neural differentiation. The findings suggest that PS80 PBCA NC too can be endocytosed to serve as an efficient vector for genes coupled to the HRE in hypoxia-sensitive cells, and activation of the PI3/Akt pathway in iPSCs by BDNF is capable of neural lineage specification.

  15. mRNA transfection of mouse and human neural stem cell cultures.

    Directory of Open Access Journals (Sweden)

    Samuel McLenachan

    Full Text Available The use of synthetic mRNA as an alternative gene delivery vector to traditional DNA-based constructs provides an effective method for inducing transient gene expression in cell cultures without genetic modification. Delivery of mRNA has been proposed as a safer alternative to viral vectors in the induction of pluripotent cells for regenerative therapies. Although mRNA transfection of fibroblasts, dendritic and embryonic stem cells has been described, mRNA delivery to neurosphere cultures has not been previously reported. Here we sought to establish an efficient method for delivering mRNA to primary neurosphere cultures. Neurospheres derived from the subventricular zone of adult mice or from human embryonic stem cells were transfected with EGFP mRNA by lipofection and electroporation. Transfection efficiency and expression levels were monitored by flow cytometry. Cell survival following transfection was examined using live cell counting and the MTT assay. Both lipofection and electroporation provided high efficiency transfection of neurospheres. In comparison with lipofection, electroporation resulted in increased transfection efficiencies, but lower expression per cell and shorter durations of expression. Additional rounds of lipofection renewed EGFP expression in neurospheres, suggesting this method may be suitable for reprogramming applications. In summary, we have developed a protocol for achieving high efficiency transfection rates in mouse and human neurosphere cell culture that can be applied for future studies of gene function studies in neural stem cells, such as defining efficient differentiation protocols for glial and neuronal linages.

  16. mRNA Transfection of Mouse and Human Neural Stem Cell Cultures

    Science.gov (United States)

    McLenachan, Samuel; Zhang, Dan; Palomo, Ana Belén Alvarez; Edel, Michael J.; Chen, Fred K.

    2013-01-01

    The use of synthetic mRNA as an alternative gene delivery vector to traditional DNA-based constructs provides an effective method for inducing transient gene expression in cell cultures without genetic modification. Delivery of mRNA has been proposed as a safer alternative to viral vectors in the induction of pluripotent cells for regenerative therapies. Although mRNA transfection of fibroblasts, dendritic and embryonic stem cells has been described, mRNA delivery to neurosphere cultures has not been previously reported. Here we sought to establish an efficient method for delivering mRNA to primary neurosphere cultures. Neurospheres derived from the subventricular zone of adult mice or from human embryonic stem cells were transfected with EGFP mRNA by lipofection and electroporation. Transfection efficiency and expression levels were monitored by flow cytometry. Cell survival following transfection was examined using live cell counting and the MTT assay. Both lipofection and electroporation provided high efficiency transfection of neurospheres. In comparison with lipofection, electroporation resulted in increased transfection efficiencies, but lower expression per cell and shorter durations of expression. Additional rounds of lipofection renewed EGFP expression in neurospheres, suggesting this method may be suitable for reprogramming applications. In summary, we have developed a protocol for achieving high efficiency transfection rates in mouse and human neurosphere cell culture that can be applied for future studies of gene function studies in neural stem cells, such as defining efficient differentiation protocols for glial and neuronal linages. PMID:24386231

  17. mRNA transfection of mouse and human neural stem cell cultures.

    Science.gov (United States)

    McLenachan, Samuel; Zhang, Dan; Palomo, Ana Belén Alvarez; Edel, Michael J; Chen, Fred K

    2013-01-01

    The use of synthetic mRNA as an alternative gene delivery vector to traditional DNA-based constructs provides an effective method for inducing transient gene expression in cell cultures without genetic modification. Delivery of mRNA has been proposed as a safer alternative to viral vectors in the induction of pluripotent cells for regenerative therapies. Although mRNA transfection of fibroblasts, dendritic and embryonic stem cells has been described, mRNA delivery to neurosphere cultures has not been previously reported. Here we sought to establish an efficient method for delivering mRNA to primary neurosphere cultures. Neurospheres derived from the subventricular zone of adult mice or from human embryonic stem cells were transfected with EGFP mRNA by lipofection and electroporation. Transfection efficiency and expression levels were monitored by flow cytometry. Cell survival following transfection was examined using live cell counting and the MTT assay. Both lipofection and electroporation provided high efficiency transfection of neurospheres. In comparison with lipofection, electroporation resulted in increased transfection efficiencies, but lower expression per cell and shorter durations of expression. Additional rounds of lipofection renewed EGFP expression in neurospheres, suggesting this method may be suitable for reprogramming applications. In summary, we have developed a protocol for achieving high efficiency transfection rates in mouse and human neurosphere cell culture that can be applied for future studies of gene function studies in neural stem cells, such as defining efficient differentiation protocols for glial and neuronal linages.

  18. Repair kinetics of DNA double-strand breaks and incidence of apoptosis in mouse neural stem/progenitor cells and their differentiated neurons exposed to ionizing radiation.

    Science.gov (United States)

    Kashiwagi, Hiroki; Shiraishi, Kazunori; Sakaguchi, Kenta; Nakahama, Tomoya; Kodama, Seiji

    2018-05-01

    Neuronal loss leads to neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Huntington's disease. Because of their long lifespans, neurons are assumed to possess highly efficient DNA repair ability and to be able to protect themselves from deleterious DNA damage such as DNA double-strand breaks (DSBs) produced by intrinsic and extrinsic sources. However, it remains largely unknown whether the DSB repair ability of neurons is more efficient compared with that of other cells. Here, we investigated the repair kinetics of X-ray-induced DSBs in mouse neural cells by scoring the number of phosphorylated 53BP1 foci post irradiation. We found that p53-independent apoptosis was induced time dependently during differentiation from neural stem/progenitor cells (NSPCs) into neurons in culture for 48 h. DSB repair in neurons differentiated from NSPCs in culture was faster than that in mouse embryonic fibroblasts (MEFs), possibly due to the higher DNA-dependent protein kinase activity, but it was similar to that in NSPCs. Further, the incidence of p53-dependent apoptosis induced by X-irradiation in neurons was significantly higher than that in NSPCs. This difference in response of X-ray-induced apoptosis between neurons and NSPCs may reflect a difference in the fidelity of non-homologous end joining or a differential sensitivity to DNA damage other than DSBs.

  19. Geminin Participates in Differentiation Decisions of Adult Neural Stem Cells Transplanted in the Hemiparkinsonian Mouse Brain.

    Science.gov (United States)

    Taouki, Ioanna; Tasiudi, Eve; Lalioti, Maria-Eleni; Kyrousi, Christina; Skavatsou, Eleni; Kaplani, Konstantina; Lygerou, Zoi; Kouvelas, Elias D; Mitsacos, Adamantia; Giompres, Panagiotis; Taraviras, Stavros

    2017-08-15

    Neural stem cells have been considered as a source of stem cells that can be used for cell replacement therapies in neurodegenerative diseases, as they can be isolated and expanded in vitro and can be used for autologous grafting. However, due to low percentages of survival and varying patterns of differentiation, strategies that will enhance the efficacy of transplantation are under scrutiny. In this article, we have examined whether alterations in Geminin's expression, a protein that coordinates the balance between self-renewal and differentiation, can improve the properties of stem cells transplanted in 6-OHDA hemiparkinsonian mouse model. Our results indicate that, in the absence of Geminin, grafted cells differentiating into dopaminergic neurons were decreased, while an increased number of oligodendrocytes were detected. The number of proliferating multipotent cells was not modified by the absence of Geminin. These findings encourage research related to the impact of Geminin on transplantations for neurodegenerative disorders, as an important molecule in influencing differentiation decisions of the cells composing the graft.

  20. Subthreshold transpupillary thermotherapy reduces experimental choroidal neovascularization in the mouse without collateral damage to the neural retina.

    Science.gov (United States)

    Ming, Yue; Algvere, Peep V; Odergren, Anne; Berglin, Lennart; van der Ploeg, Ingeborg; Seregard, Stefan; Kvanta, Anders

    2004-06-01

    Transpupillary thermotherapy (TTT) is currently being evaluated for treatment of choroidal neovascularization (CNV) in age-related macular degeneration. To optimize TTT for CNV, the effect was analyzed of invisible (subthreshold) or visible (threshold) doses of TTT on the normal mouse retina and on experimental CNV. TTT was delivered to the normal retina of 42 mice with a diode laser at increasing power settings (50, 60, 70, or 80 mW), to obtain thermal lesions ranging from invisible (subthreshold) to visible (threshold) burns. CNV was induced in 53 mice by krypton laser photocoagulation of the fundus, after which the CNV lesions were treated with TTT (50, 60, or 80 mW). Eyes were enucleated 7 days after TTT and prepared for histology, and the CNV complex was evaluated on hematoxylin-eosin stained serial sections by measuring the maximum height of the CNV lesions. Ultrastructural changes were examined by transmission electron microscopy. Increasing the TTT laser power yielded gradually more visible effects. At 50 mW, which induced subthreshold burns, no damage was seen in the neural retina, retinal pigment epithelium (RPE), or choroid at any time point. By contrast, eyes treated with higher power exhibited progressively more damage to the neural retina, including a complete disruption of the outer nuclear layer. When TTT was applied to the laser-induced CNV lesions, the height of lesions was significantly reduced (P response to all three power settings at 7 days after treatment. The mean relative thickness of the CNV lesion was 3.29 +/- 0.89 in untreated mice, whereas in TTT-treated mice it was 1.69 +/- 0.35, 1.69 +/- 0.41 and 1.70 +/- 0.17 at power settings of 50, 60, and 80 mW, respectively. The overlying neural retina showed no apparent damage with the 50- or 60-mW settings, whereas outer nuclear layer disruption occurred with a power of 80 mW. Electron microscopy confirmed the presence of vascular occlusion at 1 day and a fibrotic scar at 7 days after TTT

  1. The differentiation of embryonic stem cells seeded on electrospun nanofibers into neural lineages.

    Science.gov (United States)

    Xie, Jingwei; Willerth, Stephanie M; Li, Xiaoran; Macewan, Matthew R; Rader, Allison; Sakiyama-Elbert, Shelly E; Xia, Younan

    2009-01-01

    Due to advances in stem cell biology, embryonic stem (ES) cells can be induced to differentiate into a particular mature cell lineage when cultured as embryoid bodies. Although transplantation of ES cells-derived neural progenitor cells has been demonstrated with some success for either spinal cord injury repair in small animal model, control of ES cell differentiation into complex, viable, higher ordered tissues is still challenging. Mouse ES cells have been induced to become neural progenitors by adding retinoic acid to embryoid body cultures for 4 days. In this study, we examine the use of electrospun biodegradable polymers as scaffolds not only for enhancing the differentiation of mouse ES cells into neural lineages but also for promoting and guiding the neurite outgrowth. A combination of electrospun fiber scaffolds and ES cells-derived neural progenitor cells could lead to the development of a better strategy for nerve injury repair.

  2. Human neural stem cells over-expressing VEGF provide neuroprotection, angiogenesis and functional recovery in mouse stroke model.

    Directory of Open Access Journals (Sweden)

    Hong J Lee

    Full Text Available BACKGROUND: Intracerebral hemorrhage (ICH is a lethal stroke type. As mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs selectively migrate to the brain and induce behavioral recovery in rat ICH model, and that combined administration of NSCs and vascular endothelial growth factor (VEGF results in improved structural and functional outcome from cerebral ischemia. METHODS AND FINDINGS: We postulated that human NSCs overexpressing VEGF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs, increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by unilateral injection of bacterial collagenase into striatum. HB1.F3.VEGF human NSC line produced an amount of VEGF four times higher than parental F3 cell line in vitro, and induced behavioral improvement and 2-3 fold increase in cell survival at two weeks and eight weeks post-transplantation. CONCLUSIONS: Brain transplantation of F3 human NSCs over-expressing VEGF near ICH lesion sites provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results suggest a possible application of the human neural stem cell line, which is genetically modified to over-express VEGF, as a therapeutic agent for ICH-stroke.

  3. The role of the mesenchyme in mouse neural fold elevation. II. Patterns of hyaluronate synthesis and distribution in embryos developing in vitro

    International Nuclear Information System (INIS)

    Morris-Wiman, J.; Brinkley, L.L.

    1990-01-01

    Hyaluronate (HA) distribution patterns were examined in the cranial mesenchyme underlying the mesencephalic neural folds of mouse embryos maintained in roller tube culture. Using standard image-processing techniques, the digitized images of Alcian blue-stained or 3H-glucosamine-labeled sections digested with an enzyme specific for HA, were subtracted from adjacent, undigested sections. The resultant difference picture images (DPI) accurately depicted the distribution of stained or labeled HA within the cranial mesenchyme. 3H-glucosamine-labeled HA was distributed uniformly throughout the cranial mesenchyme as 12, 18, and 24 hr of culture. By contrast, the mesenchyme was uniformly stained with Alcian blue at 12 hr, but stain intensity decreased in the central regions of the mesenchyme at 18 and 24 hr. HA distribution patterns were also examined in the cranial mesenchyme of embryos cultured in the presence of diazo-oxo-norleucine (DON), a glutamine analogue that inhibits glycosaminoglycan and glycoprotein synthesis. In DON-treated mesenchyme, Alcian blue staining of HA was decreased from that in controls at 12, 18, and 24 hr. However, incorporation of 3H-glucosamine into HA was increased. The distribution of labeled HA within treated mesenchyme as 12, 18, and 24 hr resembled that in controls at 12 hr. These results indicate that the distribution of HA within the cranial mesenchyme of normal mouse embryos during neural fold elevation and convergence is not determined solely by regional differences in HA synthesis. We propose that HA distribution patterns result from the expansion of the HA-rich extracellular matrix of the central mesenchyme regions. This expansion may play a major role in fold elevation. These results also suggest that DON treatment reversibly inhibits HA synthesis

  4. All-trans retinoic acid promotes neural lineage entry by pluripotent embryonic stem cells via multiple pathways

    Directory of Open Access Journals (Sweden)

    Fang Bo

    2009-07-01

    Full Text Available Abstract Background All-trans retinoic acid (RA is one of the most important morphogens with pleiotropic actions. Its embryonic distribution correlates with neural differentiation in the developing central nervous system. To explore the precise effects of RA on neural differentiation of mouse embryonic stem cells (ESCs, we detected expression of RA nuclear receptors and RA-metabolizing enzymes in mouse ESCs and investigated the roles of RA in adherent monolayer culture. Results Upon addition of RA, cell differentiation was directed rapidly and exclusively into the neural lineage. Conversely, pharmacological interference with RA signaling suppressed this neural differentiation. Inhibition of fibroblast growth factor (FGF signaling did not suppress significantly neural differentiation in RA-treated cultures. Pharmacological interference with extracellular signal-regulated kinase (ERK pathway or activation of Wnt pathway effectively blocked the RA-promoted neural specification. ERK phosphorylation was enhanced in RA-treated cultures at the early stage of differentiation. Conclusion RA can promote neural lineage entry by ESCs in adherent monolayer culture systems. This effect depends on RA signaling and its crosstalk with the ERK and Wnt pathways.

  5. Aebp2 as an epigenetic regulator for neural crest cells.

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    Hana Kim

    Full Text Available Aebp2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2. We generated a mutant mouse line disrupting the transcription of Aebp2 to investigate its in vivo roles. Aebp2-mutant homozygotes were embryonic lethal while heterozygotes survived to adulthood with fertility. In developing mouse embryos, Aebp2 is expressed mainly within cells of neural crest origin. In addition, many heterozygotes display a set of phenotypes, enlarged colon and hypopigmentation, similar to those observed in human patients with Hirschsprung's disease and Waardenburg syndrome. These phenotypes are usually caused by the absence of the neural crest-derived ganglia in hindguts and melanocytes. ChIP analyses demonstrated that the majority of the genes involved in the migration and development process of neural crest cells are downstream target genes of AEBP2 and PRC2. Furthermore, expression analyses confirmed that some of these genes are indeed affected in the Aebp2 heterozygotes. Taken together, these results suggest that Aebp2 may regulate the migration and development of the neural crest cells through the PRC2-mediated epigenetic mechanism.

  6. Organic cation transporter-mediated ergothioneine uptake in mouse neural progenitor cells suppresses proliferation and promotes differentiation into neurons.

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    Takahiro Ishimoto

    Full Text Available The aim of the present study is to clarify the functional expression and physiological role in neural progenitor cells (NPCs of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO as a substrate in vivo. Real-time PCR analysis revealed that mRNA expression of OCTN1 was much higher than that of other organic cation transporters in mouse cultured cortical NPCs. Immunocytochemical analysis showed colocalization of OCTN1 with the NPC marker nestin in cultured NPCs and mouse embryonic carcinoma P19 cells differentiated into neural progenitor-like cells (P19-NPCs. These cells exhibited time-dependent [(3H]ERGO uptake. These results demonstrate that OCTN1 is functionally expressed in murine NPCs. Cultured NPCs and P19-NPCs formed neurospheres from clusters of proliferating cells in a culture time-dependent manner. Exposure of cultured NPCs to ERGO or other antioxidants (edaravone and ascorbic acid led to a significant decrease in the area of neurospheres with concomitant elimination of intracellular reactive oxygen species. Transfection of P19-NPCs with small interfering RNA for OCTN1 markedly promoted formation of neurospheres with a concomitant decrease of [(3H]ERGO uptake. On the other hand, exposure of cultured NPCs to ERGO markedly increased the number of cells immunoreactive for the neuronal marker βIII-tubulin, but decreased the number immunoreactive for the astroglial marker glial fibrillary acidic protein (GFAP, with concomitant up-regulation of neuronal differentiation activator gene Math1. Interestingly, edaravone and ascorbic acid did not affect such differentiation of NPCs, in contrast to the case of proliferation. Knockdown of OCTN1 increased the number of cells immunoreactive for GFAP, but decreased the number immunoreactive for βIII-tubulin, with concomitant down-regulation of Math1 in P19-NPCs. Thus, OCTN1-mediated uptake of ERGO in NPCs inhibits

  7. The mouse that roared: neural mechanisms of social hierarchy.

    Science.gov (United States)

    Wang, Fei; Kessels, Helmut W; Hu, Hailan

    2014-11-01

    Hierarchical social status greatly influences behavior and health. Human and animal studies have begun to identify the brain regions that are activated during the formation of social hierarchies. They point towards the prefrontal cortex (PFC) as a central regulator, with brain areas upstream of the PFC conveying information about social status, and downstream brain regions executing dominance behavior. This review summarizes our current knowledge on the neural circuits that control social status. We discuss how the neural mechanisms for various types of dominance behavior can be studied in laboratory rodents by selective manipulation of neuronal activity or synaptic plasticity. These studies may help in finding the cause of social stress-related mental and physical health problems. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy.

    Science.gov (United States)

    Lee, Hyung-Yul; Wei, Dan; Loeken, Mary R

    2014-01-01

    Adenosine monophosphate-activated protein kinase (AMPK) is stimulated in embryos during diabetic pregnancy by maternal hyperglycaemia-induced embryo oxidative stress. Stimulation of AMPK disrupts embryo gene expression and causes neural tube defects. Metformin, which may be taken during early pregnancy, has been reported to stimulate AMPK activity. Thus, the benefits of improved glycaemic control could be offset by stimulated embryo AMPK activity. Here, we investigated whether metformin can stimulate AMPK activity in mouse embryos and can adversely affect embryo gene expression and neural tube defects. Pregnant nondiabetic mice were administered metformin beginning on the first day of pregnancy. Activation of maternal and embryo AMPK [phospho-AMPK α (Thr172) relative to total AMPK], expression of Pax3, a gene required for neural tube closure, and neural tube defects were studied. Mouse embryonic stem cells were used as a cell culture model of embryonic neuroepithelium to study metformin effects on AMPK and Pax3 expression. Metformin had no effect on AMPK in embryos or maternal skeletal muscle but increased activated AMPK in maternal liver. Metformin did not inhibit Pax3 expression or increase neural tube defects. However, metformin increased activated AMPK and inhibited Pax3 expression by mouse embryonic stem cells. Mate1/Slc47a1 and Oct3/Slc22a, which encode metformin transporters, were expressed at barely detectable levels by embryos. Although metformin can have effects associated with diabetic embryopathy in vitro, the lack of effects on mouse embryos in vivo may be due to lack of metformin transporters and indicates that the benefits of metformin on glycaemic control are not counteracted by stimulation of embryo AMPK activity and consequent embryopathy. Copyright © 2013 John Wiley & Sons, Ltd.

  9. Cross-species functional analyses reveal shared and separate roles for Sox11 in frog primary neurogenesis and mouse cortical neuronal differentiation

    Directory of Open Access Journals (Sweden)

    Chao Chen

    2016-04-01

    Full Text Available A well-functioning brain requires production of the correct number and types of cells during development; cascades of transcription factors are essential for cellular coordination. Sox proteins are transcription factors that affect various processes in the development of the nervous system. Sox11, a member of the SoxC family, is expressed in differentiated neurons and supports neuronal differentiation in several systems. To understand how generalizable the actions of Sox11 are across phylogeny, its function in the development of the frog nervous system and the mouse cerebral cortex were compared. Expression of Sox11 is largely conserved between these species; in the developing frog, Sox11 is expressed in the neural plate, neural tube and throughout the segmented brain, while in the mouse cerebral cortex, Sox11 is expressed in differentiated zones, including the preplate, subplate, marginal zone and cortical plate. In both frog and mouse, data demonstrate that Sox11 supports a role in promoting neuronal differentiation, with Sox11-positive cells expressing pan-neural markers and becoming morphologically complex. However, frog and mouse Sox11 cannot substitute for one another; a functional difference likely reflected in sequence divergence. Thus, Sox11 appears to act similarly in subserving neuronal differentiation but is species-specific in frog neural development and mouse corticogenesis.

  10. Detection of different states of sleep in the rodents by the means of artificial neural networks

    Science.gov (United States)

    Musatov, Viacheslav; Dykin, Viacheslav; Pitsik, Elena; Pisarchik, Alexander

    2018-04-01

    This paper considers the possibility of classification of electroencephalogram (EEG) and electromyogram (EMG) signals corresponding to different phases of sleep and wakefulness of mice by the means of artificial neural networks. A feed-forward artificial neural network based on multilayer perceptron was created and trained on the data of one of the rodents. The trained network was used to read and classify the EEG and EMG data corresponding to different phases of sleep and wakefulness of the same mouse and other mouse. The results show a good recognition quality of all phases for the rodent on which the training was conducted (80-99%) and acceptable recognition quality for the data collected from the same mouse after a stroke.

  11. Transplantation of motoneurons derived from MASH1-transfected mouse ES cells reconstitutes neural networks and improves motor function in hemiplegic mice.

    Science.gov (United States)

    Ikeda, Ritsuko; Kurokawa, Manae S; Chiba, Shunmei; Yoshikawa, Hideshi; Hashimoto, Takuo; Tadokoro, Mamoru; Suzuki, Noboru

    2004-10-01

    Mouse embryonic stem (ES) cells were transfected with a MASH1 expression vector and G418-resistant cells were selected. The MASH1-transfected cells became neuron-like appearance and expressed betaIIItubulin and panNCAM. Glial fibrillary acidic protein (GFAP) and galactocerebroside (GalC)-expressing cells were rarely detected. Half of the neural cells differentiated into the Islet1+ motoneuron lineage. Thus, we obtained motoneuron lineage-enriched neuronal cells by transfection of ES cells with MASH1. A hemiplegic model of mice was developed by cryogenic injury of the motor cortex, and motoneuron lineage-enriched neuronal cells were transplanted underneath the injured motor cortex neighboring the periventricular region. The motor function of the recipients was assessed by a beam walking and rotarod tests, whereby the results gradually improved, but little improvement was observed in vehicle injected control mice. We found that the grafted cells not only remained close to the implantation site, but also exhibited substantial migration, penetrating into the damaged lesion in a directed manner up to the cortical region. Grafted neuronal cells that had migrated into the cortex were elongated axon-positive for neurofilament middle chain (NFM). Synaptophysin immunostaining showed a positive staining pattern around the graft, suggesting that the transplanted neurons interacted with the recipient neurons to form a neural network. Our study suggests that the motoneuron lineage can be induced from ES cells, and grafted cells adapt to the host environment and can reconstitute a neural network to improve motor function of a paralyzed limb.

  12. Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates.

    Science.gov (United States)

    Mundell, Nathan A; Labosky, Patricia A

    2011-02-01

    Neural crest (NC) progenitors generate a wide array of cell types, yet molecules controlling NC multipotency and self-renewal and factors mediating cell-intrinsic distinctions between multipotent versus fate-restricted progenitors are poorly understood. Our earlier work demonstrated that Foxd3 is required for maintenance of NC progenitors in the embryo. Here, we show that Foxd3 mediates a fate restriction choice for multipotent NC progenitors with loss of Foxd3 biasing NC toward a mesenchymal fate. Neural derivatives of NC were lost in Foxd3 mutant mouse embryos, whereas abnormally fated NC-derived vascular smooth muscle cells were ectopically located in the aorta. Cranial NC defects were associated with precocious differentiation towards osteoblast and chondrocyte cell fates, and individual mutant NC from different anteroposterior regions underwent fate changes, losing neural and increasing myofibroblast potential. Our results demonstrate that neural potential can be separated from NC multipotency by the action of a single gene, and establish novel parallels between NC and other progenitor populations that depend on this functionally conserved stem cell protein to regulate self-renewal and multipotency.

  13. Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network

    Science.gov (United States)

    Weick, Jason P.; Liu, Yan; Zhang, Su-Chun

    2011-01-01

    Whether hESC-derived neurons can fully integrate with and functionally regulate an existing neural network remains unknown. Here, we demonstrate that hESC-derived neurons receive unitary postsynaptic currents both in vitro and in vivo and adopt the rhythmic firing behavior of mouse cortical networks via synaptic integration. Optical stimulation of hESC-derived neurons expressing Channelrhodopsin-2 elicited both inhibitory and excitatory postsynaptic currents and triggered network bursting in mouse neurons. Furthermore, light stimulation of hESC-derived neurons transplanted to the hippocampus of adult mice triggered postsynaptic currents in host pyramidal neurons in acute slice preparations. Thus, hESC-derived neurons can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing both in vitro and in vivo. PMID:22106298

  14. Characterization of mouse neuro-urological dynamics in a novel decerebrate arterially perfused mouse (DAPM) preparation

    OpenAIRE

    Ito, Hiroki; Drake, Marcus J.; Fry, Christopher H.; Kanai, Anthony J.; Pickering, Anthony E.

    2018-01-01

    Aim To develop the decerebrate arterially perfused mouse (DAPM) preparation, a novel voiding model of the lower urinary tract (LUT) that enables in vitro-like access with in vivo-like neural connectivity. Methods Adult male mice were decerebrated and arterially perfused with a carbogenated, Ringer's solution to establish the DAPM. To allow distinction between central and peripheral actions of interventions, experiments were conducted in both the DAPM and in a “pithed” DAPM which has no brains...

  15. EGF–FGF2 stimulates the proliferation and improves the neuronal commitment of mouse epidermal neural crest stem cells (EPI-NCSCs)

    International Nuclear Information System (INIS)

    Bressan, Raul Bardini; Melo, Fernanda Rosene; Almeida, Patricia Alves; Bittencourt, Denise Avani; Visoni, Silvia; Jeremias, Talita Silva; Costa, Ana Paula; Leal, Rodrigo Bainy; Trentin, Andrea Gonçalves

    2014-01-01

    Epidermal neural crest stem cells (EPI-NCSCs), which reside in the bulge of hair follicles, are attractive candidates for several applications in cell therapy, drug screening and tissue engineering. As suggested remnants of the embryonic neural crest (NC) in an adult location, EPI-NCSCs are able to generate a wide variety of cell types and are readily accessible by a minimally invasive procedure. Since the combination of epidermal growth factor (EGF) and fibroblast growth factor type 2 (FGF 2 ) is mitogenic and promotes the neuronal commitment of various stem cell populations, we examined its effects in the proliferation and neuronal potential of mouse EPI-NCSCs. By using a recognized culture protocol of bulge whiskers follicles, we were able to isolate a population of EPI-NCSCs, characterized by the migratory potential, cell morphology and expression of phenotypic markers of NC cells. EPI-NCSCs expressed neuronal, glial and smooth muscle markers and exhibited the NC-like fibroblastic morphology. The treatment with the combination EGF and FGF 2 , however, increased their proliferation rate and promoted the acquisition of a neuronal-like morphology accompanied by reorganization of neural cytoskeletal proteins βIII-tubulin and nestin, as well as upregulation of the pan neuronal marker βIII-tubulin and down regulation of the undifferentiated NC, glial and smooth muscle cell markers. Moreover, the treatment enhanced the response of EPI-NCSCs to neurogenic stimulation, as evidenced by induction of GAP43, and increased expression of Mash-1 in neuron-like cell, both neuronal-specific proteins. Together, the results suggest that the combination of EGF–FGF2 stimulates the proliferation and improves the neuronal potential of EPI-NCSCs similarly to embryonic NC cells, ES cells and neural progenitor/stem cells of the central nervous system and highlights the advantage of using EGF–FGF 2 in neuronal differentiation protocols. - Highlights: • EPI-NCSCs express

  16. Identification and target prediction of miRNAs specifically expressed in rat neural tissue

    Directory of Open Access Journals (Sweden)

    Tu Kang

    2009-05-01

    Full Text Available Abstract Background MicroRNAs (miRNAs are a large group of RNAs that play important roles in regulating gene expression and protein translation. Several studies have indicated that some miRNAs are specifically expressed in human, mouse and zebrafish tissues. For example, miR-1 and miR-133 are specifically expressed in muscles. Tissue-specific miRNAs may have particular functions. Although previous studies have reported the presence of human, mouse and zebrafish tissue-specific miRNAs, there have been no detailed reports of rat tissue-specific miRNAs. In this study, Home-made rat miRNA microarrays which established in our previous study were used to investigate rat neural tissue-specific miRNAs, and mapped their target genes in rat tissues. This study will provide information for the functional analysis of these miRNAs. Results In order to obtain as complete a picture of specific miRNA expression in rat neural tissues as possible, customized miRNA microarrays with 152 selected miRNAs from miRBase were used to detect miRNA expression in 14 rat tissues. After a general clustering analysis, 14 rat tissues could be clearly classified into neural and non-neural tissues based on the obtained expression profiles with p values Conclusion Our work provides a global view of rat neural tissue-specific miRNA profiles and a target map of miRNAs, which is expected to contribute to future investigations of miRNA regulatory mechanisms in neural systems.

  17. Arctigenin protects against neuronal hearing loss by promoting neural stem cell survival and differentiation.

    Science.gov (United States)

    Huang, Xinghua; Chen, Mo; Ding, Yan; Wang, Qin

    2017-03-01

    Neuronal hearing loss has become a prevalent health problem. This study focused on the function of arctigenin (ARC) in promoting survival and neuronal differentiation of mouse cochlear neural stem cells (NSCs), and its protection against gentamicin (GMC) induced neuronal hearing loss. Mouse cochlea was used to isolate NSCs, which were subsequently cultured in vitro. The effects of ARC on NSC survival, neurosphere formation, differentiation of NSCs, neurite outgrowth, and neural excitability in neuronal network in vitro were examined. Mechanotransduction ability demonstrated by intact cochlea, auditory brainstem response (ABR), and distortion product optoacoustic emissions (DPOAE) amplitude in mice were measured to evaluate effects of ARC on GMC-induced neuronal hearing loss. ARC increased survival, neurosphere formation, neuron differentiation of NSCs in mouse cochlear in vitro. ARC also promoted the outgrowth of neurites, as well as neural excitability of the NSC-differentiated neuron culture. Additionally, ARC rescued mechanotransduction capacity, restored the threshold shifts of ABR and DPOAE in our GMC ototoxicity murine model. This study supports the potential therapeutic role of ARC in promoting both NSCs proliferation and differentiation in vitro to functional neurons, thus supporting its protective function in the therapeutic treatment of neuropathic hearing loss in vivo. © 2017 Wiley Periodicals, Inc.

  18. Regulated expression of the neural cell adhesion molecule L1 by specific patterns of neural impulses.

    Science.gov (United States)

    Itoh, K; Stevens, B; Schachner, M; Fields, R D

    1995-11-24

    Development of the mammalian nervous system is regulated by neural impulse activity, but the molecular mechanisms are not well understood. If cell recognition molecules [for example, L1 and the neural cell adhesion molecule (NCAM)] were influenced by specific patterns of impulse activity, cell-cell interactions controlling nervous system structure could be regulated by nervous system function at critical stages of development. Low-frequency electrical pulses delivered to mouse sensory neurons in culture (0.1 hertz for 5 days) down-regulated expression of L1 messenger RNA and protein (but not NCAM). Fasciculation of neurites, adhesion of neuroblastoma cells, and the number of Schwann cells on neurites was reduced after 0.1-hertz stimulation, but higher frequencies or stimulation after synaptogenesis were without effect.

  19. Neural stem cells induce bone-marrow-derived mesenchymal stem cells to generate neural stem-like cells via juxtacrine and paracrine interactions

    International Nuclear Information System (INIS)

    Alexanian, Arshak R.

    2005-01-01

    Several recent reports suggest that there is far more plasticity that previously believed in the developmental potential of bone-marrow-derived cells (BMCs) that can be induced by extracellular developmental signals of other lineages whose nature is still largely unknown. In this study, we demonstrate that bone-marrow-derived mesenchymal stem cells (MSCs) co-cultured with mouse proliferating or fixed (by paraformaldehyde or methanol) neural stem cells (NSCs) generate neural stem cell-like cells with a higher expression of Sox-2 and nestin when grown in NS-A medium supplemented with N2, NSC conditioned medium (NSCcm) and bFGF. These neurally induced MSCs eventually differentiate into β-III-tubulin and GFAP expressing cells with neuronal and glial morphology when grown an additional week in Neurobasal/B27 without bFGF. We conclude that juxtacrine interaction between NSCs and MSCs combined with soluble factors released from NSCs are important for generation of neural-like cells from bone-marrow-derived adherent MSCs

  20. Tcf7l1 protects the anterior neural fold from adopting the neural crest fate

    Czech Academy of Sciences Publication Activity Database

    Mašek, Jan; Machoň, Ondřej; Kořínek, Vladimír; Taketo, M.M.; Kozmik, Zbyněk

    2016-01-01

    Roč. 143, č. 12 (2016), s. 2206-2216 ISSN 0950-1991 R&D Projects: GA ČR GAP305/12/2042; GA ČR(CZ) GA14-33952S; GA MŠk(CZ) LK11214; GA MŠk LO1419; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:68378050 Keywords : Tcf/Lef * Wnt dignaling * neural crest * forebrain * mouse * zebrafish Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.843, year: 2016

  1. Concurrent OCT imaging of stimulus evoked retinal neural activation and hemodynamic responses

    Science.gov (United States)

    Son, Taeyoon; Wang, Benquan; Lu, Yiming; Chen, Yanjun; Cao, Dingcai; Yao, Xincheng

    2017-02-01

    It is well established that major retinal diseases involve distortions of the retinal neural physiology and blood vascular structures. However, the details of distortions in retinal neurovascular coupling associated with major eye diseases are not well understood. In this study, a multi-modal optical coherence tomography (OCT) imaging system was developed to enable concurrent imaging of retinal neural activity and vascular hemodynamics. Flicker light stimulation was applied to mouse retinas to evoke retinal neural responses and hemodynamic changes. The OCT images were acquired continuously during the pre-stimulation, light-stimulation, and post-stimulation phases. Stimulus-evoked intrinsic optical signals (IOSs) and hemodynamic changes were observed over time in blood-free and blood regions, respectively. Rapid IOSs change occurred almost immediately after stimulation. Both positive and negative signals were observed in adjacent retinal areas. The hemodynamic changes showed time delays after stimulation. The signal magnitudes induced by light stimulation were observed in blood regions and did not show significant changes in blood-free regions. These differences may arise from different mechanisms in blood vessels and neural tissues in response to light stimulation. These characteristics agreed well with our previous observations in mouse retinas. Further development of the multimodal OCT may provide a new imaging method for studying how retinal structures and metabolic and neural functions are affected by age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and other diseases, which promises novel noninvasive biomarkers for early disease detection and reliable treatment evaluations of eye diseases.

  2. Resveratrol promotes hUC-MSCs engraftment and neural repair in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Wang, Xinxin; Ma, Shanshan; Yang, Bo; Huang, Tuanjie; Meng, Nan; Xu, Ling; Xing, Qu; Zhang, Yanting; Zhang, Kun; Li, Qinghua; Zhang, Tao; Wu, Junwei; Yang, Greta Luyuan; Guan, Fangxia; Wang, Jian

    2018-02-26

    Mesenchymal stem cell transplantation is a promising therapeutic approach for Alzheimer's disease (AD). However, poor engraftment and limited survival rates are major obstacles for its clinical application. Resveratrol, an activator of silent information regulator 2, homolog 1 (SIRT1), regulates cell destiny and is beneficial for neurodegenerative disorders. The present study is designed to explore whether resveratrol regulates the fate of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and whether hUC-MSCs combined with resveratrol would be efficacious in the treatment of neurodegeneration in a mouse model of AD through SIRT1 signaling. Herein, we report that resveratrol facilitates hUC-MSCs engraftment in the hippocampus of AD mice and resveratrol enhances the therapeutic effects of hUC-MSCs in this model as demonstrated by improved learning and memory in the Morris water maze, enhanced neurogenesis and alleviated neural apoptosis in the hippocampus of the AD mice. Moreover, hUC-MSCs and resveratrol jointly regulate expression of hippocampal SIRT1, PCNA, p53, ac-p53, p21, and p16. These data strongly suggests that hUC-MSCs transplantation combined with resveratrol may be an effective therapy for AD. Copyright © 2017. Published by Elsevier B.V.

  3. Social ultrasonic vocalization in awake head-restrained mouse

    Directory of Open Access Journals (Sweden)

    Benjamin Weiner

    2016-12-01

    Full Text Available Numerous animal species emit vocalizations in response to various social stimuli. The neural basis of vocal communication has been investigated in monkeys, songbirds, rats, bats and invertebrates resulting in deep insights into motor control, neural coding and learning. Mice, which recently became very popular as a model system for mammalian neuroscience, also utilize ultrasonic vocalizations (USVs during mating behavior. However, our knowledge is lacking of both the behavior and its underlying neural mechanism. We developed a novel method for head-restrained male mice (HRMM to interact with non-restrained female mice (NRFM and show that mice can emit USVs in this context. We first recorded USVs in free arena with non-restrained male mice (NRMM and NRFM. Of the NRMM, which vocalized in the free arena, the majority could be habituated to also vocalize while head-restrained but only when a female mouse was present in proximity. The USVs emitted by HRMM are similar to the USVs of NRMM in the presence of a female mouse in their spectral structure, inter syllable interval distribution and USV sequence length, and therefore are interpreted as social USVs. By analyzing vocalizations of NRMM, we established criteria to predict which individuals are likely to vocalize while head fixed based on the USV rate and average syllable duration. To characterize the USVs emitted by HRMM, we analyzed the syllable composition of HRMM and NRMM and found that USVs emitted by HRMM have higher proportions of USVs with complex spectral representation, supporting previous studies showing that mice social USVs are context dependent. Our results suggest a way to study the neural mechanisms of production and control of social vocalization in mice using advanced methods requiring head fixation.

  4. Social Ultrasonic Vocalization in Awake Head-Restrained Mouse.

    Science.gov (United States)

    Weiner, Benjamin; Hertz, Stav; Perets, Nisim; London, Michael

    2016-01-01

    Numerous animal species emit vocalizations in response to various social stimuli. The neural basis of vocal communication has been investigated in monkeys, songbirds, rats, bats, and invertebrates resulting in deep insights into motor control, neural coding, and learning. Mice, which recently became very popular as a model system for mammalian neuroscience, also utilize ultrasonic vocalizations (USVs) during mating behavior. However, our knowledge is lacking of both the behavior and its underlying neural mechanism. We developed a novel method for head-restrained male mice (HRMM) to interact with non-restrained female mice (NRFM) and show that mice can emit USVs in this context. We first recorded USVs in a free arena with non-restrained male mice (NRMM) and NRFM. Of the NRMM, which vocalized in the free arena, the majority could be habituated to also vocalize while head-restrained but only when a female mouse was present in proximity. The USVs emitted by HRMM are similar to the USVs of NRMM in the presence of a female mouse in their spectral structure, inter-syllable interval distribution, and USV sequence length, and therefore are interpreted as social USVs. By analyzing the vocalizations of NRMM, we established criteria to predict which individuals are likely to vocalize while head fixed based on the USV rate and average syllable duration. To characterize the USVs emitted by HRMM, we analyzed the syllable composition of HRMM and NRMM and found that USVs emitted by HRMM have a higher proportion of USVs with complex spectral representation, supporting previous studies showing that mice social USVs are context dependent. Our results suggest a way to study the neural mechanisms of production and control of social vocalization in mice using advanced methods requiring head fixation.

  5. Transcriptional response of Hoxb genes to retinoid signalling is regionally restricted along the neural tube rostrocaudal axis.

    Science.gov (United States)

    Carucci, Nicoletta; Cacci, Emanuele; Nisi, Paola S; Licursi, Valerio; Paul, Yu-Lee; Biagioni, Stefano; Negri, Rodolfo; Rugg-Gunn, Peter J; Lupo, Giuseppe

    2017-04-01

    During vertebrate neural development, positional information is largely specified by extracellular morphogens. Their distribution, however, is very dynamic due to the multiple roles played by the same signals in the developing and adult neural tissue. This suggests that neural progenitors are able to modify their competence to respond to morphogen signalling and autonomously maintain positional identities after their initial specification. In this work, we take advantage of in vitro culture systems of mouse neural stem/progenitor cells (NSPCs) to show that NSPCs isolated from rostral or caudal regions of the mouse neural tube are differentially responsive to retinoic acid (RA), a pivotal morphogen for the specification of posterior neural fates. Hoxb genes are among the best known RA direct targets in the neural tissue, yet we found that RA could promote their transcription only in caudal but not in rostral NSPCs. Correlating with these effects, key RA-responsive regulatory regions in the Hoxb cluster displayed opposite enrichment of activating or repressing histone marks in rostral and caudal NSPCs. Finally, RA was able to strengthen Hoxb chromatin activation in caudal NSPCs, but was ineffective on the repressed Hoxb chromatin of rostral NSPCs. These results suggest that the response of NSPCs to morphogen signalling across the rostrocaudal axis of the neural tube may be gated by the epigenetic configuration of target patterning genes, allowing long-term maintenance of intrinsic positional values in spite of continuously changing extrinsic signals.

  6. EGF–FGF{sub 2} stimulates the proliferation and improves the neuronal commitment of mouse epidermal neural crest stem cells (EPI-NCSCs)

    Energy Technology Data Exchange (ETDEWEB)

    Bressan, Raul Bardini; Melo, Fernanda Rosene; Almeida, Patricia Alves; Bittencourt, Denise Avani; Visoni, Silvia; Jeremias, Talita Silva [Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário – Trindade, 88040-900 Florianópolis SC (Brazil); Costa, Ana Paula; Leal, Rodrigo Bainy [Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário – Trindade, 88040-900 Florianópolis SC (Brazil); Trentin, Andrea Gonçalves, E-mail: andrea.trentin@ufsc.br [Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário – Trindade, 88040-900 Florianópolis SC (Brazil)

    2014-09-10

    Epidermal neural crest stem cells (EPI-NCSCs), which reside in the bulge of hair follicles, are attractive candidates for several applications in cell therapy, drug screening and tissue engineering. As suggested remnants of the embryonic neural crest (NC) in an adult location, EPI-NCSCs are able to generate a wide variety of cell types and are readily accessible by a minimally invasive procedure. Since the combination of epidermal growth factor (EGF) and fibroblast growth factor type 2 (FGF{sub 2}) is mitogenic and promotes the neuronal commitment of various stem cell populations, we examined its effects in the proliferation and neuronal potential of mouse EPI-NCSCs. By using a recognized culture protocol of bulge whiskers follicles, we were able to isolate a population of EPI-NCSCs, characterized by the migratory potential, cell morphology and expression of phenotypic markers of NC cells. EPI-NCSCs expressed neuronal, glial and smooth muscle markers and exhibited the NC-like fibroblastic morphology. The treatment with the combination EGF and FGF{sub 2}, however, increased their proliferation rate and promoted the acquisition of a neuronal-like morphology accompanied by reorganization of neural cytoskeletal proteins βIII-tubulin and nestin, as well as upregulation of the pan neuronal marker βIII-tubulin and down regulation of the undifferentiated NC, glial and smooth muscle cell markers. Moreover, the treatment enhanced the response of EPI-NCSCs to neurogenic stimulation, as evidenced by induction of GAP43, and increased expression of Mash-1 in neuron-like cell, both neuronal-specific proteins. Together, the results suggest that the combination of EGF–FGF2 stimulates the proliferation and improves the neuronal potential of EPI-NCSCs similarly to embryonic NC cells, ES cells and neural progenitor/stem cells of the central nervous system and highlights the advantage of using EGF–FGF{sub 2} in neuronal differentiation protocols. - Highlights: • EPI

  7. Protease-activated receptor-1 negatively regulates proliferation of neural stem/progenitor cells derived from the hippocampal dentate gyrus of the adult mouse

    Directory of Open Access Journals (Sweden)

    Masayuki Tanaka

    2016-07-01

    Full Text Available Thrombin-activated protease-activated receptor (PAR-1 regulates the proliferation of neural cells following brain injury. To elucidate the involvement of PAR-1 in the neurogenesis that occurs in the adult hippocampus, we examined whether PAR-1 regulated the proliferation of neural stem/progenitor cells (NPCs derived from the murine hippocampal dentate gyrus. NPC cultures expressed PAR-1 protein and mRNA encoding all subtypes of PAR. Direct exposure of the cells to thrombin dramatically attenuated the cell proliferation without causing cell damage. This thrombin-induced attenuation was almost completely abolished by the PAR antagonist RWJ 56110, as well as by dabigatran and 4-(2-aminoethylbenzenesulfonyl fluoride (AEBSF, which are selective and non-selective thrombin inhibitors, respectively. Expectedly, the PAR-1 agonist peptide (AP SFLLR-NH2 also attenuated the cell proliferation. The cell proliferation was not affected by the PAR-1 negative control peptide RLLFT-NH2, which is an inactive peptide for PAR-1. Independently, we determined the effect of in vivo treatment with AEBSF or AP on hippocampal neurogenesis in the adult mouse. The administration of AEBSF, but not that of AP, significantly increased the number of newly-generated cells in the hippocampal subgranular zone. These data suggest that PAR-1 negatively regulated adult neurogenesis in the hippocampus by inhibiting the proliferative activity of the NPCs.

  8. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA

    Directory of Open Access Journals (Sweden)

    Andrea Luchetti

    2015-08-01

    Full Text Available Spinal muscular atrophy (SMA is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1, encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs, leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.

  9. A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA).

    Science.gov (United States)

    Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

    2015-08-06

    Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.

  10. Focal Transplantation of Human iPSC-Derived Glial-Rich Neural Progenitors Improves Lifespan of ALS Mice

    Directory of Open Access Journals (Sweden)

    Takayuki Kondo

    2014-08-01

    Full Text Available Transplantation of glial-rich neural progenitors has been demonstrated to attenuate motor neuron degeneration and disease progression in rodent models of mutant superoxide dismutase 1 (SOD1-mediated amyotrophic lateral sclerosis (ALS. However, translation of these results into a clinical setting requires a renewable human cell source. Here, we derived glial-rich neural progenitors from human iPSCs and transplanted them into the lumbar spinal cord of ALS mouse models. The transplanted cells differentiated into astrocytes, and the treated mouse group showed prolonged lifespan. Our data suggest a potential therapeutic mechanism via activation of AKT signal. The results demonstrated the efficacy of cell therapy for ALS by the use of human iPSCs as cell source.

  11. Constitutively active Notch1 converts cranial neural crest-derived frontonasal mesenchyme to perivascular cells in vivo

    Directory of Open Access Journals (Sweden)

    Sophie R. Miller

    2017-03-01

    Full Text Available Perivascular/mural cells originate from either the mesoderm or the cranial neural crest. Regardless of their origin, Notch signalling is necessary for their formation. Furthermore, in both chicken and mouse, constitutive Notch1 activation (via expression of the Notch1 intracellular domain is sufficient in vivo to convert trunk mesoderm-derived somite cells to perivascular cells, at the expense of skeletal muscle. In experiments originally designed to investigate the effect of premature Notch1 activation on the development of neural crest-derived olfactory ensheathing glial cells (OECs, we used in ovo electroporation to insert a tetracycline-inducible NotchΔE construct (encoding a constitutively active mutant of mouse Notch1 into the genome of chicken cranial neural crest cell precursors, and activated NotchΔE expression by doxycycline injection at embryonic day 4. NotchΔE-targeted cells formed perivascular cells within the frontonasal mesenchyme, and expressed a perivascular marker on the olfactory nerve. Hence, constitutively activating Notch1 is sufficient in vivo to drive not only somite cells, but also neural crest-derived frontonasal mesenchyme and perhaps developing OECs, to a perivascular cell fate. These results also highlight the plasticity of neural crest-derived mesenchyme and glia.

  12. Neural crest does not contribute to the neck and shoulder in the axolotl (Ambystoma mexicanum).

    Science.gov (United States)

    Epperlein, Hans-Henning; Khattak, Shahryar; Knapp, Dunja; Tanaka, Elly M; Malashichev, Yegor B

    2012-01-01

    A major step during the evolution of tetrapods was their transition from water to land. This process involved the reduction or complete loss of the dermal bones that made up connections to the skull and a concomitant enlargement of the endochondral shoulder girdle. In the mouse the latter is derived from three separate embryonic sources: lateral plate mesoderm, somites, and neural crest. The neural crest was suggested to sustain the muscle attachments. How this complex composition of the endochondral shoulder girdle arose during evolution and whether it is shared by all tetrapods is unknown. Salamanders that lack dermal bone within their shoulder girdle were of special interest for a possible contribution of the neural crest to the endochondral elements and muscle attachment sites, and we therefore studied them in this context. We grafted neural crest from GFP+ fluorescent transgenic axolotl (Ambystoma mexicanum) donor embryos into white (d/d) axolotl hosts and followed the presence of neural crest cells within the cartilage of the shoulder girdle and the connective tissue of muscle attachment sites of the neck-shoulder region. Strikingly, neural crest cells did not contribute to any part of the endochondral shoulder girdle or to the connective tissue at muscle attachment sites in axolotl. Our results in axolotl suggest that neural crest does not serve a general function in vertebrate shoulder muscle attachment sites as predicted by the "muscle scaffold theory," and that it is not necessary to maintain connectivity of the endochondral shoulder girdle to the skull. Our data support the possibility that the contribution of the neural crest to the endochondral shoulder girdle, which is observed in the mouse, arose de novo in mammals as a developmental basis for their skeletal synapomorphies. This further supports the hypothesis of an increased neural crest diversification during vertebrate evolution.

  13. Neural crest does not contribute to the neck and shoulder in the axolotl (Ambystoma mexicanum.

    Directory of Open Access Journals (Sweden)

    Hans-Henning Epperlein

    Full Text Available BACKGROUND: A major step during the evolution of tetrapods was their transition from water to land. This process involved the reduction or complete loss of the dermal bones that made up connections to the skull and a concomitant enlargement of the endochondral shoulder girdle. In the mouse the latter is derived from three separate embryonic sources: lateral plate mesoderm, somites, and neural crest. The neural crest was suggested to sustain the muscle attachments. How this complex composition of the endochondral shoulder girdle arose during evolution and whether it is shared by all tetrapods is unknown. Salamanders that lack dermal bone within their shoulder girdle were of special interest for a possible contribution of the neural crest to the endochondral elements and muscle attachment sites, and we therefore studied them in this context. RESULTS: We grafted neural crest from GFP+ fluorescent transgenic axolotl (Ambystoma mexicanum donor embryos into white (d/d axolotl hosts and followed the presence of neural crest cells within the cartilage of the shoulder girdle and the connective tissue of muscle attachment sites of the neck-shoulder region. Strikingly, neural crest cells did not contribute to any part of the endochondral shoulder girdle or to the connective tissue at muscle attachment sites in axolotl. CONCLUSIONS: Our results in axolotl suggest that neural crest does not serve a general function in vertebrate shoulder muscle attachment sites as predicted by the "muscle scaffold theory," and that it is not necessary to maintain connectivity of the endochondral shoulder girdle to the skull. Our data support the possibility that the contribution of the neural crest to the endochondral shoulder girdle, which is observed in the mouse, arose de novo in mammals as a developmental basis for their skeletal synapomorphies. This further supports the hypothesis of an increased neural crest diversification during vertebrate evolution.

  14. Circuit Mechanisms Governing Local vs. Global Motion Processing in Mouse Visual Cortex

    Directory of Open Access Journals (Sweden)

    Rune Rasmussen

    2017-12-01

    Full Text Available A withstanding question in neuroscience is how neural circuits encode representations and perceptions of the external world. A particularly well-defined visual computation is the representation of global object motion by pattern direction-selective (PDS cells from convergence of motion of local components represented by component direction-selective (CDS cells. However, how PDS and CDS cells develop their distinct response properties is still unresolved. The visual cortex of the mouse is an attractive model for experimentally solving this issue due to the large molecular and genetic toolbox available. Although mouse visual cortex lacks the highly ordered orientation columns of primates, it is organized in functional sub-networks and contains striate- and extrastriate areas like its primate counterparts. In this Perspective article, we provide an overview of the experimental and theoretical literature on global motion processing based on works in primates and mice. Lastly, we propose what types of experiments could illuminate what circuit mechanisms are governing cortical global visual motion processing. We propose that PDS cells in mouse visual cortex appear as the perfect arena for delineating and solving how individual sensory features extracted by neural circuits in peripheral brain areas are integrated to build our rich cohesive sensory experiences.

  15. Requirement for Foxd3 in the maintenance of neural crest progenitors.

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    Teng, Lu; Mundell, Nathan A; Frist, Audrey Y; Wang, Qiaohong; Labosky, Patricia A

    2008-05-01

    Understanding the molecular mechanisms of stem cell maintenance is crucial for the ultimate goal of manipulating stem cells for the treatment of disease. Foxd3 is required early in mouse embryogenesis; Foxd3(-/-) embryos fail around the time of implantation, cells of the inner cell mass cannot be maintained in vitro, and blastocyst-derived stem cell lines cannot be established. Here, we report that Foxd3 is required for maintenance of the multipotent mammalian neural crest. Using tissue-specific deletion of Foxd3 in the neural crest, we show that Foxd3(flox/-); Wnt1-Cre mice die perinatally with a catastrophic loss of neural crest-derived structures. Cranial neural crest tissues are either missing or severely reduced in size, the peripheral nervous system consists of reduced dorsal root ganglia and cranial nerves, and the entire gastrointestinal tract is devoid of neural crest derivatives. These results demonstrate a global role for this transcriptional repressor in all aspects of neural crest maintenance along the anterior-posterior axis, and establish an unprecedented molecular link between multiple divergent progenitor lineages of the mammalian embryo.

  16. Oxygen-controlled automated neural differentiation of mouse embryonic stem cells.

    Science.gov (United States)

    Mondragon-Teran, Paul; Tostoes, Rui; Mason, Chris; Lye, Gary J; Veraitch, Farlan S

    2013-03-01

    Automation and oxygen tension control are two tools that provide significant improvements to the reproducibility and efficiency of stem cell production processes. the aim of this study was to establish a novel automation platform capable of controlling oxygen tension during both the cell-culture and liquid-handling steps of neural differentiation processes. We built a bespoke automation platform, which enclosed a liquid-handling platform in a sterile, oxygen-controlled environment. An airtight connection was used to transfer cell culture plates to and from an automated oxygen-controlled incubator. Our results demonstrate that our system yielded comparable cell numbers, viabilities, metabolism profiles and differentiation efficiencies when compared with traditional manual processes. Interestingly, eliminating exposure to ambient conditions during the liquid-handling stage resulted in significant improvements in the yield of MAP2-positive neural cells, indicating that this level of control can improve differentiation processes. This article describes, for the first time, an automation platform capable of maintaining oxygen tension control during both the cell-culture and liquid-handling stages of a 2D embryonic stem cell differentiation process.

  17. High speed digital interfacing for a neural data acquisition system

    Directory of Open Access Journals (Sweden)

    Bahr Andreas

    2016-09-01

    Full Text Available Diseases like schizophrenia and genetic epilepsy are supposed to be caused by disorders in the early development of the brain. For the further investigation of these relationships a custom designed application specific integrated circuit (ASIC was developed that is optimized for the recording from neonatal mice [Bahr A, Abu-Saleh L, Schroeder D, Krautschneider W. 16 Channel Neural Recording Integrated Circuit with SPI Interface and Error Correction Coding. Proc. 9th BIOSTEC 2016. Biodevices: Rome, Italy, 2016; 1: 263; Bahr A, Abu-Saleh L, Schroeder D, Krautschneider W. Development of a neural recording mixed signal integrated circuit for biomedical signal acquisition. Biomed Eng Biomed Tech Abstracts 2015; 60(S1: 298–299; Bahr A, Abu-Saleh L, Schroeder D, Krautschneider WH. 16 Channel Neural Recording Mixed Signal ASIC. CDNLive EMEA 2015 Conference Proceedings, 2015.]. To enable the live display of the neural signals a multichannel neural data acquisition system with live display functionality is presented. It implements a high speed data transmission from the ASIC to a computer with a live display functionality. The system has been successfully implemented and was used in a neural recording of a head-fixed mouse.

  18. Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure

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    Kit-Yi Leung

    2017-11-01

    Full Text Available Summary: Abnormal folate one-carbon metabolism (FOCM is implicated in neural tube defects (NTDs, severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S-adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary. : Leung at al. find that embryonic neural tube closure depends both on the supply of one-carbon units to the folate cycle from glycine cleavage and on the methionine cycle. In contrast, transfer of one-carbon units from the folate cycle to the methionine cycle by MTHFR is dispensable. Keywords: one-carbon metabolism, folic acid, neural tube defects, spina bifida, glycine cleavage system, non-ketotic hyperglycinemia, eye, Mthfr, Gldc

  19. ESC-Derived BDNF-Overexpressing Neural Progenitors Differentially Promote Recovery in Huntington's Disease Models by Enhanced Striatal Differentiation

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    Tina Zimmermann

    2016-10-01

    Full Text Available Huntington's disease (HD is characterized by fatal motoric failures induced by loss of striatal medium spiny neurons. Neuronal cell death has been linked to impaired expression and axonal transport of the neurotrophin BDNF (brain-derived neurotrophic factor. By transplanting embryonic stem cell-derived neural progenitors overexpressing BDNF, we combined cell replacement and BDNF supply as a potential HD therapy approach. Transplantation of purified neural progenitors was analyzed in a quinolinic acid (QA chemical and two genetic HD mouse models (R6/2 and N171-82Q on the basis of distinct behavioral parameters, including CatWalk gait analysis. Explicit rescue of motor function by BDNF neural progenitors was found in QA-lesioned mice, whereas genetic mouse models displayed only minor improvements. Tumor formation was absent, and regeneration was attributed to enhanced neuronal and striatal differentiation. In addition, adult neurogenesis was preserved in a BDNF-dependent manner. Our findings provide significant insight for establishing therapeutic strategies for HD to ameliorate neurodegenerative symptoms.

  20. Robo signaling regulates the production of cranial neural crest cells.

    Science.gov (United States)

    Li, Yan; Zhang, Xiao-Tan; Wang, Xiao-Yu; Wang, Guang; Chuai, Manli; Münsterberg, Andrea; Yang, Xuesong

    2017-12-01

    Slit/Robo signaling plays an important role in the guidance of developing neurons in developing embryos. However, it remains obscure whether and how Slit/Robo signaling is involved in the production of cranial neural crest cells. In this study, we examined Robo1 deficient mice to reveal developmental defects of mouse cranial frontal and parietal bones, which are derivatives of cranial neural crest cells. Therefore, we determined the production of HNK1 + cranial neural crest cells in early chick embryo development after knock-down (KD) of Robo1 expression. Detection of markers for pre-migratory and migratory neural crest cells, PAX7 and AP-2α, showed that production of both was affected by Robo1 KD. In addition, we found that the transcription factor slug is responsible for the aberrant delamination/EMT of cranial neural crest cells induced by Robo1 KD, which also led to elevated expression of E- and N-Cadherin. N-Cadherin expression was enhanced when blocking FGF signaling with dominant-negative FGFR1 in half of the neural tube. Taken together, we show that Slit/Robo signaling influences the delamination/EMT of cranial neural crest cells, which is required for cranial bone development. Copyright © 2017. Published by Elsevier Inc.

  1. A mouse model for binge-like sucrose overconsumption: Contribution of enhanced motivation for sweetener consumption.

    Science.gov (United States)

    Yasoshima, Yasunobu; Shimura, Tsuyoshi

    2015-01-01

    Behavioral and neural features of binge-like sugar overconsumption have been studied using rat models. However, few mouse models are available to examine the interaction between neural and genetic underpinnings of bingeing. In the present study, we first aim to establish a simple mouse model of binge-like sucrose overconsumption using daytime limited access training in food-restricted male mice. Trained mice received 4-h limited access to both 0.5M sucrose solution and chow for 10 days. Three control groups received (1) 4-h sucrose and 20-h chow access, (2) 20-h sucrose and 4-h, or (3) 20-h chow access, respectively. Only the trained group showed progressively increased sucrose consumption during brief periods of time and developed binge-like excessive behavior. Next, we examined whether the present mouse model mimicked a human feature of binge eating known as "eating when not physically hungry." Trained mice consumed significantly more sucrose or non-caloric sweetener (saccharin) during post-training days even after they nocturnally consumed substantial chow prior to daytime sweetener access. In other trained groups, both a systemic administration of glucose and substantial chow consumption prior to the daytime limited sucrose access failed to reduce binge-like sucrose overconsumption. Our results suggest that even when caloric consumption is not necessarily required, limited access training shapes and triggers binge-like overconsumption of sweetened solution in trained mice. The binge-like behavior in trained mice may be mainly due to enhanced hedonic motivation for the sweetener's taste. The present study suggests that our mouse model for binge-like sugar overconsumption may mimic some human features of binge eating and can be used to investigate the roles of neural and genetic mechanisms in binge-like overconsumption of sweetened substances in the absence of physical hunger. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. AKT signaling displays multifaceted functions in neural crest development.

    Science.gov (United States)

    Sittewelle, Méghane; Monsoro-Burq, Anne H

    2018-05-31

    AKT signaling is an essential intracellular pathway controlling cell homeostasis, cell proliferation and survival, as well as cell migration and differentiation in adults. Alterations impacting the AKT pathway are involved in many pathological conditions in human disease. Similarly, during development, multiple transmembrane molecules, such as FGF receptors, PDGF receptors or integrins, activate AKT to control embryonic cell proliferation, migration, differentiation, and also cell fate decisions. While many studies in mouse embryos have clearly implicated AKT signaling in the differentiation of several neural crest derivatives, information on AKT functions during the earliest steps of neural crest development had remained relatively scarce until recently. However, recent studies on known and novel regulators of AKT signaling demonstrate that this pathway plays critical roles throughout the development of neural crest progenitors. Non-mammalian models such as fish and frog embryos have been instrumental to our understanding of AKT functions in neural crest development, both in neural crest progenitors and in the neighboring tissues. This review combines current knowledge acquired from all these different vertebrate animal models to describe the various roles of AKT signaling related to neural crest development in vivo. We first describe the importance of AKT signaling in patterning the tissues involved in neural crest induction, namely the dorsal mesoderm and the ectoderm. We then focus on AKT signaling functions in neural crest migration and differentiation. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Quiescent Oct4+ Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein+ NSCs in the Adult Mouse Brain.

    Science.gov (United States)

    Reeve, Rachel L; Yammine, Samantha Z; Morshead, Cindi M; van der Kooy, Derek

    2017-09-01

    Adult primitive neural stem cells (pNSCs) are a rare population of glial fibrillary acidic protein (GFAP) - Oct4 + cells in the mouse forebrain subependymal zone bordering the lateral ventricles that give rise to clonal neurospheres in leukemia inhibitory factor in vitro. pNSC neurospheres can be passaged to self-renew or give rise to GFAP + NSCs that form neurospheres in epidermal growth factor and fibroblast growth factor 2, which we collectively refer to as definitive NSCs (dNSCs). Label retention experiments using doxycycline-inducible histone-2B (H2B)-green fluorescent protein (GFP) mice and several chase periods of up to 1 year quantified the adult pNSC cell cycle time as 3-5 months. We hypothesized that while pNSCs are not very proliferative at baseline, they may exist as a reserve pool of NSCs in case of injury. To test this function of pNSCs, we obtained conditional Oct4 knockout mice, Oct4 fl/fl ;Sox1 Cre (Oct4 CKO ), which do not yield adult pNSC-derived neurospheres. When we ablated the progeny of pNSCs, namely all GFAP + dNSCs, in these Oct4 CKO mice, we found that dNSCs did not recover as they do in wild-type mice, suggesting that pNSCs are necessary for dNSC repopulation. Returning to the H2B-GFP mice, we observed that the cytosine β-d-arabinofuranoside ablation of proliferating cells including dNSCs-induced quiescent pNSCs to proliferate and significantly dilute their H2B-GFP label. In conclusion, we demonstrate that pNSCs are the most quiescent stem cells in the adult brain reported to date and that their lineage position upstream of GFAP + dNSCs allows them to repopulate a depleted neural lineage. Stem Cells 2017;35:2071-2082. © 2017 AlphaMed Press.

  4. Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus

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    Roberta eHaddad-Tóvolli

    2015-03-01

    Full Text Available Secreted protein Sonic hedgehog (Shh ventralizes the neural tube by modulating the crucial balance between activating and repressing functions (GliA, GliR of transcription factors Gli2 and Gli3. This balance—the Shh-Gli code—is species- and context-dependent and has been elucidated for the mouse spinal cord. The hypothalamus, a forebrain region regulating vital functions like homeostasis and hormone secretion, shows dynamic and intricate Shh expression as well as complex regional differentiation. Here we asked if particular combinations of Gli2 and Gli3 and of GliA and GliR functions contribute to the variety of hypothalamic regions, i.e. we wanted to clarify the hypothalamic version of the Shh-Gli code. Based on mouse mutant analysis, we show that: 1 hypothalamic regional heterogeneity is based in part on differentially stringent requirements for Gli2 or Gli3; 2 another source of diversity are differential requirements for Shh of neural vs non-neural origin; 3 Gli2 is indispensable for the specification of a medial progenitor domain generating several essential hypothalamic nuclei plus the pituitary and median eminence; 4 the suppression of Gli3R by neural and non-neural Shh is essential for hypothalamic specification. Finally, we have mapped our results on a recent model which considers the hypothalamus as a transverse region with alar and basal portions. Our data confirm the model and are explained by it.

  5. Behavioral phenotypes of genetic mouse models of autism.

    Science.gov (United States)

    Kazdoba, T M; Leach, P T; Crawley, J N

    2016-01-01

    More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  6. The response of early neural genes to FGF signaling or inhibition of BMP indicate the absence of a conserved neural induction module

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    Rogers Crystal D

    2011-12-01

    Full Text Available Abstract Background The molecular mechanism that initiates the formation of the vertebrate central nervous system has long been debated. Studies in Xenopus and mouse demonstrate that inhibition of BMP signaling is sufficient to induce neural tissue in explants or ES cells respectively, whereas studies in chick argue that instructive FGF signaling is also required for the expression of neural genes. Although additional signals may be involved in neural induction and patterning, here we focus on the roles of BMP inhibition and FGF8a. Results To address the question of necessity and sufficiency of BMP inhibition and FGF signaling, we compared the temporal expression of the five earliest genes expressed in the neuroectoderm and determined their requirements for induction at the onset of neural plate formation in Xenopus. Our results demonstrate that the onset and peak of expression of the genes vary and that they have different regulatory requirements and are therefore unlikely to share a conserved neural induction regulatory module. Even though all require inhibition of BMP for expression, some also require FGF signaling; expression of the early-onset pan-neural genes sox2 and foxd5α requires FGF signaling while other early genes, sox3, geminin and zicr1 are induced by BMP inhibition alone. Conclusions We demonstrate that BMP inhibition and FGF signaling induce neural genes independently of each other. Together our data indicate that although the spatiotemporal expression patterns of early neural genes are similar, the mechanisms involved in their expression are distinct and there are different signaling requirements for the expression of each gene.

  7. Absence of Rybp Compromises Neural Differentiation of Embryonic Stem Cells

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    Gergo Kovacs

    2016-01-01

    Full Text Available Rybp (Ring1 and Yy1 Binding Protein is a transcriptional regulator and member of the noncanonical polycomb repressive complex 1 with essential role in early embryonic development. We have previously described that alteration of Rybp dosage in mouse models induced striking neural tube defects (NTDs, exencephaly, and disorganized neurocortex. In this study we further investigated the role of Rybp in neural differentiation by utilising wild type (rybp+/+ and rybp null mutant (rybp-/- embryonic stem cells (ESCs and tried to uncover underlying molecular events that are responsible for the observed phenotypic changes. We found that rybp null mutant ESCs formed less matured neurons, astrocytes, and oligodendrocytes from existing progenitors than wild type cells. Furthermore, lack of rybp coincided with altered gene expression of key neural markers including Pax6 and Plagl1 pinpointing a possible transcriptional circuit among these genes.

  8. Effects of Toll-like receptor 3 on herpes simplex virus type-1-infected mouse neural stem cells.

    Science.gov (United States)

    Sun, Xiuning; Shi, Lihong; Zhang, Haoyun; Li, Ruifang; Liang, Ruiwen; Liu, Zhijun

    2015-03-01

    In this study, we aimed to investigate the effect of herpes simplex virus type-1 (HSV-1) infection on the phosphorylation of interferon regulatory factor 3 (IRF3) and the expression of interferon-β (IFN-β), as well as to clarify the functions of toll-like receptor 3 (TLR3) in mouse neural stem cells (NSCs) infected with HSV-1. In HSV-1-infected cultured NSCs, immunofluorescence, reverse transcription - polymerase chain reaction, Western blot, and ELISA were performed to reveal the expression patterns of TLR3, IRF3, and IFN-β. Then, lentivirus-mediated RNA interference (RNAi) was used to block the expression of TLR3, and its effect on host resistance to HSV-1 infection was investigated. Under uninfected conditions, NSCs expressed TLR3 and phosphorylated IRF3, but after infection, the expression level of TLR3 was upregulated and the phosphorylation level of IRF3 in the nucleus was significantly enhanced, while IFN-β was also expressed. After TLR3 expression was blocked by lentivirus-mediated RNAi, IRF3 phosphorylation and IFN-β expression were downregulated. Therefore, HSV-1 upregulated the expression of TLR3 in NSCs and promoted nuclear translocation after IRF3 was phosphorylated to induce IFN-β expression. TLR3 exhibited an anti-HSV-1 infection capacity via innate immune functions.

  9. Specific and spatial labeling of P0-Cre versus Wnt1-Cre in cranial neural crest in early mouse embryos.

    Science.gov (United States)

    Chen, Guiqian; Ishan, Mohamed; Yang, Jingwen; Kishigami, Satoshi; Fukuda, Tomokazu; Scott, Greg; Ray, Manas K; Sun, Chenming; Chen, Shi-You; Komatsu, Yoshihiro; Mishina, Yuji; Liu, Hong-Xiang

    2017-06-01

    P0-Cre and Wnt1-Cre mouse lines have been widely used in combination with loxP-flanked mice to label and genetically modify neural crest (NC) cells and their derivatives. Wnt1-Cre has been regarded as the gold standard and there have been concerns about the specificity of P0-Cre because it is not clear about the timing and spatial distribution of the P0-Cre transgene in labeling NC cells at early embryonic stages. We re-visited P0-Cre and Wnt1-Cre models in the labeling of NC cells in early mouse embryos with a focus on cranial NC. We found that R26-lacZ Cre reporter responded to Cre activity more reliably than CAAG-lacZ Cre reporter during early embryogenesis. Cre immunosignals in P0-Cre and reporter (lacZ and RFP) activity in P0-Cre/R26-lacZ and P0-Cre/R26-RFP embryos was detected in the cranial NC and notochord regions in E8.0-9.5 (4-19 somites) embryos. P0-Cre transgene expression was observed in migrating NC cells and was more extensive in the forebrain and hindbrain but not apparent in the midbrain. Differences in the Cre distribution patterns of P0-Cre and Wnt1-Cre were profound in the midbrain and hindbrain regions, that is, extensive in the midbrain of Wnt1-Cre and in the hindbrain of P0-Cre embryos. The difference between P0-Cre and Wnt1-Cre in labeling cranial NC may provide a better explanation of the differential distributions of their NC derivatives and of the phenotypes caused by Cre-driven genetic modifications. © 2017 Wiley Periodicals, Inc.

  10. Impaired neuronal maturation of hippocampal neural progenitor cells in mice lacking CRAF.

    Science.gov (United States)

    Pfeiffer, Verena; Götz, Rudolf; Camarero, Guadelupe; Heinsen, Helmut; Blum, Robert; Rapp, Ulf Rüdiger

    2018-01-01

    RAF kinases are major constituents of the mitogen activated signaling pathway, regulating cell proliferation, differentiation and cell survival of many cell types, including neurons. In mammals, the family of RAF proteins consists of three members, ARAF, BRAF, and CRAF. Ablation of CRAF kinase in inbred mouse strains causes major developmental defects during fetal growth and embryonic or perinatal lethality. Heterozygous germline mutations in CRAF result in Noonan syndrome, which is characterized by neurocognitive impairment that may involve hippocampal physiology. The role of CRAF signaling during hippocampal development and generation of new postnatal hippocampal granule neurons has not been examined and may provide novel insight into the cause of hippocampal dysfunction in Noonan syndrome. In this study, by crossing CRAF-deficiency to CD-1 outbred mice, a CRAF mouse model was established which enabled us to investigate the interplay of neural progenitor proliferation and postmitotic differentiation during adult neurogenesis in the hippocampus. Albeit the general morphology of the hippocampus was unchanged, CRAF-deficient mice displayed smaller granule cell layer (GCL) volume at postnatal day 30 (P30). In CRAF-deficient mice a substantial number of abnormal, chromophilic, fast dividing cells were found in the subgranular zone (SGZ) and hilus of the dentate gyrus (DG), indicating that CRAF signaling contributes to hippocampal neural progenitor proliferation. CRAF-deficient neural progenitor cells showed an increased cell death rate and reduced neuronal maturation. These results indicate that CRAF function affects postmitotic neural cell differentiation and points to a critical role of CRAF-dependent growth factor signaling pathway in the postmitotic development of adult-born neurons.

  11. CD44-positive cells are candidates for astrocyte precursor cells in developing mouse cerebellum.

    Science.gov (United States)

    Cai, Na; Kurachi, Masashi; Shibasaki, Koji; Okano-Uchida, Takayuki; Ishizaki, Yasuki

    2012-03-01

    Neural stem cells are generally considered to be committed to becoming precursor cells before terminally differentiating into either neurons or glial cells during neural development. Neuronal and oligodendrocyte precursor cells have been identified in several areas in the murine central nervous system. The presence of astrocyte precursor cells (APCs) is not so well understood. The present study provides several lines of evidence that CD44-positive cells are APCs in the early postnatal mouse cerebellum. In developing mouse cerebellum, CD44-positive cells, mostly located in the white matter, were positive for the markers of the astrocyte lineage, but negative for the markers of mature astrocytes. CD44-positive cells were purified from postnatal cerebellum by fluorescence-activated cell sorting and characterized in vitro. In the absence of any signaling molecule, many cells died by apoptosis. The surviving cells gradually expressed glial fibrillary acidic protein, a marker for mature astrocytes, indicating that differentiation into mature astrocytes is the default program for these cells. The cells produced no neurospheres nor neurons nor oligodendrocytes under any condition examined, indicating these cells are not neural stem cells. Leukemia inhibitory factor greatly promoted astrocytic differentiation of CD44-positive cells, whereas bone morphogenetic protein 4 (BMP4) did not. Fibroblast growth factor-2 was a potent mitogen for these cells, but was insufficient for survival. BMP4 inhibited activation of caspase-3 and greatly promoted survival, suggesting a novel role for BMP4 in the control of development of astrocytes in cerebellum. We isolated and characterized only CD44 strongly positive large cells and discarded small and/or CD44 weakly positive cells in this study. Further studies are necessary to characterize these cells to help determine whether CD44 is a selective and specific marker for APCs in the developing mouse cerebellum. In conclusion, we succeeded in

  12. The murine homeobox gene Msx-3 shows highly restricted expression in the developing neural tube.

    Science.gov (United States)

    Shimeld, S M; McKay, I J; Sharpe, P T

    1996-04-01

    The mouse homeobox-genes Msx-1 and Msx-2 are expressed in several areas of the developing embryo, including the neural tube, neural crest, facial processes and limb buds. Here we report the characterisation of a third mouse Msx gene, which we designate Msx-3. The embryonic expression of Msx-3 was found to differ from that of Msx-1 and -2 in that it was confined to the dorsal neural tube. In embryos with 5-8 somites a segmental pattern of expression was observed in the hindbrain, with rhombomeres 3 and 5 lacking Msx-3 while other rhombomeres expressed Msx-3. This pattern was transient, however, such that in embryos with 18 or more somites expression was continuous throughout the dorsal hindbrain and anterior dorsal spinal cord. Differentiation of dorsal cell types in the neural tube can be induced by addition of members of the Tgf-beta family. Additionally, Msx-1 and -2 have been shown to be activated by addition of the Tgf-beta family member Bmp-4. To determine if Bmp-4 could activate Msx-3, we incubated embryonic hindbrain explants with exogenous Bmp-4. The dorsal expression of Msx-3 was seen to expand into more ventral regions of the neurectoderm in Bmp-4-treated cultures, implying that Bmp-4 may be able to mimic an in vivo signal that induces Msx-3.

  13. Targeted neural differentiation of murine mesenchymal stem cells by a protocol simulating the inflammatory site of neural injury

    Czech Academy of Sciences Publication Activity Database

    Chudíčková, Milada; Brůža, M.; Zajícová, Alena; Trošan, Peter; Svobodová, Lucie; Javorková, Eliška; Kubinová, Šárka; Holáň, Vladimír

    2017-01-01

    Roč. 11, č. 5 (2017), s. 1588-1597 ISSN 1932-6254 R&D Projects: GA ČR(CZ) GAP304/11/0653; GA ČR(CZ) GA14-12580S; GA ČR(CZ) GAP301/11/1568; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk(CZ) LO1309 Institutional support: RVO:68378041 Keywords : mouse * adipose-derived mesenchymal stem cells * neural differentiation Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Cell biology Impact factor: 3.989, year: 2016

  14. In vivo Brain Delivery of v-myc Overproduced Human Neural Stem Cells via the Intranasal Pathway: Tumor Characteristics in the Lung of a Nude Mouse

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    Eun Seong Lee

    2015-01-01

    Full Text Available We aimed to monitor the successful brain delivery of stem cells via the intranasal route and to observe the long-term consequence of the immortalized human neural stem cells in the lungs of a nude mouse model. Stably immortalized HB1.F3 human neural stem cells with firefly luciferase gene (F3-effluc were intranasally delivered to BALB/c nude mice. Bioluminescence images were serially acquired until 41 days in vivo and at 4 hours and 41 days ex vivo after intranasal delivery. Lungs were evaluated by histopathology. After intranasal delivery of F3-effluc cells, the intense in vivo signals were detected in the nasal area, migrated toward the brain areas at 4 hours (4 of 13, 30.8%, and gradually decreased for 2 days. The brain signals were confirmed by ex vivo imaging (2 of 4, 50%. In the mice with initial lung signals (4 of 9, 44.4%, the lung signals disappeared for 5 days but reappeared 2 weeks later. The intense lung signals were confirmed to originate from the tumors in the lungs formed by F3-effluc cells by ex vivo imaging and histopathology. We propose that intranasal delivery of immortalized stem cells should be monitored for their successful delivery to the brain and their tumorigenicity longitudinally.

  15. Spatially Compact Neural Clusters in the Dorsal Striatum Encode Locomotion Relevant Information.

    Science.gov (United States)

    Barbera, Giovanni; Liang, Bo; Zhang, Lifeng; Gerfen, Charles R; Culurciello, Eugenio; Chen, Rong; Li, Yun; Lin, Da-Ting

    2016-10-05

    An influential striatal model postulates that neural activities in the striatal direct and indirect pathways promote and inhibit movement, respectively. Normal behavior requires coordinated activity in the direct pathway to facilitate intended locomotion and indirect pathway to inhibit unwanted locomotion. In this striatal model, neuronal population activity is assumed to encode locomotion relevant information. Here, we propose a novel encoding mechanism for the dorsal striatum. We identified spatially compact neural clusters in both the direct and indirect pathways. Detailed characterization revealed similar cluster organization between the direct and indirect pathways, and cluster activities from both pathways were correlated with mouse locomotion velocities. Using machine-learning algorithms, cluster activities could be used to decode locomotion relevant behavioral states and locomotion velocity. We propose that neural clusters in the dorsal striatum encode locomotion relevant information and that coordinated activities of direct and indirect pathway neural clusters are required for normal striatal controlled behavior. VIDEO ABSTRACT. Published by Elsevier Inc.

  16. MicroRNA-130b targets Fmr1 and regulates embryonic neural progenitor cell proliferation and differentiation

    International Nuclear Information System (INIS)

    Gong, Xi; Zhang, Kunshan; Wang, Yanlu; Wang, Junbang; Cui, Yaru; Li, Siguang; Luo, Yuping

    2013-01-01

    Highlights: •We found that the 3′ UTR of the Fmr1 mRNA is a target of miR-130b. •MiR-130b suppresses the expression of Fmr1 in mouse embryonic stem cell. •MiR-130b alters the proliferation of mouse embryonic stem cell. •MiR-130b alters fate specification of mouse embryonic stem cell. -- Abstract: Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by expansion of the CGG repeat in the 5′-untranslated region of the X-linked Fmr1 gene, which results in transcriptional silencing and loss of expression of its encoded protein FMRP. The loss of FMRP increases proliferation and alters fate specification in adult neural progenitor cells (aNPCs). However, little is known about Fmr1 mRNA regulation at the transcriptional and post-transcriptional levels. In the present study, we report that miR-130b regulated Fmr1 expression by directly targeting its 3′-untranslated region (3′ UTR). Up-regulation of miR-130b in mouse embryonic neural progenitor cells (eNPCs) decreased Fmr1 expression, markedly increased eNPC proliferation and altered the differentiation tendency of eNPCs, suggesting that antagonizing miR-130b may be a new therapeutic entry point for treating Fragile X syndrome

  17. MicroRNA-130b targets Fmr1 and regulates embryonic neural progenitor cell proliferation and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Gong, Xi [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China); Zhang, Kunshan [Department of Regenerative Medicine, Stem Cell Center, Tongji University School of Medicine, Shanghai 200092 (China); Wang, Yanlu; Wang, Junbang; Cui, Yaru [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China); Li, Siguang, E-mail: siguangli@163.com [Department of Regenerative Medicine, Stem Cell Center, Tongji University School of Medicine, Shanghai 200092 (China); Luo, Yuping, E-mail: luoyuping@163.com [State Key Laboratory of Food Science and Technology, College of Life Sciences and Food Engineering, Nanchang University, Nanchang 330047 (China)

    2013-10-04

    Highlights: •We found that the 3′ UTR of the Fmr1 mRNA is a target of miR-130b. •MiR-130b suppresses the expression of Fmr1 in mouse embryonic stem cell. •MiR-130b alters the proliferation of mouse embryonic stem cell. •MiR-130b alters fate specification of mouse embryonic stem cell. -- Abstract: Fragile X syndrome, one of the most common forms of inherited mental retardation, is caused by expansion of the CGG repeat in the 5′-untranslated region of the X-linked Fmr1 gene, which results in transcriptional silencing and loss of expression of its encoded protein FMRP. The loss of FMRP increases proliferation and alters fate specification in adult neural progenitor cells (aNPCs). However, little is known about Fmr1 mRNA regulation at the transcriptional and post-transcriptional levels. In the present study, we report that miR-130b regulated Fmr1 expression by directly targeting its 3′-untranslated region (3′ UTR). Up-regulation of miR-130b in mouse embryonic neural progenitor cells (eNPCs) decreased Fmr1 expression, markedly increased eNPC proliferation and altered the differentiation tendency of eNPCs, suggesting that antagonizing miR-130b may be a new therapeutic entry point for treating Fragile X syndrome.

  18. Study of neural cells on organic semiconductor ultra thin films

    Energy Technology Data Exchange (ETDEWEB)

    Bystrenova, Eva; Tonazzini, Ilaria; Stoliar, Pablo; Greco, Pierpaolo; Lazar, Adina; Dutta, Soumya; Dionigi, Chiara; Cacace, Marcello; Biscarini, Fabio [ISMN-CNR, Bologna (Italy); Jelitai, Marta; Madarasz, Emilia [IEM- HAS, Budapest (Hungary); Huth, Martin; Nickel, Bert [LMU, Munich (Germany); Martini, Claudia [Dept. PNPB, Univ. of Pisa (Italy)

    2008-07-01

    Many technological advances are currently being developed for nano-fabrication, offering the ability to create and control patterns of soft materials. We report the deposition of cells on organic semiconductor ultra-thin films. This is a first step towards the development of active bio/non bio systems for electrical transduction. Thin films of pentacene, whose thickness was systematically varied, were grown by high vacuum sublimation. We report adhesion, growth, and differentiation of human astroglial cells and mouse neural stem cells on an organic semiconductor. Viability of astroglial cells in time was measured as a function of the roughness and the characteristic morphology of ultra thin organic film, as well as the features of the patterned molecules. Optical fluorescence microscope coupled to atomic force microscope was used to monitor the presence, density and shape of deposited cells. Neural stem cells remain viable, differentiate by retinoic acid and form dense neuronal networks. We have shown the possibility to integrate living neural cells on organic semiconductor thin films.

  19. High-throughput isotropic mapping of whole mouse brain using multi-view light-sheet microscopy

    Science.gov (United States)

    Nie, Jun; Li, Yusha; Zhao, Fang; Ping, Junyu; Liu, Sa; Yu, Tingting; Zhu, Dan; Fei, Peng

    2018-02-01

    Light-sheet fluorescence microscopy (LSFM) uses an additional laser-sheet to illuminate selective planes of the sample, thereby enabling three-dimensional imaging at high spatial-temporal resolution. These advantages make LSFM a promising tool for high-quality brain visualization. However, even by the use of LSFM, the spatial resolution remains insufficient to resolve the neural structures across a mesoscale whole mouse brain in three dimensions. At the same time, the thick-tissue scattering prevents a clear observation from the deep of brain. Here we use multi-view LSFM strategy to solve this challenge, surpassing the resolution limit of standard light-sheet microscope under a large field-of-view (FOV). As demonstrated by the imaging of optically-cleared mouse brain labelled with thy1-GFP, we achieve a brain-wide, isotropic cellular resolution of 3μm. Besides the resolution enhancement, multi-view braining imaging can also recover complete signals from deep tissue scattering and attenuation. The identification of long distance neural projections across encephalic regions can be identified and annotated as a result.

  20. Gene expression and functional annotation of the human and mouse choroid plexus epithelium.

    Directory of Open Access Journals (Sweden)

    Sarah F Janssen

    Full Text Available BACKGROUND: The choroid plexus epithelium (CPE is a lobed neuro-epithelial structure that forms the outer blood-brain barrier. The CPE protrudes into the brain ventricles and produces the cerebrospinal fluid (CSF, which is crucial for brain homeostasis. Malfunction of the CPE is possibly implicated in disorders like Alzheimer disease, hydrocephalus or glaucoma. To study human genetic diseases and potential new therapies, mouse models are widely used. This requires a detailed knowledge of similarities and differences in gene expression and functional annotation between the species. The aim of this study is to analyze and compare gene expression and functional annotation of healthy human and mouse CPE. METHODS: We performed 44k Agilent microarray hybridizations with RNA derived from laser dissected healthy human and mouse CPE cells. We functionally annotated and compared the gene expression data of human and mouse CPE using the knowledge database Ingenuity. We searched for common and species specific gene expression patterns and function between human and mouse CPE. We also made a comparison with previously published CPE human and mouse gene expression data. RESULTS: Overall, the human and mouse CPE transcriptomes are very similar. Their major functionalities included epithelial junctions, transport, energy production, neuro-endocrine signaling, as well as immunological, neurological and hematological functions and disorders. The mouse CPE presented two additional functions not found in the human CPE: carbohydrate metabolism and a more extensive list of (neural developmental functions. We found three genes specifically expressed in the mouse CPE compared to human CPE, being ACE, PON1 and TRIM3 and no human specifically expressed CPE genes compared to mouse CPE. CONCLUSION: Human and mouse CPE transcriptomes are very similar, and display many common functionalities. Nonetheless, we also identified a few genes and pathways which suggest that the CPE

  1. High glucose suppresses embryonic stem cell differentiation into neural lineage cells

    OpenAIRE

    Yang, Penghua; Shen, Wei-bin; Reece, E. Albert; Chen, Xi; Yang, Peixin

    2016-01-01

    Abnormal neurogenesis occurs during embryonic development in human diabetic pregnancies and in animal models of diabetic embryopathy. Our previous studies in a mouse model of diabetic embryopathy have implicated that high glucose of maternal diabetes delays neurogenesis in the developing neuroepithelium leading to neural tube defects. However, the underlying process in high glucose-impaired neurogenesis is uncharacterized. Neurogenesis from embryonic stem (ES) cells provides a valuable model ...

  2. Non-Viral Generation of Neural Precursor-like Cells from Adult Human Fibroblasts

    Directory of Open Access Journals (Sweden)

    Maucksch C

    2012-01-01

    Full Text Available Recent studies have reported direct reprogramming of human fibroblasts to mature neurons by the introduction of defined neural genes. This technology has potential use in the areas of neurological disease modeling and drug development. However, use of induced neurons for large-scale drug screening and cell-based replacement strategies is limited due to their inability to expand once reprogrammed. We propose it would be more desirable to induce expandable neural precursor cells directly from human fibroblasts. To date several pluripotent and neural transcription factors have been shown to be capable of converting mouse fibroblasts to neural stem/precursor-like cells when delivered by viral vectors. Here we extend these findings and demonstrate that transient ectopic insertion of the transcription factors SOX2 and PAX6 to adult human fibroblasts through use of non-viral plasmid transfection or protein transduction allows the generation of induced neural precursor (iNP colonies expressing a range of neural stem and pro-neural genes. Upon differentiation, iNP cells give rise to neurons exhibiting typical neuronal morphologies and expressing multiple neuronal markers including tyrosine hydroxylase and GAD65/67. Importantly, iNP-derived neurons demonstrate electrophysiological properties of functionally mature neurons with the capacity to generate action potentials. In addition, iNP cells are capable of differentiating into glial fibrillary acidic protein (GFAP-expressing astrocytes. This study represents a novel virus-free approach for direct reprogramming of human fibroblasts to a neural precursor fate.

  3. CD133 (Prominin negative human neural stem cells are clonogenic and tripotent.

    Directory of Open Access Journals (Sweden)

    Yirui Sun

    Full Text Available CD133 (Prominin is widely used as a marker for the identification and isolation of neural precursor cells from normal brain or tumor tissue. However, the assumption that CD133 is expressed constitutively in neural precursor cells has not been examined.In this study, we demonstrate that CD133 and a second marker CD15 are expressed heterogeneously in uniformly undifferentiated human neural stem (NS cell cultures. After fractionation by flow cytometry, clonogenic tripotent cells are found in populations negative or positive for either marker. We further show that CD133 is down-regulated at the mRNA level in cells lacking CD133 immunoreactivity. Cell cycle profiling reveals that CD133 negative cells largely reside in G1/G0, while CD133 positive cells are predominantly in S, G2, or M phase. A similar pattern is apparent in mouse NS cell lines. Compared to mouse NS cells, however, human NS cell cultures harbour an increased proportion of CD133 negative cells and display a longer doubling time. This may in part reflect a sub-population of slow- or non-cycling cells amongst human NS cells because we find that around 5% of cells do not take up BrdU over a 14-day labelling period. Non-proliferating NS cells remain undifferentiated and at least some of them are capable of re-entry into the cell cycle and subsequent continuous expansion.The finding that a significant fraction of clonogenic neural stem cells lack the established markers CD133 and CD15, and that some of these cells may be dormant or slow-cycling, has implications for approaches to identify and isolate neural stem cells and brain cancer stem cells. Our data also suggest the possibility that CD133 may be specifically down-regulated during G0/G1, and this should be considered when this marker is used to identify and isolate other tissue and cancer stem cells.

  4. Changes in neural network homeostasis trigger neuropsychiatric symptoms.

    Science.gov (United States)

    Winkelmann, Aline; Maggio, Nicola; Eller, Joanna; Caliskan, Gürsel; Semtner, Marcus; Häussler, Ute; Jüttner, René; Dugladze, Tamar; Smolinsky, Birthe; Kowalczyk, Sarah; Chronowska, Ewa; Schwarz, Günter; Rathjen, Fritz G; Rechavi, Gideon; Haas, Carola A; Kulik, Akos; Gloveli, Tengis; Heinemann, Uwe; Meier, Jochen C

    2014-02-01

    The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.

  5. Characterization of TLX expression in neural stem cells and progenitor cells in adult brains.

    Science.gov (United States)

    Li, Shengxiu; Sun, Guoqiang; Murai, Kiyohito; Ye, Peng; Shi, Yanhong

    2012-01-01

    TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ) of adult mouse brains. Then, using a double thymidine analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-positive cells in the SVZ represented the thymidine analog-negative, relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression. Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells.

  6. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells.

    Science.gov (United States)

    Sun, GuoQiang; Ye, Peng; Murai, Kiyohito; Lang, Ming-Fei; Li, Shengxiu; Zhang, Heying; Li, Wendong; Fu, Chelsea; Yin, Jason; Wang, Allen; Ma, Xiaoxiao; Shi, Yanhong

    2011-11-08

    miR-137 is a brain-enriched microRNA. Its role in neural development remains unknown. Here we show that miR-137 has an essential role in controlling embryonic neural stem cell fate determination. miR-137 negatively regulates cell proliferation and accelerates neural differentiation of embryonic neural stem cells. In addition, we show that the histone lysine-specific demethylase 1 (LSD1), a transcriptional co-repressor of nuclear receptor TLX, is a downstream target of miR-137. In utero electroporation of miR-137 in embryonic mouse brains led to premature differentiation and outward migration of the transfected cells. Introducing a LSD1 expression vector lacking the miR-137 recognition site rescued miR-137-induced precocious differentiation. Furthermore, we demonstrate that TLX, an essential regulator of neural stem cell self-renewal, represses the expression of miR-137 by recruiting LSD1 to the genomic regions of miR-137. Thus, miR-137 forms a feedback regulatory loop with TLX and LSD1 to control the dynamics between neural stem cell proliferation and differentiation during neural development.

  7. Activin/Nodal Signaling Supports Retinal Progenitor Specification in a Narrow Time Window during Pluripotent Stem Cell Neuralization

    Directory of Open Access Journals (Sweden)

    Michele Bertacchi

    2015-10-01

    Full Text Available Retinal progenitors are initially found in the anterior neural plate region known as the eye field, whereas neighboring areas undertake telencephalic or hypothalamic development. Eye field cells become specified by switching on a network of eye field transcription factors, but the extracellular cues activating this network remain unclear. In this study, we used chemically defined media to induce in vitro differentiation of mouse embryonic stem cells (ESCs toward eye field fates. Inhibition of Wnt/β-catenin signaling was sufficient to drive ESCs to telencephalic, but not retinal, fates. Instead, retinal progenitors could be generated from competent differentiating mouse ESCs by activation of Activin/Nodal signaling within a narrow temporal window corresponding to the emergence of primitive anterior neural progenitors. Activin also promoted eye field gene expression in differentiating human ESCs. Our results reveal insights into the mechanisms of eye field specification and open new avenues toward the generation of retinal progenitors for translational medicine.

  8. MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling.

    Science.gov (United States)

    Zhao, Chunnian; Sun, GuoQiang; Li, Shengxiu; Lang, Ming-Fei; Yang, Su; Li, Wendong; Shi, Yanhong

    2010-02-02

    Neural stem cell self-renewal and differentiation is orchestrated by precise control of gene expression involving nuclear receptor TLX. Let-7b, a member of the let-7 microRNA family, is expressed in mammalian brains and exhibits increased expression during neural differentiation. However, the role of let-7b in neural stem cell proliferation and differentiation remains unknown. Here we show that let-7b regulates neural stem cell proliferation and differentiation by targeting the stem cell regulator TLX and the cell cycle regulator cyclin D1. Overexpression of let-7b led to reduced neural stem cell proliferation and increased neural differentiation, whereas antisense knockdown of let-7b resulted in enhanced proliferation of neural stem cells. Moreover, in utero electroporation of let-7b to embryonic mouse brains led to reduced cell cycle progression in neural stem cells. Introducing an expression vector of Tlx or cyclin D1 that lacks the let-7b recognition site rescued let-7b-induced proliferation deficiency, suggesting that both TLX and cyclin D1 are important targets for let-7b-mediated regulation of neural stem cell proliferation. Let-7b, by targeting TLX and cyclin D1, establishes an efficient strategy to control neural stem cell proliferation and differentiation.

  9. Characterization of Pax3 and Sox10 transgenic Xenopus laevis embryos as tools to study neural crest development.

    Science.gov (United States)

    Alkobtawi, Mansour; Ray, Heather; Barriga, Elias H; Moreno, Mauricio; Kerney, Ryan; Monsoro-Burq, Anne-Helene; Saint-Jeannet, Jean-Pierre; Mayor, Roberto

    2018-03-06

    The neural crest is a multipotent population of cells that originates a variety of cell types. Many animal models are used to study neural crest induction, migration and differentiation, with amphibians and birds being the most widely used systems. A major technological advance to study neural crest development in mouse, chick and zebrafish has been the generation of transgenic animals in which neural crest specific enhancers/promoters drive the expression of either fluorescent proteins for use as lineage tracers, or modified genes for use in functional studies. Unfortunately, no such transgenic animals currently exist for the amphibians Xenopus laevis and tropicalis, key model systems for studying neural crest development. Here we describe the generation and characterization of two transgenic Xenopus laevis lines, Pax3-GFP and Sox10-GFP, in which GFP is expressed in the pre-migratory and migratory neural crest, respectively. We show that Pax3-GFP could be a powerful tool to study neural crest induction, whereas Sox10-GFP could be used in the study of neural crest migration in living embryos. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Characterization of TLX expression in neural stem cells and progenitor cells in adult brains.

    Directory of Open Access Journals (Sweden)

    Shengxiu Li

    Full Text Available TLX has been shown to play an important role in regulating the self-renewal and proliferation of neural stem cells in adult brains. However, the cellular distribution of endogenous TLX protein in adult brains remains to be elucidated. In this study, we used immunostaining with a TLX-specific antibody to show that TLX is expressed in both neural stem cells and transit-amplifying neural progenitor cells in the subventricular zone (SVZ of adult mouse brains. Then, using a double thymidine analog labeling approach, we showed that almost all of the self-renewing neural stem cells expressed TLX. Interestingly, most of the TLX-positive cells in the SVZ represented the thymidine analog-negative, relatively quiescent neural stem cell population. Using cell type markers and short-term BrdU labeling, we demonstrated that TLX was also expressed in the Mash1+ rapidly dividing type C cells. Furthermore, loss of TLX expression dramatically reduced BrdU label-retaining neural stem cells and the actively dividing neural progenitor cells in the SVZ, but substantially increased GFAP staining and extended GFAP processes. These results suggest that TLX is essential to maintain the self-renewing neural stem cells in the SVZ and that the GFAP+ cells in the SVZ lose neural stem cell property upon loss of TLX expression. Understanding the cellular distribution of TLX and its function in specific cell types may provide insights into the development of therapeutic tools for neurodegenerative diseases by targeting TLX in neural stem/progenitors cells.

  11. The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases.

    Science.gov (United States)

    Wang, Tao; Xiong, Jian-Qiong

    2016-02-01

    The human TLX gene encodes an orphan nuclear receptor predominantly expressed in the central nervous system. Tailess and Tlx, the TLX homologues in Drosophila and mouse, play essential roles in body-pattern formation and neurogenesis during early embryogenesis and perform crucial functions in maintaining stemness and controlling the differentiation of adult neural stem cells in the central nervous system, especially the visual system. Multiple target genes and signaling pathways are regulated by TLX and its homologues in specific tissues during various developmental stages. This review aims to summarize previous studies including many recent updates from different aspects concerning TLX and its homologues in Drosophila and mouse.

  12. In vitro generation of three-dimensional substrate-adherent embryonic stem cell-derived neural aggregates for application in animal models of neurological disorders.

    Science.gov (United States)

    Hargus, Gunnar; Cui, Yi-Fang; Dihné, Marcel; Bernreuther, Christian; Schachner, Melitta

    2012-05-01

    In vitro-differentiated embryonic stem (ES) cells comprise a useful source for cell replacement therapy, but the efficiency and safety of a translational approach are highly dependent on optimized protocols for directed differentiation of ES cells into the desired cell types in vitro. Furthermore, the transplantation of three-dimensional ES cell-derived structures instead of a single-cell suspension may improve graft survival and function by providing a beneficial microenvironment for implanted cells. To this end, we have developed a new method to efficiently differentiate mouse ES cells into neural aggregates that consist predominantly (>90%) of postmitotic neurons, neural progenitor cells, and radial glia-like cells. When transplanted into the excitotoxically lesioned striatum of adult mice, these substrate-adherent embryonic stem cell-derived neural aggregates (SENAs) showed significant advantages over transplanted single-cell suspensions of ES cell-derived neural cells, including improved survival of GABAergic neurons, increased cell migration, and significantly decreased risk of teratoma formation. Furthermore, SENAs mediated functional improvement after transplantation into animal models of Parkinson's disease and spinal cord injury. This unit describes in detail how SENAs are efficiently derived from mouse ES cells in vitro and how SENAs are isolated for transplantation. Furthermore, methods are presented for successful implantation of SENAs into animal models of Huntington's disease, Parkinson's disease, and spinal cord injury to study the effects of stem cell-derived neural aggregates in a disease context in vivo.

  13. Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

    Directory of Open Access Journals (Sweden)

    Gunnar Hargus

    2014-09-01

    Full Text Available The differentiation capability of induced pluripotent stem cells (iPSCs toward certain cell types for disease modeling and drug screening assays might be influenced by their somatic cell of origin. Here, we have compared the neural induction of human iPSCs generated from fetal neural stem cells (fNSCs, dermal fibroblasts, or cord blood CD34+ hematopoietic progenitor cells. Neural progenitor cells (NPCs and neurons could be generated at similar efficiencies from all iPSCs. Transcriptomics analysis of the whole genome and of neural genes revealed a separation of neuroectoderm-derived iPSC-NPCs from mesoderm-derived iPSC-NPCs. Furthermore, we found genes that were similarly expressed in fNSCs and neuroectoderm, but not in mesoderm-derived iPSC-NPCs. Notably, these neural signatures were retained after transplantation into the cortex of mice and paralleled with increased survival of neuroectoderm-derived cells in vivo. These results indicate distinct origin-dependent neural cell identities in differentiated human iPSCs both in vitro and in vivo.

  14. Pulsed DC Electric Field-Induced Differentiation of Cortical Neural Precursor Cells.

    Directory of Open Access Journals (Sweden)

    Hui-Fang Chang

    Full Text Available We report the differentiation of neural stem and progenitor cells solely induced by direct current (DC pulses stimulation. Neural stem and progenitor cells in the adult mammalian brain are promising candidates for the development of therapeutic neuroregeneration strategies. The differentiation of neural stem and progenitor cells depends on various in vivo environmental factors, such as nerve growth factor and endogenous EF. In this study, we demonstrated that the morphologic and phenotypic changes of mouse neural stem and progenitor cells (mNPCs could be induced solely by exposure to square-wave DC pulses (magnitude 300 mV/mm at frequency of 100-Hz. The DC pulse stimulation was conducted for 48 h, and the morphologic changes of mNPCs were monitored continuously. The length of primary processes and the amount of branching significantly increased after stimulation by DC pulses for 48 h. After DC pulse treatment, the mNPCs differentiated into neurons, astrocytes, and oligodendrocytes simultaneously in stem cell maintenance medium. Our results suggest that simple DC pulse treatment could control the fate of NPCs. With further studies, DC pulses may be applied to manipulate NPC differentiation and may be used for the development of therapeutic strategies that employ NPCs to treat nervous system disorders.

  15. Pulsed DC Electric Field-Induced Differentiation of Cortical Neural Precursor Cells.

    Science.gov (United States)

    Chang, Hui-Fang; Lee, Ying-Shan; Tang, Tang K; Cheng, Ji-Yen

    2016-01-01

    We report the differentiation of neural stem and progenitor cells solely induced by direct current (DC) pulses stimulation. Neural stem and progenitor cells in the adult mammalian brain are promising candidates for the development of therapeutic neuroregeneration strategies. The differentiation of neural stem and progenitor cells depends on various in vivo environmental factors, such as nerve growth factor and endogenous EF. In this study, we demonstrated that the morphologic and phenotypic changes of mouse neural stem and progenitor cells (mNPCs) could be induced solely by exposure to square-wave DC pulses (magnitude 300 mV/mm at frequency of 100-Hz). The DC pulse stimulation was conducted for 48 h, and the morphologic changes of mNPCs were monitored continuously. The length of primary processes and the amount of branching significantly increased after stimulation by DC pulses for 48 h. After DC pulse treatment, the mNPCs differentiated into neurons, astrocytes, and oligodendrocytes simultaneously in stem cell maintenance medium. Our results suggest that simple DC pulse treatment could control the fate of NPCs. With further studies, DC pulses may be applied to manipulate NPC differentiation and may be used for the development of therapeutic strategies that employ NPCs to treat nervous system disorders.

  16. Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex

    Science.gov (United States)

    Remedios, Ryan; Kennedy, Ann; Zelikowsky, Moriel; Grewe, Benjamin F.; Schnitzer, Mark J.; Anderson, David J.

    2017-10-01

    All animals possess a repertoire of innate (or instinctive) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents. We used microendoscopy to image Esr1+ neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24 h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.

  17. CMOS On-Chip Optoelectronic Neural Interface Device with Integrated Light Source for Optogenetics

    International Nuclear Information System (INIS)

    Sawadsaringkarn, Y; Kimura, H; Maezawa, Y; Nakajima, A; Kobayashi, T; Sasagawa, K; Noda, T; Tokuda, T; Ohta, J

    2012-01-01

    A novel optoelectronic neural interface device is proposed for target applications in optogenetics for neural science. The device consists of a light emitting diode (LED) array implemented on a CMOS image sensor for on-chip local light stimulation. In this study, we designed a suitable CMOS image sensor equipped with on-chip electrodes to drive the LEDs, and developed a device structure and packaging process for LED integration. The prototype device produced an illumination intensity of approximately 1 mW with a driving current of 2.0 mA, which is expected to be sufficient to activate channelrhodopsin (ChR2). We also demonstrated the functions of light stimulation and on-chip imaging using a brain slice from a mouse as a target sample.

  18. Applications of Mesenchymal Stem Cells and Neural Crest Cells in Craniofacial Skeletal Research

    Directory of Open Access Journals (Sweden)

    Satoru Morikawa

    2016-01-01

    Full Text Available Craniofacial skeletal tissues are composed of tooth and bone, together with nerves and blood vessels. This composite material is mainly derived from neural crest cells (NCCs. The neural crest is transient embryonic tissue present during neural tube formation whose cells have high potential for migration and differentiation. Thus, NCCs are promising candidates for craniofacial tissue regeneration; however, the clinical application of NCCs is hindered by their limited accessibility. In contrast, mesenchymal stem cells (MSCs are easily accessible in adults, have similar potential for self-renewal, and can differentiate into skeletal tissues, including bones and cartilage. Therefore, MSCs may represent good sources of stem cells for clinical use. MSCs are classically identified under adherent culture conditions, leading to contamination with other cell lineages. Previous studies have identified mouse- and human-specific MSC subsets using cell surface markers. Additionally, some studies have shown that a subset of MSCs is closely related to neural crest derivatives and endothelial cells. These MSCs may be promising candidates for regeneration of craniofacial tissues from the perspective of developmental fate. Here, we review the fundamental biology of MSCs in craniofacial research.

  19. The development of a PZT-based microdrive for neural signal recording

    International Nuclear Information System (INIS)

    Park, Sangkyu; Yoon, Euisung; Park, Sukho; Lee, Sukchan; Shin, Hee-sup; Park, Hyunjun; Kim, Byungkyu; Kim, Daesoo; Park, Jongoh

    2008-01-01

    A hand-controlled microdrive has been used to obtain neural signals from rodents such as rats and mice. However, it places severe physical stress on the rodents during its manipulation, and this stress leads to alertness in the mice and low efficiency in obtaining neural signals from the mice. To overcome this issue, we developed a novel microdrive, which allows one to adjust the electrodes by a piezoelectric device (PZT) with high precision. Its mass is light enough to install on the mouse's head. The proposed microdrive has three H-type PZT actuators and their guiding structure. The operation principle of the microdrive is based on the well known inchworm mechanism. When the three PZT actuators are synchronized, linear motion of the electrode is produced along the guiding structure. The electrodes used for the recording of the neural signals from neuron cells were fixed at one of the PZT actuators. Our proposed microdrive has an accuracy of about 400 nm and a long stroke of about 5 mm. In response to formalin-induced pain, single unit activities are robustly measured at the thalamus with electrodes whose vertical depth is adjusted by the microdrive under urethane anesthesia. In addition, the microdrive was efficient in detecting neural signals from mice that were moving freely. Thus, the present study suggests that the PZT-based microdrive could be an alternative for the efficient detection of neural signals from mice during behavioral states without any stress to the mice. (technical note)

  20. Fluorescence-Activated Cell Sorting of EGFP-Labeled Neural Crest Cells From Murine Embryonic Craniofacial Tissue

    Directory of Open Access Journals (Sweden)

    Saurabh Singh

    2005-01-01

    Full Text Available During the early stages of embryogenesis, pluripotent neural crest cells (NCC are known to migrate from the neural folds to populate multiple target sites in the embryo where they differentiate into various derivatives, including cartilage, bone, connective tissue, melanocytes, glia, and neurons of the peripheral nervous system. The ability to obtain pure NCC populations is essential to enable molecular analyses of neural crest induction, migration, and/or differentiation. Crossing Wnt1-Cre and Z/EG transgenic mouse lines resulted in offspring in which the Wnt1-Cre transgene activated permanent EGFP expression only in NCC. The present report demonstrates a flow cytometric method to sort and isolate populations of EGFP-labeled NCC. The identity of the sorted neural crest cells was confirmed by assaying expression of known marker genes by TaqMan Quantitative Real-Time Polymerase Chain Reaction (QRT-PCR. The molecular strategy described in this report provides a means to extract intact RNA from a pure population of NCC thus enabling analysis of gene expression in a defined population of embryonic precursor cells critical to development.

  1. A Nestin-cre transgenic mouse is insufficient for recombination in early embryonic neural progenitors

    Directory of Open Access Journals (Sweden)

    Huixuan Liang

    2012-09-01

    Nestin-cre transgenic mice have been widely used to direct recombination to neural stem cells (NSCs and intermediate neural progenitor cells (NPCs. Here we report that a readily utilized, and the only commercially available, Nestin-cre line is insufficient for directing recombination in early embryonic NSCs and NPCs. Analysis of recombination efficiency in multiple cre-dependent reporters and a genetic mosaic line revealed consistent temporal and spatial patterns of recombination in NSCs and NPCs. For comparison we utilized a knock-in Emx1cre line and found robust recombination in NSCs and NPCs in ventricular and subventricular zones of the cerebral cortices as early as embryonic day 12.5. In addition we found that the rate of Nestin-cre driven recombination only reaches sufficiently high levels in NSCs and NPCs during late embryonic and early postnatal periods. These findings are important when commercially available cre lines are considered for directing recombination to embryonic NSCs and NPCs.

  2. The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear

    Directory of Open Access Journals (Sweden)

    Paudyal Anju

    2010-08-01

    Full Text Available Abstract Background The planar cell polarity (PCP signalling pathway is fundamental to a number of key developmental events, including initiation of neural tube closure. Disruption of the PCP pathway causes the severe neural tube defect of craniorachischisis, in which almost the entire brain and spinal cord fails to close. Identification of mouse mutants with craniorachischisis has proven a powerful way of identifying molecules that are components or regulators of the PCP pathway. In addition, identification of an allelic series of mutants, including hypomorphs and neomorphs in addition to complete nulls, can provide novel genetic tools to help elucidate the function of the PCP proteins. Results We report the identification of a new N-ethyl-N-nitrosourea (ENU-induced mutant with craniorachischisis, which we have named chuzhoi (chz. We demonstrate that chuzhoi mutant embryos fail to undergo initiation of neural tube closure, and have characteristics consistent with defective convergent extension. These characteristics include a broadened midline and reduced rate of increase of their length-to-width ratio. In addition, we demonstrate disruption in the orientation of outer hair cells in the inner ear, and defects in heart and lung development in chuzhoi mutants. We demonstrate a genetic interaction between chuzhoi mutants and both Vangl2Lp and Celsr1Crsh mutants, strengthening the hypothesis that chuzhoi is involved in regulating the PCP pathway. We demonstrate that chuzhoi maps to Chromosome 17 and carries a splice site mutation in Ptk7. This mutation results in the insertion of three amino acids into the Ptk7 protein and causes disruption of Ptk7 protein expression in chuzhoi mutants. Conclusions The chuzhoi mutant provides an additional genetic resource to help investigate the developmental basis of several congenital abnormalities including neural tube, heart and lung defects and their relationship to disruption of PCP. The chuzhoi mutation

  3. Taurine Induces Proliferation of Neural Stem Cells and Synapse Development in the Developing Mouse Brain

    Science.gov (United States)

    Shivaraj, Mattu Chetana; Marcy, Guillaume; Low, Guoliang; Ryu, Jae Ryun; Zhao, Xianfeng; Rosales, Francisco J.; Goh, Eyleen L. K.

    2012-01-01

    Taurine is a sulfur-containing amino acid present in high concentrations in mammalian tissues. It has been implicated in several processes involving brain development and neurotransmission. However, the role of taurine in hippocampal neurogenesis during brain development is still unknown. Here we show that taurine regulates neural progenitor cell (NPC) proliferation in the dentate gyrus of the developing brain as well as in cultured early postnatal (P5) hippocampal progenitor cells and hippocampal slices derived from P5 mice brains. Taurine increased cell proliferation without having a significant effect on neural differentiation both in cultured P5 NPCs as well as cultured hippocampal slices and in vivo. Expression level analysis of synaptic proteins revealed that taurine increases the expression of Synapsin 1 and PSD 95. We also found that taurine stimulates the phosphorylation of ERK1/2 indicating a possible role of the ERK pathway in mediating the changes that we observed, especially in proliferation. Taken together, our results demonstrate a role for taurine in neural stem/progenitor cell proliferation in developing brain and suggest the involvement of the ERK1/2 pathways in mediating these actions. Our study also shows that taurine influences the levels of proteins associated with synapse development. This is the first evidence showing the effect of taurine on early postnatal neuronal development using a combination of in vitro, ex-vivo and in vivo systems. PMID:22916184

  4. Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve.

    Science.gov (United States)

    Odelin, Gaëlle; Faure, Emilie; Coulpier, Fanny; Di Bonito, Maria; Bajolle, Fanny; Studer, Michèle; Avierinos, Jean-François; Charnay, Patrick; Topilko, Piotr; Zaffran, Stéphane

    2018-01-03

    Although cardiac neural crest cells are required at early stages of arterial valve development, their contribution during valvular leaflet maturation remains poorly understood. Here, we show in mouse that neural crest cells from pre-otic and post-otic regions make distinct contributions to the arterial valve leaflets. Genetic fate-mapping analysis of Krox20-expressing neural crest cells shows a large contribution to the borders and the interleaflet triangles of the arterial valves. Loss of Krox20 function results in hyperplastic aortic valve and partially penetrant bicuspid aortic valve formation. Similar defects are observed in neural crest Krox20 -deficient embryos. Genetic lineage tracing in Krox20 -/- mutant mice shows that endothelial-derived cells are normal, whereas neural crest-derived cells are abnormally increased in number and misplaced in the valve leaflets. In contrast, genetic ablation of Krox20 -expressing cells is not sufficient to cause an aortic valve defect, suggesting that adjacent cells can compensate this depletion. Our findings demonstrate a crucial role for Krox20 in arterial valve development and reveal that an excess of neural crest cells may be associated with bicuspid aortic valve. © 2018. Published by The Company of Biologists Ltd.

  5. Dynamic methylation and expression of Oct4 in early neural stem cells.

    Science.gov (United States)

    Lee, Shih-Han; Jeyapalan, Jennie N; Appleby, Vanessa; Mohamed Noor, Dzul Azri; Sottile, Virginie; Scotting, Paul J

    2010-09-01

    Neural stem cells are a multipotent population of tissue-specific stem cells with a broad but limited differentiation potential. However, recent studies have shown that over-expression of the pluripotency gene, Oct4, alone is sufficient to initiate a process by which these can form 'induced pluripotent stem cells' (iPS cells) with the same broad potential as embryonic stem cells. This led us to examine the expression of Oct4 in endogenous neural stem cells, as data regarding its expression in neural stem cells in vivo are contradictory and incomplete. In this study we have therefore analysed the expression of Oct4 and other genes associated with pluripotency throughout development of the mouse CNS and in neural stem cells grown in vitro. We find that Oct4 is still expressed in the CNS by E8.5, but that this expression declines rapidly until it is undetectable by E15.5. This decline is coincident with the gradual methylation of the Oct4 promoter and proximal enhancer. Immunostaining suggests that the Oct4 protein is predominantly cytoplasmic in location. We also found that neural stem cells from all ages expressed the pluripotency associated genes, Sox2, c-Myc, Klf4 and Nanog. These data provide an explanation for the varying behaviour of cells from the early neuroepithelium at different stages of development. The expression of these genes also provides an indication of why Oct4 alone is sufficient to induce iPS formation in neural stem cells at later stages.

  6. Isolation and culture of neural crest cells from embryonic murine neural tube.

    Science.gov (United States)

    Pfaltzgraff, Elise R; Mundell, Nathan A; Labosky, Patricia A

    2012-06-02

    The embryonic neural crest (NC) is a multipotent progenitor population that originates at the dorsal aspect of the neural tube, undergoes an epithelial to mesenchymal transition (EMT) and migrates throughout the embryo, giving rise to diverse cell types. NC also has the unique ability to influence the differentiation and maturation of target organs. When explanted in vitro, NC progenitors undergo self-renewal, migrate and differentiate into a variety of tissue types including neurons, glia, smooth muscle cells, cartilage and bone. NC multipotency was first described from explants of the avian neural tube. In vitro isolation of NC cells facilitates the study of NC dynamics including proliferation, migration, and multipotency. Further work in the avian and rat systems demonstrated that explanted NC cells retain their NC potential when transplanted back into the embryo. Because these inherent cellular properties are preserved in explanted NC progenitors, the neural tube explant assay provides an attractive option for studying the NC in vitro. To attain a better understanding of the mammalian NC, many methods have been employed to isolate NC populations. NC-derived progenitors can be cultured from post-migratory locations in both the embryo and adult to study the dynamics of post-migratory NC progenitors, however isolation of NC progenitors as they emigrate from the neural tube provides optimal preservation of NC cell potential and migratory properties. Some protocols employ fluorescence activated cell sorting (FACS) to isolate a NC population enriched for particular progenitors. However, when starting with early stage embryos, cell numbers adequate for analyses are difficult to obtain with FACS, complicating the isolation of early NC populations from individual embryos. Here, we describe an approach that does not rely on FACS and results in an approximately 96% pure NC population based on a Wnt1-Cre activated lineage reporter. The method presented here is adapted from

  7. Generation and characterization of PDGFRα-GFPCreERT2 knock-In mouse line.

    Science.gov (United States)

    Miwa, Hiroyuki; Era, Takumi

    2015-05-01

    Platelet-derived growth factor (PDGF) and its receptor play an important role in embryogenesis. PDGF receptor α (PDGFRα) is expressed specifically in the embryonic day 7.5 (E7.5) mesoderm and in the E9.5 neural crest among other tissues. PDGFRα-expressing cells and their descendants are involved in the formation of various tissues. To trace PDGFRα-expressing cells in vivo, we generated a knock-in mouse line that expressed a fusion protein of green fluorescent protein (GFP), Cre recombinase (Cre), and mutated estrogen receptor ligand-binding domain (ERT2) under the control of the PDGFRα promoter. In these mice, Cre activity in PDGFRα-expressing cells could be induced by tamoxifen treatment. Taken together, our results suggest that the knock-in mouse line generated here could be useful for studying PDGFRα-expressing cells and their descendants in vivo at various stages of development. © 2015 Wiley Periodicals, Inc.

  8. Diffusion tensor imaging using multiple coils for mouse brain connectomics.

    Science.gov (United States)

    Nouls, John C; Badea, Alexandra; Anderson, Robert B J; Cofer, Gary P; Allan Johnson, G

    2018-04-19

    The correlation between brain connectivity and psychiatric or neurological diseases has intensified efforts to develop brain connectivity mapping techniques on mouse models of human disease. The neural architecture of mouse brain specimens can be shown non-destructively and three-dimensionally by diffusion tensor imaging, which enables tractography, the establishment of a connectivity matrix and connectomics. However, experiments on cohorts of animals can be prohibitively long. To improve throughput in a 7-T preclinical scanner, we present a novel two-coil system in which each coil is shielded, placed off-isocenter along the axis of the magnet and connected to a receiver circuit of the scanner. Preservation of the quality factor of each coil is essential to signal-to-noise ratio (SNR) performance and throughput, because mouse brain specimen imaging at 7 T takes place in the coil-dominated noise regime. In that regime, we show a shielding configuration causing no SNR degradation in the two-coil system. To acquire data from several coils simultaneously, the coils are placed in the magnet bore, around the isocenter, in which gradient field distortions can bias diffusion tensor imaging metrics, affect tractography and contaminate measurements of the connectivity matrix. We quantified the experimental alterations in fractional anisotropy and eigenvector direction occurring in each coil. We showed that, when the coils were placed 12 mm away from the isocenter, measurements of the brain connectivity matrix appeared to be minimally altered by gradient field distortions. Simultaneous measurements on two mouse brain specimens demonstrated a full doubling of the diffusion tensor imaging throughput in practice. Each coil produced images devoid of shading or artifact. To further improve the throughput of mouse brain connectomics, we suggested a future expansion of the system to four coils. To better understand acceptable trade-offs between imaging throughput and connectivity

  9. Neural tube defects – recent advances, unsolved questions and controversies

    Science.gov (United States)

    Copp, Andrew J.; Stanier, Philip; Greene, Nicholas D. E.

    2014-01-01

    Neural tube defects (NTDs) are severe congenital malformations affecting around 1 in every 1000 pregnancies. Here we review recent advances and currently unsolved issues in the NTD field. An innovation in clinical management has come from the demonstration that closure of open spina bifida lesions in utero can diminish neurological dysfunction in children. Primary prevention by folic acid has been enhanced through introduction of mandatory food fortification in some countries, although not yet in UK. Genetic predisposition comprises the majority of NTD risk, and genes that regulate folate one-carbon metabolism and planar cell polarity have been strongly implicated. The sequence of human neural tube closure events remains controversial, but study of mouse NTD models shows that anencephaly, open spina bifida and craniorachischisis result from failure of primary neurulation, while skin-covered spinal dysraphism results from defective secondary neurulation. Other ‘NTD’ malformations, such as encephalocele, are likely to be post-neurulation disorders. PMID:23790957

  10. [Inhibitory effect of murine cytomegalovirus infection on neural stem cells' differentiation and its mechanisms].

    Science.gov (United States)

    Zhou, Yu-feng; Fang, Feng; Dong, Yong-sui; Zhou, Hua; Zhen, Hong; Liu, Jin; Li, Ge

    2006-07-01

    Cytomegalovirus (CMV) is the leading infectious cause of congenital anomalies of the central nervous system caused by intrauterine infection. However, the exact pathogenesis of these brain abnormalities has not been fully elucidated. It has been reported that periependymitis, periventricular necrosis and calcification are the most frequent findings in the brains of congenital CMV infection. Because a number of multipotential neural stem cells (NSCs) have been identified from ventricular zone, it is possible that NSCs in this area are primary targets for viral infection, which seems to be primarily responsible for the generation of the brain abnormalities. Therefore, the objective of the present study was to investigate the effect and mechanism of murine cytomegalovirus (MCMV) infection on neural stem cells' differentiation in vitro and its role in the mechanisms of brain abnormalities caused by congenital cytomegalovirus infection. NSCs were prepared from fetal BALB/c mouse and were infected with recombinant MCMV RM461 inserted with a report gene LacZ at 1 multiplicity of infection (MOI = 1). The effect of MCMV infection on neural stem cells' differentiation was observed by detecting the ratio of nestin, GFAP and NSE positive cells with immunohistochemistry and flow cytometry on day 2 postinfection. The effects of MCMV infection on gene expression of Wnt-1 and neurogenin 1 (Ngn1) related to neural differentiation were detected by RT-PCR. NSCs isolated from embryonic mouse brains strongly expressed nestin, a specific marker of NSCs and had the capacity to differentiate into NF-200 and NSE positive neurons or GFAP positive astrocytes. At MOI = 1, the results of flow cytometry assay showed that nestin positive cells' proportion in the infection group [(62.2 +/- 1.8)%] was higher than that in the normal group [(37.2 +/- 2.4)%] (t = 4.62, P differentiation, which may be primary causes of disorders of brain development in congenital CMV infection. The decreased

  11. YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner

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    Han, Dasol; Byun, Sung-Hyun; Park, Soojeong; Kim, Juwan; Kim, Inhee; Ha, Soobong; Kwon, Mookwang; Yoon, Keejung, E-mail: keejung@skku.edu

    2015-02-27

    Mammalian brain development is regulated by multiple signaling pathways controlling cell proliferation, migration and differentiation. Here we show that YAP/TAZ enhance embryonic neural stem cell characteristics in a cell autonomous fashion using diverse experimental approaches. Introduction of retroviral vectors expressing YAP or TAZ into the mouse embryonic brain induced cell localization in the ventricular zone (VZ), which is the embryonic neural stem cell niche. This change in cell distribution in the cortical layer is due to the increased stemness of infected cells; YAP-expressing cells were colabeled with Sox2, a neural stem cell marker, and YAP/TAZ increased the frequency and size of neurospheres, indicating enhanced self-renewal- and proliferative ability of neural stem cells. These effects appear to be TEA domain family transcription factor (Tead)–dependent; a Tead binding-defective YAP mutant lost the ability to promote neural stem cell characteristics. Consistently, in utero gene transfer of a constitutively active form of Tead2 (Tead2-VP16) recapitulated all the features of YAP/TAZ overexpression, and dominant negative Tead2-EnR resulted in marked cell exit from the VZ toward outer cortical layers. Taken together, these results indicate that the Tead-dependent YAP/TAZ signaling pathway plays important roles in neural stem cell maintenance by enhancing stemness of neural stem cells during mammalian brain development. - Highlights: • Roles of YAP and Tead in vivo during mammalian brain development are clarified. • Expression of YAP promotes embryonic neural stem cell characteristics in vivo in a cell autonomous fashion. • Enhancement of neural stem cell characteristics by YAP depends on Tead. • Transcriptionally active form of Tead alone can recapitulate the effects of YAP. • Transcriptionally repressive form of Tead severely reduces stem cell characteristics.

  12. YAP/TAZ enhance mammalian embryonic neural stem cell characteristics in a Tead-dependent manner

    International Nuclear Information System (INIS)

    Han, Dasol; Byun, Sung-Hyun; Park, Soojeong; Kim, Juwan; Kim, Inhee; Ha, Soobong; Kwon, Mookwang; Yoon, Keejung

    2015-01-01

    Mammalian brain development is regulated by multiple signaling pathways controlling cell proliferation, migration and differentiation. Here we show that YAP/TAZ enhance embryonic neural stem cell characteristics in a cell autonomous fashion using diverse experimental approaches. Introduction of retroviral vectors expressing YAP or TAZ into the mouse embryonic brain induced cell localization in the ventricular zone (VZ), which is the embryonic neural stem cell niche. This change in cell distribution in the cortical layer is due to the increased stemness of infected cells; YAP-expressing cells were colabeled with Sox2, a neural stem cell marker, and YAP/TAZ increased the frequency and size of neurospheres, indicating enhanced self-renewal- and proliferative ability of neural stem cells. These effects appear to be TEA domain family transcription factor (Tead)–dependent; a Tead binding-defective YAP mutant lost the ability to promote neural stem cell characteristics. Consistently, in utero gene transfer of a constitutively active form of Tead2 (Tead2-VP16) recapitulated all the features of YAP/TAZ overexpression, and dominant negative Tead2-EnR resulted in marked cell exit from the VZ toward outer cortical layers. Taken together, these results indicate that the Tead-dependent YAP/TAZ signaling pathway plays important roles in neural stem cell maintenance by enhancing stemness of neural stem cells during mammalian brain development. - Highlights: • Roles of YAP and Tead in vivo during mammalian brain development are clarified. • Expression of YAP promotes embryonic neural stem cell characteristics in vivo in a cell autonomous fashion. • Enhancement of neural stem cell characteristics by YAP depends on Tead. • Transcriptionally active form of Tead alone can recapitulate the effects of YAP. • Transcriptionally repressive form of Tead severely reduces stem cell characteristics

  13. A role for adult TLX-positive neural stem cells in learning and behaviour.

    Science.gov (United States)

    Zhang, Chun-Li; Zou, Yuhua; He, Weimin; Gage, Fred H; Evans, Ronald M

    2008-02-21

    Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.

  14. The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases

    OpenAIRE

    Wang, Tao; Xiong, Jian-Qiong

    2016-01-01

    The human TLX gene encodes an orphan nuclear receptor predominantly expressed in the central nervous system. Tailess and Tlx, the TLX homologues in Drosophila and mouse, play essential roles in body-pattern formation and neurogenesis during early embryogenesis and perform crucial functions in maintaining stemness and controlling the differentiation of adult neural stem cells in the central nervous system, especially the visual system. Multiple target genes and signaling pathways are regulated...

  15. Effects of leukemia inhibitory factor and basic fibroblast growth factor on free radicals and endogenous stem cell proliferation in a mouse model of cerebral infarction.

    Science.gov (United States)

    Huang, Weihui; Li, Yadan; Lin, Yufeng; Ye, Xue; Zang, Dawei

    2012-07-05

    The present study established a mouse model of cerebral infarction by middle cerebral artery occlusion, and monitored the effect of 25 μg/kg leukemia inhibitory factor and (or) basic fibroblast growth factor administration 2 hours after model establishment. Results showed that following administration, the number of endogenous neural stem cells in the infarct area significantly increased, malondialdehyde content in brain tissue homogenates significantly decreased, nitric oxide content, glutathione peroxidase and superoxide dismutase activity significantly elevated, and mouse motor function significantly improved as confirmed by the rotarod and bar grab tests. In particular, the effect of leukemia inhibitory factor in combination with basic fibroblast growth factor was the most significant. Results indicate that leukemia inhibitory factor and basic fibroblast growth factor can improve the microenvironment after cerebral infarction by altering free radical levels, improving the quantity of endogenous neural stem cells, and promoting neurological function of mice with cerebral infarction.

  16. Neural crest contribution to lingual mesenchyme, epithelium and developing taste papillae and taste buds.

    Science.gov (United States)

    Liu, Hong-Xiang; Komatsu, Yoshihiro; Mishina, Yuji; Mistretta, Charlotte M

    2012-08-15

    The epithelium of mammalian tongue hosts most of the taste buds that transduce gustatory stimuli into neural signals. In the field of taste biology, taste bud cells have been described as arising from "local epithelium", in distinction from many other receptor organs that are derived from neurogenic ectoderm including neural crest (NC). In fact, contribution of NC to both epithelium and mesenchyme in the developing tongue is not fully understood. In the present study we used two independent, well-characterized mouse lines, Wnt1-Cre and P0-Cre that express Cre recombinase in a NC-specific manner, in combination with two Cre reporter mouse lines, R26R and ZEG, and demonstrate a contribution of NC-derived cells to both tongue mesenchyme and epithelium including taste papillae and taste buds. In tongue mesenchyme, distribution of NC-derived cells is in close association with taste papillae. In tongue epithelium, labeled cells are observed in an initial scattered distribution and progress to a clustered pattern between papillae, and within papillae and early taste buds. This provides evidence for a contribution of NC to lingual epithelium. Together with previous reports for the origin of taste bud cells from local epithelium in postnatal mouse, we propose that NC cells migrate into and reside in the epithelium of the tongue primordium at an early embryonic stage, acquire epithelial cell phenotypes, and undergo cell proliferation and differentiation that is involved in the development of taste papillae and taste buds. Our findings lead to a new concept about derivation of taste bud cells that include a NC origin. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Interpretation of correlated neural variability from models of feed-forward and recurrent circuits

    Science.gov (United States)

    2018-01-01

    Neural populations respond to the repeated presentations of a sensory stimulus with correlated variability. These correlations have been studied in detail, with respect to their mechanistic origin, as well as their influence on stimulus discrimination and on the performance of population codes. A number of theoretical studies have endeavored to link network architecture to the nature of the correlations in neural activity. Here, we contribute to this effort: in models of circuits of stochastic neurons, we elucidate the implications of various network architectures—recurrent connections, shared feed-forward projections, and shared gain fluctuations—on the stimulus dependence in correlations. Specifically, we derive mathematical relations that specify the dependence of population-averaged covariances on firing rates, for different network architectures. In turn, these relations can be used to analyze data on population activity. We examine recordings from neural populations in mouse auditory cortex. We find that a recurrent network model with random effective connections captures the observed statistics. Furthermore, using our circuit model, we investigate the relation between network parameters, correlations, and how well different stimuli can be discriminated from one another based on the population activity. As such, our approach allows us to relate properties of the neural circuit to information processing. PMID:29408930

  18. Interpretation of correlated neural variability from models of feed-forward and recurrent circuits.

    Directory of Open Access Journals (Sweden)

    Volker Pernice

    2018-02-01

    Full Text Available Neural populations respond to the repeated presentations of a sensory stimulus with correlated variability. These correlations have been studied in detail, with respect to their mechanistic origin, as well as their influence on stimulus discrimination and on the performance of population codes. A number of theoretical studies have endeavored to link network architecture to the nature of the correlations in neural activity. Here, we contribute to this effort: in models of circuits of stochastic neurons, we elucidate the implications of various network architectures-recurrent connections, shared feed-forward projections, and shared gain fluctuations-on the stimulus dependence in correlations. Specifically, we derive mathematical relations that specify the dependence of population-averaged covariances on firing rates, for different network architectures. In turn, these relations can be used to analyze data on population activity. We examine recordings from neural populations in mouse auditory cortex. We find that a recurrent network model with random effective connections captures the observed statistics. Furthermore, using our circuit model, we investigate the relation between network parameters, correlations, and how well different stimuli can be discriminated from one another based on the population activity. As such, our approach allows us to relate properties of the neural circuit to information processing.

  19. Advanced multiphoton methods for in vitro and in vivo functional imaging of mouse retinal neurons (Conference Presentation)

    Science.gov (United States)

    Cohen, Noam; Schejter, Adi; Farah, Nairouz; Shoham, Shy

    2016-03-01

    Studying the responses of retinal ganglion cell (RGC) populations has major significance in vision research. Multiphoton imaging of optogenetic probes has recently become the leading approach for visualizing neural populations and has specific advantages for imaging retinal activity during visual stimulation, because it leads to reduced direct photoreceptor excitation. However, multiphoton retinal activity imaging is not straightforward: point-by-point scanning leads to repeated neural excitation while optical access through the rodent eye in vivo has proven highly challenging. Here, we present two enabling optical designs for multiphoton imaging of responses to visual stimuli in mouse retinas expressing calcium indicators. First, we present an imaging solution based on Scanning Line Temporal Focusing (SLITE) for rapidly imaging neuronal activity in vitro. In this design, we scan a temporally focused line rather than a point, increasing the scan speed and reducing the impact of repeated excitation, while maintaining high optical sectioning. Second, we present the first in vivo demonstration of two-photon imaging of RGC activity in the mouse retina. To obtain these cellular resolution recordings we integrated an illumination path into a correction-free imaging system designed using an optical model of the mouse eye. This system can image at multiple depths using an electronically tunable lens integrated into its optical path. The new optical designs presented here overcome a number of outstanding obstacles, allowing the study of rapid calcium- and potentially even voltage-indicator signals both in vitro and in vivo, thereby bringing us a step closer toward distributed monitoring of action potentials.

  20. Behavioral Consequences of a Bifacial Map in the Mouse Somatosensory Cortex.

    Science.gov (United States)

    Tsytsarev, Vassiliy; Arakawa, Hiroyuki; Zhao, Shuxin; Chédotal, Alain; Erzurumlu, Reha S

    2017-07-26

    The whisker system is an important sensory organ with extensive neural representations in the brain of the mouse. Patterned neural modules (barrelettes) in the ipsilateral principal sensory nucleus of the trigeminal nerve (PrV) correspond to the whiskers. Axons of the PrV barrelette neurons cross the midline and confer the whisker-related patterning to the contralateral ventroposteromedial nucleus of the thalamus, and subsequently to the cortex. In this way, specific neural modules called barreloids and barrels in the contralateral thalamus and cortex represent each whisker. Partial midline crossing of the PrV axons, in a conditional Robo3 mutant ( Robo3 R3-5 cKO ) mouse line, leads to the formation of bilateral whisker maps in the ventroposteromedial, as well as the barrel cortex. We used voltage-sensitive dye optical imaging and somatosensory and motor behavioral tests to characterize the consequences of bifacial maps in the thalamocortical system. Voltage-sensitive dye optical imaging verified functional, bilateral whisker representation in the barrel cortex and activation of distinct cortical loci following ipsilateral and contralateral stimulation of the specific whiskers. The mutant animals were comparable with the control animals in sensorimotor tests. However, they showed noticeable deficits in all of the whisker-dependent or -related tests, including Y-maze exploration, horizontal surface approach, bridge crossing, gap crossing, texture discrimination, floating in water, and whisking laterality. Our results indicate that bifacial maps along the thalamocortical system do not offer a functional advantage. Instead, they lead to impairments, possibly due to the smaller size of the whisker-related modules and interference between the ipsilateral and contralateral whisker representations in the same thalamus and cortex. SIGNIFICANCE STATEMENT The whisker sensory system plays a quintessentially important role in exploratory behavior of mice and other nocturnal

  1. Neonatal disease environment limits the efficacy of retinal transplantation in the LCA8 mouse model

    OpenAIRE

    Cho, Seo-Hee; Song, Ji Yun; Shin, Jinyeon; Kim, Seonhee

    2016-01-01

    Background Mutations of Crb1 gene cause irreversible and incurable visual impairment in humans. This study aims to use an LCA8-like mouse model to identify host-mediated responses that might interfere with survival, retinal integration and differentiation of grafted cells during neonatal cell therapy. Methods Mixed retinal donor cells (1?~?2???104) isolated from neural retinas of neonatal eGFP transgenic mice were injected into the subretinal space of LCA8-like model neonatal mice. Markers of...

  2. Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis

    OpenAIRE

    Kawaguchi, Daichi; Furutachi, Shohei; Kawai, Hiroki; Hozumi, Katsuto; Gotoh, Yukiko

    2013-01-01

    Stem cells often divide asymmetrically to produce one stem cell and one differentiating cell, thus maintaining the stem cell pool. Although neural stem cells (NSCs) in the adult mouse subventricular zone have been suggested to divide asymmetrically, intrinsic cell fate determinants for asymmetric NSC division are largely unknown. Stem cell niches are important for stem cell maintenance, but the niche for the maintenance of adult quiescent NSCs has remained obscure. Here we show that the Notch...

  3. Gene array analysis of neural crest cells identifies transcription factors necessary for direct conversion of embryonic fibroblasts into neural crest cells

    Directory of Open Access Journals (Sweden)

    Tsutomu Motohashi

    2016-03-01

    Full Text Available Neural crest cells (NC cells are multipotent cells that emerge from the edge of the neural folds and migrate throughout the developing embryo. Although the gene regulatory network for generation of NC cells has been elucidated in detail, it has not been revealed which of the factors in the network are pivotal to directing NC identity. In this study we analyzed the gene expression profile of a pure NC subpopulation isolated from Sox10-IRES-Venus mice and investigated whether these genes played a key role in the direct conversion of Sox10-IRES-Venus mouse embryonic fibroblasts (MEFs into NC cells. The comparative molecular profiles of NC cells and neural tube cells in 9.5-day embryos revealed genes including transcription factors selectively expressed in developing trunk NC cells. Among 25 NC cell-specific transcription factor genes tested, SOX10 and SOX9 were capable of converting MEFs into SOX10-positive (SOX10+ cells. The SOX10+ cells were then shown to differentiate into neurons, glial cells, smooth muscle cells, adipocytes and osteoblasts. These SOX10+ cells also showed limited self-renewal ability, suggesting that SOX10 and SOX9 directly converted MEFs into NC cells. Conversely, the remaining transcription factors, including well-known NC cell specifiers, were unable to convert MEFs into SOX10+ NC cells. These results suggest that SOX10 and SOX9 are the key factors necessary for the direct conversion of MEFs into NC cells.

  4. Efficient derivation of multipotent neural stem/progenitor cells from non-human primate embryonic stem cells.

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    Hiroko Shimada

    Full Text Available The common marmoset (Callithrix jacchus is a small New World primate that has been used as a non-human primate model for various biomedical studies. We previously demonstrated that transplantation of neural stem/progenitor cells (NS/PCs derived from mouse and human embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs promote functional locomotor recovery of mouse spinal cord injury models. However, for the clinical application of such a therapeutic approach, we need to evaluate the efficacy and safety of pluripotent stem cell-derived NS/PCs not only by xenotransplantation, but also allotransplantation using non-human primate models to assess immunological rejection and tumorigenicity. In the present study, we established a culture method to efficiently derive NS/PCs as neurospheres from common marmoset ESCs. Marmoset ESC-derived neurospheres could be passaged repeatedly and showed sequential generation of neurons and astrocytes, similar to that of mouse ESC-derived NS/PCs, and gave rise to functional neurons as indicated by calcium imaging. Although marmoset ESC-derived NS/PCs could not differentiate into oligodendrocytes under default culture conditions, these cells could abundantly generate oligodendrocytes by incorporating additional signals that recapitulate in vivo neural development. Moreover, principal component analysis of microarray data demonstrated that marmoset ESC-derived NS/PCs acquired similar gene expression profiles to those of fetal brain-derived NS/PCs by repeated passaging. Therefore, marmoset ESC-derived NS/PCs may be useful not only for accurate evaluation by allotransplantation of NS/PCs into non-human primate models, but are also applicable to analysis of iPSCs established from transgenic disease model marmosets.

  5. Dataset of TWIST1-regulated genes in the cranial mesoderm and a transcriptome comparison of cranial mesoderm and cranial neural crest

    Directory of Open Access Journals (Sweden)

    Heidi Bildsoe

    2016-12-01

    Full Text Available This article contains data related to the research article entitled “Transcriptional targets of TWIST1 in the cranial mesoderm regulate cell-matrix interactions and mesenchyme maintenance” by Bildsoe et al. (2016 [1]. The data presented here are derived from: (1 a microarray-based comparison of sorted cranial mesoderm (CM and cranial neural crest (CNC cells from E9.5 mouse embryos; (2 comparisons of transcription profiles of head tissues from mouse embryos with a CM-specific loss-of-function of Twist1 and control mouse embryos collected at E8.5 and E9.5; (3 ChIP-seq using a TWIST1-specific monoclonal antibody with chromatin extracts from TWIST1-expressing MDCK cells, a model for a TWIST1-dependent mesenchymal state.

  6. Orphan nuclear receptor TLX activates Wnt/β-catenin signalling to stimulate neural stem cell proliferation and self-renewal

    Science.gov (United States)

    Qu, Qiuhao; Sun, Guoqiang; Li, Wenwu; Yang, Su; Ye, Peng; Zhao, Chunnian; Yu, Ruth T.; Gage, Fred H.; Evans, Ronald M.; Shi, Yanhong

    2010-01-01

    The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/β-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/β-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active β-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a β-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active β-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active β-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active β-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/β-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode. PMID:20010817

  7. Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal.

    Science.gov (United States)

    Qu, Qiuhao; Sun, Guoqiang; Li, Wenwu; Yang, Su; Ye, Peng; Zhao, Chunnian; Yu, Ruth T; Gage, Fred H; Evans, Ronald M; Shi, Yanhong

    2010-01-01

    The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/beta-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/beta-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active beta-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a beta-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active beta-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active beta-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active beta-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/beta-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode.

  8. Centralized mouse repositories.

    Science.gov (United States)

    Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

    2012-10-01

    Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

  9. Dyadic social interaction of C57BL/6 mice versus interaction with a toy mouse: conditioned place preference/aversion, substrain differences, and no development of a hierarchy.

    Science.gov (United States)

    Pinheiro, Barbara S; Seidl, Simon S; Habazettl, Eva; Gruber, Bernadette E; Bregolin, Tanja; Zernig, Gerald

    2016-04-01

    Impaired social interaction is a hallmark symptom of many psychiatric diseases, including dependence syndromes (substance use disorders). Helping the addict reorient her/his behavior away from the drug of abuse toward social interaction would be of considerable therapeutic benefit. To study the neural basis of such a reorientation, we have developed several animal models in which the attractiveness of a dyadic (i.e. one-to-one) social interaction (DSI) can be compared directly with that of cocaine as a prototypical drug of abuse. Our models are based on the conditioned place preference (CPP) paradigm. In an ongoing effort to validate our experimental paradigms in C57BL/6 mice to make use of the plethora of transgenic models available in this genus, we found the following: (a) DSI with a live mouse produced CPP, whereas an interaction with an inanimate mouse-like object (i.e. a 'toy mouse'; toy mouse interaction) led to conditioned place aversion - but only in the Jackson substrain (C57BL/6J). (b) In the NIH substrain (C57BL/6N), both DSI and toy mouse interaction produced individual aversion in more than 50% of the tested mice. (c) Four 15 min DSI episodes did not result in the development of an observable hierarchy, that is, dominance/subordination behavior in the overwhelming majority (i.e. 30 of 32) of the tested Jackson mouse pairs. Therefore, dominance/subordination does not seem to be a confounding variable in our paradigm, at least not in C57BL/6J mice. Respective data for NIH mice were too limited to allow any conclusion. The present findings indicate that (a) DSI with a live mouse produces CPP to a greater degree than an interaction with an inanimate object resembling a mouse and that (b) certain substrain differences with respect to CPP/aversion to DSI do exist between the Jax and NIH substrain of C57BL/6 mice. These differences have to be considered when choosing a proper mouse substrain model for investigating the neural basis of DSI reward versus

  10. Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate

    Science.gov (United States)

    Mederacke, Ingmar; Komatsu, Yoshihiro; Stice, Steve; Schwabe, Robert F.; Mistretta, Charlotte M.; Mishina, Yuji; Liu, Hong-Xiang

    2016-01-01

    Taste buds, the sensory organs for taste, have been described as arising solely from the surrounding epithelium, which is in distinction from other sensory receptors that are known to originate from neural precursors, i.e., neural ectoderm that includes neural crest (NC). Our previous study suggested a potential contribution of NC derived cells to early immature fungiform taste buds in late embryonic (E18.5) and young postnatal (P1-10) mice. In the present study we demonstrated the contribution of the underlying connective tissue (CT) to mature taste buds in mouse tongue and soft palate. Three independent mouse models were used for fate mapping of NC and NC derived connective tissue cells: (1) P0-Cre/R26-tdTomato (RFP) to label NC, NC derived Schwann cells and derivatives; (2) Dermo1-Cre/RFP to label mesenchymal cells and derivatives; and (3) Vimentin-CreER/mGFP to label Vimentin-expressing CT cells and derivatives upon tamoxifen treatment. Both P0-Cre/RFP and Dermo1-Cre/RFP labeled cells were abundant in mature taste buds in lingual taste papillae and soft palate, but not in the surrounding epithelial cells. Concurrently, labeled cells were extensively distributed in the underlying CT. RFP signals were seen in the majority of taste buds and all three types (I, II, III) of differentiated taste bud cells, with the neuronal-like type III cells labeled at a greater proportion. Further, Vimentin-CreER labeled cells were found in the taste buds of 3-month-old mice whereas Vimentin immunoreactivity was only seen in the CT. Taken together, our data demonstrate a previously unrecognized origin of taste bud cells from the underlying CT, a conceptually new finding in our knowledge of taste bud cell derivation, i.e., from both the surrounding epithelium and the underlying CT that is primarily derived from NC. PMID:26741369

  11. Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate.

    Directory of Open Access Journals (Sweden)

    Kristin Boggs

    Full Text Available Taste buds, the sensory organs for taste, have been described as arising solely from the surrounding epithelium, which is in distinction from other sensory receptors that are known to originate from neural precursors, i.e., neural ectoderm that includes neural crest (NC. Our previous study suggested a potential contribution of NC derived cells to early immature fungiform taste buds in late embryonic (E18.5 and young postnatal (P1-10 mice. In the present study we demonstrated the contribution of the underlying connective tissue (CT to mature taste buds in mouse tongue and soft palate. Three independent mouse models were used for fate mapping of NC and NC derived connective tissue cells: (1 P0-Cre/R26-tdTomato (RFP to label NC, NC derived Schwann cells and derivatives; (2 Dermo1-Cre/RFP to label mesenchymal cells and derivatives; and (3 Vimentin-CreER/mGFP to label Vimentin-expressing CT cells and derivatives upon tamoxifen treatment. Both P0-Cre/RFP and Dermo1-Cre/RFP labeled cells were abundant in mature taste buds in lingual taste papillae and soft palate, but not in the surrounding epithelial cells. Concurrently, labeled cells were extensively distributed in the underlying CT. RFP signals were seen in the majority of taste buds and all three types (I, II, III of differentiated taste bud cells, with the neuronal-like type III cells labeled at a greater proportion. Further, Vimentin-CreER labeled cells were found in the taste buds of 3-month-old mice whereas Vimentin immunoreactivity was only seen in the CT. Taken together, our data demonstrate a previously unrecognized origin of taste bud cells from the underlying CT, a conceptually new finding in our knowledge of taste bud cell derivation, i.e., from both the surrounding epithelium and the underlying CT that is primarily derived from NC.

  12. Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate.

    Science.gov (United States)

    Boggs, Kristin; Venkatesan, Nandakumar; Mederacke, Ingmar; Komatsu, Yoshihiro; Stice, Steve; Schwabe, Robert F; Mistretta, Charlotte M; Mishina, Yuji; Liu, Hong-Xiang

    2016-01-01

    Taste buds, the sensory organs for taste, have been described as arising solely from the surrounding epithelium, which is in distinction from other sensory receptors that are known to originate from neural precursors, i.e., neural ectoderm that includes neural crest (NC). Our previous study suggested a potential contribution of NC derived cells to early immature fungiform taste buds in late embryonic (E18.5) and young postnatal (P1-10) mice. In the present study we demonstrated the contribution of the underlying connective tissue (CT) to mature taste buds in mouse tongue and soft palate. Three independent mouse models were used for fate mapping of NC and NC derived connective tissue cells: (1) P0-Cre/R26-tdTomato (RFP) to label NC, NC derived Schwann cells and derivatives; (2) Dermo1-Cre/RFP to label mesenchymal cells and derivatives; and (3) Vimentin-CreER/mGFP to label Vimentin-expressing CT cells and derivatives upon tamoxifen treatment. Both P0-Cre/RFP and Dermo1-Cre/RFP labeled cells were abundant in mature taste buds in lingual taste papillae and soft palate, but not in the surrounding epithelial cells. Concurrently, labeled cells were extensively distributed in the underlying CT. RFP signals were seen in the majority of taste buds and all three types (I, II, III) of differentiated taste bud cells, with the neuronal-like type III cells labeled at a greater proportion. Further, Vimentin-CreER labeled cells were found in the taste buds of 3-month-old mice whereas Vimentin immunoreactivity was only seen in the CT. Taken together, our data demonstrate a previously unrecognized origin of taste bud cells from the underlying CT, a conceptually new finding in our knowledge of taste bud cell derivation, i.e., from both the surrounding epithelium and the underlying CT that is primarily derived from NC.

  13. Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome

    Directory of Open Access Journals (Sweden)

    Susan J. Harrison

    2012-05-01

    Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ∼10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5. These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS.

  14. Influence of neural adaptation on dynamics and equilibrium state of neural activities in a ring neural network

    Science.gov (United States)

    Takiyama, Ken

    2017-12-01

    How neural adaptation affects neural information processing (i.e. the dynamics and equilibrium state of neural activities) is a central question in computational neuroscience. In my previous works, I analytically clarified the dynamics and equilibrium state of neural activities in a ring-type neural network model that is widely used to model the visual cortex, motor cortex, and several other brain regions. The neural dynamics and the equilibrium state in the neural network model corresponded to a Bayesian computation and statistically optimal multiple information integration, respectively, under a biologically inspired condition. These results were revealed in an analytically tractable manner; however, adaptation effects were not considered. Here, I analytically reveal how the dynamics and equilibrium state of neural activities in a ring neural network are influenced by spike-frequency adaptation (SFA). SFA is an adaptation that causes gradual inhibition of neural activity when a sustained stimulus is applied, and the strength of this inhibition depends on neural activities. I reveal that SFA plays three roles: (1) SFA amplifies the influence of external input in neural dynamics; (2) SFA allows the history of the external input to affect neural dynamics; and (3) the equilibrium state corresponds to the statistically optimal multiple information integration independent of the existence of SFA. In addition, the equilibrium state in a ring neural network model corresponds to the statistically optimal integration of multiple information sources under biologically inspired conditions, independent of the existence of SFA.

  15. SINs and SOMs: Neural microcircuits for size tuning in the zebrafish and mouse visual pathway.

    Directory of Open Access Journals (Sweden)

    Alison J. Barker

    2013-05-01

    Full Text Available In many animals, a fast and reliable circuit for discriminating between predator-sized objects and edible (prey-sized objects is necessary for survival. How are receptive fields in visual brain areas organized to extract information about size? Recent studies from the zebrafish optic tectum and the mouse visual cortex suggest de novo shaping of receptive fields by subtypes of inhibitory neurons. Del Bene et al. (2010 describe a population of GABAergic neurons in the zebrafish optic tectum (Superficial Interneurons, SINs that are necessary for size filtering during prey capture. Adesnik et al. (2012 describe a somatostatin-expressing interneuron population (SOMs that confers surround suppression on layer II/III pyramidal cells in mouse V1. Strikingly both the SINs and the SOMs, display size-dependent response properties. Increasing visual stimulus size increases excitatory input to these neurons. Dampening SIN or SOM activity alters tuning of neighboring circuits such that they lose preference for small objects. Both results provide exciting evidence for mechanisms of size filtering in visual circuits. Here we review the roles of the SINs and the SOMs and speculate on the similarity of such spatial filters across species.

  16. Tissue distribution and developmental expression of type XVI collagen in the mouse.

    Science.gov (United States)

    Lai, C H; Chu, M L

    1996-04-01

    The expression of a recently identified collagen, alpha 1 (XVI), in adult mouse tissue and developing mouse embryo was examined by immunohistochemistry and in situ hybridization. A polyclonal antiserum was raised against a recombinant fusion protein, which contained a segment of 161 amino acids in the N-terminal noncollagenous domain of the human alpha 1 (XVI) collagen. Immunoprecipitation of metabolically labelled human or mouse fibroblast cell lysates with this antibody revealed a major, bacterial collagenase sensitive polypeptide of approximately 210 kDa. The size agrees with the prediction from the full-length cDNA. Immunofluorescence examination of adult mouse tissues using the affinity purified antibody revealed a rather broad distribution of the protein. The heart, kidney, intestine, ovary, testis, eye, arterial walls and smooth muscles all exhibited significant levels of expression, while the skeletal muscle, lung and brain showed very restricted and low signals. During development, no significant expression of the mRNA or protein was observed in embryo of day 8 of gestation, but strong signals was detected in placental trophoblasts. Expression in embryos was detectable first after day 11 of gestation with weak positive signals appearing in the heart. In later stages of development, stronger RNA hybridizations were observed in a variety of tissues, particularly in atrial and ventricular walls of the developing heart, spinal root neural fibers and skin. These data demonstrate that type XVI collagen represents another collagenous component widely distributed in the extracellular matrix and may contribute to the structural integrity of various tissues.

  17. Polysialic acid enters the cell nucleus attached to a fragment of the neural cell adhesion molecule NCAM to regulate the circadian rhythm in mouse brain.

    Science.gov (United States)

    Westphal, Nina; Kleene, Ralf; Lutz, David; Theis, Thomas; Schachner, Melitta

    2016-07-01

    In the mammalian nervous system, the neural cell adhesion molecule NCAM is the major carrier of the glycan polymer polysialic acid (PSA) which confers important functions to NCAM's protein backbone. PSA attached to NCAM contributes not only to cell migration, neuritogenesis, synaptic plasticity, and behavior, but also to regulation of the circadian rhythm by yet unknown molecular mechanisms. Here, we show that a PSA-carrying transmembrane NCAM fragment enters the nucleus after stimulation of cultured neurons with surrogate NCAM ligands, a phenomenon that depends on the circadian rhythm. Enhanced nuclear import of the PSA-carrying NCAM fragment is associated with altered expression of clock-related genes, as shown by analysis of cultured neuronal cells deprived of PSA by specific enzymatic removal. In vivo, levels of nuclear PSA in different mouse brain regions depend on the circadian rhythm and clock-related gene expression in suprachiasmatic nucleus and cerebellum is affected by the presence of PSA-carrying NCAM in the cell nucleus. Our conceptually novel observations reveal that PSA attached to a transmembrane proteolytic NCAM fragment containing part of the extracellular domain enters the cell nucleus, where PSA-carrying NCAM contributes to the regulation of clock-related gene expression and of the circadian rhythm. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Bioluminescence Imaging of Olig2-Neural Stem Cells Reveals Improved Engraftment in a Demyelination Mouse Model

    NARCIS (Netherlands)

    Sher, Falak; van Dam, Go; Boddeke, Erik; Copray, Sjef

    2009-01-01

    A major issue in the potential application of neural stem cell (NSC)-based cell replacement therapy for demyelinating diseases is the question of the survival, functional behavior, and stability of implanted NSC-derived oligodendrocyte precursor cells (OPCs) over an extended period. To address this

  19. A Role of Endogenous Progesterone in Stroke Cerebroprotection Revealed by the Neural-Specific Deletion of Its Intracellular Receptors.

    Science.gov (United States)

    Zhu, Xiaoyan; Fréchou, Magalie; Liere, Philippe; Zhang, Shaodong; Pianos, Antoine; Fernandez, Neïké; Denier, Christian; Mattern, Claudia; Schumacher, Michael; Guennoun, Rachida

    2017-11-08

    Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult. Here, we used steroid profiling by gas chromatography-tandem mass spectrometry (GC-MS/MS) for exploring adaptive and sex-specific changes in brain levels of progesterone and its metabolites after MCAO. We show that, in the male mouse brain, progesterone is mainly metabolized via 5α-reduction leading to 5α-dihydroprogesterone (5α-DHP), also a progesterone receptor (PR) agonist ligand in neural cells, then to 3α,5α-tetrahydroprogesterone (3α,5α-THP). In the female mouse brain, levels of 5α-DHP and 3α,5α-THP are lower and levels of 20α-DHP are higher than in males. After MCAO, levels of progesterone and 5α-DHP are upregulated rapidly to pregnancy-like levels in the male but not in the female brain. To assess whether endogenous progesterone and 5α-DHP contribute to the resistance of neural cells to ischemic damage, we inactivated PR selectively in the CNS. Deletion of PR in the brain reduced its resistance to MCAO, resulting in increased infarct volumes and neurological deficits in both sexes. Importantly, endogenous PR ligands continue to protect the brain of aging mice. These results uncover the unexpected importance of endogenous progesterone and its metabolites in cerebroprotection. They also reveal that the female reproductive hormone progesterone is an endogenous cerebroprotective neurosteroid in both sexes. SIGNIFICANCE STATEMENT The brain responds to injury with protective signaling and has a remarkable capacity to protect itself. We show here that, in response to ischemic stroke, levels of progesterone and its neuroactive metabolite 5α-dihydroprogesterone are upregulated rapidly in the male mouse brain but not in the

  20. Slit/Robo1 signaling regulates neural tube development by balancing neuroepithelial cell proliferation and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Guang; Li, Yan; Wang, Xiao-yu [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China); Han, Zhe [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Chuai, Manli [College of Life Sciences Biocentre, University of Dundee, Dundee DD1 5EH (United Kingdom); Wang, Li-jing [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Ho Lee, Kenneth Ka [Stem Cell and Regeneration Thematic Research Programme, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Geng, Jian-guo, E-mail: jgeng@umich.edu [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510224 (China); Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109 (United States); Yang, Xuesong, E-mail: yang_xuesong@126.com [Key Laboratory for Regenerative Medicine of The Ministry of Education, Department of Histology and Embryology, School of Medicine, Jinan University, Guangzhou 510632 (China)

    2013-05-01

    development by tightly coordinating cell proliferation and differentiation during neurulation. - Highlights: ► The role of Slit/Robo1 signaling was investigated with chick and mouse models. ► Disturbance of Slit/Robo1 signaling resulted in neural tube defects. ► Slit/Robo1 signaling regulated the proliferation of neural tube cells. ► Slit/Robo1 signaling modulated the differentiation of neural tube cells. ► Slit/Robo1 signaling balanced the proliferation and differentiation of neural tube.

  1. Differentiation-Dependent Motility-Responses of Developing Neural Progenitors to Optogenetic Stimulation

    Directory of Open Access Journals (Sweden)

    Tímea Köhidi

    2017-12-01

    Full Text Available During neural tissue genesis, neural stem/progenitor cells are exposed to bioelectric stimuli well before synaptogenesis and neural circuit formation. Fluctuations in the electrochemical potential in the vicinity of developing cells influence the genesis, migration and maturation of neuronal precursors. The complexity of the in vivo environment and the coexistence of various progenitor populations hinder the understanding of the significance of ionic/bioelectric stimuli in the early phases of neuronal differentiation. Using optogenetic stimulation, we investigated the in vitro motility responses of radial glia-like neural stem/progenitor populations to ionic stimuli. Radial glia-like neural stem cells were isolated from CAGloxpStoploxpChR2(H134-eYFP transgenic mouse embryos. After transfection with Cre-recombinase, ChR2(channelrhodopsin-2-expressing and non-expressing cells were separated by eYFP fluorescence. Expression of light-gated ion channels were checked by patch clamp and fluorescence intensity assays. Neurogenesis by ChR2-expressing and non-expressing cells was induced by withdrawal of EGF from the medium. Cells in different (stem cell, migrating progenitor and maturing precursor stages of development were illuminated with laser light (λ = 488 nm; 1.3 mW/mm2; 300 ms in every 5 min for 12 h. The displacement of the cells was analyzed on images taken at the end of each light pulse. Results demonstrated that the migratory activity decreased with the advancement of neuronal differentiation regardless of stimulation. Light-sensitive cells, however, responded on a differentiation-dependent way. In non-differentiated ChR2-expressing stem cell populations, the motility did not change significantly in response to light-stimulation. The displacement activity of migrating progenitors was enhanced, while the motility of differentiating neuronal precursors was markedly reduced by illumination.

  2. Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells into the Developing Mouse Eye

    International Nuclear Information System (INIS)

    Lee, Eun-Shil; Yu, Song-Hee; Jang, Yu-Jin; Hwang, Dong-Youn; Jeon, Chang-Jin

    2011-01-01

    Mesenchymal stem cells (MSCs) have been studied widely for their potential to differentiate into various lineage cells including neural cells in vitro and in vivo. To investigate the influence of the developing host environment on the integration and morphological and molecular differentiation of MSCs, human bone marrow-derived mesenchymal stem cells (BM-MSCs) were transplanted into the developing mouse retina. Enhanced green fluorescent protein (GFP)-expressing BM-MSCs were transplanted by intraocular injections into mice, ranging in ages from 1 day postnatal (PN) to 10 days PN. The survival dates ranged from 7 days post-transplantation (DPT) to 28DPT, at which time an immunohistochemical analysis was performed on the eyes. The transplanted BM-MSCs survived and showed morphological differentiation into neural cells and some processes within the host retina. Some transplanted cells expressed microtubule associated protein 2 (MAP2ab, marker for mature neural cells) or glial fibrillary acid protein (GFAP, marker for glial cells) at 5PN 7DPT. In addition, some transplanted cells integrated into the developing retina. The morphological and molecular differentiation and integration within the 5PN 7DPT eye was greater than those of other-aged host eye. The present findings suggest that the age of the host environment can strongly influence the differentiation and integration of BM-MSCs

  3. Understanding the Basis of Auriculocondylar Syndrome: Insights From Human and Mouse Genetic Studies

    Science.gov (United States)

    Clouthier, David E.; Passos Bueno, Maria Rita; Tavares, Andre L.P.; Lyonnet, Stanislas; Amiel, Jeanne; Gordon, Christopher T.

    2014-01-01

    Among human birth defect syndromes, malformations affecting the face are perhaps the most striking due to cultural and psychological expectations of facial shape. One such syndrome is auriculocondylar syndrome (ACS), in which patients present with defects in ear and mandible development. Affected structures arise from cranial neural crest cells, a population of cells in the embryo that reside in the pharyngeal arches and give rise to most of the bone, cartilage and connective tissue of the face. Recent studies have found that most cases of ACS arise from defects in signaling molecules associated with the endothelin signaling pathway. Disruption of this signaling pathway in both mouse and zebrafish results in loss of identity of neural crest cells of the mandibular portion of the first pharyngeal arch and the subsequent repatterning of these cells, leading to homeosis of lower jaw structures into more maxillary-like structures. These findings illustrate the importance of endothelin signaling in normal human craniofacial development and illustrate how clinical and basic science approaches can coalesce to improve our understanding of the genetic basis of human birth syndromes. Further, understanding the genetic basis for ACS that lies outside of known endothelin signaling components may help elucidate unknown aspects critical to the establishment of neural crest cell patterning during facial morphogenesis. PMID:24123988

  4. Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice.

    Science.gov (United States)

    Huang, Chih-Yu; Yao, Hui-Wen; Wang, Li-Chiu; Shen, Fang-Hsiu; Hsu, Sheng-Min; Chen, Shun-Hua

    2017-02-15

    Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484-490, 1994, https://doi.org/10.1006/viro.1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30- to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1. Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drug-resistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised

  5. Deletion of OTX2 in neural ectoderm delays anterior pituitary development

    Science.gov (United States)

    Mortensen, Amanda H.; Schade, Vanessa; Lamonerie, Thomas; Camper, Sally A.

    2015-01-01

    OTX2 is a homeodomain transcription factor that is necessary for normal head development in mouse and man. Heterozygosity for loss-of-function alleles causes an incompletely penetrant, haploinsufficiency disorder. Affected individuals exhibit a spectrum of features that range from developmental defects in eye and/or pituitary development to acephaly. To investigate the mechanism underlying the pituitary defects, we used different cre lines to inactivate Otx2 in early head development and in the prospective anterior and posterior lobes. Mice homozygous for Otx2 deficiency in early head development and pituitary oral ectoderm exhibit craniofacial defects and pituitary gland dysmorphology, but normal pituitary cell specification. The morphological defects mimic those observed in humans and mice with OTX2 heterozygous mutations. Mice homozygous for Otx2 deficiency in the pituitary neural ectoderm exhibited altered patterning of gene expression and ablation of FGF signaling. The posterior pituitary lobe and stalk, which normally arise from neural ectoderm, were extremely hypoplastic. Otx2 expression was intact in Rathke's pouch, the precursor to the anterior lobe, but the anterior lobe was hypoplastic. The lack of FGF signaling from the neural ectoderm was sufficient to impair anterior lobe growth, but not the differentiation of hormone-producing cells. This study demonstrates that Otx2 expression in the neural ectoderm is important intrinsically for the development of the posterior lobe and pituitary stalk, and it has significant extrinsic effects on anterior pituitary growth. Otx2 expression early in head development is important for establishing normal craniofacial features including development of the brain, eyes and pituitary gland. PMID:25315894

  6. Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter

    DEFF Research Database (Denmark)

    Brown, Angus M; Sickmann, Helle M; Fosgerau, Keld

    2005-01-01

    We tested the hypothesis that inhibiting glycogen degradation accelerates compound action potential (CAP) failure in mouse optic nerve (MON) during aglycemia or high-intensity stimulation. Axon function was assessed as the evoked CAP, and glycogen content was measured biochemically. Isofagomine, ...

  7. The 128-channel fully differential digital integrated neural recording and stimulation interface.

    Science.gov (United States)

    Shahrokhi, Farzaneh; Abdelhalim, Karim; Serletis, Demitre; Carlen, Peter L; Genov, Roman

    2010-06-01

    We present a fully differential 128-channel integrated neural interface. It consists of an array of 8 X 16 low-power low-noise signal-recording and generation circuits for electrical neural activity monitoring and stimulation, respectively. The recording channel has two stages of signal amplification and conditioning with and a fully differential 8-b column-parallel successive approximation (SAR) analog-to-digital converter (ADC). The total measured power consumption of each recording channel, including the SAR ADC, is 15.5 ¿W. The measured input-referred noise is 6.08 ¿ Vrms over a 5-kHz bandwidth, resulting in a noise efficiency factor of 5.6. The stimulation channel performs monophasic or biphasic voltage-mode stimulation, with a maximum stimulation current of 5 mA and a quiescent power dissipation of 51.5 ¿W. The design is implemented in 0.35-¿m complementary metal-oxide semiconductor technology with the channel pitch of 200 ¿m for a total die size of 3.4 mm × 2.5 mm and a total power consumption of 9.33 mW. The neural interface was validated in in vitro recording of a low-Mg(2+)/high-K(+) epileptic seizure model in an intact hippocampus of a mouse.

  8. Identification of neural outgrowth genes using genome-wide RNAi.

    Directory of Open Access Journals (Sweden)

    Katharine J Sepp

    2008-07-01

    Full Text Available While genetic screens have identified many genes essential for neurite outgrowth, they have been limited in their ability to identify neural genes that also have earlier critical roles in the gastrula, or neural genes for which maternally contributed RNA compensates for gene mutations in the zygote. To address this, we developed methods to screen the Drosophila genome using RNA-interference (RNAi on primary neural cells and present the results of the first full-genome RNAi screen in neurons. We used live-cell imaging and quantitative image analysis to characterize the morphological phenotypes of fluorescently labelled primary neurons and glia in response to RNAi-mediated gene knockdown. From the full genome screen, we focused our analysis on 104 evolutionarily conserved genes that when downregulated by RNAi, have morphological defects such as reduced axon extension, excessive branching, loss of fasciculation, and blebbing. To assist in the phenotypic analysis of the large data sets, we generated image analysis algorithms that could assess the statistical significance of the mutant phenotypes. The algorithms were essential for the analysis of the thousands of images generated by the screening process and will become a valuable tool for future genome-wide screens in primary neurons. Our analysis revealed unexpected, essential roles in neurite outgrowth for genes representing a wide range of functional categories including signalling molecules, enzymes, channels, receptors, and cytoskeletal proteins. We also found that genes known to be involved in protein and vesicle trafficking showed similar RNAi phenotypes. We confirmed phenotypes of the protein trafficking genes Sec61alpha and Ran GTPase using Drosophila embryo and mouse embryonic cerebral cortical neurons, respectively. Collectively, our results showed that RNAi phenotypes in primary neural culture can parallel in vivo phenotypes, and the screening technique can be used to identify many new

  9. Dyadic social interaction of C57BL/6 mice versus interaction with a toy mouse: conditioned place preference/aversion, substrain differences, and no development of a hierarchy

    Science.gov (United States)

    Pinheiro, Barbara S.; Seidl, Simon S.; Habazettl, Eva; Gruber, Bernadette E.; Bregolin, Tanja

    2016-01-01

    Impaired social interaction is a hallmark symptom of many psychiatric diseases, including dependence syndromes (substance use disorders). Helping the addict reorient her/his behavior away from the drug of abuse toward social interaction would be of considerable therapeutic benefit. To study the neural basis of such a reorientation, we have developed several animal models in which the attractiveness of a dyadic (i.e. one-to-one) social interaction (DSI) can be compared directly with that of cocaine as a prototypical drug of abuse. Our models are based on the conditioned place preference (CPP) paradigm. In an ongoing effort to validate our experimental paradigms in C57BL/6 mice to make use of the plethora of transgenic models available in this genus, we found the following: (a) DSI with a live mouse produced CPP, whereas an interaction with an inanimate mouse-like object (i.e. a ‘toy mouse’; toy mouse interaction) led to conditioned place aversion – but only in the Jackson substrain (C57BL/6J). (b) In the NIH substrain (C57BL/6N), both DSI and toy mouse interaction produced individual aversion in more than 50% of the tested mice. (c) Four 15 min DSI episodes did not result in the development of an observable hierarchy, that is, dominance/subordination behavior in the overwhelming majority (i.e. 30 of 32) of the tested Jackson mouse pairs. Therefore, dominance/subordination does not seem to be a confounding variable in our paradigm, at least not in C57BL/6J mice. Respective data for NIH mice were too limited to allow any conclusion. The present findings indicate that (a) DSI with a live mouse produces CPP to a greater degree than an interaction with an inanimate object resembling a mouse and that (b) certain substrain differences with respect to CPP/aversion to DSI do exist between the Jax and NIH substrain of C57BL/6 mice. These differences have to be considered when choosing a proper mouse substrain model for investigating the neural basis of DSI reward

  10. Neural Differentiation in HDAC1-Depleted Cells Is Accompanied by Coilin Downregulation and the Accumulation of Cajal Bodies in Nucleoli.

    Science.gov (United States)

    Krejčí, Jana; Legartová, Soňa; Bártová, Eva

    2017-01-01

    Cajal bodies (CBs) are important compartments containing accumulated proteins that preferentially regulate RNA-related nuclear events, including splicing. Here, we studied the nuclear distribution pattern of CBs in neurogenesis. In adult brains, coilin was present at a high density, but CB formation was absent in the nuclei of the choroid plexus of the lateral ventricles. Cells of the adult hippocampus were characterized by a crescent-like morphology of coilin protein. We additionally observed a 70 kDa splice variant of coilin in adult mouse brains, which was different to embryonic brains and mouse pluripotent embryonic stem cells (mESCs), characterized by the 80 kDa standard variant of coilin. Here, we also showed that depletion of coilin is induced during neural differentiation and HDAC1 deficiency in mESCs caused coilin accumulation inside the fibrillarin-positive region of the nucleoli. A similar distribution pattern was observed in adult brain hippocampi, characterized by lower levels of both coilin and HDAC1. In summary, we observed that neural differentiation and HDAC1 deficiency lead to coilin depletion and coilin accumulation in body-like structures inside the nucleoli.

  11. CD133-enriched Xeno-Free human embryonic-derived neural stem cells expand rapidly in culture and do not form teratomas in immunodeficient mice

    Directory of Open Access Journals (Sweden)

    Daniel L. Haus

    2014-09-01

    Full Text Available Common methods for the generation of human embryonic-derived neural stem cells (hNSCs result in cells with potentially compromised safety profiles due to maintenance of cells in conditions containing non-human proteins (e.g. in bovine serum or on mouse fibroblast feeders. Additionally, sufficient expansion of resulting hNSCs for scaling out or up in a clinically relevant time frame has proven to be difficult. Here, we report a strategy that produces hNSCs in completely “Xeno-Free” culture conditions. Furthermore, we have enriched the hNSCs for the cell surface marker CD133 via magnetic sorting, which has led to an increase in the expansion rate and neuronal fate specification of the hNSCs in vitro. Critically, we have also confirmed neural lineage specificity upon sorted hNSC transplantation into the immunodeficient NOD-scid mouse brain. The future use or adaptation of these protocols has the potential to better facilitate the advancement of pre-clinical strategies from the bench to the bedside.

  12. ELHnet: a convolutional neural network for classifying cochlear endolymphatic hydrops imaged with optical coherence tomography.

    Science.gov (United States)

    Liu, George S; Zhu, Michael H; Kim, Jinkyung; Raphael, Patrick; Applegate, Brian E; Oghalai, John S

    2017-10-01

    Detection of endolymphatic hydrops is important for diagnosing Meniere's disease, and can be performed non-invasively using optical coherence tomography (OCT) in animal models as well as potentially in the clinic. Here, we developed ELHnet, a convolutional neural network to classify endolymphatic hydrops in a mouse model using learned features from OCT images of mice cochleae. We trained ELHnet on 2159 training and validation images from 17 mice, using only the image pixels and observer-determined labels of endolymphatic hydrops as the inputs. We tested ELHnet on 37 images from 37 mice that were previously not used, and found that the neural network correctly classified 34 of the 37 mice. This demonstrates an improvement in performance from previous work on computer-aided classification of endolymphatic hydrops. To the best of our knowledge, this is the first deep CNN designed for endolymphatic hydrops classification.

  13. High content screening of defined chemical libraries using normal and glioma-derived neural stem cell lines.

    Science.gov (United States)

    Danovi, Davide; Folarin, Amos A; Baranowski, Bart; Pollard, Steven M

    2012-01-01

    Small molecules with potent biological effects on the fate of normal and cancer-derived stem cells represent both useful research tools and new drug leads for regenerative medicine and oncology. Long-term expansion of mouse and human neural stem cells is possible using adherent monolayer culture. These cultures represent a useful cellular resource to carry out image-based high content screening of small chemical libraries. Improvements in automated microscopy, desktop computational power, and freely available image processing tools, now means that such chemical screens are realistic to undertake in individual academic laboratories. Here we outline a cost effective and versatile time lapse imaging strategy suitable for chemical screening. Protocols are described for the handling and screening of human fetal Neural Stem (NS) cell lines and their malignant counterparts, Glioblastoma-derived neural stem cells (GNS). We focus on identification of cytostatic and cytotoxic "hits" and discuss future possibilities and challenges for extending this approach to assay lineage commitment and differentiation. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Analysis of epigenetic factors in mouse embryonic neural stem cells exposed to hyperglycemia.

    Directory of Open Access Journals (Sweden)

    Sukanya Shyamasundar

    Full Text Available BACKGROUND: Maternal diabetes alters gene expression leading to neural tube defects (NTDs in the developing brain. The mechanistic pathways that deregulate the gene expression remain unknown. It is hypothesized that exposure of neural stem cells (NSCs to high glucose/hyperglycemia results in activation of epigenetic mechanisms which alter gene expression and cell fate during brain development. METHODS AND FINDINGS: NSCs were isolated from normal pregnancy and streptozotocin induced-diabetic pregnancy and cultured in physiological glucose. In order to examine hyperglycemia induced epigenetic changes in NSCs, chromatin reorganization, global histone status at lysine 9 residue of histone H3 (acetylation and trimethylation and global DNA methylation were examined and found to be altered by hyperglycemia. In NSCs, hyperglycemia increased the expression of Dcx (Doublecortin and Pafah1b1 (Platelet activating factor acetyl hydrolase, isoform 1b, subunit 1 proteins concomitant with decreased expression of four microRNAs (mmu-miR-200a, mmu-miR-200b, mmu-miR-466a-3p and mmu-miR-466 d-3p predicted to target these genes. Knockdown of specific microRNAs in NSCs resulted in increased expression of Dcx and Pafah1b1 proteins confirming target prediction and altered NSC fate by increasing the expression of neuronal and glial lineage markers. CONCLUSION/INTERPRETATION: This study revealed that hyperglycemia alters the epigenetic mechanisms in NSCs, resulting in altered expression of some development control genes which may form the basis for the NTDs. Since epigenetic changes are reversible, they may be valuable therapeutic targets in order to improve fetal outcomes in diabetic pregnancy.

  15. Mouse allergen exposure and immunologic responses: IgE-mediated mouse sensitization and mouse specific IgG and IgG4 levels

    NARCIS (Netherlands)

    Matsui, Elizabeth C.; Krop, Esmeralda J. M.; Diette, Gregory B.; Aalberse, Rob C.; Smith, Abigail L.; Eggleston, Peyton A.

    2004-01-01

    Although there is evidence that contact with mice is associated with IgE-mediated mouse sensitization and mouse specific antibody responses, the exposure-response relationships remain unclear. To determine whether IgE-mediated mouse sensitization and mouse specific IgG (mIgG) and mIgG4 levels

  16. Generation of thalamic neurons from mouse embryonic stem cells.

    Science.gov (United States)

    Shiraishi, Atsushi; Muguruma, Keiko; Sasai, Yoshiki

    2017-04-01

    The thalamus is a diencephalic structure that plays crucial roles in relaying and modulating sensory and motor information to the neocortex. The thalamus develops in the dorsal part of the neural tube at the level of the caudal forebrain. However, the molecular mechanisms that are essential for thalamic differentiation are still unknown. Here, we have succeeded in generating thalamic neurons from mouse embryonic stem cells (mESCs) by modifying the default method that induces the most-anterior neural type in self-organizing culture. A low concentration of the caudalizing factor insulin and a MAPK/ERK kinase inhibitor enhanced the expression of the caudal forebrain markers Otx2 and Pax6. BMP7 promoted an increase in thalamic precursors such as Tcf7l2 + /Gbx2 + and Tcf7l2 + /Olig3 + cells. mESC thalamic precursors began to express the glutamate transporter vGlut2 and the axon-specific marker VGF, similar to mature projection neurons. The mESC thalamic neurons extended their axons to cortical layers in both organotypic culture and subcortical transplantation. Thus, we have identified the minimum elements sufficient for in vitro generation of thalamic neurons. These findings expand our knowledge of thalamic development. © 2017. Published by The Company of Biologists Ltd.

  17. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome.

    Science.gov (United States)

    Li, Yue; Stockton, Michael E; Bhuiyan, Ismat; Eisinger, Brian E; Gao, Yu; Miller, Jessica L; Bhattacharyya, Anita; Zhao, Xinyu

    2016-04-27

    Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome. Copyright © 2016, American Association for the Advancement of Science.

  18. Evolvable synthetic neural system

    Science.gov (United States)

    Curtis, Steven A. (Inventor)

    2009-01-01

    An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

  19. Neural electrical activity and neural network growth.

    Science.gov (United States)

    Gafarov, F M

    2018-05-01

    The development of central and peripheral neural system depends in part on the emergence of the correct functional connectivity in its input and output pathways. Now it is generally accepted that molecular factors guide neurons to establish a primary scaffold that undergoes activity-dependent refinement for building a fully functional circuit. However, a number of experimental results obtained recently shows that the neuronal electrical activity plays an important role in the establishing of initial interneuronal connections. Nevertheless, these processes are rather difficult to study experimentally, due to the absence of theoretical description and quantitative parameters for estimation of the neuronal activity influence on growth in neural networks. In this work we propose a general framework for a theoretical description of the activity-dependent neural network growth. The theoretical description incorporates a closed-loop growth model in which the neural activity can affect neurite outgrowth, which in turn can affect neural activity. We carried out the detailed quantitative analysis of spatiotemporal activity patterns and studied the relationship between individual cells and the network as a whole to explore the relationship between developing connectivity and activity patterns. The model, developed in this work will allow us to develop new experimental techniques for studying and quantifying the influence of the neuronal activity on growth processes in neural networks and may lead to a novel techniques for constructing large-scale neural networks by self-organization. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Predicting carcinogenicity of diverse chemicals using probabilistic neural network modeling approaches

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Kunwar P., E-mail: kpsingh_52@yahoo.com [Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research, New Delhi (India); Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India); Gupta, Shikha; Rai, Premanjali [Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research, New Delhi (India); Environmental Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box 80, Mahatma Gandhi Marg, Lucknow 226 001 (India)

    2013-10-15

    Robust global models capable of discriminating positive and non-positive carcinogens; and predicting carcinogenic potency of chemicals in rodents were developed. The dataset of 834 structurally diverse chemicals extracted from Carcinogenic Potency Database (CPDB) was used which contained 466 positive and 368 non-positive carcinogens. Twelve non-quantum mechanical molecular descriptors were derived. Structural diversity of the chemicals and nonlinearity in the data were evaluated using Tanimoto similarity index and Brock–Dechert–Scheinkman statistics. Probabilistic neural network (PNN) and generalized regression neural network (GRNN) models were constructed for classification and function optimization problems using the carcinogenicity end point in rat. Validation of the models was performed using the internal and external procedures employing a wide series of statistical checks. PNN constructed using five descriptors rendered classification accuracy of 92.09% in complete rat data. The PNN model rendered classification accuracies of 91.77%, 80.70% and 92.08% in mouse, hamster and pesticide data, respectively. The GRNN constructed with nine descriptors yielded correlation coefficient of 0.896 between the measured and predicted carcinogenic potency with mean squared error (MSE) of 0.44 in complete rat data. The rat carcinogenicity model (GRNN) applied to the mouse and hamster data yielded correlation coefficient and MSE of 0.758, 0.71 and 0.760, 0.46, respectively. The results suggest for wide applicability of the inter-species models in predicting carcinogenic potency of chemicals. Both the PNN and GRNN (inter-species) models constructed here can be useful tools in predicting the carcinogenicity of new chemicals for regulatory purposes. - Graphical abstract: Figure (a) shows classification accuracies (positive and non-positive carcinogens) in rat, mouse, hamster, and pesticide data yielded by optimal PNN model. Figure (b) shows generalization and predictive

  1. Alteration in neonatal nutrition causes perturbations in hypothalamic neural circuits controlling reproductive function.

    Science.gov (United States)

    Caron, Emilie; Ciofi, Philippe; Prevot, Vincent; Bouret, Sebastien G

    2012-08-15

    It is increasingly accepted that alterations of the early life environment may have lasting impacts on physiological functions. In particular, epidemiological and animal studies have indicated that changes in growth and nutrition during childhood and adolescence can impair reproductive function. However, the precise biological mechanisms that underlie these programming effects of neonatal nutrition on reproduction are still poorly understood. Here, we used a mouse model of divergent litter size to investigate the effects of early postnatal overnutrition and undernutrition on the maturation of hypothalamic circuits involved in reproductive function. Neonatally undernourished females display attenuated postnatal growth associated with delayed puberty and defective development of axonal projections from the arcuate nucleus to the preoptic region. These alterations persist into adulthood and specifically affect the organization of neural projections containing kisspeptin, a key neuropeptide involved in pubertal activation and fertility. Neonatal overfeeding also perturbs the development of neural projections from the arcuate nucleus to the preoptic region, but it does not result in alterations in kisspeptin projections. These studies indicate that alterations in the early nutritional environment cause lasting and deleterious effects on the organization of neural circuits involved in the control of reproduction, and that these changes are associated with lifelong functional perturbations.

  2. Apoptosis induced by glufosinate ammonium in the neuroepithelium of developing mouse embryos in culture.

    Science.gov (United States)

    Watanabe, T

    1997-01-24

    Glufosinate ammonium structurally resembles glutamate and blocks glutamine synthetase. Glufosinate was recently found to be dysmorphogenic in mammals in vitro. The present study examined the cell death induced specifically by glufosinate in the neuroepithelium of mouse embryos. Electron micrograph revealed characteristic chromatin condensation and segregation, extracellular apoptotic bodies, and cell fragments phagocytosed in macrophages in the neuroepithelium of the brain vesicle and neural tube. Moreover neuroepithelial cells undergoing DNA fragmentation were histochemically identified. DNA gel electrophoresis of the neuroepithelial layer revealed a DNA ladder. These observations demonstrate that glufosinate specifically induced apoptosis in the neuroepithelium of embryos.

  3. Detection of mouse endogenous type B astrocytes migrating towards brain lesions

    Directory of Open Access Journals (Sweden)

    Gema Elvira

    2015-01-01

    Full Text Available Neuroblasts represent the predominant migrating cell type in the adult mouse brain. There are, however, increasing evidences of migration of other neural precursors. This work aims at identifying in vivo endogenous early neural precursors, different from neuroblasts, able to migrate in response to brain injuries. The monoclonal antibody Nilo1, which unequivocally identifies type B astrocytes and embryonic radial glia, was coupled to magnetic glyconanoparticles (mGNPs. Here we show that Nilo1–mGNPs in combination with magnetic resonance imaging in living mice allowed the in vivo identification of endogenous type B astrocytes at their niche, as well as their migration to the lesion site in response to glioblastoma, demyelination, cryolesion or mechanical injuries. In addition, Nilo1+ adult radial glia-like structures were identified at the lesion site a few hours after damage. For all damage models used, type B astrocyte migration was fast and orderly. Identification of Nilo1+ cells surrounding an induced glioblastoma was also possible after intraperitoneal injection of the antibody. This opens up the possibility of an early identification of the initial damage site(s after brain insults, by the migration of type B astrocytes.

  4. Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model.

    Science.gov (United States)

    Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E; Shi, Yanhong

    2014-06-24

    The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.

  5. Dll1 maintains quiescence of adult neural stem cells and segregates asymmetrically during mitosis.

    Science.gov (United States)

    Kawaguchi, Daichi; Furutachi, Shohei; Kawai, Hiroki; Hozumi, Katsuto; Gotoh, Yukiko

    2013-01-01

    Stem cells often divide asymmetrically to produce one stem cell and one differentiating cell, thus maintaining the stem cell pool. Although neural stem cells (NSCs) in the adult mouse subventricular zone have been suggested to divide asymmetrically, intrinsic cell fate determinants for asymmetric NSC division are largely unknown. Stem cell niches are important for stem cell maintenance, but the niche for the maintenance of adult quiescent NSCs has remained obscure. Here we show that the Notch ligand Delta-like 1 (Dll1) is required to maintain quiescent NSCs in the adult mouse subventricular zone. Dll1 protein is induced in activated NSCs and segregates to one daughter cell during mitosis. Dll1-expressing cells reside in close proximity to quiescent NSCs, suggesting a feedback signal for NSC maintenance by their sister cells and progeny. Our data suggest a model in which NSCs produce their own niche cells for their maintenance through asymmetric Dll1 inheritance at mitosis.

  6. Mouse adhalin

    DEFF Research Database (Denmark)

    Liu, L; Vachon, P H; Kuang, W

    1997-01-01

    . To analyze the biological roles of adhalin, we cloned the mouse adhalin cDNA, raised peptide-specific antibodies to its cytoplasmic domain, and examined its expression and localization in vivo and in vitro. The mouse adhalin sequence was 80% identical to that of human, rabbit, and hamster. Adhalin...... was specifically expressed in striated muscle cells and their immediate precursors, and absent in many other cell types. Adhalin expression in embryonic mouse muscle was coincident with primary myogenesis. Its expression was found to be up-regulated at mRNA and protein levels during myogenic differentiation...

  7. A Mouse Model of Visual Perceptual Learning Reveals Alterations in Neuronal Coding and Dendritic Spine Density in the Visual Cortex

    OpenAIRE

    Wang, Yan; Wu, Wei; Zhang, Xian; Hu, Xu; Li, Yue; Lou, Shihao; Ma, Xiao; An, Xu; Liu, Hui; Peng, Jing; Ma, Danyi; Zhou, Yifeng; Yang, Yupeng

    2016-01-01

    Visual perceptual learning (VPL) can improve spatial vision in normally sighted and visually impaired individuals. Although previous studies of humans and large animals have explored the neural basis of VPL, elucidation of the underlying cellular and molecular mechanisms remains a challenge. Owing to the advantages of molecular genetic and optogenetic manipulations, the mouse is a promising model for providing a mechanistic understanding of VPL. Here, we thoroughly evaluated the effects and p...

  8. Differential arousal regulation by prokineticin 2 signaling in the nocturnal mouse and the diurnal monkey.

    Science.gov (United States)

    Zhou, Qun-Yong; Burton, Katherine J; Neal, Matthew L; Qiao, Yu; Kanthasamy, Anumantha G; Sun, Yanjun; Xu, Xiangmin; Ma, Yuanye; Li, Xiaohan

    2016-08-18

    The temporal organization of activity/rest or sleep/wake rhythms for mammals is regulated by the interaction of light/dark cycle and circadian clocks. The neural and molecular mechanisms that confine the active phase to either day or night period for the diurnal and the nocturnal mammals are unclear. Here we report that prokineticin 2, previously shown as a circadian clock output molecule, is expressed in the intrinsically photosensitive retinal ganglion cells, and the expression of prokineticin 2 in the intrinsically photosensitive retinal ganglion cells is oscillatory in a clock-dependent manner. We further show that the prokineticin 2 signaling is required for the activity and arousal suppression by light in the mouse. Between the nocturnal mouse and the diurnal monkey, a signaling receptor for prokineticin 2 is differentially expressed in the retinorecipient suprachiasmatic nucleus and the superior colliculus, brain projection targets of the intrinsically photosensitive retinal ganglion cells. Blockade with a selective antagonist reveals the respectively inhibitory and stimulatory effect of prokineticin 2 signaling on the arousal levels for the nocturnal mouse and the diurnal monkey. Thus, the mammalian diurnality or nocturnality is likely determined by the differential signaling of prokineticin 2 from the intrinsically photosensitive retinal ganglion cells onto their retinorecipient brain targets.

  9. Neural stem cells promote nerve regeneration through IL12-induced Schwann cell differentiation.

    Science.gov (United States)

    Lee, Don-Ching; Chen, Jong-Hang; Hsu, Tai-Yu; Chang, Li-Hsun; Chang, Hsu; Chi, Ya-Hui; Chiu, Ing-Ming

    2017-03-01

    Regeneration of injured peripheral nerves is a slow, complicated process that could be improved by implantation of neural stem cells (NSCs) or nerve conduit. Implantation of NSCs along with conduits promotes the regeneration of damaged nerve, likely because (i) conduit supports and guides axonal growth from one nerve stump to the other, while preventing fibrous tissue ingrowth and retaining neurotrophic factors; and (ii) implanted NSCs differentiate into Schwann cells and maintain a growth factor enriched microenvironment, which promotes nerve regeneration. In this study, we identified IL12p80 (homodimer of IL12p40) in the cell extracts of implanted nerve conduit combined with NSCs by using protein antibody array and Western blotting. Levels of IL12p80 in these conduits are 1.6-fold higher than those in conduits without NSCs. In the sciatic nerve injury mouse model, implantation of NSCs combined with nerve conduit and IL12p80 improves motor recovery and increases the diameter up to 4.5-fold, at the medial site of the regenerated nerve. In vitro study further revealed that IL12p80 stimulates the Schwann cell differentiation of mouse NSCs through the phosphorylation of signal transducer and activator of transcription 3 (Stat3). These results suggest that IL12p80 can trigger Schwann cell differentiation of mouse NSCs through Stat3 phosphorylation and enhance the functional recovery and the diameter of regenerated nerves in a mouse sciatic nerve injury model. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Radiation-Induced Alterations in Mouse Brain Development Characterized by Magnetic Resonance Imaging

    International Nuclear Information System (INIS)

    Gazdzinski, Lisa M.; Cormier, Kyle; Lu, Fred G.; Lerch, Jason P.; Wong, C. Shun; Nieman, Brian J.

    2012-01-01

    Purpose: The purpose of this study was to identify regions of altered development in the mouse brain after cranial irradiation using longitudinal magnetic resonance imaging (MRI). Methods and Materials: Female C57Bl/6 mice received a whole-brain radiation dose of 7 Gy at an infant-equivalent age of 2.5 weeks. MRI was performed before irradiation and at 3 time points following irradiation. Deformation-based morphometry was used to quantify volume and growth rate changes following irradiation. Results: Widespread developmental deficits were observed in both white and gray matter regions following irradiation. Most of the affected brain regions suffered an initial volume deficit followed by growth at a normal rate, remaining smaller in irradiated brains compared with controls at all time points examined. The one exception was the olfactory bulb, which in addition to an early volume deficit, grew at a slower rate thereafter, resulting in a progressive volume deficit relative to controls. Immunohistochemical assessment revealed demyelination in white matter and loss of neural progenitor cells in the subgranular zone of the dentate gyrus and subventricular zone. Conclusions: MRI can detect regional differences in neuroanatomy and brain growth after whole-brain irradiation in the developing mouse. Developmental deficits in neuroanatomy persist, or even progress, and may serve as useful markers of late effects in mouse models. The high-throughput evaluation of brain development enabled by these methods may allow testing of strategies to mitigate late effects after pediatric cranial irradiation.

  11. Radiation-Induced Alterations in Mouse Brain Development Characterized by Magnetic Resonance Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Gazdzinski, Lisa M.; Cormier, Kyle [Mouse Imaging Centre, Hospital for Sick Children, Toronto (Canada); Lu, Fred G. [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto (Canada); Lerch, Jason P. [Mouse Imaging Centre, Hospital for Sick Children, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada); Wong, C. Shun [Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada); Department of Radiation Oncology, University of Toronto, Toronto (Canada); Nieman, Brian J., E-mail: bjnieman@phenogenomics.ca [Mouse Imaging Centre, Hospital for Sick Children, Toronto (Canada); Department of Medical Biophysics, University of Toronto, Toronto (Canada)

    2012-12-01

    Purpose: The purpose of this study was to identify regions of altered development in the mouse brain after cranial irradiation using longitudinal magnetic resonance imaging (MRI). Methods and Materials: Female C57Bl/6 mice received a whole-brain radiation dose of 7 Gy at an infant-equivalent age of 2.5 weeks. MRI was performed before irradiation and at 3 time points following irradiation. Deformation-based morphometry was used to quantify volume and growth rate changes following irradiation. Results: Widespread developmental deficits were observed in both white and gray matter regions following irradiation. Most of the affected brain regions suffered an initial volume deficit followed by growth at a normal rate, remaining smaller in irradiated brains compared with controls at all time points examined. The one exception was the olfactory bulb, which in addition to an early volume deficit, grew at a slower rate thereafter, resulting in a progressive volume deficit relative to controls. Immunohistochemical assessment revealed demyelination in white matter and loss of neural progenitor cells in the subgranular zone of the dentate gyrus and subventricular zone. Conclusions: MRI can detect regional differences in neuroanatomy and brain growth after whole-brain irradiation in the developing mouse. Developmental deficits in neuroanatomy persist, or even progress, and may serve as useful markers of late effects in mouse models. The high-throughput evaluation of brain development enabled by these methods may allow testing of strategies to mitigate late effects after pediatric cranial irradiation.

  12. Morphological neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Ritter, G.X.; Sussner, P. [Univ. of Florida, Gainesville, FL (United States)

    1996-12-31

    The theory of artificial neural networks has been successfully applied to a wide variety of pattern recognition problems. In this theory, the first step in computing the next state of a neuron or in performing the next layer neural network computation involves the linear operation of multiplying neural values by their synaptic strengths and adding the results. Thresholding usually follows the linear operation in order to provide for nonlinearity of the network. In this paper we introduce a novel class of neural networks, called morphological neural networks, in which the operations of multiplication and addition are replaced by addition and maximum (or minimum), respectively. By taking the maximum (or minimum) of sums instead of the sum of products, morphological network computation is nonlinear before thresholding. As a consequence, the properties of morphological neural networks are drastically different than those of traditional neural network models. In this paper we consider some of these differences and provide some particular examples of morphological neural network.

  13. Dusp16 Deficiency Causes Congenital Obstructive Hydrocephalus and Brain Overgrowth by Expansion of the Neural Progenitor Pool

    Directory of Open Access Journals (Sweden)

    Ksenija Zega

    2017-11-01

    Full Text Available Hydrocephalus can occur in children alone or in combination with other neurodevelopmental disorders that are often associated with brain overgrowth. Despite the severity of these disorders, the molecular and cellular mechanisms underlying these pathologies and their comorbidity are poorly understood. Here, we studied the consequences of genetically inactivating in mice dual-specificity phosphatase 16 (Dusp16, which is known to negatively regulate mitogen-activated protein kinases (MAPKs and which has never previously been implicated in brain development and disorders. Mouse mutants lacking a functional Dusp16 gene (Dusp16−/− developed fully-penetrant congenital obstructive hydrocephalus together with brain overgrowth. The midbrain aqueduct in Dusp16−/− mutants was obstructed during mid-gestation by an expansion of neural progenitors, and during later gestational stages by neurons resulting in a blockage of cerebrospinal fluid (CSF outflow. In contrast, the roof plate and ependymal cells developed normally. We identified a delayed cell cycle exit of neural progenitors in Dusp16−/− mutants as a cause of progenitor overproliferation during mid-gestation. At later gestational stages, this expanded neural progenitor pool generated an increased number of neurons associated with enlarged brain volume. Taken together, we found that Dusp16 plays a critical role in neurogenesis by balancing neural progenitor cell proliferation and neural differentiation. Moreover our results suggest that a lack of functional Dusp16 could play a central role in the molecular mechanisms linking brain overgrowth and hydrocephalus.

  14. Neural Networks

    International Nuclear Information System (INIS)

    Smith, Patrick I.

    2003-01-01

    Physicists use large detectors to measure particles created in high-energy collisions at particle accelerators. These detectors typically produce signals indicating either where ionization occurs along the path of the particle, or where energy is deposited by the particle. The data produced by these signals is fed into pattern recognition programs to try to identify what particles were produced, and to measure the energy and direction of these particles. Ideally, there are many techniques used in this pattern recognition software. One technique, neural networks, is particularly suitable for identifying what type of particle caused by a set of energy deposits. Neural networks can derive meaning from complicated or imprecise data, extract patterns, and detect trends that are too complex to be noticed by either humans or other computer related processes. To assist in the advancement of this technology, Physicists use a tool kit to experiment with several neural network techniques. The goal of this research is interface a neural network tool kit into Java Analysis Studio (JAS3), an application that allows data to be analyzed from any experiment. As the final result, a physicist will have the ability to train, test, and implement a neural network with the desired output while using JAS3 to analyze the results or output. Before an implementation of a neural network can take place, a firm understanding of what a neural network is and how it works is beneficial. A neural network is an artificial representation of the human brain that tries to simulate the learning process [5]. It is also important to think of the word artificial in that definition as computer programs that use calculations during the learning process. In short, a neural network learns by representative examples. Perhaps the easiest way to describe the way neural networks learn is to explain how the human brain functions. The human brain contains billions of neural cells that are responsible for processing

  15. Distinct spatiotemporal expression of ISM1 during mouse and chick development.

    Science.gov (United States)

    Osório, Liliana; Wu, Xuewei; Zhou, Zhongjun

    2014-01-01

    Isthmin 1 (ISM1) constitutes the founder of a new family of secreted proteins characterized by the presence of 2 functional domains: thrombospondin type 1 repeat (TSR1) and adhesion-associated domain in MUC4 and other proteins (AMOP). ISM1 was identified in the frog embryo as a member of the FGF8 synexpression group due to its expression in the brain midbrain-hindbrain boundary (MHB) or isthmus. In zebrafish, ISM1 was described as a WNT- and NODAL-regulated gene. The function of ISM1 remains largely elusive. So far, ISM1 has been described as an angiogenesis inhibitor that has a dual function in endothelial cell survival and cell death. For a better understanding of ISM1 function, we examined its spatiotemporal distribution in mouse and chick using RT-PCR, ISH, and IHC analyses. In the mouse, ISM1 transcripts are found in tissues such as the anterior mesendoderm, paraxial and lateral plate mesoderm, MHB and trunk neural tube, as well as in the somites and dermomyotome. In the newborn and adult, ISM1 is prominently expressed in the lung and brain. In addition to its putative role during embryonic and postnatal development, ISM1 may also be important for organ homeostasis in the adult. In the chick embryo, ISM1 transcripts are strongly detected in the ear, eye, and spinal cord primordia. Remarkable differences in ISM1 spatiotemporal expression were found during mouse and chick development, despite the high homology of ISM1 orthologs in these species.

  16. Potential translational targets revealed by linking mouse grooming behavioral phenotypes to gene expression using public databases.

    Science.gov (United States)

    Roth, Andrew; Kyzar, Evan J; Cachat, Jonathan; Stewart, Adam Michael; Green, Jeremy; Gaikwad, Siddharth; O'Leary, Timothy P; Tabakoff, Boris; Brown, Richard E; Kalueff, Allan V

    2013-01-10

    Rodent self-grooming is an important, evolutionarily conserved behavior, highly sensitive to pharmacological and genetic manipulations. Mice with aberrant grooming phenotypes are currently used to model various human disorders. Therefore, it is critical to understand the biology of grooming behavior, and to assess its translational validity to humans. The present in-silico study used publicly available gene expression and behavioral data obtained from several inbred mouse strains in the open-field, light-dark box, elevated plus- and elevated zero-maze tests. As grooming duration differed between strains, our analysis revealed several candidate genes with significant correlations between gene expression in the brain and grooming duration. The Allen Brain Atlas, STRING, GoMiner and Mouse Genome Informatics databases were used to functionally map and analyze these candidate mouse genes against their human orthologs, assessing the strain ranking of their expression and the regional distribution of expression in the mouse brain. This allowed us to identify an interconnected network of candidate genes (which have expression levels that correlate with grooming behavior), display altered patterns of expression in key brain areas related to grooming, and underlie important functions in the brain. Collectively, our results demonstrate the utility of large-scale, high-throughput data-mining and in-silico modeling for linking genomic and behavioral data, as well as their potential to identify novel neural targets for complex neurobehavioral phenotypes, including grooming. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Restriction of neural precursor ability to respond to Nurr1 by early regional specification.

    Directory of Open Access Journals (Sweden)

    Chiara Soldati

    Full Text Available During neural development, spatially regulated expression of specific transcription factors is crucial for central nervous system (CNS regionalization, generation of neural precursors (NPs and subsequent differentiation of specific cell types within defined regions. A critical role in dopaminergic differentiation in the midbrain (MB has been assigned to the transcription factor Nurr1. Nurr1 controls the expression of key genes involved in dopamine (DA neurotransmission, e.g. tyrosine hydroxylase (TH and the DA transporter (DAT, and promotes the dopaminergic phenotype in embryonic stem cells. We investigated whether cells derived from different areas of the mouse CNS could be directed to differentiate into dopaminergic neurons in vitro by forced expression of the transcription factor Nurr1. We show that Nurr1 overexpression can promote dopaminergic cell fate specification only in NPs obtained from E13.5 ganglionic eminence (GE and MB, but not in NPs isolated from E13.5 cortex (CTX and spinal cord (SC or from the adult subventricular zone (SVZ. Confirming previous studies, we also show that Nurr1 overexpression can increase the generation of TH-positive neurons in mouse embryonic stem cells. These data show that Nurr1 ability to induce a dopaminergic phenotype becomes restricted during CNS development and is critically dependent on the region of NPs derivation. Our results suggest that the plasticity of NPs and their ability to activate a dopaminergic differentiation program in response to Nurr1 is regulated during early stages of neurogenesis, possibly through mechanisms controlling CNS regionalization.

  18. Catalog of gene expression in adult neural stem cells and their in vivo microenvironment

    International Nuclear Information System (INIS)

    Williams, Cecilia; Wirta, Valtteri; Meletis, Konstantinos; Wikstroem, Lilian; Carlsson, Leif; Frisen, Jonas; Lundeberg, Joakim

    2006-01-01

    Stem cells generally reside in a stem cell microenvironment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique stemness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research

  19. Neural Based Orthogonal Data Fitting The EXIN Neural Networks

    CERN Document Server

    Cirrincione, Giansalvo

    2008-01-01

    Written by three leaders in the field of neural based algorithms, Neural Based Orthogonal Data Fitting proposes several neural networks, all endowed with a complete theory which not only explains their behavior, but also compares them with the existing neural and traditional algorithms. The algorithms are studied from different points of view, including: as a differential geometry problem, as a dynamic problem, as a stochastic problem, and as a numerical problem. All algorithms have also been analyzed on real time problems (large dimensional data matrices) and have shown accurate solutions. Wh

  20. Nanosized zinc oxide particles induce neural stem cell apoptosis

    International Nuclear Information System (INIS)

    Deng Xiaoyong; Luan Qixia; Wu Minghong; Zhang Haijiao; Jiao Zheng; Chen Wenting; Wang Yanli

    2009-01-01

    Given the intensive application of nanoscale zinc oxide (ZnO) materials in our life, growing concerns have arisen about its unintentional health and environmental impacts. In this study, the neurotoxicity of different sized ZnO nanoparticles in mouse neural stem cells (NSCs) was investigated. A cell viability assay indicated that ZnO nanoparticles manifested dose-dependent, but no size-dependent toxic effects on NSCs. Apoptotic cells were observed and analyzed by confocal microscopy, transmission electron microscopy examination, and flow cytometry. All the results support the viewpoint that the ZnO nanoparticle toxicity comes from the dissolved Zn 2+ in the culture medium or inside cells. Our results highlight the need for caution during the use and disposal of ZnO manufactured nanomaterials to prevent the unintended environmental and health impacts.

  1. Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model

    DEFF Research Database (Denmark)

    Tønnesen, Jan; Parish, Clare L; Sørensen, Andreas T

    2011-01-01

    Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral...... of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation...... using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying...

  2. Direct lineage reprogramming of mouse fibroblasts to functional midbrain dopaminergic neuronal progenitors

    Directory of Open Access Journals (Sweden)

    Han-Seop Kim

    2014-01-01

    Full Text Available The direct lineage reprogramming of somatic cells to other lineages by defined factors has led to innovative cell-fate-change approaches for providing patient-specific cells. Recent reports have demonstrated that four pluripotency factors (Oct4, Sox2, Klf4, and c-Myc are sufficient to directly reprogram fibroblasts to other specific cells, including induced neural stem cells (iNSCs. Here, we show that mouse fibroblasts can be directly reprogrammed into midbrain dopaminergic neuronal progenitors (DPs by temporal expression of the pluripotency factors and environment containing sonic hedgehog and fibroblast growth factor 8. Within thirteen days, self-renewing and functional induced DPs (iDPs were generated. Interestingly, the inhibition of both Jak and Gsk3β notably enhanced the iDP reprogramming efficiency. We confirmed the functionality of the iDPs by showing that the dopaminergic neurons generated from iDPs express midbrain markers, release dopamine, and show typical electrophysiological profiles. Our results demonstrate that the pluripotency factors-mediated direct reprogramming is an invaluable strategy for supplying functional and proliferating iDPs and may be useful for other neural progenitors required for disease modeling and cell therapies for neurodegenerative disorders.

  3. Automated Computational Processing of 3-D MR Images of Mouse Brain for Phenotyping of Living Animals.

    Science.gov (United States)

    Medina, Christopher S; Manifold-Wheeler, Brett; Gonzales, Aaron; Bearer, Elaine L

    2017-07-05

    Magnetic resonance (MR) imaging provides a method to obtain anatomical information from the brain in vivo that is not typically available by optical imaging because of this organ's opacity. MR is nondestructive and obtains deep tissue contrast with 100-µm 3 voxel resolution or better. Manganese-enhanced MRI (MEMRI) may be used to observe axonal transport and localized neural activity in the living rodent and avian brain. Such enhancement enables researchers to investigate differences in functional circuitry or neuronal activity in images of brains of different animals. Moreover, once MR images of a number of animals are aligned into a single matrix, statistical analysis can be done comparing MR intensities between different multi-animal cohorts comprising individuals from different mouse strains or different transgenic animals, or at different time points after an experimental manipulation. Although preprocessing steps for such comparisons (including skull stripping and alignment) are automated for human imaging, no such automated processing has previously been readily available for mouse or other widely used experimental animals, and most investigators use in-house custom processing. This protocol describes a stepwise method to perform such preprocessing for mouse. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  4. Neural networks

    International Nuclear Information System (INIS)

    Denby, Bruce; Lindsey, Clark; Lyons, Louis

    1992-01-01

    The 1980s saw a tremendous renewal of interest in 'neural' information processing systems, or 'artificial neural networks', among computer scientists and computational biologists studying cognition. Since then, the growth of interest in neural networks in high energy physics, fueled by the need for new information processing technologies for the next generation of high energy proton colliders, can only be described as explosive

  5. Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation through activating the NR2B subunits of NMDA receptors

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Wen-Zhu [Anesthesia and Operation Center, Hainan Branch of Chinese PLA General Hospital, Hainan 572013 (China); Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China); Miao, Yu-Liang [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Guo, Wen-Zhi [Department of Anesthesiology, Beijing Military General Hospital of Chinese People’s Liberation Army, Beijing 100700 (China); Wu, Wei, E-mail: wwzwgk@163.com [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); Li, Bao-Wei [Department of Head and Neck Surgery of Otolaryngology, PLA No. 306 Hospital, Beijing 100101 (China); An, Li-Na [Department of Anesthesiology, Armed Police General Hospital, Beijing 100039 (China); Fang, Wei-Wu [Department of Anesthesiology, PLA No. 306 Hospital, Beijing 100101 (China); Mi, Wei-Dong, E-mail: elite2005gg@163.com [Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing 100853 (China)

    2014-04-25

    Highlights: • Leptin promotes the proliferation of neural stem cells isolated from embryonic mouse hippocampus. • Leptin reverses corticosterone-induced inhibition of neural stem cell proliferation. • The effects of leptin are partially mediated by upregulating NR2B subunits. - Abstract: Corticosterone inhibits the proliferation of hippocampal neural stem cells (NSCs). The removal of corticosterone-induced inhibition of NSCs proliferation has been reported to contribute to neural regeneration. Leptin has been shown to regulate brain development, improve angiogenesis, and promote neural regeneration; however, its effects on corticosterone-induced inhibition of NSCs proliferation remain unclear. Here we reported that leptin significantly promoted the proliferation of hippocampal NSCs in a concentration-dependent pattern. Also, leptin efficiently reversed the inhibition of NSCs proliferation induced by corticosterone. Interestingly, pre-treatment with non-specific NMDA antagonist MK-801, specific NR2B antagonist Ro 25-6981, or small interfering RNA (siRNA) targeting NR2B, significantly blocked the effect of leptin on corticosterone-induced inhibition of NSCs proliferation. Furthermore, corticosterone significantly reduced the protein expression of NR2B, whereas pre-treatment with leptin greatly reversed the attenuation of NR2B expression caused by corticosterone in cultured hippocampal NSCs. Our findings demonstrate that leptin reverses the corticosterone-induced inhibition of NSCs proliferation. This process is, at least partially mediated by increased expression of NR2B subunits of NMDA receptors.

  6. A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve

    Science.gov (United States)

    Caravaca, A. S.; Tsaava, T.; Goldman, L.; Silverman, H.; Riggott, G.; Chavan, S. S.; Bouton, C.; Tracey, K. J.; Desimone, R.; Boyden, E. S.; Sohal, H. S.; Olofsson, P. S.

    2017-12-01

    Objective. Neural reflexes regulate immune responses and homeostasis. Advances in bioelectronic medicine indicate that electrical stimulation of the vagus nerve can be used to treat inflammatory disease, yet the understanding of neural signals that regulate inflammation is incomplete. Current interfaces with the vagus nerve do not permit effective chronic stimulation or recording in mouse models, which is vital to studying the molecular and neurophysiological mechanisms that control inflammation homeostasis in health and disease. We developed an implantable, dual purpose, multi-channel, flexible ‘microelectrode’ array, for recording and stimulation of the mouse vagus nerve. Approach. The array was microfabricated on an 8 µm layer of highly biocompatible parylene configured with 16 sites. The microelectrode was evaluated by studying the recording and stimulation performance. Mice were chronically implanted with devices for up to 12 weeks. Main results. Using the microelectrode in vivo, high fidelity signals were recorded during physiological challenges (e.g potassium chloride and interleukin-1β), and electrical stimulation of the vagus nerve produced the expected significant reduction of blood levels of tumor necrosis factor (TNF) in endotoxemia. Inflammatory cell infiltration at the microelectrode 12 weeks of implantation was limited according to radial distribution analysis of inflammatory cells. Significance. This novel device provides an important step towards a viable chronic interface for cervical vagus nerve stimulation and recording in mice.

  7. Expression, crystallization and preliminary X-ray analysis of the extracellular Ig modules I–IV and F3 modules I–III of the neural cell-adhesion molecule L1

    International Nuclear Information System (INIS)

    Kulahin, Nikolaj; Kasper, Christina; Kristensen, Ole; Kastrup, Jette Sandholm; Berezin, Vladimir; Bock, Elisabeth; Gajhede, Michael

    2005-01-01

    Mouse L1 modules Ig I–IV and F3 I–III were crystallized. The crystals diffracted X-rays to 3.5 and 2.8 Å resolution, respectively. Four amino-terminal immunoglobulin (Ig) modules and three fibronectin type III (F3) modules of the mouse neural cell-adhesion molecule L1 have been expressed in Drosophila S2 cells. The Ig modules I–IV of L1 crystallized in a trigonal space group, with unit-cell parameters a = b = 239.6, c = 99.3 Å, and the crystals diffracted X-rays to a resolution of about 3.5 Å. The F3 modules I–III of L1 crystallized in a tetragonal space group, with unit-cell parameters a = b = 80.1, c = 131 Å, and the crystals diffracted X-rays to 2.8 Å resolution. This is a step towards the structure determination of the multimodular constructs of the neural cell-adhesion molecule L1 in order to understand the function of L1 on a structural basis

  8. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells.

    Science.gov (United States)

    van den Brink, Susanne C; Baillie-Johnson, Peter; Balayo, Tina; Hadjantonakis, Anna-Katerina; Nowotschin, Sonja; Turner, David A; Martinez Arias, Alfonso

    2014-11-01

    Mouse embryonic stem cells (mESCs) are clonal populations derived from preimplantation mouse embryos that can be propagated in vitro and, when placed into blastocysts, contribute to all tissues of the embryo and integrate into the normal morphogenetic processes, i.e. they are pluripotent. However, although they can be steered to differentiate in vitro into all cell types of the organism, they cannot organise themselves into structures that resemble embryos. When aggregated into embryoid bodies they develop disorganised masses of different cell types with little spatial coherence. An exception to this rule is the emergence of retinas and anterior cortex-like structures under minimal culture conditions. These structures emerge from the cultures without any axial organisation. Here, we report that small aggregates of mESCs, of about 300 cells, self-organise into polarised structures that exhibit collective behaviours reminiscent of those that cells exhibit in early mouse embryos, including symmetry breaking, axial organisation, germ layer specification and cell behaviour, as well as axis elongation. The responses are signal specific and uncouple processes that in the embryo are tightly associated, such as specification of the anteroposterior axis and anterior neural development, or endoderm specification and axial elongation. We discuss the meaning and implications of these observations and the potential uses of these structures which, because of their behaviour, we suggest to call 'gastruloids'. © 2014. Published by The Company of Biologists Ltd.

  9. Functional studies of signaling pathways in peri-implantation development of the mouse embryo by RNAi

    Directory of Open Access Journals (Sweden)

    Bell Graham

    2005-12-01

    Full Text Available Abstract Background Studies of gene function in the mouse have relied mainly on gene targeting via homologous recombination. However, this approach is difficult to apply in specific windows of time, and to simultaneously knock-down multiple genes. Here we report an efficient method for dsRNA-mediated gene silencing in late cleavage-stage mouse embryos that permits examination of phenotypes at post-implantation stages. Results We show that introduction of Bmp4 dsRNA into intact blastocysts by electroporation recapitulates the genetic Bmp4 null phenotype at gastrulation. It also reveals a novel role for Bmp4 in the regulation the anterior visceral endoderm specific gene expression and its positioning. We also show that RNAi can be used to simultaneously target several genes. When applied to the three murine isoforms of Dishevelled, it leads to earlier defects than previously observed in double knock-outs. These include severe delays in post-implantation development and defects in the anterior midline and neural folds at headfold stages. Conclusion Our results indicate that the BMP4 signalling pathway contributes to the development of the anterior visceral endoderm, and reveal an early functional redundancy between the products of the murine Dishevelled genes. The proposed approach constitutes a powerful tool to screen the functions of genes that govern the development of the mouse embryo.

  10. The neuro-glial properties of adipose-derived adult stromal (ADAS) cells are not regulated by Notch 1 and are not derived from neural crest lineage.

    Science.gov (United States)

    Wrage, Philip C; Tran, Thi; To, Khai; Keefer, Edward W; Ruhn, Kelly A; Hong, John; Hattangadi, Supriya; Treviño, Isaac; Tansey, Malú G

    2008-01-16

    We investigated whether adipose-derived adult stromal (ADAS) are of neural crest origin and the extent to which Notch 1 regulates their growth and differentiation. Mouse ADAS cells cultured in media formulated for neural stem cells (NSC) displayed limited capacity for self-renewal, clonogenicity, and neurosphere formation compared to NSC from the subventricular zone in the hippocampus. Although ADAS cells expressed Nestin, GFAP, NSE and Tuj1 in vitro, exposure to NSC differentiation supplements did not induce mature neuronal marker expression. In contrast, in mesenchymal stem cell (MSC) media, ADAS cells retained their ability to proliferate and differentiate beyond 20 passages and expressed high levels of Nestin. In neuritizing cocktails, ADAS cells extended processes, downregulated Nestin expression, and displayed depolarization-induced Ca(2+) transients but no spontaneous or evoked neural network activity on Multi-Electrode Arrays. Deletion of Notch 1 in ADAS cell cultures grown in NSC proliferation medium did not significantly alter their proliferative potential in vitro or the differentiation-induced downregulation of Nestin. Co-culture of ADAS cells with fibroblasts that stably expressed the Notch ligand Jagged 1 or overexpression of the Notch intracellular domain (NICD) did not alter ADAS cell growth, morphology, or cellular marker expression. ADAS cells did not display robust expression of neural crest transcription factors or genes (Sox, CRABP2, and TH); and lineage tracing analyses using Wnt1-Cre;Rosa26R-lacZ or -EYFP reporter mice confirmed that fewer than 2% of the ADAS cell population derived from a Wnt1-positive population during development. In summary, although media formulations optimized for MSCs or NSCs enable expansion of mouse ADAS cells in vitro, we find no evidence that these cells are of neural crest origin, that they can undergo robust terminal differentiation into functionally mature neurons, and that Notch 1 is likely to be a key

  11. Epigenetic regulation of gene expression in porcine epiblast, hypoblast, trophectoderm and epiblast-derived neural progenitor cells

    DEFF Research Database (Denmark)

    Gao, Yu; Jammes, Helen; Rasmussen, Mikkel Aabech

    2011-01-01

    in this process. In this study, we investigated the relationship between DNA methylation and expression of pluripotency-associated genes (OCT4, NANOG and SOX2), a trophectoderm (TE)-specific gene (ELF5), and genes associated with neural differentiation (SOX2 and VIMENTIN) in porcine Day 10 (E10) epiblast......, hypoblast, and TE as well as in epiblast-derived neural progenitor cells (NPCs). We found that OCT4, NANOG, and SOX2 were highly expressed in the epiblast and hypoblast, while VIMENTIN was only highly expressed in the epiblast. Moreover, low expression of OCT4, NANOG, SOX2 and VIMENTIN was noted in the TE....... Most CpG sites of OCT4, NANOG, SOX2 and VIMENTIN displayed low methylation levels in the epiblast and hypoblast and, strikingly, also in the TE. Hence, the expression patterns of these genes were not directly related to levels of DNA methylation in the TE in contrast to the situation in the mouse...

  12. miR-342-5p Regulates Neural Stem Cell Proliferation and Differentiation Downstream to Notch Signaling in Mice

    Directory of Open Access Journals (Sweden)

    Fang Gao

    2017-04-01

    Full Text Available Summary: Notch signaling is critically involved in neural development, but the downstream effectors remain incompletely understood. In this study, we cultured neurospheres from Nestin-Cre-mediated conditional Rbp-j knockout (Rbp-j cKO and control embryos and compared their miRNA expression profiles using microarray. Among differentially expressed miRNAs, miR-342-5p showed upregulated expression as Notch signaling was genetically or pharmaceutically interrupted. Consistently, the promoter of the miR-342-5p host gene, the Ena-vasodilator stimulated phosphoprotein-like (Evl, was negatively regulated by Notch signaling, probably through HES5. Transfection of miR-342-5p promoted the differentiation of neural stem cells (NSCs into intermediate neural progenitors (INPs in vitro and reduced the stemness of NSCs in vivo. Furthermore, miR-342-5p inhibited the differentiation of neural stem/intermediate progenitor cells into astrocytes, likely mediated by targeting GFAP directly. Our results indicated that miR-342-5p could function as a downstream effector of Notch signaling to regulate the differentiation of NSCs into INPs and astrocytes commitment. : In this article, Han and colleagues show that miR-342-5p acts as a downstream effector of Notch signaling in the mouse CNS. Notch signal inhibits miR-342-5p expression by regulating its host gene Evl. And with attenuated Notch signal in NSCs, miR-342-5p is upregulated to promote NSCs transition into INPs, and to inhibit astrocyte commitment by targeting GFAP. Keywords: neural stem cells, intermediate neural progenitors, Notch, RBP-J, neuron, glia, miR-342-5p

  13. Neural glycoprotein M6a is released in extracellular vesicles and modulated by chronic stressors in blood

    OpenAIRE

    Monteleone, Melisa C.; Billi, Silvia C.; Brocco, Marcela A.; Frasch, Alberto C.

    2017-01-01

    Membrane neuronal glycoprotein M6a is highly expressed in the brain and contributes to neural plasticity promoting neurite growth and spine and synapse formation. We have previously showed that chronic stressors alter hippocampal M6a mRNA levels in rodents and tree shrews. We now show that M6a glycoprotein can be detected in mouse blood. M6a is a transmembrane glycoprotein and, as such, unlikely to be free in blood. Here we demonstrate that, in blood, M6a is transported in extracellular vesic...

  14. Evolvable Neural Software System

    Science.gov (United States)

    Curtis, Steven A.

    2009-01-01

    The Evolvable Neural Software System (ENSS) is composed of sets of Neural Basis Functions (NBFs), which can be totally autonomously created and removed according to the changing needs and requirements of the software system. The resulting structure is both hierarchical and self-similar in that a given set of NBFs may have a ruler NBF, which in turn communicates with other sets of NBFs. These sets of NBFs may function as nodes to a ruler node, which are also NBF constructs. In this manner, the synthetic neural system can exhibit the complexity, three-dimensional connectivity, and adaptability of biological neural systems. An added advantage of ENSS over a natural neural system is its ability to modify its core genetic code in response to environmental changes as reflected in needs and requirements. The neural system is fully adaptive and evolvable and is trainable before release. It continues to rewire itself while on the job. The NBF is a unique, bilevel intelligence neural system composed of a higher-level heuristic neural system (HNS) and a lower-level, autonomic neural system (ANS). Taken together, the HNS and the ANS give each NBF the complete capabilities of a biological neural system to match sensory inputs to actions. Another feature of the NBF is the Evolvable Neural Interface (ENI), which links the HNS and ANS. The ENI solves the interface problem between these two systems by actively adapting and evolving from a primitive initial state (a Neural Thread) to a complicated, operational ENI and successfully adapting to a training sequence of sensory input. This simulates the adaptation of a biological neural system in a developmental phase. Within the greater multi-NBF and multi-node ENSS, self-similar ENI s provide the basis for inter-NBF and inter-node connectivity.

  15. Formate supplementation enhances folate-dependent nucleotide biosynthesis and prevents spina bifida in a mouse model of folic acid-resistant neural tube defects.

    Science.gov (United States)

    Sudiwala, Sonia; De Castro, Sandra C P; Leung, Kit-Yi; Brosnan, John T; Brosnan, Margaret E; Mills, Kevin; Copp, Andrew J; Greene, Nicholas D E

    2016-07-01

    The curly tail mouse provides a model for neural tube defects (spina bifida and exencephaly) that are resistant to prevention by folic acid. The major ct gene, responsible for spina bifida, corresponds to a hypomorphic allele of grainyhead-like 3 (Grhl3) but the frequency of NTDs is strongly influenced by modifiers in the genetic background. Moreover, exencephaly in the curly tail strain is not prevented by reinstatement of Grhl3 expression. In the current study we found that expression of Mthfd1L, encoding a key component of mitochondrial folate one-carbon metabolism (FOCM), is significantly reduced in ct/ct embryos compared to a partially congenic wild-type strain. This expression change is not attributable to regulation by Grhl3 or the genetic background at the Mthfd1L locus. Mitochondrial FOCM provides one-carbon units as formate for FOCM reactions in the cytosol. We found that maternal supplementation with formate prevented NTDs in curly tail embryos and also resulted in increased litter size. Analysis of the folate profile of neurulation-stage embryos showed that formate supplementation resulted in an increased proportion of formyl-THF and THF but a reduction in proportion of 5-methyl THF. In contrast, THF decreased and 5-methyl THF was relatively more abundant in the liver of supplemented dams than in controls. In embryos cultured through the period of spinal neurulation, incorporation of labelled thymidine and adenine into genomic DNA was suppressed by supplemental formate, suggesting that de novo folate-dependent biosynthesis of nucleotides (thymidylate and purines) was enhanced. We hypothesise that reduced Mthfd1L expression may contribute to susceptibility to NTDs in the curly tail strain and that formate acts as a one-carbon donor to prevent NTDs. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Chaotic diagonal recurrent neural network

    International Nuclear Information System (INIS)

    Wang Xing-Yuan; Zhang Yi

    2012-01-01

    We propose a novel neural network based on a diagonal recurrent neural network and chaos, and its structure and learning algorithm are designed. The multilayer feedforward neural network, diagonal recurrent neural network, and chaotic diagonal recurrent neural network are used to approach the cubic symmetry map. The simulation results show that the approximation capability of the chaotic diagonal recurrent neural network is better than the other two neural networks. (interdisciplinary physics and related areas of science and technology)

  17. Computational modeling of neural plasticity for self-organization of neural networks.

    Science.gov (United States)

    Chrol-Cannon, Joseph; Jin, Yaochu

    2014-11-01

    Self-organization in biological nervous systems during the lifetime is known to largely occur through a process of plasticity that is dependent upon the spike-timing activity in connected neurons. In the field of computational neuroscience, much effort has been dedicated to building up computational models of neural plasticity to replicate experimental data. Most recently, increasing attention has been paid to understanding the role of neural plasticity in functional and structural neural self-organization, as well as its influence on the learning performance of neural networks for accomplishing machine learning tasks such as classification and regression. Although many ideas and hypothesis have been suggested, the relationship between the structure, dynamics and learning performance of neural networks remains elusive. The purpose of this article is to review the most important computational models for neural plasticity and discuss various ideas about neural plasticity's role. Finally, we suggest a few promising research directions, in particular those along the line that combines findings in computational neuroscience and systems biology, and their synergetic roles in understanding learning, memory and cognition, thereby bridging the gap between computational neuroscience, systems biology and computational intelligence. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

    Science.gov (United States)

    Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

    2015-01-01

    The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  19. Optimization of the virtual mouse HeadMouse to foster its classroom use by children with physical disabilities

    Directory of Open Access Journals (Sweden)

    Merce TEIXIDO

    2014-03-01

    Full Text Available This paper presents the optimization of a virtual mouse called HeadMouse in order to foster its classroom use by children with physical disabilities. HeadMouse is an absolute virtual mouse that converts head movements in cursor displacement and facial gestures in click actions. The virtual mouse combines different image processing algorithms: face detection, pattern matching and optical flow in order to emulate the behaviour of a conventional computer mouse. The original implementation of HeadMouse requires large computational power and this paper proposes specific optimizations in order to enable its use by children with disabilities in standard low cost classroom computers.

  20. Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia

    Science.gov (United States)

    Ferland, Russell J.; Batiz, Luis Federico; Neal, Jason; Lian, Gewei; Bundock, Elizabeth; Lu, Jie; Hsiao, Yi-Chun; Diamond, Rachel; Mei, Davide; Banham, Alison H.; Brown, Philip J.; Vanderburg, Charles R.; Joseph, Jeffrey; Hecht, Jonathan L.; Folkerth, Rebecca; Guerrini, Renzo; Walsh, Christopher A.; Rodriguez, Esteban M.; Sheen, Volney L.

    2009-01-01

    Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in ‘Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'. Neuron, 21, 1315–1325, 1998; Sheen et al. in ‘Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex'. Nat. Genet., 36, 69–76, 2004). Recent studies have shown that mutations in mitogen-activated protein kinase kinase kinase-4 (Mekk4), an indirect interactor with FlnA, also lead to periventricular nodule formation in mice (Sarkisian et al. in ‘MEKK4 signaling regulates filamin expression and neuronal migration'. Neuron, 52, 789–801, 2006). Here we show that neurons in post-mortem human PH brains migrated appropriately into the cortex, that periventricular nodules were primarily composed of later-born neurons, and that the neuroependyma was disrupted in all PH cases. As studied in the mouse, loss of FlnA or Big2 function in neural precursors impaired neuronal migration from the germinal zone, disrupted cell adhesion and compromised neuroepithelial integrity. Finally, the hydrocephalus with hop gait (hyh) mouse, which harbors a mutation in Napa [encoding N-ethylmaleimide-sensitive factor attachment protein alpha (α-SNAP)], also develops a progressive denudation of the neuroepithelium, leading to periventicular nodule formation. Previous studies have shown that Arfgef2 and Napa direct vesicle trafficking and fusion, whereas FlnA associates dynamically with the Golgi membranes during budding and trafficking of transport vesicles. Our current findings suggest that PH formation arises from a final common pathway involving disruption of vesicle trafficking, leading to impaired cell

  1. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development.

    Directory of Open Access Journals (Sweden)

    Karl B Shpargel

    2012-09-01

    Full Text Available UTX (KDM6A and UTY are homologous X and Y chromosome members of the Histone H3 Lysine 27 (H3K27 demethylase gene family. UTX can demethylate H3K27; however, in vitro assays suggest that human UTY has lost enzymatic activity due to sequence divergence. We produced mouse mutations in both Utx and Uty. Homozygous Utx mutant female embryos are mid-gestational lethal with defects in neural tube, yolk sac, and cardiac development. We demonstrate that mouse UTY is devoid of in vivo demethylase activity, so hemizygous X(Utx- Y(+ mutant male embryos should phenocopy homozygous X(Utx- X(Utx- females. However, X(Utx- Y(+ mutant male embryos develop to term; although runted, approximately 25% survive postnatally reaching adulthood. Hemizygous X(+ Y(Uty- mutant males are viable. In contrast, compound hemizygous X(Utx- Y(Uty- males phenocopy homozygous X(Utx- X(Utx- females. Therefore, despite divergence of UTX and UTY in catalyzing H3K27 demethylation, they maintain functional redundancy during embryonic development. Our data suggest that UTX and UTY are able to regulate gene activity through demethylase independent mechanisms. We conclude that UTX H3K27 demethylation is non-essential for embryonic viability.

  2. Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis.

    Science.gov (United States)

    Saito, Kanako; Dubreuil, Veronique; Arai, Yoko; Wilsch-Bräuninger, Michaela; Schwudke, Dominik; Saher, Gesine; Miyata, Takaki; Breier, Georg; Thiele, Christoph; Shevchenko, Andrej; Nave, Klaus-Armin; Huttner, Wieland B

    2009-05-19

    Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain, the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed. Here we have conditionally ablated the activity of squalene synthase (SQS), a key enzyme for endogenous cholesterol production, in the neural stem and progenitor cells of the ventricular zone (VZ) of the embryonic mouse brain. Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers, and died at birth. Analyses of the E11.5-E15.5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons, implying that this progeny of the SQS-ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival. Interestingly, the neural stem and progenitor cells of the VZ, the primary target of SQS inactivation, did not undergo significant apoptosis. Instead, vascular endothelial growth factor (VEGF) expression in these cells was strongly upregulated via a hypoxia-inducible factor-1-independent pathway, and angiogenesis in the VZ was increased. Consistent with an increased supply of lipoproteins to these cells, the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated. Our study establishes a direct link between intracellular cholesterol levels, VEGF expression, and angiogenesis. Moreover, our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis.

  3. Visual pigment coexpression in all cones of two rodents, the Siberian hamster, and the pouched mouse.

    Science.gov (United States)

    Lukáts, Akos; Dkhissi-Benyahya, Ouria; Szepessy, Zsuzsanna; Röhlich, Pál; Vígh, Béla; Bennett, Nigel C; Cooper, Howard M; Szél, Agoston

    2002-07-01

    To decide whether the identical topography of short- and middle-wavelength cone photoreceptors in two species of rodents reflects the presence of both opsins in all cone cells. Double-label immunocytochemistry using antibodies directed against short-wavelength (S)-and middle- to long-wavelength (M/L)-sensitive opsin were used to determine the presence of visual pigments in cones of two species of rodents, the Siberian hamster (Phodopus sungorus) and the pouched mouse (Saccostomus campestris) from South Africa. Topographical distribution was determined from retinal whole-mounts, and the colocalization of visual pigments was examined using confocal laser scanning microscopy. Opsin colocalization was also confirmed in consecutive semithin tangential sections. The immunocytochemical results demonstrate that in both the Siberian hamster and the pouched mouse all retinal cones contain two visual pigments. No dorsoventral gradient in the differential expression of the two opsins is observed. The retina of the Siberian hamster and the pouched mouse is the first example to show a uniform coexpression of M and S cone opsins in all cones, without any topographical gradient in opsin expression. This finding makes these two species good models for the study of molecular control mechanisms in opsin coexpression in rodents, and renders them suitable as sources of dual cones for future investigations on the role and neural connections of this cone type.

  4. Neural Parallel Engine: A toolbox for massively parallel neural signal processing.

    Science.gov (United States)

    Tam, Wing-Kin; Yang, Zhi

    2018-05-01

    Large-scale neural recordings provide detailed information on neuronal activities and can help elicit the underlying neural mechanisms of the brain. However, the computational burden is also formidable when we try to process the huge data stream generated by such recordings. In this study, we report the development of Neural Parallel Engine (NPE), a toolbox for massively parallel neural signal processing on graphical processing units (GPUs). It offers a selection of the most commonly used routines in neural signal processing such as spike detection and spike sorting, including advanced algorithms such as exponential-component-power-component (EC-PC) spike detection and binary pursuit spike sorting. We also propose a new method for detecting peaks in parallel through a parallel compact operation. Our toolbox is able to offer a 5× to 110× speedup compared with its CPU counterparts depending on the algorithms. A user-friendly MATLAB interface is provided to allow easy integration of the toolbox into existing workflows. Previous efforts on GPU neural signal processing only focus on a few rudimentary algorithms, are not well-optimized and often do not provide a user-friendly programming interface to fit into existing workflows. There is a strong need for a comprehensive toolbox for massively parallel neural signal processing. A new toolbox for massively parallel neural signal processing has been created. It can offer significant speedup in processing signals from large-scale recordings up to thousands of channels. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Neural chips, neural computers and application in high and superhigh energy physics experiments

    International Nuclear Information System (INIS)

    Nikityuk, N.M.; )

    2001-01-01

    Architecture peculiarity and characteristics of series of neural chips and neural computes used in scientific instruments are considered. Tendency of development and use of them in high energy and superhigh energy physics experiments are described. Comparative data which characterize the efficient use of neural chips for useful event selection, classification elementary particles, reconstruction of tracks of charged particles and for search of hypothesis Higgs particles are given. The characteristics of native neural chips and accelerated neural boards are considered [ru

  6. Closed-Loop Real-Time Imaging Enables Fully Automated Cell-Targeted Patch-Clamp Neural Recording In Vivo.

    Science.gov (United States)

    Suk, Ho-Jun; van Welie, Ingrid; Kodandaramaiah, Suhasa B; Allen, Brian; Forest, Craig R; Boyden, Edward S

    2017-08-30

    Targeted patch-clamp recording is a powerful method for characterizing visually identified cells in intact neural circuits, but it requires skill to perform. We previously developed an algorithm that automates "blind" patching in vivo, but full automation of visually guided, targeted in vivo patching has not been demonstrated, with currently available approaches requiring human intervention to compensate for cell movement as a patch pipette approaches a targeted neuron. Here we present a closed-loop real-time imaging strategy that automatically compensates for cell movement by tracking cell position and adjusting pipette motion while approaching a target. We demonstrate our system's ability to adaptively patch, under continuous two-photon imaging and real-time analysis, fluorophore-expressing neurons of multiple types in the living mouse cortex, without human intervention, with yields comparable to skilled human experimenters. Our "imagepatching" robot is easy to implement and will help enable scalable characterization of identified cell types in intact neural circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Synergic Functions of miRNAs Determine Neuronal Fate of Adult Neural Stem Cells

    Directory of Open Access Journals (Sweden)

    Meritxell Pons-Espinal

    2017-04-01

    Full Text Available Summary: Adult neurogenesis requires the precise control of neuronal versus astrocyte lineage determination in neural stem cells. While microRNAs (miRNAs are critically involved in this step during development, their actions in adult hippocampal neural stem cells (aNSCs has been unclear. As entry point to address that question we chose DICER, an endoribonuclease essential for miRNA biogenesis and other RNAi-related processes. By specific ablation of Dicer in aNSCs in vivo and in vitro, we demonstrate that miRNAs are required for the generation of new neurons, but not astrocytes, in the adult murine hippocampus. Moreover, we identify 11 miRNAs, of which 9 have not been previously characterized in neurogenesis, that determine neurogenic lineage fate choice of aNSCs at the expense of astrogliogenesis. Finally, we propose that the 11 miRNAs sustain adult hippocampal neurogenesis through synergistic modulation of 26 putative targets from different pathways. : In this article, the authors demonstrate that Dicer-dependent miRNAs are required for the generation of new neurons, but not astrocytes, in the adult hippocampus in vivo and in vitro. The authors identify a new set of 11 miRNAs that synergistically converge on multiple targets in different pathways to sustain neurogenic lineage fate commitment in aNSCs. Keywords: mouse, hippocampus, neural stem cells, fate choice, adult neurogenesis, astrogliogenesis, DICER, microRNAs, synergy

  8. Neural tissue-spheres

    DEFF Research Database (Denmark)

    Andersen, Rikke K; Johansen, Mathias; Blaabjerg, Morten

    2007-01-01

    By combining new and established protocols we have developed a procedure for isolation and propagation of neural precursor cells from the forebrain subventricular zone (SVZ) of newborn rats. Small tissue blocks of the SVZ were dissected and propagated en bloc as free-floating neural tissue...... content, thus allowing experimental studies of neural precursor cells and their niche...

  9. Unpredictable chronic mild stress differentially impairs social and contextual discrimination learning in two inbred mouse strains.

    Science.gov (United States)

    van Boxelaere, Michiel; Clements, Jason; Callaerts, Patrick; D'Hooge, Rudi; Callaerts-Vegh, Zsuzsanna

    2017-01-01

    Alterations in the social and cognitive domain are considered important indicators for increased disability in many stress-related disorders. Similar impairments have been observed in rodents chronically exposed to stress, mimicking potential endophenotypes of stress-related psychopathologies such as major depression disorder (MDD), anxiety, conduct disorder, and posttraumatic stress disorder (PTSD). Data from numerous studies suggest that deficient plasticity mechanisms in hippocampus (HC) and prefrontal cortex (PFC) might underlie these social and cognitive deficits. Specifically, stress-induced deficiencies in neural plasticity have been associated with a hypodopaminergic state and reduced neural plasticity persistence. Here we assessed the effects of unpredictable chronic mild stress (UCMS) on exploratory, social and cognitive behavior of females of two inbred mouse strains (C57BL/6J and DBA/2J) that differ in their dopaminergic profile. Exposure to chronic stress resulted in impaired circadian rhythmicity, sociability and social cognition in both inbred strains, but differentially affected activity patterns and contextual discrimination performance. These stress-induced behavioral impairments were accompanied by reduced expression levels of brain derived neurotrophic factor (BDNF) in the prefrontal cortex. The strain-specific cognitive impairment was coexistent with enhanced plasma corticosterone levels and reduced expression of genes related to dopamine signaling in hippocampus. These results underline the importance of assessing different strains with multiple test batteries to elucidate the neural and genetic basis of social and cognitive impairments related to chronic stress.

  10. Development of mPMab-1, a Mouse-Rat Chimeric Antibody Against Mouse Podoplanin.

    Science.gov (United States)

    Yamada, Shinji; Kaneko, Mika K; Nakamura, Takuro; Ichii, Osamu; Konnai, Satoru; Kato, Yukinari

    2017-04-01

    Podoplanin (PDPN), the ligand of C-type lectin-like receptor-2, is used as a lymphatic endothelial marker. We previously established clone PMab-1 of rat IgG 2a as a specific monoclonal antibody (mAb) against mouse PDPN. PMab-1 is also very sensitive in immunohistochemical analysis; however, rat mAbs seem to be unfavorable for pathologists because anti-mouse IgG and anti-rabbit IgG are usually used as secondary antibodies in commercially available kits for immunohistochemical analysis. In this study, we develop a mouse-rat chimeric antibody, mPMab-1 of mouse IgG 2a , which was derived from rat PMab-1 mAb. Immunohistochemical analysis shows that mPMab-1 detects podocytes of the kidney, lymphatic endothelial cells of the colon, and type I alveolar cells of the lung. Importantly, mPMab-1 is more sensitive than PMab-1. This conversion strategy from rat mAb to mouse mAb could be applicable to other mAbs.

  11. Gaze beats mouse

    DEFF Research Database (Denmark)

    Mateo, Julio C.; San Agustin, Javier; Hansen, John Paulin

    2008-01-01

    Facial EMG for selection is fast, easy and, combined with gaze pointing, it can provide completely hands-free interaction. In this pilot study, 5 participants performed a simple point-and-select task using mouse or gaze for pointing and a mouse button or a facial-EMG switch for selection. Gaze...

  12. Neuroprotective effect of the endogenous neural peptide apelin in cultured mouse cortical neurons

    International Nuclear Information System (INIS)

    Zeng, Xiang Jun; Yu, Shan Ping; Zhang, Like; Wei, Ling

    2010-01-01

    The adipocytokine apelin and its G protein-coupled APJ receptor were initially isolated from a bovine stomach and have been detected in the brain and cardiovascular system. Recent studies suggest that apelin can protect cardiomyocytes from ischemic injury. Here, we investigated the effect of apelin on apoptosis in mouse primary cultures of cortical neurons. Exposure of the cortical cultures to a serum-free medium for 24 h induced nuclear fragmentation and apoptotic death; apelin-13 (1.0-5.0 nM) markedly prevented the neuronal apoptosis. Apelin neuroprotective effects were mediated by multiple mechanisms. Apelin-13 reduced serum deprivation (SD)-induced ROS generation, mitochondria depolarization, cytochrome c release and activation of caspase-3. Apelin-13 prevented SD-induced changes in phosphorylation status of Akt and ERK1/2. In addition, apelin-13 attenuated NMDA-induced intracellular Ca 2+ accumulation. These results indicate that apelin is an endogenous neuroprotective adipocytokine that may block apoptosis and excitotoxic death via cellular and molecular mechanisms. It is suggested that apelins may be further explored as a potential neuroprotective reagent for ischemia-induced brain damage.

  13. Human neural progenitors derived from integration-free iPSCs for SCI therapy

    Directory of Open Access Journals (Sweden)

    Ying Liu

    2017-03-01

    Full Text Available As a potentially unlimited autologous cell source, patient induced pluripotent stem cells (iPSCs provide great capability for tissue regeneration, particularly in spinal cord injury (SCI. However, despite significant progress made in translation of iPSC-derived neural progenitor cells (NPCs to clinical settings, a few hurdles remain. Among them, non-invasive approach to obtain source cells in a timely manner, safer integration-free delivery of reprogramming factors, and purification of NPCs before transplantation are top priorities to overcome. In this study, we developed a safe and cost-effective pipeline to generate clinically relevant NPCs. We first isolated cells from patients' urine and reprogrammed them into iPSCs by non-integrating Sendai viral vectors, and carried out experiments on neural differentiation. NPCs were purified by A2B5, an antibody specifically recognizing a glycoganglioside on the cell surface of neural lineage cells, via fluorescence activated cell sorting. Upon further in vitro induction, NPCs were able to give rise to neurons, oligodendrocytes and astrocytes. To test the functionality of the A2B5+ NPCs, we grafted them into the contused mouse thoracic spinal cord. Eight weeks after transplantation, the grafted cells survived, integrated into the injured spinal cord, and differentiated into neurons and glia. Our specific focus on cell source, reprogramming, differentiation and purification method purposely addresses timing and safety issues of transplantation to SCI models. It is our belief that this work takes one step closer on using human iPSC derivatives to SCI clinical settings.

  14. Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.

    Directory of Open Access Journals (Sweden)

    Jan Tønnesen

    Full Text Available Intrastriatal grafts of stem cell-derived dopamine (DA neurons induce behavioral recovery in animal models of Parkinson's disease (PD, but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2 and halorhodopsin (NpHR, respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.

  15. Novel botanical drug DA-9803 prevents deficits in Alzheimer's mouse models.

    Science.gov (United States)

    Pagnier, Guillaume J; Kastanenka, Ksenia V; Sohn, Miwon; Choi, Sangzin; Choi, Song-Hyen; Soh, HyeYeon; Bacskai, Brian J

    2018-01-29

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by deposition of amyloid plaques and disruption of neural circuitry, leading to cognitive decline. Animal models of AD deposit senile plaques and exhibit structural and functional deficits in neurons and neural networks. An effective treatment would prevent or restore these deficits, including calcium dyshomeostasis observed with in-vivo imaging. We examined the effects of DA-9803, a multimodal botanical drug, in 5XFAD and APP/PS1 transgenic mice which underwent daily oral treatment with 30 or 100 mg/kg DA-9803 or vehicle alone. Behavioral testing and longitudinal imaging of amyloid deposits and intracellular calcium in neurons with multiphoton microscopy was performed. Chronic administration of DA-9803 restored behavioral deficits in 5XFAD mice and reduced amyloid-β levels. DA-9803 also prevented progressive amyloid plaque deposition in APP/PS1 mice. Elevated calcium, detected in a subset of neurons before the treatment, was restored and served as a functional indicator of treatment efficacy in addition to the behavioral readout. In contrast, mice treated with vehicle alone continued to progressively accumulate amyloid plaques and calcium overload. In summary, treatment with DA-9803 prevented structural and functional outcome measures in mouse models of AD. Thus, DA-9803 shows promise as a novel therapeutic approach for Alzheimer's disease.

  16. Conversion of Human Fibroblasts to Stably Self-Renewing Neural Stem Cells with a Single Zinc-Finger Transcription Factor

    Directory of Open Access Journals (Sweden)

    Ebrahim Shahbazi

    2016-04-01

    Full Text Available Direct conversion of somatic cells into neural stem cells (NSCs by defined factors holds great promise for mechanistic studies, drug screening, and potential cell therapies for different neurodegenerative diseases. Here, we report that a single zinc-finger transcription factor, Zfp521, is sufficient for direct conversion of human fibroblasts into long-term self-renewable and multipotent NSCs. In vitro, Zfp521-induced NSCs maintained their characteristics in the absence of exogenous factor expression and exhibited morphological, molecular, developmental, and functional properties that were similar to control NSCs. In addition, the single-seeded induced NSCs were able to form NSC colonies with efficiency comparable with control NSCs and expressed NSC markers. The converted cells were capable of surviving, migrating, and attaining neural phenotypes after transplantation into neonatal mouse and adult rat brains, without forming tumors. Moreover, the Zfp521-induced NSCs predominantly expressed rostral genes. Our results suggest a facilitated approach for establishing human NSCs through Zfp521-driven conversion of fibroblasts.

  17. Neural networks for aircraft control

    Science.gov (United States)

    Linse, Dennis

    1990-01-01

    Current research in Artificial Neural Networks indicates that networks offer some potential advantages in adaptation and fault tolerance. This research is directed at determining the possible applicability of neural networks to aircraft control. The first application will be to aircraft trim. Neural network node characteristics, network topology and operation, neural network learning and example histories using neighboring optimal control with a neural net are discussed.

  18. Differential distribution of cubilin and megalin expression in the mouse embryo.

    Science.gov (United States)

    Drake, Christopher J; Fleming, Paul A; Larue, Amanda C; Barth, Jeremy L; Chintalapudi, Mastan R; Argraves, W Scott

    2004-03-01

    Cubilin and megalin are cell surface proteins that work cooperatively in many absorptive epithelia to mediate endocytosis of lipoproteins, vitamin carriers, and other proteins. Here we have investigated the coordinate expression of these receptors during mouse development. Our findings indicate that while there are sites where the receptors are co-expressed, there are other tissues where expression is not overlapping. Apical cubilin expression is pronounced in the extraembryonic visceral endoderm (VE) of 6-9.5 days postcoitum (dpc) embryos. By contrast, little megalin expression is evident in the VE at 6 dpc. However, megalin expression in the VE increases as development progresses (7.5-9.5 dpc), although it is not as uniformly distributed as cubilin. Punctate expression of megalin is also apparent in the region of the ectoplacental cone associated with decidual cells, whereas cubilin expression is not seen in association with the ectoplacenta. Strong expression of megalin is observed in the neural ectoderm, neural plate and neural tube (6-8.5 dpc), but cubilin expression is not apparent in any of these tissues. At 8.5 dpc, megalin is expressed in the developing endothelial cells of blood islands, whereas cubilin is absent from these cells. Finally, cubilin, but not megalin, is expressed by a subpopulation of cells dispersed within the 7.5 dpc embryonic endoderm and having a migratory morphology. In summary, the co-expression of cubilin and megalin in the VE is consistent with the two proteins functioning jointly in this tissue. However, the differential distribution pattern indicates that the proteins also function independent of one another. Furthermore, the finding of megalin expression in blood island endothelial cells and cubilin expression in embryonic endoderm highlight potential new developmental roles for these proteins. Copyright 2004 Wiley-Liss, Inc.

  19. Region-specific RNA m6A methylation represents a new layer of control in the gene regulatory network in the mouse brain.

    Science.gov (United States)

    Chang, Mengqi; Lv, Hongyi; Zhang, Weilong; Ma, Chunhui; He, Xue; Zhao, Shunli; Zhang, Zhi-Wei; Zeng, Yi-Xin; Song, Shuhui; Niu, Yamei; Tong, Wei-Min

    2017-09-01

    N 6 -methyladenosine (m 6 A) is the most abundant epitranscriptomic mark found on mRNA and has important roles in various physiological processes. Despite the relatively high m 6 A levels in the brain, its potential functions in the brain remain largely unexplored. We performed a transcriptome-wide methylation analysis using the mouse brain to depict its region-specific methylation profile. RNA methylation levels in mouse cerebellum are generally higher than those in the cerebral cortex. Heterogeneity of RNA methylation exists across different brain regions and different types of neural cells including the mRNAs to be methylated, their methylation levels and methylation site selection. Common and region-specific methylation have different preferences for methylation site selection and thereby different impacts on their biological functions. In addition, high methylation levels of fragile X mental retardation protein (FMRP) target mRNAs suggest that m 6 A methylation is likely to be used for selective recognition of target mRNAs by FMRP in the synapse. Overall, we provide a region-specific map of RNA m 6 A methylation and characterize the distinct features of specific and common methylation in mouse cerebellum and cerebral cortex. Our results imply that RNA m 6 A methylation is a newly identified element in the region-specific gene regulatory network in the mouse brain. © 2017 The Authors.

  20. Circulating neural antibodies in unselected children with new-onset seizures.

    Science.gov (United States)

    Garcia-Tarodo, Stephanie; Datta, Alexandre N; Ramelli, Gian P; Maréchal-Rouiller, Fabienne; Bien, Christian G; Korff, Christian M

    2018-05-01

    The role of autoimmunity and neural antibodies is increasingly recognized in different forms of seizures and epilepsy. Their prevalence in new-onset epilepsy has also recently been the focus of several clinical cohorts in the adult and pediatric population, with positive titers in 10-11% of cases. Our aim was to determine the seropositivity at the first seizure onset in a non-selective group of children. We conducted a prospective multicenter cohort study recruiting children aged 0-16 years with new-onset seizures presenting at the In- and Outpatient Pediatric Neurology Departments of three Children's Hospitals in Switzerland between September 2013 and April 2016. Neural antibodies were screened within the first 6 months of a first seizure and when positive, repeated at 1 month and 6 months follow-up. A total of 103 children were enrolled with a mean age at presentation of 5 years (range 1 day-15 years 9 months). The majority (n = 75) presented with generalized seizures and 6 had status epilepticus lasting > 30 min. At the time of onset, 55% of patients had fever, 24% required emergency seizure treatment and 27% hospitalization. Epilepsy was diagnosed at follow-up in 18%. No specific antibody was found. Serum antibodies against the VGKC complex, without binding to the specific antigens LGI1 and CASPR2, were found in two patients. Four patients harbored not otherwise characterized antibodies against mouse neuropil. Specific neural antibodies are rarely found in an unselected population of children that present with a first seizure. Applying an extensive neuronal antibody profile in a child with new-onset seizures does not appear to be justified. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  1. Biophysical characteristics reveal neural stem cell differentiation potential.

    Directory of Open Access Journals (Sweden)

    Fatima H Labeed

    Full Text Available Distinguishing human neural stem/progenitor cell (huNSPC populations that will predominantly generate neurons from those that produce glia is currently hampered by a lack of sufficient cell type-specific surface markers predictive of fate potential. This limits investigation of lineage-biased progenitors and their potential use as therapeutic agents. A live-cell biophysical and label-free measure of fate potential would solve this problem by obviating the need for specific cell surface markers.We used dielectrophoresis (DEP to analyze the biophysical, specifically electrophysiological, properties of cortical human and mouse NSPCs that vary in differentiation potential. Our data demonstrate that the electrophysiological property membrane capacitance inversely correlates with the neurogenic potential of NSPCs. Furthermore, as huNSPCs are continually passaged they decrease neuron generation and increase membrane capacitance, confirming that this parameter dynamically predicts and negatively correlates with neurogenic potential. In contrast, differences in membrane conductance between NSPCs do not consistently correlate with the ability of the cells to generate neurons. DEP crossover frequency, which is a quantitative measure of cell behavior in DEP, directly correlates with neuron generation of NSPCs, indicating a potential mechanism to separate stem cells biased to particular differentiated cell fates.We show here that whole cell membrane capacitance, but not membrane conductance, reflects and predicts the neurogenic potential of human and mouse NSPCs. Stem cell biophysical characteristics therefore provide a completely novel and quantitative measure of stem cell fate potential and a label-free means to identify neuron- or glial-biased progenitors.

  2. The Neural Border: Induction, Specification and Maturation of the territory that generates Neural Crest cells.

    Science.gov (United States)

    Pla, Patrick; Monsoro-Burq, Anne H

    2018-05-28

    The neural crest is induced at the edge between the neural plate and the nonneural ectoderm, in an area called the neural (plate) border, during gastrulation and neurulation. In recent years, many studies have explored how this domain is patterned, and how the neural crest is induced within this territory, that also participates to the prospective dorsal neural tube, the dorsalmost nonneural ectoderm, as well as placode derivatives in the anterior area. This review highlights the tissue interactions, the cell-cell signaling and the molecular mechanisms involved in this dynamic spatiotemporal patterning, resulting in the induction of the premigratory neural crest. Collectively, these studies allow building a complex neural border and early neural crest gene regulatory network, mostly composed by transcriptional regulations but also, more recently, including novel signaling interactions. Copyright © 2018. Published by Elsevier Inc.

  3. Assessment of plasminogen synthesis in vitro by mouse tumor cells using a competition radioimmunoassay for mouse plasminogen

    International Nuclear Information System (INIS)

    Roblin, R.O.; Bell, T.E.; Young, P.L.

    1978-01-01

    A sensitive, specific competition radioimmunoassay for mouse plasmin(ogen) has been developed in order to determine whether mouse tumor cells can synthesize plasminogen in vitro. The rabbit anti-BALB/c mouse plasminogen antibodies used in the assay react with the plasminogen present in serum from BALB/c, C3H, AKR and C57BL/6 mice, and also recognized mouse plasmin. The competition radiommunoassay can detect as little as 50 ng of mouse plasminogen. No competition was observed with preparations of fetal calf, human and rabbit plasminogens. A variety of virus-transformed and mouse tumor cell lines were all found to contain less than 100 ng mouse plasminogen/mg of cell extract protein. Thus, if the plasminogen activator/plasmin system is important in the growth or movement of this group of tumor cells, the cells will be dependent upon the circulatory system of the host for their plasminogen supply. (Auth.)

  4. Structural organization and chromosomal assignment of the mouse embryonic TEA domain-containing factor (ETF) gene.

    Science.gov (United States)

    Suzuki, K; Yasunami, M; Matsuda, Y; Maeda, T; Kobayashi, H; Terasaki, H; Ohkubo, H

    1996-09-01

    Embryonic TEA domain-containing factor (ETF) belongs to the family of proteins structurally related to transcriptional enhancer factor-1 (TEF-1) and is implicated in neural development. Isolation and characterization of the cosmid clones encoding the mouse ETF gene (Etdf) revealed that Etdf spans approximately 17.9 kb and consists of 12 exons. The exon-intron structure of Etdf closely resembles that of the Drosophila scalloped gene, indicating that these genes may have evolved from a common ancestor. The multiple transcription initiation sites revealed by S1 protection and primer extension analyses are consistent with the absence of the canonical TATA and CAAT boxes in the 5'-flanking region, which contains many potential regulatory sequences, such as the E-box, N-box, Sp1 element, GATA-1 element, TAATGARAT element, and B2 short interspersed element (SINE) as well as several direct and inverted repeat sequences. The Etdf locus was assigned to the proximal region of mouse chromosome 7 using fluorescence in situ hybridization and linkage mapping analyses. These results provide the molecular basis for studying the regulation, in vivo function, and evolution of Etdf.

  5. Mouse Rad9b is essential for embryonic development and promotes resistance to DNA damage

    Science.gov (United States)

    Leloup, Corinne; Hopkins, Kevin M.; Wang, Xiangyuan; Zhu, Aiping; Wolgemuth, Debra J.; Lieberman, Howard B.

    2010-01-01

    RAD9 participates in promoting resistance to DNA damage, cell cycle checkpoint control, DNA repair, apoptosis, embryogenesis, and regulation of transcription. A paralogue of RAD9 (named RAD9B) has been identified. To define the function of mouse Rad9b (Mrad9b), embryonic stem (ES) cells with a targeted gene deletion were constructed and used to generate Mrad9b mutant mice. Mrad9b−/− embryos are resorbed after E7.5 while some of the heterozygotes die between E12.5 and a few days after birth. Mrad9b is expressed in embryonic brain and Mrad9b+/− embryos exhibit abnormal neural tube closure. Mrad9b−/− mouse embryonic fibroblasts are not viable. Mrad9b−/− ES cells are more sensitive to gamma rays and mitomycin C than Mrad9b+/+ controls, but show normal gamma-ray-induced G2/M checkpoint control. There is no evidence of spontaneous genomic instability in Mrad9b−/− cells. Our findings thus indicate that Mrad9b is essential for embryonic development and mediates resistance to certain DNA damaging agents. PMID:20842695

  6. Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3.

    Science.gov (United States)

    Ting, Stephen B; Wilanowski, Tomasz; Auden, Alana; Hall, Mark; Voss, Anne K; Thomas, Tim; Parekh, Vishwas; Cunningham, John M; Jane, Stephen M

    2003-12-01

    The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype. The NTDs in Grhl3-null mice are more severe than those in the curly tail strain, as the Grhl3 alleles in ct/ct mice are hypomorphic. Spina bifida in ct/ct mice is folate resistant, but its incidence can be markedly reduced by maternal inositol supplementation periconceptually. The NTDs in Grhl3-/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol. These findings suggest that residual Grhl3 expression in ct/ct mice may be required for inositol rescue of folate-resistant NTDs.

  7. Nigral dopaminergic neuron replenishment in adult mice through VE-cadherin-expressing neural progenitor cells

    Directory of Open Access Journals (Sweden)

    Abir A Rahman

    2017-01-01

    Full Text Available The function of dopaminergic neurons in the substantia nigra is of central importance to the coordination of movement by the brain's basal ganglia circuitry. This is evidenced by the loss of these neurons, resulting in the cardinal motor deficits associated with Parkinson's disease. In order to fully understand the physiology of these key neurons and develop potential therapies for their loss, it is essential to determine if and how dopaminergic neurons are replenished in the adult brain. Recent work has presented evidence for adult neurogenesis of these neurons by Nestin+/Sox2– neural progenitor cells. We sought to further validate this finding and explore a potential atypical origin for these progenitor cells. Since neural progenitor cells have a proximal association with the vasculature of the brain and subsets of endothelial cells are Nestin+, we hypothesized that dopaminergic neural progenitors might share a common cell lineage. Therefore, we employed a VE-cadherin promoter-driven CREERT2:THlox/THlox transgenic mouse line to ablate the tyrosine hydroxylase gene from endothelial cells in adult animals. After 26 weeks, but not 13 weeks, following the genetic blockade of tyrosine hydroxylase expression in VE-cadherin+ cells, we observed a significant reduction in tyrosine hydroxylase+ neurons in the substantia nigra. The results from this genetic lineage tracing study suggest that dopaminergic neurons are replenished in adult mice by a VE-cadherin+ progenitor cell population potentially arising from an endothelial lineage.

  8. Early life stress accelerates behavioral and neural maturation of the hippocampus in male mice.

    Science.gov (United States)

    Bath, K; Manzano-Nieves, G; Goodwill, H

    2016-06-01

    Early life stress (ELS) increases the risk for later cognitive and emotional dysfunction. ELS is known to truncate neural development through effects on suppressing cell birth, increasing cell death, and altering neuronal morphology, effects that have been associated with behavioral profiles indicative of precocious maturation. However, how earlier silencing of growth drives accelerated behavioral maturation has remained puzzling. Here, we test the novel hypothesis that, ELS drives a switch from growth to maturation to accelerate neural and behavioral development. To test this, we used a mouse model of ELS, fragmented maternal care, and a cross-sectional dense sampling approach focusing on hippocampus and measured effects of ELS on the ontogeny of behavioral development and biomarkers of neural maturation. Consistent with previous work, ELS was associated with an earlier developmental decline in expression of markers of cell proliferation (Ki-67) and differentiation (doublecortin). However, ELS also led to a precocious arrival of Parvalbumin-positive cells, led to an earlier switch in NMDA receptor subunit expression (marker of synaptic maturity), and was associated with an earlier rise in myelin basic protein expression (key component of the myelin sheath). In addition, in a contextual fear-conditioning task, ELS accelerated the timed developmental suppression of contextual fear. Together, these data provide support for the hypothesis that ELS serves to switch neurodevelopment from processes of growth to maturation and promotes accelerated development of some forms of emotional learning. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Neutralization of LINGO-1 during in vitro differentiation of neural stem cells results in proliferation of immature neurons.

    Directory of Open Access Journals (Sweden)

    Camilla Lööv

    Full Text Available Identifying external factors that can be used to control neural stem cells division and their differentiation to neurons, astrocytes and oligodendrocytes is of high scientific and clinical interest. Here we show that the Nogo-66 receptor interacting protein LINGO-1 is a potent regulator of neural stem cell maturation to neurons. LINGO-1 is expressed by cortical neural stem cells from E14 mouse embryos and inhibition of LINGO-1 during the first days of neural stem cell differentiation results in decreased neuronal maturation. Compared to neurons in control cultures, which after 6 days of differentiation have long extending neurites, neurons in cultures treated with anti-LINGO-1 antibodies retain an immature, round phenotype with only very short processes. Furthermore, neutralization of LINGO-1 results in a threefold increase in βIII tubulin-positive cells compared to untreated control cultures. By using BrdU incorporation assays we show that the immature neurons in LINGO-1 neutralized cultures are dividing neuroblasts. In contrast to control cultures, in which no cells were double positive for βIII tubulin and BrdU, 36% of the neurons in cultures treated with anti-LINGO-1 antibodies were proliferating after three days of differentiation. TUNEL assays revealed that the amount of cells going through apoptosis during the early phase of differentiation was significantly decreased in cultures treated with anti-LINGO-1 antibodies compared to untreated control cultures. Taken together, our results demonstrate a novel role for LINGO-1 in neural stem cell differentiation to neurons and suggest a possibility to use LINGO-1 inhibitors to compensate for neuronal cell loss in the injured brain.

  10. Neural network regulation driven by autonomous neural firings

    Science.gov (United States)

    Cho, Myoung Won

    2016-07-01

    Biological neurons naturally fire spontaneously due to the existence of a noisy current. Such autonomous firings may provide a driving force for network formation because synaptic connections can be modified due to neural firings. Here, we study the effect of autonomous firings on network formation. For the temporally asymmetric Hebbian learning, bidirectional connections lose their balance easily and become unidirectional ones. Defining the difference between reciprocal connections as new variables, we could express the learning dynamics as if Ising model spins interact with each other in magnetism. We present a theoretical method to estimate the interaction between the new variables in a neural system. We apply the method to some network systems and find some tendencies of autonomous neural network regulation.

  11. The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

    Science.gov (United States)

    Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

    2017-11-01

    Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

  12. Dynamics of neural cryptography.

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

    2007-05-01

    Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible.

  13. Dynamics of neural cryptography

    International Nuclear Information System (INIS)

    Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

    2007-01-01

    Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible

  14. Dynamics of neural cryptography

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

    2007-05-01

    Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible.

  15. Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis

    KAUST Repository

    Merzaban, Jasmeen S.

    2015-09-13

    Neural stem cell (NSC)-based therapies offer potential for neural repair in central nervous system (CNS) inflammatory and degenerative disorders. Typically, these conditions present with multifocal CNS lesions making it impractical to inject NSCs locally, thus mandating optimization of vascular delivery of the cells to involved sites. Here, we analyzed NSCs for expression of molecular effectors of cell migration and found that these cells are natively devoid of E-selectin ligands. Using glycosyltransferase-programmed stereosubstitution (GPS), we glycan engineered the cell surface of NSCs ("GPS-NSCs") with resultant enforced expression of the potent E-selectin ligand HCELL (hematopoietic cell E-/L-selectin ligand) and of an E-selectin-binding glycoform of neural cell adhesion molecule ("NCAM-E"). Following intravenous (i.v.) injection, short-term homing studies demonstrated that, compared with buffer-treated (control) NSCs, GPS-NSCs showed greater neurotropism. Administration of GPS-NSC significantly attenuated the clinical course of experimental autoimmune encephalomyelitis (EAE), with markedly decreased inflammation and improved oligodendroglial and axonal integrity, but without evidence of long-term stem cell engraftment. Notably, this effect of NSC is not a universal property of adult stem cells, as administration of GPS-engineered mouse hematopoietic stem/progenitor cells did not improve EAE clinical course. These findings highlight the utility of cell surface glycan engineering to boost stem cell delivery in neuroinflammatory conditions and indicate that, despite the use of a neural tissue-specific progenitor cell population, neural repair in EAE results from endogenous repair and not from direct, NSC-derived cell replacement.

  16. Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia

    Science.gov (United States)

    Crabtree, Gregg W.; Gogos, Joseph A.

    2014-01-01

    Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations. PMID:25505409

  17. Bioprinting for Neural Tissue Engineering.

    Science.gov (United States)

    Knowlton, Stephanie; Anand, Shivesh; Shah, Twisha; Tasoglu, Savas

    2018-01-01

    Bioprinting is a method by which a cell-encapsulating bioink is patterned to create complex tissue architectures. Given the potential impact of this technology on neural research, we review the current state-of-the-art approaches for bioprinting neural tissues. While 2D neural cultures are ubiquitous for studying neural cells, 3D cultures can more accurately replicate the microenvironment of neural tissues. By bioprinting neuronal constructs, one can precisely control the microenvironment by specifically formulating the bioink for neural tissues, and by spatially patterning cell types and scaffold properties in three dimensions. We review a range of bioprinted neural tissue models and discuss how they can be used to observe how neurons behave, understand disease processes, develop new therapies and, ultimately, design replacement tissues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Dose-response relationship of cadmium or radiation-induced embryotoxicity in mouse whole embryo culture

    International Nuclear Information System (INIS)

    Nakashima, Kiyohito; Kawamata, Akitoshi; Matsuoka, Masato; Wakisaka, Takashi; Fujiki, Yoshishige

    1988-01-01

    Mouse embryos of B6C3F 1 strain were exposed in vitro to 1.2 to 2.2 μM cadmium chloride (Cd) or to 100 to 320 R x-rays, and the effects of the exposure on development were examined after 39 h of culture. Development of embryos was assessed from lethality, formation of the neural tube defect, diameter and protein of yolk sac, crown-rump and head lengths, embryonic protein, and number of somites. Incidence of the neural tube defect increased from 3.4 to 100% by 1.2 to 2.0 μM Cd, while embryo deaths increased from 13.8 to 93.3% by 2.0 to 2.2 μM Cd. Embryonic protein was significantly reduced at the teratogenic range, but the number of somites was only affected by 1.6 to 2.0 μM Cd. X-irradiation at 100 to 320 R induced the neural tube defect in 2.9 to 72.7% of the embryos. An embryolethal effect was observed only at the 320 R dose. Crown-rump and head lengths and embryonic protein were significantly affected at the teratogenic range, but the diameter and protein of yolk sac and number of somites were hardly affected. Cadmium- or radiation-induced response data of both teratogenicity and endpoints indicating inhibition of embryonic development were acceptably fitted to a linear log-probit regression. These regressions suggest that as an estimation of interference in development of embryos, embryonic protein and head length are sensitive endpoints while the number of somites is an insensitive criterion. (author)

  19. Optimization of a GCaMP calcium indicator for neural activity imaging.

    Science.gov (United States)

    Akerboom, Jasper; Chen, Tsai-Wen; Wardill, Trevor J; Tian, Lin; Marvin, Jonathan S; Mutlu, Sevinç; Calderón, Nicole Carreras; Esposti, Federico; Borghuis, Bart G; Sun, Xiaonan Richard; Gordus, Andrew; Orger, Michael B; Portugues, Ruben; Engert, Florian; Macklin, John J; Filosa, Alessandro; Aggarwal, Aman; Kerr, Rex A; Takagi, Ryousuke; Kracun, Sebastian; Shigetomi, Eiji; Khakh, Baljit S; Baier, Herwig; Lagnado, Leon; Wang, Samuel S-H; Bargmann, Cornelia I; Kimmel, Bruce E; Jayaraman, Vivek; Svoboda, Karel; Kim, Douglas S; Schreiter, Eric R; Looger, Loren L

    2012-10-03

    Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Recent efforts in protein engineering have significantly increased the performance of GECIs. The state-of-the art single-wavelength GECI, GCaMP3, has been deployed in a number of model organisms and can reliably detect three or more action potentials in short bursts in several systems in vivo. Through protein structure determination, targeted mutagenesis, high-throughput screening, and a battery of in vitro assays, we have increased the dynamic range of GCaMP3 by severalfold, creating a family of "GCaMP5" sensors. We tested GCaMP5s in several systems: cultured neurons and astrocytes, mouse retina, and in vivo in Caenorhabditis chemosensory neurons, Drosophila larval neuromuscular junction and adult antennal lobe, zebrafish retina and tectum, and mouse visual cortex. Signal-to-noise ratio was improved by at least 2- to 3-fold. In the visual cortex, two GCaMP5 variants detected twice as many visual stimulus-responsive cells as GCaMP3. By combining in vivo imaging with electrophysiology we show that GCaMP5 fluorescence provides a more reliable measure of neuronal activity than its predecessor GCaMP3. GCaMP5 allows more sensitive detection of neural activity in vivo and may find widespread applications for cellular imaging in general.

  20. AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy.

    Science.gov (United States)

    Morabito, Giuseppe; Giannelli, Serena G; Ordazzo, Gabriele; Bido, Simone; Castoldi, Valerio; Indrigo, Marzia; Cabassi, Tommaso; Cattaneo, Stefano; Luoni, Mirko; Cancellieri, Cinzia; Sessa, Alessandro; Bacigaluppi, Marco; Taverna, Stefano; Leocani, Letizia; Lanciego, José L; Broccoli, Vania

    2017-12-06

    The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern. We then established multiple procedures of viral transduction to control gene expression or inactivate gene function exclusively in the adult nervous system and assessed the underlying behavioral effects. Building on these results, we established an effective gene therapy strategy to counteract the widespread accumulation of α-synuclein deposits throughout the forebrain in a mouse model of synucleinopathy. Transduction of A53T-SCNA transgenic mice with AAV-PHP.B-GBA1 restored physiological levels of the enzyme, reduced α-synuclein pathology, and produced significant behavioral recovery. Finally, we provided evidence that AAV-PHP.B brain penetration does not lead to evident dysfunctions in blood-brain barrier integrity or permeability. Altogether, the AAV-PHP.B viral platform enables non-invasive, widespread, and long-lasting global neural expression of therapeutic genes, such as GBA1, providing an invaluable approach to treat neurodegenerative diseases with diffuse brain pathology such as synucleinopathies. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  1. The Effect of Agmatine on Expression of IL-1β and TLX Which Promotes Neuronal Differentiation in Lipopolysaccharide-Treated Neural Progenitors.

    Science.gov (United States)

    Song, Juhyun; Kumar, Bokara Kiran; Kang, Somang; Park, Kyung Ah; Lee, Won Taek; Lee, Jong Eun

    2013-12-01

    Differentiation of neural progenitor cells (NPCs) is important for protecting neural cells and brain tissue during inflammation. Interleukin-1 beta (IL-1β) is the most common pro- inflammatory cytokine in brain inflammation, and increased IL-1β levels can decrease the proliferation of NPCs. We aimed to investigate whether agmatine (Agm), a primary polyamine that protects neural cells, could trigger differentiation of NPCs by activating IL-1β in vitro. The cortex of ICR mouse embryos (E14) was dissociated to culture NPCs. NPCs were stimulated by lipopolysaccharide (LPS). After 6 days, protein expression of stem cell markers and differentiation signal factors was confirmed by using western blot analysis. Also, immunocytochemistry was used to confirm the cell fate. Agm treatment activated NPC differentiation significantly more than in the control group, which was evident by the increased expression of a neuronal marker, MAP2, in the LPS-induced, Agm-treated group. Differentiation of LPS-induced, Agm-treated NPCs was regulated by the MAPK pathway and is thought to be related to IL-1β activation and decreased expression of TLX, a transcription factor that regulates NPC differentiation. Our results reveal that Agm can promote NPC differentiation to neural stem cells by modulating IL-1β expression under inflammatory condition, and they suggest that Agm may be a novel therapeutic strategy for neuroinflammatory diseases.

  2. Neural correlates and neural computations in posterior parietal cortex during perceptual decision-making

    Directory of Open Access Journals (Sweden)

    Alexander eHuk

    2012-10-01

    Full Text Available A recent line of work has found remarkable success in relating perceptual decision-making and the spiking activity in the macaque lateral intraparietal area (LIP. In this review, we focus on questions about the neural computations in LIP that are not answered by demonstrations of neural correlates of psychological processes. We highlight three areas of limitations in our current understanding of the precise neural computations that might underlie neural correlates of decisions: (1 empirical questions not yet answered by existing data; (2 implementation issues related to how neural circuits could actually implement the mechanisms suggested by both physiology and psychology; and (3 ecological constraints related to the use of well-controlled laboratory tasks and whether they provide an accurate window on sensorimotor computation. These issues motivate the adoption of a more general encoding-decoding framework that will be fruitful for more detailed contemplation of how neural computations in LIP relate to the formation of perceptual decisions.

  3. A mouse model of prenatal ethanol exposure using a voluntary drinking paradigm.

    Science.gov (United States)

    Allan, Andrea M; Chynoweth, Julie; Tyler, Lani A; Caldwell, Kevin K

    2003-12-01

    The incidence of fetal alcohol spectrum disorders is estimated to be as high as 1 in 100 births. Efforts to better understand the basis of prenatal ethanol-induced impairments in brain functioning, and the mechanisms by which ethanol produces these defects, will rely on the use of animal models of fetal alcohol exposure (FAE). Using a saccharin-sweetened alcohol solution, we developed a free-choice, moderate alcohol access model of prenatal alcohol exposure. Stable drinking of a saccharin solution (0.066%) was established in female mice. Ethanol then was added to the saccharin in increasing concentrations (2%, 5%, 10% w/v) every 2 days. Water was always available, and mice consumed standard pellet chow. Control mice drank saccharin solution without ethanol. After a stable baseline of ethanol consumption (14 g/kg/day) was obtained, females were impregnated. Ethanol consumption continued throughout pregnancy and then was decreased to 0% in a step-wise fashion over a period of 6 days after pups were delivered. Characterization of the model included measurements of maternal drinking patterns, blood alcohol levels, food consumption, litter size, pup weight, pup retrieval times for the dams, and effects of FAE on performance in fear-conditioned learning and novelty exploration. Maternal food consumption, maternal care, and litter size and number were all found to be similar for the alcohol-exposed and saccharin control animals. FAE did not alter locomotor activity in an open field but did increase the time spent inspecting a novel object introduced into the open field. FAE mice displayed reduced contextual fear when trained using a delay fear conditioning procedure. The mouse model should be a useful tool in testing hypotheses about the neural mechanisms underlying the learning deficits present in fetal alcohol spectrum disorders. Moreover, a mouse prenatal ethanol model should increase the opportunity to use the power of genetically defined and genetically altered mouse

  4. Deep Learning Neural Networks and Bayesian Neural Networks in Data Analysis

    Directory of Open Access Journals (Sweden)

    Chernoded Andrey

    2017-01-01

    Full Text Available Most of the modern analyses in high energy physics use signal-versus-background classification techniques of machine learning methods and neural networks in particular. Deep learning neural network is the most promising modern technique to separate signal and background and now days can be widely and successfully implemented as a part of physical analysis. In this article we compare Deep learning and Bayesian neural networks application as a classifiers in an instance of top quark analysis.

  5. Neural Tube Defects

    Science.gov (United States)

    Neural tube defects are birth defects of the brain, spine, or spinal cord. They happen in the ... that she is pregnant. The two most common neural tube defects are spina bifida and anencephaly. In ...

  6. The Mouse That Soared

    Science.gov (United States)

    2004-09-01

    Astronomers have used an X-ray image to make the first detailed study of the behavior of high-energy particles around a fast moving pulsar. The image, from NASA's Chandra X-ray Observatory, shows the shock wave created as a pulsar plows supersonically through interstellar space. These results will provide insight into theories for the production of powerful winds of matter and antimatter by pulsars. Chandra's image of the glowing cloud, known as the Mouse, shows a stubby bright column of high-energy particles, about four light years in length, swept back by the pulsar's interaction with interstellar gas. The intense source at the head of the X-ray column is the pulsar, estimated to be moving through space at about 1.3 million miles per hour. VLA Radio Image of the Mouse, Full Field VLA Radio Image of the Mouse, Full Field A cone-shaped cloud of radio-wave-emitting particles envelopes the X-ray column. The Mouse, a.k.a. G359.23-0.82, was discovered in 1987 by radio astronomers using the National Science Foundation's Very Large Array in New Mexico. It gets its name from its appearance in radio images that show a compact snout, a bulbous body, and a remarkable long, narrow, tail that extends for about 55 light years. "A few dozen pulsar wind nebulae are known, including the spectacular Crab Nebula, but none have the Mouse's combination of relatively young age and incredibly rapid motion through interstellar space," said Bryan Gaensler of the Harvard-Smithsonian Center for Astrophysics and lead author of a paper on the Mouse that will appear in an upcoming issue of The Astrophysical Journal. "We effectively are seeing a supersonic cosmic wind tunnel, in which we can study the effects of a pulsar's motion on its pulsar wind nebula, and test current theories." Illustration of the Mouse System Illustration of the Mouse System Pulsars are known to be rapidly spinning, highly magnetized neutron stars -- objects so dense that a mass equal to that of the Sun is packed into a

  7. Unpredictable chronic mild stress differentially impairs social and contextual discrimination learning in two inbred mouse strains.

    Directory of Open Access Journals (Sweden)

    Michiel van Boxelaere

    Full Text Available Alterations in the social and cognitive domain are considered important indicators for increased disability in many stress-related disorders. Similar impairments have been observed in rodents chronically exposed to stress, mimicking potential endophenotypes of stress-related psychopathologies such as major depression disorder (MDD, anxiety, conduct disorder, and posttraumatic stress disorder (PTSD. Data from numerous studies suggest that deficient plasticity mechanisms in hippocampus (HC and prefrontal cortex (PFC might underlie these social and cognitive deficits. Specifically, stress-induced deficiencies in neural plasticity have been associated with a hypodopaminergic state and reduced neural plasticity persistence. Here we assessed the effects of unpredictable chronic mild stress (UCMS on exploratory, social and cognitive behavior of females of two inbred mouse strains (C57BL/6J and DBA/2J that differ in their dopaminergic profile. Exposure to chronic stress resulted in impaired circadian rhythmicity, sociability and social cognition in both inbred strains, but differentially affected activity patterns and contextual discrimination performance. These stress-induced behavioral impairments were accompanied by reduced expression levels of brain derived neurotrophic factor (BDNF in the prefrontal cortex. The strain-specific cognitive impairment was coexistent with enhanced plasma corticosterone levels and reduced expression of genes related to dopamine signaling in hippocampus. These results underline the importance of assessing different strains with multiple test batteries to elucidate the neural and genetic basis of social and cognitive impairments related to chronic stress.

  8. Burn mouse models

    DEFF Research Database (Denmark)

    Calum, Henrik; Høiby, Niels; Moser, Claus

    2014-01-01

    Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third-degree b......Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third...... with infected burn wound compared with the burn wound only group. The burn mouse model resembles the clinical situation and provides an opportunity to examine or develop new strategies like new antibiotics and immune therapy, in handling burn wound victims much....

  9. A Transgenic Tri-Modality Reporter Mouse

    OpenAIRE

    Yan, Xinrui; Ray, Pritha; Paulmurugan, Ramasamy; Tong, Ricky; Gong, Yongquan; Sathirachinda, Ataya; Wu, Joseph C.; Gambhir, Sanjiv S.

    2013-01-01

    Transgenic mouse with a stably integrated reporter gene(s) can be a valuable resource for obtaining uniformly labeled stem cells, tissues, and organs for various applications. We have generated a transgenic mouse model that ubiquitously expresses a tri-fusion reporter gene (fluc2-tdTomato-ttk) driven by a constitutive chicken β-actin promoter. This "Tri-Modality Reporter Mouse" system allows one to isolate most cells from this donor mouse and image them for bioluminescent (fluc2), fluorescent...

  10. Quantitative Analyses of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture.

    Science.gov (United States)

    Deng, Liting; Ng, Lindsay; Ozawa, Tatsuya; Stella, Nephi

    2017-01-01

    Evidence suggests that the nonpsychotropic cannabis-derived compound, cannabidiol (CBD), has antineoplastic activity in multiple types of cancers, including glioblastoma multiforme (GBM). DNA-damaging agents remain the main standard of care treatment available for patients diagnosed with GBM. Here we studied the antiproliferative and cell-killing activity of CBD alone and in combination with DNA-damaging agents (temozolomide, carmustine, or cisplatin) in several human GBM cell lines and in mouse primary GBM cells in cultures. This activity was also studied in mouse neural progenitor cells (NPCs) in culture to assess for potential central nervous system toxicity. We found that CBD induced a dose-dependent reduction of both proliferation and viability of all cells with similar potencies, suggesting no preferential activity for cancer cells. Hill plot analysis indicates an allosteric mechanism of action triggered by CBD in all cells. Cotreatment regimens combining CBD and DNA-damaging agents produced synergistic antiproliferating and cell-killing responses over a limited range of concentrations in all human GBM cell lines and mouse GBM cells as well as in mouse NPCs. Remarkably, antagonistic responses occurred at low concentrations in select human GBM cell lines and in mouse GBM cells. Our study suggests limited synergistic activity when combining CBD and DNA-damaging agents in treating GBM cells, along with little to no therapeutic window when considering NPCs. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  11. Induction of Functional 3D Ciliary Epithelium-Like Structure From Mouse Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Kinoshita, Hirofumi; Suzuma, Kiyoshi; Kaneko, Jun; Mandai, Michiko; Kitaoka, Takashi; Takahashi, Masayo

    2016-01-01

    To generate ciliary epithelium (CE) from mouse induced pluripotent stem (iPS) cells. Recently, a protocol for self-organizing optic cup morphogenesis in three-dimensional culture was reported, and it was suggested that ocular tissue derived from neural ectoderm could be differentiated. We demonstrated that a CE-like double-layered structure could be induced in simple culture by using a modified Eiraku differentiation protocol. Differentiation of a CE-like double-layered structure could be promoted by glycogen synthase kinase 3β (GSK-3β) inhibitor. Connexin43 and aquaporin1 were expressed in both thin layers, and induced CE-like cells expressed ciliary marker genes, such as cyclinD2, zic1, tgfb2, aldh1a3, wfdc1, otx1, BMP4, and BMP7. Increases in cytoplasmic and nuclear β-catenin in aggregates of the CE-like double-layered structure were confirmed by Western blot analysis. In addition, tankyrase inhibitor prevented the induction of the CE-like double-layered structure by GSK-3β inhibitor. Dye movement from pigmented cells to nonpigmented cells in the mouse iPS cell-derived CE-like structure was observed in a fluid movement experiment, consistent with the physiological function of CE in vivo. We could differentiate CE from mouse iPS cells in the present study. In the future, we hope that this CE-like complex will become useful as a graft for transplantation therapy in pathologic ocular hypotension due to CE dysfunction, and as a screening tool for the development of drugs for diseases associated with CE function.

  12. Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains.

    Science.gov (United States)

    Wiltshire, T; Ervin, R B; Duan, H; Bogue, M A; Zamboni, W C; Cook, S; Chung, W; Zou, F; Tarantino, L M

    2015-03-01

    Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  13. A neural flow estimator

    DEFF Research Database (Denmark)

    Jørgensen, Ivan Harald Holger; Bogason, Gudmundur; Bruun, Erik

    1995-01-01

    This paper proposes a new way to estimate the flow in a micromechanical flow channel. A neural network is used to estimate the delay of random temperature fluctuations induced in a fluid. The design and implementation of a hardware efficient neural flow estimator is described. The system...... is implemented using switched-current technique and is capable of estimating flow in the μl/s range. The neural estimator is built around a multiplierless neural network, containing 96 synaptic weights which are updated using the LMS1-algorithm. An experimental chip has been designed that operates at 5 V...

  14. Hidden neural networks

    DEFF Research Database (Denmark)

    Krogh, Anders Stærmose; Riis, Søren Kamaric

    1999-01-01

    A general framework for hybrids of hidden Markov models (HMMs) and neural networks (NNs) called hidden neural networks (HNNs) is described. The article begins by reviewing standard HMMs and estimation by conditional maximum likelihood, which is used by the HNN. In the HNN, the usual HMM probability...... parameters are replaced by the outputs of state-specific neural networks. As opposed to many other hybrids, the HNN is normalized globally and therefore has a valid probabilistic interpretation. All parameters in the HNN are estimated simultaneously according to the discriminative conditional maximum...... likelihood criterion. The HNN can be viewed as an undirected probabilistic independence network (a graphical model), where the neural networks provide a compact representation of the clique functions. An evaluation of the HNN on the task of recognizing broad phoneme classes in the TIMIT database shows clear...

  15. NeuroMEMS: Neural Probe Microtechnologies

    Directory of Open Access Journals (Sweden)

    Sam Musallam

    2008-10-01

    Full Text Available Neural probe technologies have already had a significant positive effect on our understanding of the brain by revealing the functioning of networks of biological neurons. Probes are implanted in different areas of the brain to record and/or stimulate specific sites in the brain. Neural probes are currently used in many clinical settings for diagnosis of brain diseases such as seizers, epilepsy, migraine, Alzheimer’s, and dementia. We find these devices assisting paralyzed patients by allowing them to operate computers or robots using their neural activity. In recent years, probe technologies were assisted by rapid advancements in microfabrication and microelectronic technologies and thus are enabling highly functional and robust neural probes which are opening new and exciting avenues in neural sciences and brain machine interfaces. With a wide variety of probes that have been designed, fabricated, and tested to date, this review aims to provide an overview of the advances and recent progress in the microfabrication techniques of neural probes. In addition, we aim to highlight the challenges faced in developing and implementing ultralong multi-site recording probes that are needed to monitor neural activity from deeper regions in the brain. Finally, we review techniques that can improve the biocompatibility of the neural probes to minimize the immune response and encourage neural growth around the electrodes for long term implantation studies.

  16. Vitamin E-Mediated Modulation of Glutamate Receptor Expression in an Oxidative Stress Model of Neural Cells Derived from Embryonic Stem Cell Cultures

    Directory of Open Access Journals (Sweden)

    Afifah Abd Jalil

    2017-01-01

    Full Text Available Glutamate is the primary excitatory neurotransmitter in the central nervous system. Excessive concentrations of glutamate in the brain can be excitotoxic and cause oxidative stress, which is associated with Alzheimer’s disease. In the present study, the effects of vitamin E in the form of tocotrienol-rich fraction (TRF and alpha-tocopherol (α-TCP in modulating the glutamate receptor and neuron injury markers in an in vitro model of oxidative stress in neural-derived embryonic stem (ES cell cultures were elucidated. A transgenic mouse ES cell line (46C was differentiated into a neural lineage in vitro via induction with retinoic acid. These cells were then subjected to oxidative stress with a significantly high concentration of glutamate. Measurement of reactive oxygen species (ROS was performed after inducing glutamate excitotoxicity, and recovery from this toxicity in response to vitamin E was determined. The gene expression levels of glutamate receptors and neuron-specific enolase were elucidated using real-time PCR. The results reveal that neural cells derived from 46C cells and subjected to oxidative stress exhibit downregulation of NMDA, kainate receptor, and NSE after posttreatment with different concentrations of TRF and α-TCP, a sign of neurorecovery. Treatment of either TRF or α-TCP reduced the levels of ROS in neural cells subjected to glutamate-induced oxidative stress; these results indicated that vitamin E is a potent antioxidant.

  17. Inca: a novel p21-activated kinase-associated protein required for cranial neural crest development.

    Science.gov (United States)

    Luo, Ting; Xu, Yanhua; Hoffman, Trevor L; Zhang, Tailin; Schilling, Thomas; Sargent, Thomas D

    2007-04-01

    Inca (induced in neural crest by AP2) is a novel protein discovered in a microarray screen for genes that are upregulated in Xenopus embryos by the transcriptional activator protein Tfap2a. It has no significant similarity to any known protein, but is conserved among vertebrates. In Xenopus, zebrafish and mouse embryos, Inca is expressed predominantly in the premigratory and migrating neural crest (NC). Knockdown experiments in frog and fish using antisense morpholinos reveal essential functions for Inca in a subset of NC cells that form craniofacial cartilage. Cells lacking Inca migrate successfully but fail to condense into skeletal primordia. Overexpression of Inca disrupts cortical actin and prevents formation of actin "purse strings", which are required for wound healing in Xenopus embryos. We show that Inca physically interacts with p21-activated kinase 5 (PAK5), a known regulator of the actin cytoskeleton that is co-expressed with Inca in embryonic ectoderm, including in the NC. These results suggest that Inca and PAK5 cooperate in restructuring cytoskeletal organization and in the regulation of cell adhesion in the early embryo and in NC cells during craniofacial development.

  18. MicroCT and microMRI imaging of a prenatal mouse model of increased brain size

    Science.gov (United States)

    López, Elisabeth K. N.; Stock, Stuart R.; Taketo, Makoto M.; Chenn, Anjen; Ravosa, Matthew J.

    2008-08-01

    There are surprisingly few experimental models of neural growth and cranial integration. This and the dearth of information regarding fetal brain development detract from a mechanistic understanding of cranial integration and its relevance to the patterning of skull form, specifically the role of encephalization on basicranial flexion. To address this shortcoming, our research uses transgenic mice expressing a stabilized form of β-catenin to isolate the effects of relative brain size on craniofacial development. These mice develop highly enlarged brains due to an increase in neural precursors, and differences between transgenic and wild-type mice are predicted to result solely from variation in brain size. Comparisons of wild-type and transgenic mice at several prenatal ages were performed using microCT (Scanco Medical MicroCT 40) and microMRI (Avance 600 WB MR spectrometer). Statistical analyses show that the larger brain of the transgenic mice is associated with a larger neurocranium and an altered basicranial morphology. However, body size and postcranial ossification do not seem to be affected by the transgene. Comparisons of the rate of postcranial and cranial ossification using microCT also point to an unexpected effect of neural growth on skull development: increased fetal encephalization may result in a compensatory decrease in the level of cranial ossification. Therefore, if other life history factors are held constant, the ontogeny of a metabolically costly structure such as a brain may occur at the expense of other cranial structures. These analyses indicate the benefits of a multifactorial approach to cranial integration using a mouse model.

  19. Developmental expression of membrane type 4-matrix metalloproteinase (Mt4-mmp/Mmp17) in the mouse embryo

    Science.gov (United States)

    Clemente, Cristina; Montalvo, María Gregoria; Seiki, Motoharu; Arroyo, Alicia G.

    2017-01-01

    Matrix metalloproteinases (MMPs) constitute a large group of endoproteases that play important functions during embryonic development, tumor metastasis and angiogenesis by degrading components of the extracellular matrix. Within this family, we focused our study on Mt4-mmp (also called Mmp17) that belongs to a distinct subset that is anchored to the cell surface via a glycosylphosphatidylinositol (GPI) moiety and with the catalytic site exposed to the extracellular space. Information about its function and substrates is very limited to date, and little has been reported on its role in the developing embryo. Here, we report a detailed expression analysis of Mt4-mmp during mouse embryonic development by using a LacZ reporter transgenic mouse line. We showed that Mt4-mmp is detected from early stages of development to postnatal stages following a dynamic and restricted pattern of expression. Mt4-mmp was first detected at E8.5 limited to the intersomitic vascularization, the endocardial endothelium and the dorsal aorta. Mt4-mmpLacZ/+ cells were also observed in the neural crest cells, somites, floor plate and notochord at early stages. From E10.5, expression localized in the limb buds and persists during limb development. A strong expression in the brain begins at E12.5 and continues to postnatal stages. Specifically, staining was observed in the olfactory bulb, cerebral cortex, hippocampus, striatum, septum, dorsal thalamus and the spinal cord. In addition, LacZ-positive cells were also detected during eye development, initially at the hyaloid artery and later on located in the lens and the neural retina. Mt4-mmp expression was confirmed by quantitative RT-PCR and western blot analysis in some embryonic tissues. Our data point to distinct functions for this metalloproteinase during embryonic development, particularly during brain formation, angiogenesis and limb development. PMID:28926609

  20. Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse

    Science.gov (United States)

    Schill, Ellen Merrick; Lake, Jonathan I.; Tusheva, Olga A.; Nagy, Nandor; Bery, Saya K.; Foster, Lynne; Avetisyan, Marina; Johnson, Stephen L.; Stenson, William F.; Goldstein, Allan M.; Heuckeroth, Robert O.

    2016-01-01

    Hirschsprung Disease (HSCR) is a potentially deadly birth defect characterized by the absence of the enteric nervous system (ENS) in distal bowel. Although HSCR has clear genetic causes, no HSCR-associated mutation is 100% penetrant, suggesting gene-gene and gene-environment interactions determine HSCR occurrence. To test the hypothesis that certain medicines might alter HSCR risk we treated zebrafish with medications commonly used during early human pregnancy and discovered that ibuprofen caused HSCR-like absence of enteric neurons in distal bowel. Using fetal CF-1 mouse gut slice cultures, we found that ibuprofen treated enteric neural crest-derived cells (ENCDC) had reduced migration, fewer lamellipodia and lower levels of active RAC1/CDC42. Additionally, inhibiting ROCK, a RHOA effector and known RAC1 antagonist, reversed ibuprofen effects on migrating mouse ENCDC in culture. Ibuprofen also inhibited colonization of Ret+/− mouse bowel by ENCDC in vivo and dramatically reduced bowel colonization by chick ENCDC in culture. Interestingly, ibuprofen did not affect ENCDC migration until after at least three hours of exposure. Furthermore, mice deficient in Ptgs1 (COX 1) and Ptgs2 (COX 2) had normal bowel colonization by ENCDC and normal ENCDC migration in vitro suggesting COX-independent effects. Consistent with selective and strain specific effects on ENCDC, ibuprofen did not affect migration of gut mesenchymal cells, NIH3T3, or WT C57BL/6 ENCDC, and did not affect dorsal root ganglion cell precursor migration in zebrafish. Thus, ibuprofen inhibits ENCDC migration in vitro and bowel colonization by ENCDC in vivo in zebrafish, mouse and chick, but there are cell type and strain specific responses. These data raise concern that ibuprofen may increase Hirschsprung disease risk in some genetically susceptible children. PMID:26586201

  1. Neural Networks: Implementations and Applications

    OpenAIRE

    Vonk, E.; Veelenturf, L.P.J.; Jain, L.C.

    1996-01-01

    Artificial neural networks, also called neural networks, have been used successfully in many fields including engineering, science and business. This paper presents the implementation of several neural network simulators and their applications in character recognition and other engineering areas

  2. Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Manuel E. Lopez

    2013-09-01

    Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

  3. Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction.

    Science.gov (United States)

    Yu, Tao; Guo, Ming; Garza, Jacob; Rendon, Samantha; Sun, Xue-Li; Zhang, Wei; Lu, Xin-Yun

    2011-04-01

    Human depression is associated with cognitive deficits. It is critical to have valid animal models in order to investigate mechanisms and treatment strategies for these associated conditions. The goal of this study was to determine the association of cognitive dysfunction with depression-like behaviour in an animal model of depression and investigate the neural circuits underlying the behaviour. Mice that were exposed to social defeat for 14 d developed depression-like behaviour, i.e. anhedonia and social avoidance as indicated by reduced sucrose preference and decreased social interaction. The assessment of cognitive performance of defeated mice demonstrated impaired working memory in the T-maze continuous alternation task and enhanced fear memory in the contextual and cued fear-conditioning tests. In contrast, reference learning and memory in the Morris water maze test were intact in defeated mice. Neuronal activation following chronic social defeat was investigated by c-fosin-situ hybridization. Defeated mice exhibited preferential neural activity in the prefrontal cortex, cingulate cortex, hippocampal formation, septum, amygdala, and hypothalamic nuclei. Taken together, our results suggest that the chronic social defeat mouse model could serve as a valid animal model to study depression with cognitive impairments. The patterns of neuronal activation provide a neural basis for social defeat-induced changes in behaviour.

  4. Immunohistochemical Examination for the Distribution of Podoplanin-Expressing Cells in Developing Mouse Molar Tooth Germs

    Science.gov (United States)

    Imaizumi, Yuri; Amano, Ikuko; Tsuruga, Eichi; Kojima, Hiroshi; Sawa, Yoshihiko

    2010-01-01

    We recently reported the expression of podoplanin in the apical bud of adult mouse incisal tooth. This study was aimed to investigate the distribution of podoplanin-expressing cells in mouse tooth germs at several developing stages. At the bud stage podoplanin was expressed in oral mucous epithelia and in a tooth bud. At the cap stage podoplanin was expressed on inner and outer enamel epithelia but not in mesenchymal cells expressing the neural crest stem cell marker nestin. At the early bell stage nestin and podoplanin were expressed in cervical loop and odontoblasts. At the root formation stage both nestin and podoplanin were weakly expressed in odontoblasts generating radicular dentin. Podoplanin expression was also found in the Hertwig epithelial sheath. These results suggest that epithelial cells of developing tooth germ acquire the ability to express nestin, and that tooth germ epithelial cells maintain the ability to express podoplanin in oral mucous epithelia. The expression of podoplanin in odontoblasts was induced as tooth germ development advanced, but was suppressed with the completion of the primary dentin, suggesting that podoplanin may be involved in the cell growth of odontoblasts. Nestin may function as an intermediate filament that binds podoplanin in odontoblasts. PMID:21060740

  5. Differential Contribution of the Guanylyl Cyclase-Cyclic GMP-Protein Kinase G Pathway to the Proliferation of Neural Stem Cells Stimulated by Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Bruno P. Carreira

    2012-02-01

    Full Text Available Nitric oxide (NO is an important inflammatory mediator involved in the initial boost in the proliferation of neural stem cells following brain injury. However, the mechanisms underlying the proliferative effect of NO are still unclear. The aim of this work was to investigate whether cyclic GMP (cGMP and the cGMP-dependent kinase (PKG are involved in the proliferative effect triggered by NO in neural stem cells. For this purpose, cultures of neural stem cells isolated from the mouse subventricular zone (SVZ were used. We observed that long-term exposure to the NO donor (24 h, NOC-18, increased the proliferation of SVZ cells in a cGMP-dependent manner, since the guanylate cyclase inhibitor, ODQ, prevented cell proliferation. Similarly to NOC-18, the cGMP analogue, 8-Br-cGMP, also increased cell proliferation. Interestingly, shorter exposures to NO (6 h increased cell proliferation in a cGMP-independent manner via the ERK/MAP kinase pathway. The selective inhibitor of PKG, KT5823, prevented the proliferative effect induced by NO at 24 h but not at 6 h. In conclusion, the proliferative effect of NO is initially mediated by the ERK/MAPK pathway, and at later stages by the GC/cGMP/PKG pathway. Thus, our work shows that NO induces neural stem cell proliferation by targeting these two pathways in a biphasic manner.

  6. Neurophysiology and neural engineering: a review.

    Science.gov (United States)

    Prochazka, Arthur

    2017-08-01

    Neurophysiology is the branch of physiology concerned with understanding the function of neural systems. Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, enhance, or otherwise exploit the properties and functions of neural systems. In most cases neural engineering involves the development of an interface between electronic devices and living neural tissue. This review describes the origins of neural engineering, the explosive development of methods and devices commencing in the late 1950s, and the present-day devices that have resulted. The barriers to interfacing electronic devices with living neural tissues are many and varied, and consequently there have been numerous stops and starts along the way. Representative examples are discussed. None of this could have happened without a basic understanding of the relevant neurophysiology. I also consider examples of how neural engineering is repaying the debt to basic neurophysiology with new knowledge and insight. Copyright © 2017 the American Physiological Society.

  7. Fast and Efficient Asynchronous Neural Computation with Adapting Spiking Neural Networks

    NARCIS (Netherlands)

    D. Zambrano (Davide); S.M. Bohte (Sander)

    2016-01-01

    textabstractBiological neurons communicate with a sparing exchange of pulses - spikes. It is an open question how real spiking neurons produce the kind of powerful neural computation that is possible with deep artificial neural networks, using only so very few spikes to communicate. Building on

  8. Factors Released from Endothelial Cells Exposed to Flow Impact Adhesion, Proliferation, and Fate Choice in the Adult Neural Stem Cell Lineage.

    Science.gov (United States)

    Dumont, Courtney M; Piselli, Jennifer M; Kazi, Nadeem; Bowman, Evan; Li, Guoyun; Linhardt, Robert J; Temple, Sally; Dai, Guohao; Thompson, Deanna M

    2017-08-15

    The microvasculature within the neural stem cell (NSC) niche promotes self-renewal and regulates lineage progression. Previous work identified endothelial-produced soluble factors as key regulators of neural progenitor cell (NPC) fate and proliferation; however, endothelial cells (ECs) are sensitive to local hemodynamics, and the effect of this key physiological process has not been defined. In this study, we evaluated adult mouse NPC response to soluble factors isolated from static or dynamic (flow) EC cultures. Endothelial factors generated under dynamic conditions significantly increased neuronal differentiation, while those released under static conditions stimulated oligodendrocyte differentiation. Flow increases EC release of neurogenic factors and of heparin sulfate glycosaminoglycans that increase their bioactivity, likely underlying the enhanced neuronal differentiation. Additionally, endothelial factors, especially from static conditions, promoted adherent growth. Together, our data suggest that blood flow may impact proliferation, adhesion, and the neuron-glial fate choice of adult NPCs, with implications for diseases and aging that reduce flow.

  9. Touchscreen learning deficits in Ube3a, Ts65Dn and Mecp2 mouse models of neurodevelopmental disorders with intellectual disabilities.

    Science.gov (United States)

    Leach, P T; Crawley, J N

    2017-12-20

    Mutant mouse models of neurodevelopmental disorders with intellectual disabilities provide useful translational research tools, especially in cases where robust cognitive deficits are reproducibly detected. However, motor, sensory and/or health issues consequent to the mutation may introduce artifacts that preclude testing in some standard cognitive assays. Touchscreen learning and memory tasks in small operant chambers have the potential to circumvent these confounds. Here we use touchscreen visual discrimination learning to evaluate performance in the maternally derived Ube3a mouse model of Angelman syndrome, the Ts65Dn trisomy mouse model of Down syndrome, and the Mecp2 Bird mouse model of Rett syndrome. Significant deficits in acquisition of a 2-choice visual discrimination task were detected in both Ube3a and Ts65Dn mice. Procedural control measures showed no genotype differences during pretraining phases or during acquisition. Mecp2 males did not survive long enough for touchscreen training, consistent with previous reports. Most Mecp2 females failed on pretraining criteria. Significant impairments on Morris water maze spatial learning were detected in both Ube3a and Ts65Dn, replicating previous findings. Abnormalities on rotarod in Ube3a, and on open field in Ts65Dn, replicating previous findings, may have contributed to the observed acquisition deficits and swim speed abnormalities during water maze performance. In contrast, these motor phenotypes do not appear to have affected touchscreen procedural abilities during pretraining or visual discrimination training. Our findings of slower touchscreen learning in 2 mouse models of neurodevelopmental disorders with intellectual disabilities indicate that operant tasks offer promising outcome measures for the preclinical discovery of effective pharmacological therapeutics. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  10. Artificial neural networks in NDT

    International Nuclear Information System (INIS)

    Abdul Aziz Mohamed

    2001-01-01

    Artificial neural networks, simply known as neural networks, have attracted considerable interest in recent years largely because of a growing recognition of the potential of these computational paradigms as powerful alternative models to conventional pattern recognition or function approximation techniques. The neural networks approach is having a profound effect on almost all fields, and has been utilised in fields Where experimental inter-disciplinary work is being carried out. Being a multidisciplinary subject with a broad knowledge base, Nondestructive Testing (NDT) or Nondestructive Evaluation (NDE) is no exception. This paper explains typical applications of neural networks in NDT/NDE. Three promising types of neural networks are highlighted, namely, back-propagation, binary Hopfield and Kohonen's self-organising maps. (Author)

  11. Mouse SNP Miner: an annotated database of mouse functional single nucleotide polymorphisms

    Directory of Open Access Journals (Sweden)

    Ramensky Vasily E

    2007-01-01

    Full Text Available Abstract Background The mapping of quantitative trait loci in rat and mouse has been extremely successful in identifying chromosomal regions associated with human disease-related phenotypes. However, identifying the specific phenotype-causing DNA sequence variations within a quantitative trait locus has been much more difficult. The recent availability of genomic sequence from several mouse inbred strains (including C57BL/6J, 129X1/SvJ, 129S1/SvImJ, A/J, and DBA/2J has made it possible to catalog DNA sequence differences within a quantitative trait locus derived from crosses between these strains. However, even for well-defined quantitative trait loci ( Description To help identify functional DNA sequence variations within quantitative trait loci we have used the Ensembl annotated genome sequence to compile a database of mouse single nucleotide polymorphisms (SNPs that are predicted to cause missense, nonsense, frameshift, or splice site mutations (available at http://bioinfo.embl.it/SnpApplet/. For missense mutations we have used the PolyPhen and PANTHER algorithms to predict whether amino acid changes are likely to disrupt protein function. Conclusion We have developed a database of mouse SNPs predicted to cause missense, nonsense, frameshift, and splice-site mutations. Our analysis revealed that 20% and 14% of missense SNPs are likely to be deleterious according to PolyPhen and PANTHER, respectively, and 6% are considered deleterious by both algorithms. The database also provides gene expression and functional annotations from the Symatlas, Gene Ontology, and OMIM databases to further assess candidate phenotype-causing mutations. To demonstrate its utility, we show that Mouse SNP Miner successfully finds a previously identified candidate SNP in the taste receptor, Tas1r3, that underlies sucrose preference in the C57BL/6J strain. We also use Mouse SNP Miner to derive a list of candidate phenotype-causing mutations within a previously

  12. Fractional Hopfield Neural Networks: Fractional Dynamic Associative Recurrent Neural Networks.

    Science.gov (United States)

    Pu, Yi-Fei; Yi, Zhang; Zhou, Ji-Liu

    2017-10-01

    This paper mainly discusses a novel conceptual framework: fractional Hopfield neural networks (FHNN). As is commonly known, fractional calculus has been incorporated into artificial neural networks, mainly because of its long-term memory and nonlocality. Some researchers have made interesting attempts at fractional neural networks and gained competitive advantages over integer-order neural networks. Therefore, it is naturally makes one ponder how to generalize the first-order Hopfield neural networks to the fractional-order ones, and how to implement FHNN by means of fractional calculus. We propose to introduce a novel mathematical method: fractional calculus to implement FHNN. First, we implement fractor in the form of an analog circuit. Second, we implement FHNN by utilizing fractor and the fractional steepest descent approach, construct its Lyapunov function, and further analyze its attractors. Third, we perform experiments to analyze the stability and convergence of FHNN, and further discuss its applications to the defense against chip cloning attacks for anticounterfeiting. The main contribution of our work is to propose FHNN in the form of an analog circuit by utilizing a fractor and the fractional steepest descent approach, construct its Lyapunov function, prove its Lyapunov stability, analyze its attractors, and apply FHNN to the defense against chip cloning attacks for anticounterfeiting. A significant advantage of FHNN is that its attractors essentially relate to the neuron's fractional order. FHNN possesses the fractional-order-stability and fractional-order-sensitivity characteristics.

  13. Novel mouse model for simulating microsurgical tumor excision with facial nerve preservation.

    Science.gov (United States)

    Lim, Jae H; Boyle, Glen M; Panizza, Benedict

    2016-01-01

    To determine the feasibility of using a mouse tumor model as a microsurgical training tool for otolaryngology-head and neck surgery (OHNS) trainees. Animal study. We injected athymic nude mice with human cutaneous squamous cell carcinoma (A431 cell line) deep to the parotid region overlying the masseter muscle. We sacrificed the animals 1 to 3 weeks postinjection, once a visible tumor growth was confirmed. We then asked 10 OHNS trainees to excise the tumor with preservation of the facial nerves under a high-magnification dissecting microscope. The trainees graded the tasks in several areas of specific measures using a visual analogue scale (VAS) including 1) tumor texture, 2) surgical realism, 3) usefulness, and 4) difficulty of the task. Noticeable tumor growth occurred within 5 days following A431 cell injection and reached measureable size (0.5-1.5 cm) within 1 to 3 weeks. The tumor displaced the facial nerve laterally and medially, with few demonstrating infiltration of the nerve. VAS scores (± standard deviation) were 8.1 (± 1.7), 7.7 (± 2.5), 9.0 (± 0.9) and 6.6 (± 1.9) for tumor texture, surgical realism, usefulness, and the difficulty of the task, respectively. We demonstrate a novel, reliable and cost-effective mouse model for simulating tumor extirpation microsurgery with preservation of important neural structures. OHNS trainees have found this simulation model to be realistic, useful, and appropriately challenging. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

  14. Bidirectional neural interface: Closed-loop feedback control for hybrid neural systems.

    Science.gov (United States)

    Chou, Zane; Lim, Jeffrey; Brown, Sophie; Keller, Melissa; Bugbee, Joseph; Broccard, Frédéric D; Khraiche, Massoud L; Silva, Gabriel A; Cauwenberghs, Gert

    2015-01-01

    Closed-loop neural prostheses enable bidirectional communication between the biological and artificial components of a hybrid system. However, a major challenge in this field is the limited understanding of how these components, the two separate neural networks, interact with each other. In this paper, we propose an in vitro model of a closed-loop system that allows for easy experimental testing and modification of both biological and artificial network parameters. The interface closes the system loop in real time by stimulating each network based on recorded activity of the other network, within preset parameters. As a proof of concept we demonstrate that the bidirectional interface is able to establish and control network properties, such as synchrony, in a hybrid system of two neural networks more significantly more effectively than the same system without the interface or with unidirectional alternatives. This success holds promise for the application of closed-loop systems in neural prostheses, brain-machine interfaces, and drug testing.

  15. A new perspective on behavioral inconsistency and neural noise in aging: Compensatory speeding of neural communication

    Directory of Open Access Journals (Sweden)

    S. Lee Hong

    2012-09-01

    Full Text Available This paper seeks to present a new perspective on the aging brain. Here, we make connections between two key phenomena of brain aging: 1 increased neural noise or random background activity; and 2 slowing of brain activity. Our perspective proposes the possibility that the slowing of neural processing due to decreasing nerve conduction velocities leads to a compensatory speeding of neuron firing rates. These increased firing rates lead to a broader distribution of power in the frequency spectrum of neural oscillations, which we propose, can just as easily be interpreted as neural noise. Compensatory speeding of neural activity, as we present, is constrained by the: A availability of metabolic energy sources; and B competition for frequency bandwidth needed for neural communication. We propose that these constraints lead to the eventual inability to compensate for age-related declines in neural function that are manifested clinically as deficits in cognition, affect, and motor behavior.

  16. Anatomical and electrophysiological characterization of a population of dI6 interneurons in the neonatal mouse spinal cord.

    Science.gov (United States)

    Griener, Anna; Zhang, Wei; Kao, Henry; Haque, Farhia; Gosgnach, Simon

    2017-10-24

    The locomotor central pattern generator is a neural network located in the ventral aspect of the caudal spinal cord that underlies stepping in mammals. While many genetically defined interneurons that are thought to comprise this neural network have been identified and characterized, the dI6 cells- which express the transcription factors WT1 and/or DMRT3- are one population that settle in this region, are active during locomotion, whose function is poorly understood. These cells were originally hypothesized to be commissural premotor interneurons, however evidence in support of this is sparse. Here we characterize this population of cells using the TgDbx1 Cre ;R26 EFP ;Dbx1 LacZ transgenic mouse line, which has been shown to be an effective marker of dI6 interneurons. We show dI6 cells to be abundant in laminae VII and VIII along the entire spinal cord and provide evidence that subtypes outside the WT1/DMRT3 expressing dI6 cells may exist. Retrograde tracing experiments indicate that the majority of dI6 cells project descending axons, and some make monosynaptic or disynaptic contacts onto motoneurons on either side of the spinal cord. Analysis of their activity during non-resetting deletions, which occur during bouts of fictive locomotion, suggests that these cells are involved in both locomotor rhythm generation and pattern formation. This study provides a thorough characterization of the dI6 cells labeled in the TgDbx1 Cre ;R26 EFP ;Dbx1 LacZ transgenic mouse, and supports previous work suggesting that these cells play multiple roles during locomotor activity. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Reward-related behavioral paradigms for addiction research in the mouse: performance of common inbred strains.

    Directory of Open Access Journals (Sweden)

    Lauren Lederle

    2011-01-01

    behavior (food magazine head entries. Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research.

  18. Reward-related behavioral paradigms for addiction research in the mouse: performance of common inbred strains.

    Science.gov (United States)

    Lederle, Lauren; Weber, Susanna; Wright, Tara; Feyder, Michael; Brigman, Jonathan L; Crombag, Hans S; Saksida, Lisa M; Bussey, Timothy J; Holmes, Andrew

    2011-01-10

    magazine head entries). Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research.

  19. Sequential neural models with stochastic layers

    DEFF Research Database (Denmark)

    Fraccaro, Marco; Sønderby, Søren Kaae; Paquet, Ulrich

    2016-01-01

    How can we efficiently propagate uncertainty in a latent state representation with recurrent neural networks? This paper introduces stochastic recurrent neural networks which glue a deterministic recurrent neural network and a state space model together to form a stochastic and sequential neural...... generative model. The clear separation of deterministic and stochastic layers allows a structured variational inference network to track the factorization of the model's posterior distribution. By retaining both the nonlinear recursive structure of a recurrent neural network and averaging over...

  20. FGF signalling regulates chromatin organisation during neural differentiation via mechanisms that can be uncoupled from transcription.

    Directory of Open Access Journals (Sweden)

    Nishal S Patel

    Full Text Available Changes in higher order chromatin organisation have been linked to transcriptional regulation; however, little is known about how such organisation alters during embryonic development or how it is regulated by extrinsic signals. Here we analyse changes in chromatin organisation as neural differentiation progresses, exploiting the clear spatial separation of the temporal events of differentiation along the elongating body axis of the mouse embryo. Combining fluorescence in situ hybridisation with super-resolution structured illumination microscopy, we show that chromatin around key differentiation gene loci Pax6 and Irx3 undergoes both decompaction and displacement towards the nuclear centre coincident with transcriptional onset. Conversely, down-regulation of Fgf8 as neural differentiation commences correlates with a more peripheral nuclear position of this locus. During normal neural differentiation, fibroblast growth factor (FGF signalling is repressed by retinoic acid, and this vitamin A derivative is further required for transcription of neural genes. We show here that exposure to retinoic acid or inhibition of FGF signalling promotes precocious decompaction and central nuclear positioning of differentiation gene loci. Using the Raldh2 mutant as a model for retinoid deficiency, we further find that such changes in higher order chromatin organisation are dependent on retinoid signalling. In this retinoid deficient condition, FGF signalling persists ectopically in the elongating body, and importantly, we find that inhibiting FGF receptor (FGFR signalling in Raldh2-/- embryos does not rescue differentiation gene transcription, but does elicit both chromatin decompaction and nuclear position change. These findings demonstrate that regulation of higher order chromatin organisation during differentiation in the embryo can be uncoupled from the machinery that promotes transcription and, for the first time, identify FGF as an extrinsic signal that

  1. Steroid metabolism in the mouse placenta

    International Nuclear Information System (INIS)

    Okker-Reitsma, G.H.

    1976-01-01

    The purpose of the study described in this thesis was to investigate the capacity for steroid synthesis of the mouse placenta - especially the production of progesterone, androgens and estrogens - and to determine, if possible, the relation of steroid synthesis to special cell types. In an introductory chapter the androgen production in the mouse placenta is surveyed by means of a histochemical and bioindicator study of different stages of development of the placenta. The metabolism of [ 3 H]-dehydroepiandrosterone and [ 3 H]-progesterone by mouse placental tissue in vitro is studied. The metabolism of [ 3 H]-progesterone by the mouse fetal adrenal in vitro is also studied

  2. Enteric Neural Cells From Hirschsprung Disease Patients Form Ganglia in Autologous Aneuronal ColonSummary

    Directory of Open Access Journals (Sweden)

    Benjamin N. Rollo

    2016-01-01

    Full Text Available Background & Aims: Hirschsprung disease (HSCR is caused by failure of cells derived from the neural crest (NC to colonize the distal bowel in early embryogenesis, resulting in absence of the enteric nervous system (ENS and failure of intestinal transit postnatally. Treatment is by distal bowel resection, but neural cell replacement may be an alternative. We tested whether aneuronal (aganglionic colon tissue from patients may be colonized by autologous ENS-derived cells. Methods: Cells were obtained and cryopreserved from 31 HSCR patients from the proximal resection margin of colon, and ENS cells were isolated using flow cytometry for the NC marker p75 (nine patients. Aneuronal colon tissue was obtained from the distal resection margin (23 patients. ENS cells were assessed for NC markers immunohistologically and by quantitative reverse-transcription polymerase chain reaction, and mitosis was detected by ethynyl-2′-deoxyuridine labeling. The ability of human HSCR postnatal ENS-derived cells to colonize the embryonic intestine was demonstrated by organ coculture with avian embryo gut, and the ability of human postnatal HSCR aneuronal colon muscle to support ENS formation was tested by organ coculture with embryonic mouse ENS cells. Finally, the ability of HSCR patient ENS cells to colonize autologous aneuronal colon muscle tissue was assessed. Results: ENS-derived p75-sorted cells from patients expressed multiple NC progenitor and differentiation markers and proliferated in culture under conditions simulating Wnt signaling. In organ culture, patient ENS cells migrated appropriately in aneural quail embryo gut, and mouse embryo ENS cells rapidly spread, differentiated, and extended axons in patient aneuronal colon muscle tissue. Postnatal ENS cells derived from HSCR patients colonized autologous aneuronal colon tissue in cocultures, proliferating and differentiating as neurons and glia. Conclusions: NC-lineage cells can be obtained from HSCR

  3. Reduced acoustic startle response and peripheral hearing loss in the 5xFAD mouse model of Alzheimer's disease.

    Science.gov (United States)

    O'Leary, T P; Shin, S; Fertan, E; Dingle, R N; Almuklass, A; Gunn, R K; Yu, Z; Wang, J; Brown, R E

    2017-06-01

    Hearing dysfunction has been associated with Alzheimer's disease (AD) in humans, but there is little data on the auditory function of mouse models of AD. Furthermore, characterization of hearing ability in mouse models is needed to ensure that tests of cognition that use auditory stimuli are not confounded by hearing dysfunction. Therefore, we assessed acoustic startle response and pre-pulse inhibition in the double transgenic 5xFAD mouse model of AD from 3-4 to 16 months of age. The 5xFAD mice showed an age-related decline in acoustic startle as early as 3-4 months of age. We subsequently tested auditory brainstem response (ABR) thresholds at 4 and 13-14 months of age using tone bursts at frequencies of 2-32 kHz. The 5xFAD mice showed increased ABR thresholds for tone bursts between 8 and 32 kHz at 13-14 months of age. Finally, cochleae were extracted and basilar membranes were dissected to count hair cell loss across the cochlea. The 5xFAD mice showed significantly greater loss of both inner and outer hair cells at the apical and basal ends of the basilar membrane than wild-type mice at 15-16 months of age. These results indicate that the 5xFAD mouse model of AD shows age-related decreases in acoustic startle responses, which are at least partially due to age-related peripheral hearing loss. Therefore, we caution against the use of cognitive tests that rely on audition in 5xFAD mice over 3-4 months of age, without first confirming that performance is not confounded by hearing dysfunction. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  4. Parallel consensual neural networks.

    Science.gov (United States)

    Benediktsson, J A; Sveinsson, J R; Ersoy, O K; Swain, P H

    1997-01-01

    A new type of a neural-network architecture, the parallel consensual neural network (PCNN), is introduced and applied in classification/data fusion of multisource remote sensing and geographic data. The PCNN architecture is based on statistical consensus theory and involves using stage neural networks with transformed input data. The input data are transformed several times and the different transformed data are used as if they were independent inputs. The independent inputs are first classified using the stage neural networks. The output responses from the stage networks are then weighted and combined to make a consensual decision. In this paper, optimization methods are used in order to weight the outputs from the stage networks. Two approaches are proposed to compute the data transforms for the PCNN, one for binary data and another for analog data. The analog approach uses wavelet packets. The experimental results obtained with the proposed approach show that the PCNN outperforms both a conjugate-gradient backpropagation neural network and conventional statistical methods in terms of overall classification accuracy of test data.

  5. Creative-Dynamics Approach To Neural Intelligence

    Science.gov (United States)

    Zak, Michail A.

    1992-01-01

    Paper discusses approach to mathematical modeling of artificial neural networks exhibiting complicated behaviors reminiscent of creativity and intelligence of biological neural networks. Neural network treated as non-Lipschitzian dynamical system - as described in "Non-Lipschitzian Dynamics For Modeling Neural Networks" (NPO-17814). System serves as tool for modeling of temporal-pattern memories and recognition of complicated spatial patterns.

  6. Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse.

    Science.gov (United States)

    Law, MeiYee; Shaw, David R

    2018-01-01

    Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration.

  7. Synaptic molecular imaging in spared and deprived columns of mouse barrel cortex with array tomography.

    Science.gov (United States)

    Weiler, Nicholas C; Collman, Forrest; Vogelstein, Joshua T; Burns, Randal; Smith, Stephen J

    2014-01-01

    A major question in neuroscience is how diverse subsets of synaptic connections in neural circuits are affected by experience dependent plasticity to form the basis for behavioral learning and memory. Differences in protein expression patterns at individual synapses could constitute a key to understanding both synaptic diversity and the effects of plasticity at different synapse populations. Our approach to this question leverages the immunohistochemical multiplexing capability of array tomography (ATomo) and the columnar organization of mouse barrel cortex to create a dataset comprising high resolution volumetric images of spared and deprived cortical whisker barrels stained for over a dozen synaptic molecules each. These dataset has been made available through the Open Connectome Project for interactive online viewing, and may also be downloaded for offline analysis using web, Matlab, and other interfaces.

  8. Neural stem cells achieve and maintain pluripotency without feeder cells.

    Directory of Open Access Journals (Sweden)

    Hyun Woo Choi

    Full Text Available BACKGROUND: Differentiated cells can be reprogrammed into pluripotency by transduction of four defined transcription factors. Induced pluripotent stem cells (iPS cells are expected to be useful for regenerative medicine as well as basic research. Recently, the report showed that mouse embryonic fibroblasts (MEF cells are not essential for reprogramming. However, in using fibroblasts as donor cells for reprogramming, individual fibroblasts that had failed to reprogram could function as feeder cells. METHODOLOGY/PRINCIPAL FINDING: Here, we show that adult mouse neural stem cells (NSCs, which are not functional feeder cells, can be reprogrammed into iPS cells using defined four factors (Oct4, Sox2, Klf4, and c-Myc under feeder-free conditions. The iPS cells, generated from NSCs expressing the Oct4-GFP reporter gene, could proliferate for more than two months (passage 20. Generated and maintained without feeder cells, these iPS cells expressed pluripotency markers (Oct4 and Nanog, the promoter regions of Oct4 and Nanog were hypomethylated, could differentiated into to all three germ layers in vitro, and formed a germline chimera. These data indicate that NSCs can achieve and maintain pluripotency under feeder-free conditions. CONCLUSION/SIGNIFICANCE: This study suggested that factors secreted by feeder cells are not essential in the initial/early stages of reprogramming and for pluripotency maintenance. This technology might be useful for a human system, as a feeder-free reprogramming system may help generate iPS cells of a clinical grade for tissue or organ regeneration.

  9. Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse.

    Science.gov (United States)

    Razzoli, Maria; Carboni, Lucia; Andreoli, Michela; Michielin, Francesca; Ballottari, Alice; Arban, Roberto

    2011-01-01

    Social stress is a risk factor for affective disorders in vulnerable individuals. Although the biological nature of stress susceptibility/resilience remains to be elucidated, genetic variation is considered amongst the principal contributors to brain disorders. Furthermore, genetic predisposition may be determinant for the therapeutic outcome, as proposed for antidepressant treatments. In the present studies we compared the inherently diverse genetic backgrounds of 2 mouse strains by assessing the efficacy of a chronic antidepressant treatment in a repeated social stress procedure. C57BL/6J and BalbC mice underwent 10-day social defeats followed by 28-day fluoxetine treatment (10 mg/kg/mL, p.o.). In C57BL/6J, most of the social defeat-induced changes were of metabolic nature including persistently altered feed efficiency and decreased abdominal fat stores that were ameliorated by fluoxetine. BalbC mouse behavior was persistently affected by social defeat both in the social avoidance and the forced swim tests, and in either procedure it was restored by chronic fluoxetine, whereas their endocrine parameters were mostly unaffected. The highlighted strain-specific responsivity to the metabolic and behavioral consequences of social defeat and to the chronic antidepressant treatment offers a promising research tool to further explore the underlying neural mechanisms and genetic basis of stress susceptibility and treatment response. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. MouseMine: a new data warehouse for MGI.

    Science.gov (United States)

    Motenko, H; Neuhauser, S B; O'Keefe, M; Richardson, J E

    2015-08-01

    MouseMine (www.mousemine.org) is a new data warehouse for accessing mouse data from Mouse Genome Informatics (MGI). Based on the InterMine software framework, MouseMine supports powerful query, reporting, and analysis capabilities, the ability to save and combine results from different queries, easy integration into larger workflows, and a comprehensive Web Services layer. Through MouseMine, users can access a significant portion of MGI data in new and useful ways. Importantly, MouseMine is also a member of a growing community of online data resources based on InterMine, including those established by other model organism databases. Adopting common interfaces and collaborating on data representation standards are critical to fostering cross-species data analysis. This paper presents a general introduction to MouseMine, presents examples of its use, and discusses the potential for further integration into the MGI interface.

  11. The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis.

    Directory of Open Access Journals (Sweden)

    Stephen N Sansom

    2009-06-01

    Full Text Available Neural stem cell self-renewal, neurogenesis, and cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the cellular networks controlling neural stem cell self-renewal and neurogenesis in stem cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem cell self-renewal, basal progenitor cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor cell genesis by increasing expression of a cohort of basal progenitor cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of self-renewal. Removing Pax6 reduces cortical stem cell self-renewal by decreasing expression of key cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem cells self-renew, generate cortical neurons, or generate basal progenitor cells

  12. Ferulic acid promotes survival and differentiation of neural stem cells to prevent gentamicin-induced neuronal hearing loss.

    Science.gov (United States)

    Gu, Lintao; Cui, Xinhua; Wei, Wei; Yang, Jia; Li, Xuezhong

    2017-11-15

    Neural stem cells (NSCs) have exhibited promising potential in therapies against neuronal hearing loss. Ferulic acid (FA) has been widely reported to enhance neurogenic differentiation of different stem cells. We investigated the role of FA in promoting NSC transplant therapy to prevent gentamicin-induced neuronal hearing loss. NSCs were isolated from mouse cochlear tissues to establish in vitro culture, which were then treated with FA. The survival and differentiation of NSCs were evaluated. Subsequently, neurite outgrowth and excitability of the in vitro neuronal network were assessed. Gentamicin was used to induce neuronal hearing loss in mice, in the presence and absence of FA, followed by assessments of auditory brainstem response (ABR) and distortion product optoacoustic emissions (DPOAE) amplitude. FA promoted survival, neurosphere formation and differentiation of NSCs, as well as neurite outgrowth and excitability of in vitro neuronal network. Furthermore, FA restored ABR threshold shifts and DPOAE in gentamicin-induced neuronal hearing loss mouse model in vivo. Our data, for the first time, support potential therapeutic efficacy of FA in promoting survival and differentiation of NSCs to prevent gentamicin-induced neuronal hearing loss. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects.

    Science.gov (United States)

    Sequerra, Eduardo B; Goyal, Raman; Castro, Patricio A; Levin, Jacqueline B; Borodinsky, Laura N

    2018-05-16

    Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation. SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy. Copyright © 2018 the authors 0270-6474/18/384762-12$15.00/0.

  14. Neural Networks in R Using the Stuttgart Neural Network Simulator: RSNNS

    Directory of Open Access Journals (Sweden)

    Christopher Bergmeir

    2012-01-01

    Full Text Available Neural networks are important standard machine learning procedures for classification and regression. We describe the R package RSNNS that provides a convenient interface to the popular Stuttgart Neural Network Simulator SNNS. The main features are (a encapsulation of the relevant SNNS parts in a C++ class, for sequential and parallel usage of different networks, (b accessibility of all of the SNNSalgorithmic functionality from R using a low-level interface, and (c a high-level interface for convenient, R-style usage of many standard neural network procedures. The package also includes functions for visualization and analysis of the models and the training procedures, as well as functions for data input/output from/to the original SNNSfile formats.

  15. Enteric Neuron Imbalance and Proximal Dysmotility in Ganglionated Intestine of the Sox10Dom/+ Hirschsprung Mouse ModelSummary

    Directory of Open Access Journals (Sweden)

    Melissa A. Musser

    2015-01-01

    Full Text Available Background & Aims: In Hirschsprung disease (HSCR, neural crest-derived progenitors (NCPs fail to completely colonize the intestine so that the enteric nervous system is absent from distal bowel. Despite removal of the aganglionic region, many HSCR patients suffer from residual intestinal dysmotility. To test the hypothesis that inappropriate lineage segregation of NCPs in proximal ganglionated regions of the bowel could contribute to such postoperative disease, we investigated neural crest (NC-derived lineages and motility in ganglionated, postnatal intestine of the Sox10Dom/+ HSCR mouse model. Methods: Cre-mediated fate-mapping was applied to evaluate relative proportions of NC-derived cell types. Motility assays were performed to assess gastric emptying and small intestine motility while colonic inflammation was assessed by histopathology for Sox10Dom/+ mutants relative to wild-type controls. Results: Sox10Dom/+ mice showed regional alterations in neuron and glia proportions as well as calretinin+ and neuronal nitric oxide synthase (nNOS+ neuronal subtypes. In the colon, imbalance of enteric NC derivatives correlated with the extent of aganglionosis. All Sox10Dom/+ mice exhibited reduced small intestinal transit at 4 weeks of age; at 6 weeks of age, Sox10Dom/+ males had increased gastric emptying rates. Sox10Dom/+ mice surviving to 6 weeks of age had little or no colonic inflammation when compared with wild-type littermates, suggesting that these changes in gastrointestinal motility are neurally mediated. Conclusions: The Sox10Dom mutation disrupts the balance of NC-derived lineages and affects gastrointestinal motility in the proximal, ganglionated intestine of adult animals. This is the first report identifying alterations in enteric neuronal classes in Sox10Dom/+ mutants, which suggests a previously unrecognized role for Sox10 in neuronal subtype specification. Keywords: Aganglionosis, Enteric Nervous System, Neural Crest

  16. High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain.

    Science.gov (United States)

    Zhou, Ting; Tan, Lei; Cederquist, Gustav Y; Fan, Yujie; Hartley, Brigham J; Mukherjee, Suranjit; Tomishima, Mark; Brennand, Kristen J; Zhang, Qisheng; Schwartz, Robert E; Evans, Todd; Studer, Lorenz; Chen, Shuibing

    2017-08-03

    Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Neural fields theory and applications

    CERN Document Server

    Graben, Peter; Potthast, Roland; Wright, James

    2014-01-01

    With this book, the editors present the first comprehensive collection in neural field studies, authored by leading scientists in the field - among them are two of the founding-fathers of neural field theory. Up to now, research results in the field have been disseminated across a number of distinct journals from mathematics, computational neuroscience, biophysics, cognitive science and others. Starting with a tutorial for novices in neural field studies, the book comprises chapters on emergent patterns, their phase transitions and evolution, on stochastic approaches, cortical development, cognition, robotics and computation, large-scale numerical simulations, the coupling of neural fields to the electroencephalogram and phase transitions in anesthesia. The intended readership are students and scientists in applied mathematics, theoretical physics, theoretical biology, and computational neuroscience. Neural field theory and its applications have a long-standing tradition in the mathematical and computational ...

  18. The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cells.

    Science.gov (United States)

    Park, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min; Oh, Se-Yeong; Kim, Sung-Hak; Nam, Do-Hyun; Kim, Hyunggee

    2010-11-01

    A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was observed in a number of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf(-/-) astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf(-/-) astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.

  19. Chondroitin sulfate effects on neural stem cell differentiation.

    Science.gov (United States)

    Canning, David R; Brelsford, Natalie R; Lovett, Neil W

    2016-01-01

    We have investigated the role chondroitin sulfate has on cell interactions during neural plate formation in the early chick embryo. Using tissue culture isolates from the prospective neural plate, we have measured neural gene expression profiles associated with neural stem cell differentiation. Removal of chondroitin sulfate from stage 4 neural plate tissue leads to altered associations of N-cadherin-positive neural progenitors and causes changes in the normal sequence of neural marker gene expression. Absence of chondroitin sulfate in the neural plate leads to reduced Sox2 expression and is accompanied by an increase in the expression of anterior markers of neural regionalization. Results obtained in this study suggest that the presence of chondroitin sulfate in the anterior chick embryo is instrumental in maintaining cells in the neural precursor state.

  20. Low-dose/dose-rate γ radiation depresses neural differentiation and alters protein expression profiles in neuroblastoma SH-SY5Y cells and C17.2 neural stem cells.

    Science.gov (United States)

    Bajinskis, Ainars; Lindegren, Heléne; Johansson, Lotta; Harms-Ringdahl, Mats; Forsby, Anna

    2011-02-01

    The effects of low doses of ionizing radiation on cellular development in the nervous system are presently unclear. The focus of the present study was to examine low-dose γ-radiation-induced effects on the differentiation of neuronal cells and on the development of neural stem cells to glial cells. Human neuroblastoma SH-SY5Y cells were exposed to (137)Cs γ rays at different stages of retinoic acid-induced neuronal differentiation, and neurite formation was determined 6 days after exposure. When SH-SY5Y cells were exposed to low-dose-rate γ rays at the onset of differentiation, the number of neurites formed per cell was significantly less after exposure to either 10, 30 or 100 mGy compared to control cells. Exposure to 10 and 30 mGy attenuated differentiation of immature C17.2 mouse-derived neural stem cells to glial cells, as verified by the diminished expression of glial fibrillary acidic protein. Proteomic analysis of the neuroblastoma cells by 2D-PAGE after 30 mGy irradiation showed that proteins involved in neuronal development were downregulated. Proteins involved in cell cycle and proliferation were altered in both cell lines after exposure to 30 mGy; however, the rate of cell proliferation was not affected in the low-dose range. The radiation-induced attenuation of differentiation and the persistent changes in protein expression is indicative of an epigenetic rather than a cytotoxic mechanism.

  1. Neural processing of auditory signals and modular neural control for sound tropism of walking machines

    DEFF Research Database (Denmark)

    Manoonpong, Poramate; Pasemann, Frank; Fischer, Joern

    2005-01-01

    and a neural preprocessing system together with a modular neural controller are used to generate a sound tropism of a four-legged walking machine. The neural preprocessing network is acting as a low-pass filter and it is followed by a network which discerns between signals coming from the left or the right....... The parameters of these networks are optimized by an evolutionary algorithm. In addition, a simple modular neural controller then generates the desired different walking patterns such that the machine walks straight, then turns towards a switched-on sound source, and then stops near to it....

  2. Neural Elements for Predictive Coding

    Directory of Open Access Journals (Sweden)

    Stewart SHIPP

    2016-11-01

    possible by transgenic neural engineering in the mouse. The exercise highlights a number of recurring themes, amongst them the consideration of interneuron diversity as a spur to theoretical development and the potential for specifying a pyramidal neuron’s function by its individual ‘connectome’, combining its extrinsic projection (forward, backward or subcortical with evaluation of its intrinsic network (e.g. unidirectional versus bidirectional connections with other pyramidal neurons.

  3. Neural Elements for Predictive Coding.

    Science.gov (United States)

    Shipp, Stewart

    2016-01-01

    Predictive coding theories of sensory brain function interpret the hierarchical construction of the cerebral cortex as a Bayesian, generative model capable of predicting the sensory data consistent with any given percept. Predictions are fed backward in the hierarchy and reciprocated by prediction error in the forward direction, acting to modify the representation of the outside world at increasing levels of abstraction, and so to optimize the nature of perception over a series of iterations. This accounts for many 'illusory' instances of perception where what is seen (heard, etc.) is unduly influenced by what is expected, based on past experience. This simple conception, the hierarchical exchange of prediction and prediction error, confronts a rich cortical microcircuitry that is yet to be fully documented. This article presents the view that, in the current state of theory and practice, it is profitable to begin a two-way exchange: that predictive coding theory can support an understanding of cortical microcircuit function, and prompt particular aspects of future investigation, whilst existing knowledge of microcircuitry can, in return, influence theoretical development. As an example, a neural inference arising from the earliest formulations of predictive coding is that the source populations of forward and backward pathways should be completely separate, given their functional distinction; this aspect of circuitry - that neurons with extrinsically bifurcating axons do not project in both directions - has only recently been confirmed. Here, the computational architecture prescribed by a generalized (free-energy) formulation of predictive coding is combined with the classic 'canonical microcircuit' and the laminar architecture of hierarchical extrinsic connectivity to produce a template schematic, that is further examined in the light of (a) updates in the microcircuitry of primate visual cortex, and (b) rapid technical advances made possible by transgenic neural

  4. 9 CFR 113.33 - Mouse safety tests.

    Science.gov (United States)

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Mouse safety tests. 113.33 Section 113.33 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Procedures § 113.33 Mouse safety tests. One of the mouse safety tests provided in this section shall be...

  5. Crypto-rhombomeres of the mouse medulla oblongata, defined by molecular and morphological features.

    Science.gov (United States)

    Tomás-Roca, Laura; Corral-San-Miguel, Rubén; Aroca, Pilar; Puelles, Luis; Marín, Faustino

    2016-03-01

    The medulla oblongata is the caudal portion of the vertebrate hindbrain. It contains major ascending and descending fiber tracts as well as several motor and interneuron populations, including neural centers that regulate the visceral functions and the maintenance of bodily homeostasis. In the avian embryo, it has been proposed that the primordium of this region is subdivided into five segments or crypto-rhombomeres (r7-r11), which were defined according to either their parameric position relative to intersomitic boundaries (Cambronero and Puelles, in J Comp Neurol 427:522-545, 2000) or a stepped expression of Hox genes (Marín et al., in Dev Biol 323:230-247, 2008). In the present work, we examine the implied similar segmental organization of the mouse medulla oblongata. To this end, we analyze the expression pattern of Hox genes from groups 3 to 8, comparing them to the expression of given cytoarchitectonic and molecular markers, from mid-gestational to perinatal stages. As a result of this approach, we conclude that the mouse medulla oblongata is segmentally organized, similarly as in avian embryos. Longitudinal structures such as the nucleus of the solitary tract, the dorsal vagal motor nucleus, the hypoglossal motor nucleus, the descending trigeminal and vestibular columns, or the reticular formation appear subdivided into discrete segmental units. Additionally, our analysis identified an internal molecular organization of the migrated pontine nuclei that reflects a differential segmental origin of their neurons as assessed by Hox gene expression.

  6. Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Tesla, Rachel; Wolf, Hamilton Parker; Xu, Pin; Drawbridge, Jordan; Estill, Sandi Jo; Huntington, Paula; McDaniel, Latisha; Knobbe, Whitney; Burket, Aaron; Tran, Stephanie; Starwalt, Ruth; Morlock, Lorraine; Naidoo, Jacinth; Williams, Noelle S; Ready, Joseph M; McKnight, Steven L; Pieper, Andrew A

    2012-10-16

    We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS.

  7. Neural overlap in processing music and speech

    Science.gov (United States)

    Peretz, Isabelle; Vuvan, Dominique; Lagrois, Marie-Élaine; Armony, Jorge L.

    2015-01-01

    Neural overlap in processing music and speech, as measured by the co-activation of brain regions in neuroimaging studies, may suggest that parts of the neural circuitries established for language may have been recycled during evolution for musicality, or vice versa that musicality served as a springboard for language emergence. Such a perspective has important implications for several topics of general interest besides evolutionary origins. For instance, neural overlap is an important premise for the possibility of music training to influence language acquisition and literacy. However, neural overlap in processing music and speech does not entail sharing neural circuitries. Neural separability between music and speech may occur in overlapping brain regions. In this paper, we review the evidence and outline the issues faced in interpreting such neural data, and argue that converging evidence from several methodologies is needed before neural overlap is taken as evidence of sharing. PMID:25646513

  8. Prediction and characterisation of a highly conserved, remote and cAMP responsive enhancer that regulates Msx1 gene expression in cardiac neural crest and outflow tract.

    Science.gov (United States)

    Miller, Kerry Ann; Davidson, Scott; Liaros, Angela; Barrow, John; Lear, Marissa; Heine, Danielle; Hoppler, Stefan; MacKenzie, Alasdair

    2008-05-15

    Double knockouts of the Msx1 and Msx2 genes in the mouse result in severe cardiac outflow tract malformations similar to those frequently found in newborn infants. Despite the known role of the Msx genes in cardiac formation little is known of the regulatory systems (ligand receptor, signal transduction and protein-DNA interactions) that regulate the tissue-specific expression of the Msx genes in mammals during the formation of the outflow tract. In the present study we have used a combination of multi-species comparative genomics, mouse transgenic analysis and in-situ hybridisation to predict and validate the existence of a remote ultra-conserved enhancer that supports the expression of the Msx1 gene in migrating mouse cardiac neural crest and the outflow tract primordia. Furthermore, culturing of embryonic explants derived from transgenic lines with agonists of the PKC and PKA signal transduction systems demonstrates that this remote enhancer is influenced by PKA but not PKC dependent gene regulatory systems. These studies demonstrate the efficacy of combining comparative genomics and transgenic analyses and provide a platform for the study of the possible roles of Msx gene mis-regulation in the aetiology of congenital heart malformation.

  9. Cerebral vessels segmentation for light-sheet microscopy image using convolutional neural networks

    Science.gov (United States)

    Hu, Chaoen; Hui, Hui; Wang, Shuo; Dong, Di; Liu, Xia; Yang, Xin; Tian, Jie

    2017-03-01

    Cerebral vessel segmentation is an important step in image analysis for brain function and brain disease studies. To extract all the cerebrovascular patterns, including arteries and capillaries, some filter-based methods are used to segment vessels. However, the design of accurate and robust vessel segmentation algorithms is still challenging, due to the variety and complexity of images, especially in cerebral blood vessel segmentation. In this work, we addressed a problem of automatic and robust segmentation of cerebral micro-vessels structures in cerebrovascular images acquired by light-sheet microscope for mouse. To segment micro-vessels in large-scale image data, we proposed a convolutional neural networks (CNNs) architecture trained by 1.58 million pixels with manual label. Three convolutional layers and one fully connected layer were used in the CNNs model. We extracted a patch of size 32x32 pixels in each acquired brain vessel image as training data set to feed into CNNs for classification. This network was trained to output the probability that the center pixel of input patch belongs to vessel structures. To build the CNNs architecture, a series of mouse brain vascular images acquired from a commercial light sheet fluorescence microscopy (LSFM) system were used for training the model. The experimental results demonstrated that our approach is a promising method for effectively segmenting micro-vessels structures in cerebrovascular images with vessel-dense, nonuniform gray-level and long-scale contrast regions.

  10. Neural network to diagnose lining condition

    Science.gov (United States)

    Yemelyanov, V. A.; Yemelyanova, N. Y.; Nedelkin, A. A.; Zarudnaya, M. V.

    2018-03-01

    The paper presents data on the problem of diagnosing the lining condition at the iron and steel works. The authors describe the neural network structure and software that are designed and developed to determine the lining burnout zones. The simulation results of the proposed neural networks are presented. The authors note the low learning and classification errors of the proposed neural networks. To realize the proposed neural network, the specialized software has been developed.

  11. The effect of the neural activity on topological properties of growing neural networks.

    Science.gov (United States)

    Gafarov, F M; Gafarova, V R

    2016-09-01

    The connectivity structure in cortical networks defines how information is transmitted and processed, and it is a source of the complex spatiotemporal patterns of network's development, and the process of creation and deletion of connections is continuous in the whole life of the organism. In this paper, we study how neural activity influences the growth process in neural networks. By using a two-dimensional activity-dependent growth model we demonstrated the neural network growth process from disconnected neurons to fully connected networks. For making quantitative investigation of the network's activity influence on its topological properties we compared it with the random growth network not depending on network's activity. By using the random graphs theory methods for the analysis of the network's connections structure it is shown that the growth in neural networks results in the formation of a well-known "small-world" network.

  12. Galectin-1 is expressed in early-type neural progenitor cells and down-regulates neurogenesis in the adult hippocampus

    Directory of Open Access Journals (Sweden)

    Imaizumi Yoichi

    2011-01-01

    Full Text Available Abstract Background In the adult mammalian brain, neural stem cells (NSCs proliferate in the dentate gyrus (DG of the hippocampus and generate new neurons throughout life. A multimodal protein, Galectin-1, is expressed in neural progenitor cells (NPCs and implicated in the proliferation of the NPCs in the DG. However, little is known about its detailed expression profile in the NPCs and functions in adult neurogenesis in the DG. Results Our immunohistochemical and morphological analysis showed that Galectin-1 was expressed in the type 1 and 2a cells, which are putative NSCs, in the subgranular zone (SGZ of the adult mouse DG. To study Galectin-1's function in adult hippocampal neurogenesis, we made galectin-1 knock-out mice on the C57BL6 background and characterized the effects on neurogenesis. In the SGZ of the galectin-1 knock-out mice, increased numbers of type 1 cells, DCX-positive immature progenitors, and NeuN-positive newborn neurons were observed. Using triple-labeling immunohistochemistry and morphological analyses, we found that the proliferation of the type-1 cells was increased in the SGZ of the galectin-1 knock-out mice, and we propose that this proliferation is the mechanism for the net increase in the adult neurogenesis in these knock-out mice DG. Conclusions Galectin-1 is expressed in the neural stem cells and down-regulates neurogenesis in the adult hippocampus.

  13. Neural overlap in processing music and speech.

    Science.gov (United States)

    Peretz, Isabelle; Vuvan, Dominique; Lagrois, Marie-Élaine; Armony, Jorge L

    2015-03-19

    Neural overlap in processing music and speech, as measured by the co-activation of brain regions in neuroimaging studies, may suggest that parts of the neural circuitries established for language may have been recycled during evolution for musicality, or vice versa that musicality served as a springboard for language emergence. Such a perspective has important implications for several topics of general interest besides evolutionary origins. For instance, neural overlap is an important premise for the possibility of music training to influence language acquisition and literacy. However, neural overlap in processing music and speech does not entail sharing neural circuitries. Neural separability between music and speech may occur in overlapping brain regions. In this paper, we review the evidence and outline the issues faced in interpreting such neural data, and argue that converging evidence from several methodologies is needed before neural overlap is taken as evidence of sharing. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  14. Complex-Valued Neural Networks

    CERN Document Server

    Hirose, Akira

    2012-01-01

    This book is the second enlarged and revised edition of the first successful monograph on complex-valued neural networks (CVNNs) published in 2006, which lends itself to graduate and undergraduate courses in electrical engineering, informatics, control engineering, mechanics, robotics, bioengineering, and other relevant fields. In the second edition the recent trends in CVNNs research are included, resulting in e.g. almost a doubled number of references. The parametron invented in 1954 is also referred to with discussion on analogy and disparity. Also various additional arguments on the advantages of the complex-valued neural networks enhancing the difference to real-valued neural networks are given in various sections. The book is useful for those beginning their studies, for instance, in adaptive signal processing for highly functional sensing and imaging, control in unknown and changing environment, robotics inspired by human neural systems, and brain-like information processing, as well as interdisciplina...

  15. Memristor-based neural networks

    International Nuclear Information System (INIS)

    Thomas, Andy

    2013-01-01

    The synapse is a crucial element in biological neural networks, but a simple electronic equivalent has been absent. This complicates the development of hardware that imitates biological architectures in the nervous system. Now, the recent progress in the experimental realization of memristive devices has renewed interest in artificial neural networks. The resistance of a memristive system depends on its past states and exactly this functionality can be used to mimic the synaptic connections in a (human) brain. After a short introduction to memristors, we present and explain the relevant mechanisms in a biological neural network, such as long-term potentiation and spike time-dependent plasticity, and determine the minimal requirements for an artificial neural network. We review the implementations of these processes using basic electric circuits and more complex mechanisms that either imitate biological systems or could act as a model system for them. (topical review)

  16. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Yu, E-mail: tanyu2048@163.com; Fu, Runqing, E-mail: furunqing@sjtu.edu.cn; Liu, Jiaqiang, E-mail: liujqmj@163.com; Wu, Yong, E-mail: wyonger@gmail.com; Wang, Bo, E-mail: wb228@126.com; Jiang, Ning, E-mail: 179639060@qq.com; Nie, Ping, E-mail: nieping1011@sina.com; Cao, Haifeng, E-mail: 0412chf@163.com; Yang, Zhi, E-mail: wcums1981@163.com; Fang, Bing, E-mail: fangbing@sjtu.edu.cn

    2016-07-08

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. -- Highlights: •We firstly reported that ADAM10 was essentially involved in maxillofacial bone development. •ADAM10 cKO mice present craniofacial dysmorphia and bone defects. •Impaired osteoblast differentiation,proliferation and apoptosis underlie the bone deformity.

  17. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

    International Nuclear Information System (INIS)

    Tan, Yu; Fu, Runqing; Liu, Jiaqiang; Wu, Yong; Wang, Bo; Jiang, Ning; Nie, Ping; Cao, Haifeng; Yang, Zhi; Fang, Bing

    2016-01-01

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. -- Highlights: •We firstly reported that ADAM10 was essentially involved in maxillofacial bone development. •ADAM10 cKO mice present craniofacial dysmorphia and bone defects. •Impaired osteoblast differentiation,proliferation and apoptosis underlie the bone deformity.

  18. BMP7 and SHH regulate Pax2 in mouse retinal astrocytes by relieving TLX repression.

    Science.gov (United States)

    Sehgal, Rachna; Sheibani, Nader; Rhodes, Simon J; Belecky Adams, Teri L

    2009-08-15

    Pax2 is essential for development of the neural tube, urogenital system, optic vesicle, optic cup and optic tract. In the eye, Pax2 deficiency is associated with coloboma, a loss of astrocytes in the optic nerve and retina, and abnormal axonal pathfinding of the ganglion cell axons at the optic chiasm. Thus, appropriate expression of Pax2 is essential for astrocyte determination and differentiation. Although BMP7 and SHH have been shown to regulate Pax2 expression, the molecular mechanism by which this regulation occurs is not well understood. In this study, we determined that BMP7 and SHH activate Pax2 expression in mouse retinal astrocyte precursors in vitro. SHH appeared to play a dual role in Pax2 regulation; 1) SHH may regulate BMP7 expression, and 2) the SHH pathway cooperates with the BMP pathway to regulate Pax2 expression. BMP and SHH pathway members can interact separately or together with TLX, a repressor protein in the tailless transcription factor family. Here we show that the interaction of both pathways with TLX relieves the repression of Pax2 expression in mouse retinal astrocytes. Together these data reveal a new mechanism for the cooperative actions of signaling pathways in astrocyte determination and differentiation and suggest interactions of regulatory pathways that are applicable to other developmental programs.

  19. Mouse androgenetic embryonic stem cells differentiated to multiple cell lineages in three embryonic germ layers in vitro.

    Science.gov (United States)

    Teramura, Takeshi; Onodera, Yuta; Murakami, Hideki; Ito, Syunsuke; Mihara, Toshihiro; Takehara, Toshiyuki; Kato, Hiromi; Mitani, Tasuku; Anzai, Masayuki; Matsumoto, Kazuya; Saeki, Kazuhiro; Fukuda, Kanji; Sagawa, Norimasa; Osoi, Yoshihiko

    2009-06-01

    The embryos of some rodents and primates can precede early development without the process of fertilization; however, they cease to develop after implantation because of restricted expressions of imprinting genes. Asexually developed embryos are classified into parthenote/gynogenote and androgenote by their genomic origins. Embryonic stem cells (ESCs) derived from asexual origins have also been reported. To date, ESCs derived from parthenogenetic embryos (PgESCs) have been established in some species, including humans, and the possibility to be alternative sources for autologous cell transplantation in regenerative medicine has been proposed. However, some developmental characteristics, which might be important for therapeutic applications, such as multiple differentiation capacity and transplantability of the ESCs of androgenetic origin (AgESCs) are uncertain. Here, we induced differentiation of mouse AgESCs and observed derivation of neural cells, cardiomyocytes and hepatocytes in vitro. Following differentiated embryoid body (EB) transplantation in various mouse strains including the strain of origin, we found that the EBs could engraft in theoretically MHC-matched strains. Our results indicate that AgESCs possess at least two important characteristics, multiple differentiation properties in vitro and transplantability after differentiation, and suggest that they can also serve as a source of histocompatible tissues for transplantation.

  20. Neural crest contributions to the lamprey head

    Science.gov (United States)

    McCauley, David W.; Bronner-Fraser, Marianne

    2003-01-01

    The neural crest is a vertebrate-specific cell population that contributes to the facial skeleton and other derivatives. We have performed focal DiI injection into the cranial neural tube of the developing lamprey in order to follow the migratory pathways of discrete groups of cells from origin to destination and to compare neural crest migratory pathways in a basal vertebrate to those of gnathostomes. The results show that the general pathways of cranial neural crest migration are conserved throughout the vertebrates, with cells migrating in streams analogous to the mandibular and hyoid streams. Caudal branchial neural crest cells migrate ventrally as a sheet of cells from the hindbrain and super-pharyngeal region of the neural tube and form a cylinder surrounding a core of mesoderm in each pharyngeal arch, similar to that seen in zebrafish and axolotl. In addition to these similarities, we also uncovered important differences. Migration into the presumptive caudal branchial arches of the lamprey involves both rostral and caudal movements of neural crest cells that have not been described in gnathostomes, suggesting that barriers that constrain rostrocaudal movement of cranial neural crest cells may have arisen after the agnathan/gnathostome split. Accordingly, neural crest cells from a single axial level contributed to multiple arches and there was extensive mixing between populations. There was no apparent filling of neural crest derivatives in a ventral-to-dorsal order, as has been observed in higher vertebrates, nor did we find evidence of a neural crest contribution to cranial sensory ganglia. These results suggest that migratory constraints and additional neural crest derivatives arose later in gnathostome evolution.

  1. The Virtual Mouse Brain: A Computational Neuroinformatics Platform to Study Whole Mouse Brain Dynamics.

    Science.gov (United States)

    Melozzi, Francesca; Woodman, Marmaduke M; Jirsa, Viktor K; Bernard, Christophe

    2017-01-01

    Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brain's structure-function relationship, necessitating the close integration of diverse neuroinformatics fields. Here we extend the open-source simulation software The Virtual Brain (TVB) to whole mouse brain network modeling based on individual diffusion magnetic resonance imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain (TVMB) to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease. TVMB enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions.

  2. Immunohistochemical localization of translationally controlled tumor protein in the mouse digestive system.

    Science.gov (United States)

    Sheverdin, Vadim; Jung, Jiwon; Lee, Kyunglim

    2013-09-01

    Translationally controlled tumor protein (TCTP) is a housekeeping protein, highly conserved among various species. It plays a major role in cell differentiation, growth, proliferation, apoptosis and carcinogenesis. Studies reported so far on TCTP expression in different digestive organs have not led to any understanding of the role of TCTP in digestion, so we localized TCTP in organs of the mouse digestive system employing immunohistochemical techniques. Translationally controlled tumor protein was found expressed in all organs studied: tongue, salivary glands, esophagus, stomach, small and large intestines, liver and pancreas. The expression of TCTP was found to be predominant in epithelia and neurons of myenteric nerve ganglia; high in serous glands (parotid, submandibular, gastric, intestinal crypts, pancreatic acini) and in neurons of myenteric nerve ganglia, and moderate to low in epithelia. In epithelia, expression of TCTP varied depending on its type and location. In enteric neurons, TCTP was predominantly expressed in the processes. Translationally controlled tumor protein expression in the liver followed porto-central gradient with higher expression in pericentral hepatocytes. In the pancreas, TCTP was expressed in both acini and islet cells. Our finding of nearly universal localization and expression of TCTP in mouse digestive organs points to the hitherto unrecognized functional importance of TCTP in the digestive system and suggests the need for further studies of the possible role of TCTP in the proliferation, secretion, absorption and neural regulation of the digestive process and its importance in the physiology and pathology of digestive process. © 2013 Anatomical Society.

  3. Signal Processing and Neural Network Simulator

    Science.gov (United States)

    Tebbe, Dennis L.; Billhartz, Thomas J.; Doner, John R.; Kraft, Timothy T.

    1995-04-01

    The signal processing and neural network simulator (SPANNS) is a digital signal processing simulator with the capability to invoke neural networks into signal processing chains. This is a generic tool which will greatly facilitate the design and simulation of systems with embedded neural networks. The SPANNS is based on the Signal Processing WorkSystemTM (SPWTM), a commercial-off-the-shelf signal processing simulator. SPW provides a block diagram approach to constructing signal processing simulations. Neural network paradigms implemented in the SPANNS include Backpropagation, Kohonen Feature Map, Outstar, Fully Recurrent, Adaptive Resonance Theory 1, 2, & 3, and Brain State in a Box. The SPANNS was developed by integrating SAIC's Industrial Strength Neural Networks (ISNN) Software into SPW.

  4. The Effects of GABAergic Polarity Changes on Episodic Neural Network Activity in Developing Neural Systems

    Directory of Open Access Journals (Sweden)

    Wilfredo Blanco

    2017-09-01

    Full Text Available Early in development, neural systems have primarily excitatory coupling, where even GABAergic synapses are excitatory. Many of these systems exhibit spontaneous episodes of activity that have been characterized through both experimental and computational studies. As development progress the neural system goes through many changes, including synaptic remodeling, intrinsic plasticity in the ion channel expression, and a transformation of GABAergic synapses from excitatory to inhibitory. What effect each of these, and other, changes have on the network behavior is hard to know from experimental studies since they all happen in parallel. One advantage of a computational approach is that one has the ability to study developmental changes in isolation. Here, we examine the effects of GABAergic synapse polarity change on the spontaneous activity of both a mean field and a neural network model that has both glutamatergic and GABAergic coupling, representative of a developing neural network. We find some intuitive behavioral changes as the GABAergic neurons go from excitatory to inhibitory, shared by both models, such as a decrease in the duration of episodes. We also find some paradoxical changes in the activity that are only present in the neural network model. In particular, we find that during early development the inter-episode durations become longer on average, while later in development they become shorter. In addressing this unexpected finding, we uncover a priming effect that is particularly important for a small subset of neurons, called the “intermediate neurons.” We characterize these neurons and demonstrate why they are crucial to episode initiation, and why the paradoxical behavioral change result from priming of these neurons. The study illustrates how even arguably the simplest of developmental changes that occurs in neural systems can present non-intuitive behaviors. It also makes predictions about neural network behavioral changes

  5. Podocalyxin Is a Novel Polysialylated Neural Adhesion Protein with Multiple Roles in Neural Development and Synapse Formation

    Science.gov (United States)

    Vitureira, Nathalia; Andrés, Rosa; Pérez-Martínez, Esther; Martínez, Albert; Bribián, Ana; Blasi, Juan; Chelliah, Shierley; López-Doménech, Guillermo; De Castro, Fernando; Burgaya, Ferran; McNagny, Kelly; Soriano, Eduardo

    2010-01-01

    Neural development and plasticity are regulated by neural adhesion proteins, including the polysialylated form of NCAM (PSA-NCAM). Podocalyxin (PC) is a renal PSA-containing protein that has been reported to function as an anti-adhesin in kidney podocytes. Here we show that PC is widely expressed in neurons during neural development. Neural PC interacts with the ERM protein family, and with NHERF1/2 and RhoA/G. Experiments in vitro and phenotypic analyses of podxl-deficient mice indicate that PC is involved in neurite growth, branching and axonal fasciculation, and that PC loss-of-function reduces the number of synapses in the CNS and in the neuromuscular system. We also show that whereas some of the brain PC functions require PSA, others depend on PC per se. Our results show that PC, the second highly sialylated neural adhesion protein, plays multiple roles in neural development. PMID:20706633

  6. Immunostimulatory mouse granuloma protein.

    Science.gov (United States)

    Fontan, E; Fauve, R M; Hevin, B; Jusforgues, H

    1983-10-01

    Earlier studies have shown that from subcutaneous talc-induced granuloma in mice, a fraction could be extracted that fully protected mice against Listeria monocytogenes. Using standard biochemical procedures--i.e., ammonium sulfate fractionation, preparative electrophoresis, gel filtration chromatography, isoelectric focusing, and preparative polyacrylamide gel electrophoresis--we have now purified an active factor to homogeneity. A single band was obtained in NaDodSO4/polyacrylamide gel with an apparent Mr of 55,000. It migrated with alpha 1-globulins and the isoelectric point was 5 +/- 0.1. The biological activity was destroyed with Pronase but not with trypsin and a monospecific polyclonal rabbit antiserum was obtained. The intravenous injection of 5 micrograms of this "mouse granuloma protein" fully protects mice against a lethal inoculum of L. monocytogenes. Moreover, after their incubation with 10 nM mouse granuloma protein, mouse peritoneal cells became cytostatic against Lewis carcinoma cells.

  7. Genetic Disruption of the Sh3pxd2a Gene Reveals an Essential Role in Mouse Development and the Existence of a Novel Isoform of Tks5

    OpenAIRE

    Cejudo-Martin, Pilar; Yuen, Angela; Vlahovich, Nicole; Lock, Peter; Courtneidge, Sara A.; Díaz, Begoña

    2014-01-01

    Tks5 is a scaffold protein and Src substrate involved in cell migration and matrix degradation through its essential role in invadosome formation and function. We have previously described that Tks5 is fundamental for zebrafish neural crest cell migration in vivo. In the present study, we sought to investigate the function of Tks5 in mammalian development by analyzing mice mutant for sh3pxd2a, the gene encoding Tks5. Homozygous disruption of the sh3pxd2a gene by gene-trapping in mouse resulte...

  8. The syntactic organization of pasta-eating and the structure of reach movements in the head-fixed mouse.

    Science.gov (United States)

    Whishaw, Ian Q; Faraji, Jamshid; Kuntz, Jessica R; Mirza Agha, Behroo; Metz, Gerlinde A S; Mohajerani, Majid H

    2017-09-08

    Mice are adept in the use of their hands for activities such as feeding, which has led to their use in investigations of the neural basis of skilled-movements. We describe the syntactic organization of pasta-eating and the structure of hand movements used for pasta manipulation by the head-fixed mouse. An ethogram of mice consuming pieces of spaghetti reveals that they eat in bite/chew bouts. A bout begins with pasta lifted to the mouth and then manipulated with hand movements into a preferred orientation for biting. Manipulation involves many hand release-reach movements, each with a similar structure. A hand is advanced from a digit closed and flexed (collect) position to a digit extended and open position (overgrasp) and then to a digit closed and flexed (grasp) position. Reach distance, hand shaping, and grasp patterns featuring precision grasps or whole hand grasps are related. To bite, mice display hand preference and asymmetric grasps; one hand (guide grasp) directs food into the mouth and the other stabilizes the pasta for biting. When chewing after biting, the hands hold the pasta in a symmetric resting position. Pasta-eating is organized and features structured hand movements and so lends itself to the neural investigation of skilled-movements.

  9. MicroRNA Cluster miR-17-92 Regulates Neural Stem Cell Expansion and Transition to Intermediate Progenitors in the Developing Mouse Neocortex

    Directory of Open Access Journals (Sweden)

    Shan Bian

    2013-05-01

    Full Text Available During development of the embryonic neocortex, tightly regulated expansion of neural stem cells (NSCs and their transition to intermediate progenitors (IPs are critical for normal cortical formation and function. Molecular mechanisms that regulate NSC expansion and transition remain unclear. Here, we demonstrate that the microRNA (miRNA miR-17-92 cluster is required for maintaining proper populations of cortical radial glial cells (RGCs and IPs through repression of Pten and Tbr2 protein. Knockout of miR-17-92 and its paralogs specifically in the developing neocortex restricts NSC proliferation, suppresses RGC expansion, and promotes transition of RGCs to IPs. Moreover, Pten and Tbr2 protectors specifically block silencing activities of endogenous miR-17-92 and control proper numbers of RGCs and IPs in vivo. Our results demonstrate a critical role for miRNAs in promoting NSC proliferation and modulating the cell-fate decision of generating distinct neural progenitors in the developing neocortex.

  10. Neural plasticity of development and learning.

    Science.gov (United States)

    Galván, Adriana

    2010-06-01

    Development and learning are powerful agents of change across the lifespan that induce robust structural and functional plasticity in neural systems. An unresolved question in developmental cognitive neuroscience is whether development and learning share the same neural mechanisms associated with experience-related neural plasticity. In this article, I outline the conceptual and practical challenges of this question, review insights gleaned from adult studies, and describe recent strides toward examining this topic across development using neuroimaging methods. I suggest that development and learning are not two completely separate constructs and instead, that they exist on a continuum. While progressive and regressive changes are central to both, the behavioral consequences associated with these changes are closely tied to the existing neural architecture of maturity of the system. Eventually, a deeper, more mechanistic understanding of neural plasticity will shed light on behavioral changes across development and, more broadly, about the underlying neural basis of cognition. (c) 2010 Wiley-Liss, Inc.

  11. A study of the relative importance of the peroxiredoxin-, catalase-, and glutathione-dependent systems in neural peroxide metabolism.

    Science.gov (United States)

    Mitozo, Péricles Arruda; de Souza, Luiz Felipe; Loch-Neckel, Gecioni; Flesch, Samira; Maris, Angelica Francesca; Figueiredo, Cláudia Pinto; Dos Santos, Adair Roberto Soares; Farina, Marcelo; Dafre, Alcir Luiz

    2011-07-01

    Cells are endowed with several overlapping peroxide-degrading systems whose relative importance is a matter of debate. In this study, three different sources of neural cells (rat hippocampal slices, rat C6 glioma cells, and mouse N2a neuroblastoma cells) were used as models to understand the relative contributions of individual peroxide-degrading systems. After a pretreatment (30 min) with specific inhibitors, each system was challenged with either H₂O₂ or cumene hydroperoxide (CuOOH), both at 100 μM. Hippocampal slices, C6 cells, and N2a cells showed a decrease in the H₂O₂ decomposition rate (23-28%) by a pretreatment with the catalase inhibitor aminotriazole. The inhibition of glutathione reductase (GR) by BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) significantly decreased H₂O₂ and CuOOH decomposition rates (31-77%). Inhibition of catalase was not as effective as BCNU at decreasing cell viability (MTT assay) and cell permeability or at increasing DNA damage (comet test). Impairing the thioredoxin (Trx)-dependent peroxiredoxin (Prx) recycling by thioredoxin reductase (TrxR) inhibition with auranofin neither potentiated peroxide toxicity nor decreased the peroxide-decomposition rate. The results indicate that neural peroxidatic systems depending on Trx/TrxR for recycling are not as important as those depending on GSH/GR. Dimer formation, which leads to Prx2 inactivation, was observed in hippocampal slices and N2a cells treated with H₂O₂, but not in C6 cells. However, Prx-SO₃ formation, another form of Prx inactivation, was observed in all neural cell types tested, indicating that redox-mediated signaling pathways can be modulated in neural cells. These differences in Prx2 dimerization suggest specific redox regulation mechanisms in glia-derived (C6) compared to neuron-derived (N2a) cells and hippocampal slices. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Moving Ahead with the Schizophrenia Concept: From the Elephant to the Mouse

    Science.gov (United States)

    Keshavan, Matcheri S; Nasrallah, Henry A; Tandon, Rajiv

    2012-01-01

    The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our “facts” series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to “connect the dots” (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a “fuzzy cluster” of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families

  13. Mouse Resource Browser-a database of mouse databases

    NARCIS (Netherlands)

    Zouberakis, Michael; Chandras, Christina; Swertz, Morris; Smedley, Damian; Gruenberger, Michael; Bard, Jonathan; Schughart, Klaus; Rosenthal, Nadia; Hancock, John M.; Schofield, Paul N.; Kollias, George; Aidinis, Vassilis

    2010-01-01

    The laboratory mouse has become the organism of choice for discovering gene function and unravelling pathogenetic mechanisms of human diseases through the application of various functional genomic approaches. The resulting deluge of data has led to the deployment of numerous online resources and the

  14. Trimaran Resistance Artificial Neural Network

    Science.gov (United States)

    2011-01-01

    11th International Conference on Fast Sea Transportation FAST 2011, Honolulu, Hawaii, USA, September 2011 Trimaran Resistance Artificial Neural Network Richard...Trimaran Resistance Artificial Neural Network 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e... Artificial Neural Network and is restricted to the center and side-hull configurations tested. The value in the parametric model is that it is able to

  15. Adult plasticity in the subcortical auditory pathway of the maternal mouse.

    Directory of Open Access Journals (Sweden)

    Jason A Miranda

    Full Text Available Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.

  16. Adult plasticity in the subcortical auditory pathway of the maternal mouse.

    Science.gov (United States)

    Miranda, Jason A; Shepard, Kathryn N; McClintock, Shannon K; Liu, Robert C

    2014-01-01

    Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.

  17. Consciousness and neural plasticity

    DEFF Research Database (Denmark)

    changes or to abandon the strong identity thesis altogether. Were one to pursue a theory according to which consciousness is not an epiphenomenon to brain processes, consciousness may in fact affect its own neural basis. The neural correlate of consciousness is often seen as a stable structure, that is...

  18. Spatial Impairment and Memory in Genetic Disorders: Insights from Mouse Models

    Directory of Open Access Journals (Sweden)

    Sang Ah Lee

    2017-02-01

    Full Text Available Research across the cognitive and brain sciences has begun to elucidate some of the processes that guide navigation and spatial memory. Boundary geometry and featural landmarks are two distinct classes of environmental cues that have dissociable neural correlates in spatial representation and follow different patterns of learning. Consequently, spatial navigation depends both on the type of cue available and on the type of learning provided. We investigated this interaction between spatial representation and memory by administering two different tasks (working memory, reference memory using two different environmental cues (rectangular geometry, striped landmark in mouse models of human genetic disorders: Prader-Willi syndrome (PWScrm+/p− mice, n = 12 and Beta-catenin mutation (Thr653Lys-substituted mice, n = 12. This exploratory study provides suggestive evidence that these models exhibit different abilities and impairments in navigating by boundary geometry and featural landmarks, depending on the type of memory task administered. We discuss these data in light of the specific deficits in cognitive and brain function in these human syndromes and their animal model counterparts.

  19. c-Fos expression in the paternal mouse brain induced by communicative interaction with maternal mates.

    Science.gov (United States)

    Zhong, Jing; Liang, Mingkun; Akther, Shirin; Higashida, Chiharu; Tsuji, Takahiro; Higashida, Haruhiro

    2014-09-11

    Appropriate parental care by fathers greatly facilitates health in human family life. Much less is known from animal studies regarding the factors and neural circuitry that affect paternal behavior compared with those affecting maternal behavior. We recently reported that ICR mouse sires displayed maternal-like retrieval behavior when they were separated from pups and caged with their mates (co-housing) because the sires receive communicative interactions via ultrasonic and pheromone signals from the dams. We investigated the brain structures involved in regulating this activity by quantifying c-Fos-immunoreactive cells as neuronal activation markers in the neural pathway of male parental behavior. c-Fos expression in the medial preoptic area (mPOA) was significantly higher in sires that exhibited retrieval behavior (retrievers) than those with no such behavior (non-retrievers). Identical increased expression was found in the mPOA region in the retrievers stimulated by ultrasonic vocalizations or pheromones from their mates. Such increases in expression were not observed in the ventral tegmental area (VTA), nucleus accumbens (NAcc) or ventral palladium (VP). On the following day that we identified the families of the retrievers or non-retrievers, c-Fos expression in neuronal subsets in the mPOA, VTA, NAcc and VP was much higher in the retriever sires when they isolated together with their mates in new cages. This difference was not observed in the singly isolated retriever sires in new cages. The non-retriever sires did not display expression changes in the four brain regions that were assessed. The mPOA neurons appeared to be activated by direct communicative interactions with mate dams, including ultrasonic vocalizations and pheromones. The mPOA-VTA-NAcc-VP neural circuit appears to be involved in paternal retrieval behavior.

  20. Wnt3 and Gata4 regulate axon regeneration in adult mouse DRG neurons.

    Science.gov (United States)

    Duan, Run-Shan; Liu, Pei-Pei; Xi, Feng; Wang, Wei-Hua; Tang, Gang-Bin; Wang, Rui-Ying; Saijilafu; Liu, Chang-Mei

    2018-05-05

    Neurons in the adult central nervous system (CNS) have a poor intrinsic axon growth potential after injury, but the underlying mechanisms are largely unknown. Wingless-related mouse mammary tumor virus integration site (WNT) family members regulate neural stem cell proliferation, axon tract and forebrain development in the nervous system. Here we report that Wnt3 is an important modulator of axon regeneration. Downregulation or overexpression of Wnt3 in adult dorsal root ganglion (DRG) neurons enhances or inhibits their axon regeneration ability respectively in vitro and in vivo. Especially, we show that Wnt3 modulates axon regeneration by repressing mRNA translation of the important transcription factor Gata4 via binding to the three prime untranslated region (3'UTR). Downregulation of Gata4 could restore the phenotype exhibited by Wnt3 downregulation in DRG neurons. Taken together, these data indicate that Wnt3 is a key intrinsic regulator of axon growth ability of the nervous system. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Simplified LQG Control with Neural Networks

    DEFF Research Database (Denmark)

    Sørensen, O.

    1997-01-01

    A new neural network application for non-linear state control is described. One neural network is modelled to form a Kalmann predictor and trained to act as an optimal state observer for a non-linear process. Another neural network is modelled to form a state controller and trained to produce...

  2. EuroPhenome and EMPReSS: online mouse phenotyping resource.

    Science.gov (United States)

    Mallon, Ann-Marie; Blake, Andrew; Hancock, John M

    2008-01-01

    EuroPhenome (http://www.europhenome.org) and EMPReSS (http://empress.har.mrc.ac.uk/) form an integrated resource to provide access to data and procedures for mouse phenotyping. EMPReSS describes 96 Standard Operating Procedures for mouse phenotyping. EuroPhenome contains data resulting from carrying out EMPReSS protocols on four inbred laboratory mouse strains. As well as web interfaces, both resources support web services to enable integration with other mouse phenotyping and functional genetics resources, and are committed to initiatives to improve integration of mouse phenotype databases. EuroPhenome will be the repository for a recently initiated effort to carry out large-scale phenotyping on a large number of knockout mouse lines (EUMODIC).

  3. Fuzzy neural network theory and application

    CERN Document Server

    Liu, Puyin

    2004-01-01

    This book systematically synthesizes research achievements in the field of fuzzy neural networks in recent years. It also provides a comprehensive presentation of the developments in fuzzy neural networks, with regard to theory as well as their application to system modeling and image restoration. Special emphasis is placed on the fundamental concepts and architecture analysis of fuzzy neural networks. The book is unique in treating all kinds of fuzzy neural networks and their learning algorithms and universal approximations, and employing simulation examples which are carefully designed to he

  4. Practical neural network recipies in C++

    CERN Document Server

    Masters

    2014-01-01

    This text serves as a cookbook for neural network solutions to practical problems using C++. It will enable those with moderate programming experience to select a neural network model appropriate to solving a particular problem, and to produce a working program implementing that network. The book provides guidance along the entire problem-solving path, including designing the training set, preprocessing variables, training and validating the network, and evaluating its performance. Though the book is not intended as a general course in neural networks, no background in neural works is assum

  5. Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions

    Directory of Open Access Journals (Sweden)

    Li-juan Ye

    2016-01-01

    Full Text Available Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells. Therefore, neural stem cell transplantation can be used to promote functional recovery of the nervous system. Rhesus monkey neural stem cells (1 × 105 cells/μL were injected into bilateral hippocampi of rats with hippocampal lesions. Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well. Transplanted cells were detected at the lesion site, but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum. Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall, and integrated into the recipient brain. Behavioral tests revealed that spatial learning and memory ability improved, indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.

  6. Teratology studies in the mouse.

    Science.gov (United States)

    Marsden, Edward; Leroy, Mariline

    2013-01-01

    The rat is the routine species of choice as the rodent model for regulatory safety testing of xenobiotics such as medicinal products, food additives, and other chemicals. However, the rat is not always suitable for pharmacological, toxicological, immunogenic, pharmacokinetic, or even practical reasons. Under such circumstances, the mouse offers an alternative for finding a suitable rodent model acceptable to the regulatory authorities. Since all essential routes of administration are possible, the short reproductive cycle and large litter size of the mouse make it a species well adapted for use in teratology studies. Given that good quality animals, including virgin mated females, can be acquired relatively easily and inexpensively, the mouse has been used in reproductive toxicity studies for decades and study protocols are well established.

  7. Global Robust Stability of Switched Interval Neural Networks with Discrete and Distributed Time-Varying Delays of Neural Type

    Directory of Open Access Journals (Sweden)

    Huaiqin Wu

    2012-01-01

    Full Text Available By combing the theories of the switched systems and the interval neural networks, the mathematics model of the switched interval neural networks with discrete and distributed time-varying delays of neural type is presented. A set of the interval parameter uncertainty neural networks with discrete and distributed time-varying delays of neural type are used as the individual subsystem, and an arbitrary switching rule is assumed to coordinate the switching between these networks. By applying the augmented Lyapunov-Krasovskii functional approach and linear matrix inequality (LMI techniques, a delay-dependent criterion is achieved to ensure to such switched interval neural networks to be globally asymptotically robustly stable in terms of LMIs. The unknown gain matrix is determined by solving this delay-dependent LMIs. Finally, an illustrative example is given to demonstrate the validity of the theoretical results.

  8. Adaptive eye-gaze tracking using neural-network-based user profiles to assist people with motor disability.

    Science.gov (United States)

    Sesin, Anaelis; Adjouadi, Malek; Cabrerizo, Mercedes; Ayala, Melvin; Barreto, Armando

    2008-01-01

    This study developed an adaptive real-time human-computer interface (HCI) that serves as an assistive technology tool for people with severe motor disability. The proposed HCI design uses eye gaze as the primary computer input device. Controlling the mouse cursor with raw eye coordinates results in sporadic motion of the pointer because of the saccadic nature of the eye. Even though eye movements are subtle and completely imperceptible under normal circumstances, they considerably affect the accuracy of an eye-gaze-based HCI. The proposed HCI system is novel because it adapts to each specific user's different and potentially changing jitter characteristics through the configuration and training of an artificial neural network (ANN) that is structured to minimize the mouse jitter. This task is based on feeding the ANN a user's initially recorded eye-gaze behavior through a short training session. The ANN finds the relationship between the gaze coordinates and the mouse cursor position based on the multilayer perceptron model. An embedded graphical interface is used during the training session to generate user profiles that make up these unique ANN configurations. The results with 12 subjects in test 1, which involved following a moving target, showed an average jitter reduction of 35%; the results with 9 subjects in test 2, which involved following the contour of a square object, showed an average jitter reduction of 53%. For both results, the outcomes led to trajectories that were significantly smoother and apt at reaching fixed or moving targets with relative ease and within a 5% error margin or deviation from desired trajectories. The positive effects of such jitter reduction are presented graphically for visual appreciation.

  9. Introduction to Artificial Neural Networks

    DEFF Research Database (Denmark)

    Larsen, Jan

    1999-01-01

    The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks.......The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks....

  10. Spike Neural Models Part II: Abstract Neural Models

    Directory of Open Access Journals (Sweden)

    Johnson, Melissa G.

    2018-02-01

    Full Text Available Neurons are complex cells that require a lot of time and resources to model completely. In spiking neural networks (SNN though, not all that complexity is required. Therefore simple, abstract models are often used. These models save time, use less computer resources, and are easier to understand. This tutorial presents two such models: Izhikevich's model, which is biologically realistic in the resulting spike trains but not in the parameters, and the Leaky Integrate and Fire (LIF model which is not biologically realistic but does quickly and easily integrate input to produce spikes. Izhikevich's model is based on Hodgkin-Huxley's model but simplified such that it uses only two differentiation equations and four parameters to produce various realistic spike patterns. LIF is based on a standard electrical circuit and contains one equation. Either of these two models, or any of the many other models in literature can be used in a SNN. Choosing a neural model is an important task that depends on the goal of the research and the resources available. Once a model is chosen, network decisions such as connectivity, delay, and sparseness, need to be made. Understanding neural models and how they are incorporated into the network is the first step in creating a SNN.

  11. Circadian oscillators in the mouse brain

    DEFF Research Database (Denmark)

    Rath, Martin F; Rovsing, Louise; Møller, Morten

    2014-01-01

    with conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje...... and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes...... are similar in the neocortex and cerebellum, but they are delayed by 5 h as compared to the SCN, suggestively reflecting a master-slave relationship between the SCN and extra-hypothalamic oscillators. Furthermore, ARNTL protein products are detectable in neurons of the mouse neocortex and cerebellum...

  12. Number and location of mouse mammary tumor virus proviral DNA in mouse DNA of normal tissue and of mammary tumors.

    Science.gov (United States)

    Groner, B; Hynes, N E

    1980-01-01

    The Southern DNA filter transfer technique was used to characterize the genomic location of the mouse mammary tumor proviral DNA in different inbred strains of mice. Two of the strains (C3H and CBA) arose from a cross of a Bagg albino (BALB/c) mouse and a DBA mouse. The mouse mammary tumor virus-containing restriction enzyme DNA fragments of these strains had similar patterns, suggesting that the proviruses of these mice are in similar genomic locations. Conversely, the pattern arising from the DNA of the GR mouse, a strain genetically unrelated to the others, appeared different, suggesting that its mouse mammary tumor proviruses are located in different genomic sites. The structure of another gene, that coding for beta-globin, was also compared. The mice strains which we studied can be categorized into two classes, expressing either one or two beta-globin proteins. The macroenvironment of the beta-globin gene appeared similar among the mice strains belonging to one genetic class. Female mice of the C3H strain exogenously transmit mouse mammary tumor virus via the milk, and their offspring have a high incidence of mammary tumor occurrence. DNA isolated from individual mammary tumors taken from C3H mice or from BALB/c mice foster nursed on C3H mothers was analyzed by the DNA filter transfer technique. Additional mouse mammary tumor virus-containing fragments were found in the DNA isolated from each mammary tumor. These proviral sequences were integrated into different genomic sites in each tumor. Images PMID:6245257

  13. Noradrenergic modulation of neural erotic stimulus perception.

    Science.gov (United States)

    Graf, Heiko; Wiegers, Maike; Metzger, Coraline Danielle; Walter, Martin; Grön, Georg; Abler, Birgit

    2017-09-01

    We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing. Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental activations under reboxetine within the caudate nucleus corresponding to motivational components of sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested effects on further neural components. We now investigated the same sample under these two agents with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe further neural treatment effects of reboxetine. 19 healthy males were investigated under reboxetine, amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static erotic picture were presented with preceding anticipation periods. Subjective sexual functions were assessed by a self-reported questionnaire. Neural activations were attenuated within the caudate nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride altered differential neural activations during anticipation of erotic stimuli. Our results verified detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic components of sexual behavior. Considering the overlap of neural network alterations with those evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and noradrenergic agents on common neural pathways relevant for sexual behavior. Copyright © 2017 Elsevier B.V. and

  14. Emerging trends in neuro engineering and neural computation

    CERN Document Server

    Lee, Kendall; Garmestani, Hamid; Lim, Chee

    2017-01-01

    This book focuses on neuro-engineering and neural computing, a multi-disciplinary field of research attracting considerable attention from engineers, neuroscientists, microbiologists and material scientists. It explores a range of topics concerning the design and development of innovative neural and brain interfacing technologies, as well as novel information acquisition and processing algorithms to make sense of the acquired data. The book also highlights emerging trends and advances regarding the applications of neuro-engineering in real-world scenarios, such as neural prostheses, diagnosis of neural degenerative diseases, deep brain stimulation, biosensors, real neural network-inspired artificial neural networks (ANNs) and the predictive modeling of information flows in neuronal networks. The book is broadly divided into three main sections including: current trends in technological developments, neural computation techniques to make sense of the neural behavioral data, and application of these technologie...

  15. Active Neural Localization

    OpenAIRE

    Chaplot, Devendra Singh; Parisotto, Emilio; Salakhutdinov, Ruslan

    2018-01-01

    Localization is the problem of estimating the location of an autonomous agent from an observation and a map of the environment. Traditional methods of localization, which filter the belief based on the observations, are sub-optimal in the number of steps required, as they do not decide the actions taken by the agent. We propose "Active Neural Localizer", a fully differentiable neural network that learns to localize accurately and efficiently. The proposed model incorporates ideas of tradition...

  16. Artificial Neural Network Analysis System

    Science.gov (United States)

    2001-02-27

    Contract No. DASG60-00-M-0201 Purchase request no.: Foot in the Door-01 Title Name: Artificial Neural Network Analysis System Company: Atlantic... Artificial Neural Network Analysis System 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Powell, Bruce C 5d. PROJECT NUMBER 5e. TASK NUMBER...34) 27-02-2001 Report Type N/A Dates Covered (from... to) ("DD MON YYYY") 28-10-2000 27-02-2001 Title and Subtitle Artificial Neural Network Analysis

  17. The mouse-human anatomy ontology mapping project.

    Science.gov (United States)

    Hayamizu, Terry F; de Coronado, Sherri; Fragoso, Gilberto; Sioutos, Nicholas; Kadin, James A; Ringwald, Martin

    2012-01-01

    The overall objective of the Mouse-Human Anatomy Project (MHAP) was to facilitate the mapping and harmonization of anatomical terms used for mouse and human models by Mouse Genome Informatics (MGI) and the National Cancer Institute (NCI). The anatomy resources designated for this study were the Adult Mouse Anatomy (MA) ontology and the set of anatomy concepts contained in the NCI Thesaurus (NCIt). Several methods and software tools were identified and evaluated, then used to conduct an in-depth comparative analysis of the anatomy ontologies. Matches between mouse and human anatomy terms were determined and validated, resulting in a highly curated set of mappings between the two ontologies that has been used by other resources. These mappings will enable linking of data from mouse and human. As the anatomy ontologies have been expanded and refined, the mappings have been updated accordingly. Insights are presented into the overall process of comparing and mapping between ontologies, which may prove useful for further comparative analyses and ontology mapping efforts, especially those involving anatomy ontologies. Finally, issues concerning further development of the ontologies, updates to the mapping files, and possible additional applications and significance were considered. DATABASE URL: http://obofoundry.org/cgi-bin/detail.cgi?id=ma2ncit.

  18. The equilibrium of neural firing: A mathematical theory

    Energy Technology Data Exchange (ETDEWEB)

    Lan, Sizhong, E-mail: lsz@fuyunresearch.org [Fuyun Research, Beijing, 100055 (China)

    2014-12-15

    Inspired by statistical thermodynamics, we presume that neuron system has equilibrium condition with respect to neural firing. We show that, even with dynamically changeable neural connections, it is inevitable for neural firing to evolve to equilibrium. To study the dynamics between neural firing and neural connections, we propose an extended communication system where noisy channel has the tendency towards fixed point, implying that neural connections are always attracted into fixed points such that equilibrium can be reached. The extended communication system and its mathematics could be useful back in thermodynamics.

  19. Parameterization Of Solar Radiation Using Neural Network

    International Nuclear Information System (INIS)

    Jiya, J. D.; Alfa, B.

    2002-01-01

    This paper presents a neural network technique for parameterization of global solar radiation. The available data from twenty-one stations is used for training the neural network and the data from other ten stations is used to validate the neural model. The neural network utilizes latitude, longitude, altitude, sunshine duration and period number to parameterize solar radiation values. The testing data was not used in the training to demonstrate the performance of the neural network in unknown stations to parameterize solar radiation. The results indicate a good agreement between the parameterized solar radiation values and actual measured values

  20. Neural Architectures for Control

    Science.gov (United States)

    Peterson, James K.

    1991-01-01

    The cerebellar model articulated controller (CMAC) neural architectures are shown to be viable for the purposes of real-time learning and control. Software tools for the exploration of CMAC performance are developed for three hardware platforms, the MacIntosh, the IBM PC, and the SUN workstation. All algorithm development was done using the C programming language. These software tools were then used to implement an adaptive critic neuro-control design that learns in real-time how to back up a trailer truck. The truck backer-upper experiment is a standard performance measure in the neural network literature, but previously the training of the controllers was done off-line. With the CMAC neural architectures, it was possible to train the neuro-controllers on-line in real-time on a MS-DOS PC 386. CMAC neural architectures are also used in conjunction with a hierarchical planning approach to find collision-free paths over 2-D analog valued obstacle fields. The method constructs a coarse resolution version of the original problem and then finds the corresponding coarse optimal path using multipass dynamic programming. CMAC artificial neural architectures are used to estimate the analog transition costs that dynamic programming requires. The CMAC architectures are trained in real-time for each obstacle field presented. The coarse optimal path is then used as a baseline for the construction of a fine scale optimal path through the original obstacle array. These results are a very good indication of the potential power of the neural architectures in control design. In order to reach as wide an audience as possible, we have run a seminar on neuro-control that has met once per week since 20 May 1991. This seminar has thoroughly discussed the CMAC architecture, relevant portions of classical control, back propagation through time, and adaptive critic designs.

  1. mouseTube – a database to collaboratively unravel mouse ultrasonic communication [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Nicolas Torquet

    2016-09-01

    Full Text Available Ultrasonic vocalisation is a broadly used proxy to evaluate social communication in mouse models of neuropsychiatric disorders. The efficacy and robustness of testing these models suffer from limited knowledge of the structure and functions of these vocalisations as well as of the way to analyse the data. We created mouseTube, an open database with a web interface, to facilitate sharing and comparison of ultrasonic vocalisations data and metadata attached to a recording file. Metadata describe 1 the acquisition procedure, e.g., hardware, software, sampling frequency, bit depth; 2 the biological protocol used to elicit ultrasonic vocalisations; 3 the characteristics of the individual emitting ultrasonic vocalisations (e.g., strain, sex, age. To promote open science and enable reproducibility, data are made freely available. The website provides searching functions to facilitate the retrieval of recording files of interest. It is designed to enable comparisons of ultrasonic vocalisation emission between strains, protocols or laboratories, as well as to test different analysis algorithms and to search for protocols established to elicit mouse ultrasonic vocalisations. Over the long term, users will be able to download and compare different analysis results for each data file. Such application will boost the knowledge on mouse ultrasonic communication and stimulate sharing and comparison of automatic analysis methods to refine phenotyping techniques in mouse models of neuropsychiatric disorders.

  2. Recycling signals in the neural crest

    OpenAIRE

    Taneyhill, Lisa A.; Bronner-Fraser, Marianne E.

    2006-01-01

    Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

  3. Recycling signals in the neural crest.

    Science.gov (United States)

    Taneyhill, Lisa A; Bronner-Fraser, Marianne

    2005-01-01

    Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

  4. Neural control of magnetic suspension systems

    Science.gov (United States)

    Gray, W. Steven

    1993-01-01

    The purpose of this research program is to design, build and test (in cooperation with NASA personnel from the NASA Langley Research Center) neural controllers for two different small air-gap magnetic suspension systems. The general objective of the program is to study neural network architectures for the purpose of control in an experimental setting and to demonstrate the feasibility of the concept. The specific objectives of the research program are: (1) to demonstrate through simulation and experimentation the feasibility of using neural controllers to stabilize a nonlinear magnetic suspension system; (2) to investigate through simulation and experimentation the performance of neural controllers designs under various types of parametric and nonparametric uncertainty; (3) to investigate through simulation and experimentation various types of neural architectures for real-time control with respect to performance and complexity; and (4) to benchmark in an experimental setting the performance of neural controllers against other types of existing linear and nonlinear compensator designs. To date, the first one-dimensional, small air-gap magnetic suspension system has been built, tested and delivered to the NASA Langley Research Center. The device is currently being stabilized with a digital linear phase-lead controller. The neural controller hardware is under construction. Two different neural network paradigms are under consideration, one based on hidden layer feedforward networks trained via back propagation and one based on using Gaussian radial basis functions trained by analytical methods related to stability conditions. Some advanced nonlinear control algorithms using feedback linearization and sliding mode control are in simulation studies.

  5. Neural components of altruistic punishment

    Directory of Open Access Journals (Sweden)

    Emily eDu

    2015-02-01

    Full Text Available Altruistic punishment, which occurs when an individual incurs a cost to punish in response to unfairness or a norm violation, may play a role in perpetuating cooperation. The neural correlates underlying costly punishment have only recently begun to be explored. Here we review the current state of research on the neural basis of altruism from the perspectives of costly punishment, emphasizing the importance of characterizing elementary neural processes underlying a decision to punish. In particular, we emphasize three cognitive processes that contribute to the decision to altruistically punish in most scenarios: inequity aversion, cost-benefit calculation, and social reference frame to distinguish self from others. Overall, we argue for the importance of understanding the neural correlates of altruistic punishment with respect to the core computations necessary to achieve a decision to punish.

  6. Critical Branching Neural Networks

    Science.gov (United States)

    Kello, Christopher T.

    2013-01-01

    It is now well-established that intrinsic variations in human neural and behavioral activity tend to exhibit scaling laws in their fluctuations and distributions. The meaning of these scaling laws is an ongoing matter of debate between isolable causes versus pervasive causes. A spiking neural network model is presented that self-tunes to critical…

  7. Utrophin Compensates dystrophin Loss during Mouse Spermatogenesis

    OpenAIRE

    Chen, Hung-Chih; Chin, Yu-Feng; Lundy, David J.; Liang, Chung-Tiang; Chi, Ya-Hui; Kuo, Paolin; Hsieh, Patrick C. H.

    2017-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the dystrophin gene. The mdx/utrn ?/? mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using dystrophin deficient mdx mouse and utrophin haplodeficient mdx/utrn +/? mouse models, we demonstrate the contribution of Dp427 (f...

  8. Neural computation and the computational theory of cognition.

    Science.gov (United States)

    Piccinini, Gualtiero; Bahar, Sonya

    2013-04-01

    We begin by distinguishing computationalism from a number of other theses that are sometimes conflated with it. We also distinguish between several important kinds of computation: computation in a generic sense, digital computation, and analog computation. Then, we defend a weak version of computationalism-neural processes are computations in the generic sense. After that, we reject on empirical grounds the common assimilation of neural computation to either analog or digital computation, concluding that neural computation is sui generis. Analog computation requires continuous signals; digital computation requires strings of digits. But current neuroscientific evidence indicates that typical neural signals, such as spike trains, are graded like continuous signals but are constituted by discrete functional elements (spikes); thus, typical neural signals are neither continuous signals nor strings of digits. It follows that neural computation is sui generis. Finally, we highlight three important consequences of a proper understanding of neural computation for the theory of cognition. First, understanding neural computation requires a specially designed mathematical theory (or theories) rather than the mathematical theories of analog or digital computation. Second, several popular views about neural computation turn out to be incorrect. Third, computational theories of cognition that rely on non-neural notions of computation ought to be replaced or reinterpreted in terms of neural computation. Copyright © 2012 Cognitive Science Society, Inc.

  9. Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage.

    Directory of Open Access Journals (Sweden)

    Kyeung Min Joo

    Full Text Available Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.

  10. ANT Advanced Neural Tool

    Energy Technology Data Exchange (ETDEWEB)

    Labrador, I.; Carrasco, R.; Martinez, L.

    1996-07-01

    This paper describes a practical introduction to the use of Artificial Neural Networks. Artificial Neural Nets are often used as an alternative to the traditional symbolic manipulation and first order logic used in Artificial Intelligence, due the high degree of difficulty to solve problems that can not be handled by programmers using algorithmic strategies. As a particular case of Neural Net a Multilayer Perception developed by programming in C language on OS9 real time operating system is presented. A detailed description about the program structure and practical use are included. Finally, several application examples that have been treated with the tool are presented, and some suggestions about hardware implementations. (Author) 15 refs.

  11. ANT Advanced Neural Tool

    International Nuclear Information System (INIS)

    Labrador, I.; Carrasco, R.; Martinez, L.

    1996-01-01

    This paper describes a practical introduction to the use of Artificial Neural Networks. Artificial Neural Nets are often used as an alternative to the traditional symbolic manipulation and first order logic used in Artificial Intelligence, due the high degree of difficulty to solve problems that can not be handled by programmers using algorithmic strategies. As a particular case of Neural Net a Multilayer Perception developed by programming in C language on OS9 real time operating system is presented. A detailed description about the program structure and practical use are included. Finally, several application examples that have been treated with the tool are presented, and some suggestions about hardware implementations. (Author) 15 refs

  12. Dynamic decomposition of spatiotemporal neural signals.

    Directory of Open Access Journals (Sweden)

    Luca Ambrogioni

    2017-05-01

    Full Text Available Neural signals are characterized by rich temporal and spatiotemporal dynamics that reflect the organization of cortical networks. Theoretical research has shown how neural networks can operate at different dynamic ranges that correspond to specific types of information processing. Here we present a data analysis framework that uses a linearized model of these dynamic states in order to decompose the measured neural signal into a series of components that capture both rhythmic and non-rhythmic neural activity. The method is based on stochastic differential equations and Gaussian process regression. Through computer simulations and analysis of magnetoencephalographic data, we demonstrate the efficacy of the method in identifying meaningful modulations of oscillatory signals corrupted by structured temporal and spatiotemporal noise. These results suggest that the method is particularly suitable for the analysis and interpretation of complex temporal and spatiotemporal neural signals.

  13. Neural networks with discontinuous/impact activations

    CERN Document Server

    Akhmet, Marat

    2014-01-01

    This book presents as its main subject new models in mathematical neuroscience. A wide range of neural networks models with discontinuities are discussed, including impulsive differential equations, differential equations with piecewise constant arguments, and models of mixed type. These models involve discontinuities, which are natural because huge velocities and short distances are usually observed in devices modeling the networks. A discussion of the models, appropriate for the proposed applications, is also provided. This book also: Explores questions related to the biological underpinning for models of neural networks\\ Considers neural networks modeling using differential equations with impulsive and piecewise constant argument discontinuities Provides all necessary mathematical basics for application to the theory of neural networks Neural Networks with Discontinuous/Impact Activations is an ideal book for researchers and professionals in the field of engineering mathematics that have an interest in app...

  14. Implantable neurotechnologies: a review of integrated circuit neural amplifiers.

    Science.gov (United States)

    Ng, Kian Ann; Greenwald, Elliot; Xu, Yong Ping; Thakor, Nitish V

    2016-01-01

    Neural signal recording is critical in modern day neuroscience research and emerging neural prosthesis programs. Neural recording requires the use of precise, low-noise amplifier systems to acquire and condition the weak neural signals that are transduced through electrode interfaces. Neural amplifiers and amplifier-based systems are available commercially or can be designed in-house and fabricated using integrated circuit (IC) technologies, resulting in very large-scale integration or application-specific integrated circuit solutions. IC-based neural amplifiers are now used to acquire untethered/portable neural recordings, as they meet the requirements of a miniaturized form factor, light weight and low power consumption. Furthermore, such miniaturized and low-power IC neural amplifiers are now being used in emerging implantable neural prosthesis technologies. This review focuses on neural amplifier-based devices and is presented in two interrelated parts. First, neural signal recording is reviewed, and practical challenges are highlighted. Current amplifier designs with increased functionality and performance and without penalties in chip size and power are featured. Second, applications of IC-based neural amplifiers in basic science experiments (e.g., cortical studies using animal models), neural prostheses (e.g., brain/nerve machine interfaces) and treatment of neuronal diseases (e.g., DBS for treatment of epilepsy) are highlighted. The review concludes with future outlooks of this technology and important challenges with regard to neural signal amplification.

  15. Mousetrap: An integrated, open-source mouse-tracking package.

    Science.gov (United States)

    Kieslich, Pascal J; Henninger, Felix

    2017-10-01

    Mouse-tracking - the analysis of mouse movements in computerized experiments - is becoming increasingly popular in the cognitive sciences. Mouse movements are taken as an indicator of commitment to or conflict between choice options during the decision process. Using mouse-tracking, researchers have gained insight into the temporal development of cognitive processes across a growing number of psychological domains. In the current article, we present software that offers easy and convenient means of recording and analyzing mouse movements in computerized laboratory experiments. In particular, we introduce and demonstrate the mousetrap plugin that adds mouse-tracking to OpenSesame, a popular general-purpose graphical experiment builder. By integrating with this existing experimental software, mousetrap allows for the creation of mouse-tracking studies through a graphical interface, without requiring programming skills. Thus, researchers can benefit from the core features of a validated software package and the many extensions available for it (e.g., the integration with auxiliary hardware such as eye-tracking, or the support of interactive experiments). In addition, the recorded data can be imported directly into the statistical programming language R using the mousetrap package, which greatly facilitates analysis. Mousetrap is cross-platform, open-source and available free of charge from https://github.com/pascalkieslich/mousetrap-os .

  16. Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome.

    Science.gov (United States)

    Castro, Hoanna; Kul, Emre; Buijsen, Ronald A M; Severijnen, Lies-Anne W F M; Willemsen, Rob; Hukema, Renate K; Stork, Oliver; Santos, Mónica

    2017-06-01

    A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model. P90CGG mice display heightened anxiety, deficits in motor coordination and impaired gait and represent the first FXTAS model that exhibits an ataxia phenotype as observed in patients. The behavioural phenotype is accompanied by the formation of ubiquitin/FMRpolyglycine-positive intranuclear inclusions, as another hallmark of FXTAS, in the cerebellum, hippocampus and amygdala. Strikingly, upon cessation of transgene induction the anxiety phenotype of mice recovers along with a reduction of intranuclear inclusions in dentate gyrus and amygdala. In contrast, motor function deteriorates further and no reduction in intranuclear inclusions can be observed in the cerebellum. Our data thus demonstrate that expression of a 90CGG premutation expansion outside of the FMR1 context is sufficient to evoke an FXTAS-like behavioural phenotype. Brain region-specific neuropathology and (partial) behavioural reversibility make the inducible P90CGG a valuable mouse model for testing pathogenic mechanisms and therapeutic intervention methods. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. A CMOS IC–based multisite measuring system for stimulation and recording in neural preparations in vitro

    Directory of Open Access Journals (Sweden)

    Takashi eTateno

    2014-10-01

    Full Text Available In this report, we describe the system integration of a complementary metal oxide semiconductor (CMOS integrated circuit (IC chip, capable of both stimulation and recording of neurons or neural tissues, to investigate electrical signal propagation within cellular networks in vitro. The overall system consisted of three major subunits: a 5.0 mm × 5.0 mm CMOS IC chip, a reconfigurable logic device (field-programmable gate array, FPGA, and a PC. To test the system, microelectrode arrays (MEAs were used to extracellularly measure the activity of cultured rat cortical neurons and mouse cortical slices. The MEA had 64 bidirectional (stimulation and recording electrodes. In addition, the CMOS IC chip was equipped with dedicated analog filters, amplification stages, and a stimulation buffer. Signals from the electrodes were sampled at 15.6 kHz with 16-bit resolution. The measured input-referred circuitry noise was 10.1 μV root mean square (10 Hz to 100 kHz, which allowed reliable detection of neural signals ranging from several millivolts down to approximately 33 μVpp. Experiments were performed involving the stimulation of neurons with several spatiotemporal patterns and the recording of the triggered activity. An advantage over current MEAs, as demonstrated by our experiments, includes the ability to stimulate (voltage stimulation, 5-bit resolution spatiotemporal patterns in arbitrary subsets of electrodes. Furthermore, the fast stimulation reset mechanism allowed us to record neuronal signals from a stimulating electrode around 3 ms after stimulation. We demonstrate that the system can be directly applied to, for example, auditory neural prostheses in conjunction with an acoustic sensor and a sound processing system.

  18. Stability of a neural predictive controller scheme on a neural model

    DEFF Research Database (Denmark)

    Luther, Jim Benjamin; Sørensen, Paul Haase

    2009-01-01

    In previous works presenting various forms of neural-network-based predictive controllers, the main emphasis has been on the implementation aspects, i.e. the development of a robust optimization algorithm for the controller, which will be able to perform in real time. However, the stability issue....... The resulting controller is tested on a nonlinear pneumatic servo system.......In previous works presenting various forms of neural-network-based predictive controllers, the main emphasis has been on the implementation aspects, i.e. the development of a robust optimization algorithm for the controller, which will be able to perform in real time. However, the stability issue...... has not been addressed specifically for these controllers. On the other hand a number of results concerning the stability of receding horizon controllers on a nonlinear system exist. In this paper we present a proof of stability for a predictive controller controlling a neural network model...

  19. PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC

    Directory of Open Access Journals (Sweden)

    A. Cimini

    2007-01-01

    Full Text Available PPAR isotypes are involved in the regulation of cell proliferation, death, and differentiation, with different roles and mechanisms depending on the specific isotype and ligand and on the differentiated, undifferentiated, or transformed status of the cell. Differentiation stimuli are integrated by key transcription factors which regulate specific sets of specialized genes to allow proliferative cells to exit the cell cycle and acquire specialized functions. The main differentiation programs known to be controlled by PPARs both during development and in the adult are placental differentiation, adipogenesis, osteoblast differentiation, skin differentiation, and gut differentiation. PPARs may also be involved in the differentiation of macrophages, brain, and breast. However, their functions in this cell type and organs still awaits further elucidation. PPARs may be involved in cell proliferation and differentiation processes of neural stem cells (NSC. To this aim, in this work the expression of the three PPAR isotypes and RXRs in NSC has been investigated.

  20. Differentiation between non-neural and neural contributors to ankle joint stiffness in cerebral palsy

    NARCIS (Netherlands)

    De Gooijer-van de Groep, K.L.; De Vlugt, E.; De Groot, J.H.; Van der Heijden-Maessen, H.C.M.; Wielheesen, D.H.M.; Van Wijlen-Hempel, R.M.S.; Arendzen, J.H.; Meskers, C.G.M.

    2013-01-01

    Background Spastic paresis in cerebral palsy (CP) is characterized by increased joint stiffness that may be of neural origin, i.e. improper muscle activation caused by e.g. hyperreflexia or non-neural origin, i.e. altered tissue viscoelastic properties (clinically: “spasticity” vs. “contracture”).

  1. Infrared neural stimulation (INS) inhibits electrically evoked neural responses in the deaf white cat

    Science.gov (United States)

    Richter, Claus-Peter; Rajguru, Suhrud M.; Robinson, Alan; Young, Hunter K.

    2014-03-01

    Infrared neural stimulation (INS) has been used in the past to evoke neural activity from hearing and partially deaf animals. All the responses were excitatory. In Aplysia californica, Duke and coworkers demonstrated that INS also inhibits neural responses [1], which similar observations were made in the vestibular system [2, 3]. In deaf white cats that have cochleae with largely reduced spiral ganglion neuron counts and a significant degeneration of the organ of Corti, no cochlear compound action potentials could be observed during INS alone. However, the combined electrical and optical stimulation demonstrated inhibitory responses during irradiation with infrared light.

  2. Melatonin enhances neural stem cell differentiation and engraftment by increasing mitochondrial function.

    Science.gov (United States)

    Mendivil-Perez, Miguel; Soto-Mercado, Viviana; Guerra-Librero, Ana; Fernandez-Gil, Beatriz I; Florido, Javier; Shen, Ying-Qiang; Tejada, Miguel A; Capilla-Gonzalez, Vivian; Rusanova, Iryna; Garcia-Verdugo, José M; Acuña-Castroviejo, Darío; López, Luis Carlos; Velez-Pardo, Carlos; Jimenez-Del-Rio, Marlene; Ferrer, José M; Escames, Germaine

    2017-09-01

    Neural stem cells (NSCs) are regarded as a promising therapeutic approach to protecting and restoring damaged neurons in neurodegenerative diseases (NDs) such as Parkinson's disease and Alzheimer's disease (PD and AD, respectively). However, new research suggests that NSC differentiation is required to make this strategy effective. Several studies have demonstrated that melatonin increases mature neuronal markers, which reflects NSC differentiation into neurons. Nevertheless, the possible involvement of mitochondria in the effects of melatonin during NSC differentiation has not yet been fully established. We therefore tested the impact of melatonin on NSC proliferation and differentiation in an attempt to determine whether these actions depend on modulating mitochondrial activity. We measured proliferation and differentiation markers, mitochondrial structural and functional parameters as well as oxidative stress indicators and also evaluated cell transplant engraftment. This enabled us to show that melatonin (25 μM) induces NSC differentiation into oligodendrocytes and neurons. These effects depend on increased mitochondrial mass/DNA/complexes, mitochondrial respiration, and membrane potential as well as ATP synthesis in NSCs. It is also interesting to note that melatonin prevented oxidative stress caused by high levels of mitochondrial activity. Finally, we found that melatonin enriches NSC engraftment in the ND mouse model following transplantation. We concluded that a combined therapy involving transplantation of NSCs pretreated with pharmacological doses of melatonin could efficiently restore neuronal cell populations in PD and AD mouse models depending on mitochondrial activity promotion. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Neurosecurity: security and privacy for neural devices.

    Science.gov (United States)

    Denning, Tamara; Matsuoka, Yoky; Kohno, Tadayoshi

    2009-07-01

    An increasing number of neural implantable devices will become available in the near future due to advances in neural engineering. This discipline holds the potential to improve many patients' lives dramatically by offering improved-and in some cases entirely new-forms of rehabilitation for conditions ranging from missing limbs to degenerative cognitive diseases. The use of standard engineering practices, medical trials, and neuroethical evaluations during the design process can create systems that are safe and that follow ethical guidelines; unfortunately, none of these disciplines currently ensure that neural devices are robust against adversarial entities trying to exploit these devices to alter, block, or eavesdrop on neural signals. The authors define "neurosecurity"-a version of computer science security principles and methods applied to neural engineering-and discuss why neurosecurity should be a critical consideration in the design of future neural devices.

  4. Promoted neuronal differentiation after activation of alpha4/beta2 nicotinic acetylcholine receptors in undifferentiated neural progenitors.

    Directory of Open Access Journals (Sweden)

    Takeshi Takarada

    Full Text Available BACKGROUND: Neural progenitor is a generic term used for undifferentiated cell populations of neural stem, neuronal progenitor and glial progenitor cells with abilities for proliferation and differentiation. We have shown functional expression of ionotropic N-methyl-D-aspartate (NMDA and gamma-aminobutyrate type-A receptors endowed to positively and negatively regulate subsequent neuronal differentiation in undifferentiated neural progenitors, respectively. In this study, we attempted to evaluate the possible functional expression of nicotinic acetylcholine receptor (nAChR by undifferentiated neural progenitors prepared from neocortex of embryonic rodent brains. METHODOLOGY/PRINCIPAL FINDINGS: Reverse transcription polymerase chain reaction analysis revealed mRNA expression of particular nAChR subunits in undifferentiated rat and mouse progenitors prepared before and after the culture with epidermal growth factor under floating conditions. Sustained exposure to nicotine significantly inhibited the formation of neurospheres composed of clustered proliferating cells and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction activity at a concentration range of 1 µM to 1 mM without affecting cell survival. In these rodent progenitors previously exposed to nicotine, marked promotion was invariably seen for subsequent differentiation into cells immunoreactive for a neuronal marker protein following the culture of dispersed cells under adherent conditions. Both effects of nicotine were significantly prevented by the heteromeric α4β2 nAChR subtype antagonists dihydro-β-erythroidine and 4-(5-ethoxy-3-pyridinyl-N-methyl-(3E-3-buten-1-amine, but not by the homomeric α7 nAChR subtype antagonist methyllycaconitine, in murine progenitors. Sustained exposure to nicotine preferentially increased the expression of Math1 among different basic helix-loop-helix proneural genes examined. In undifferentiated progenitors from embryonic mice

  5. GDNF/GFRα1 Complex Abrogates Self-Renewing Activity of Cortical Neural Precursors Inducing Their Differentiation

    Directory of Open Access Journals (Sweden)

    Antonela Bonafina

    2018-03-01

    Full Text Available Summary: The balance between factors leading to proliferation and differentiation of cortical neural precursors (CNPs determines the correct cortical development. In this work, we show that GDNF and its receptor GFRα1 are expressed in the neocortex during the period of cortical neurogenesis. We show that the GDNF/GFRα1 complex inhibits the self-renewal capacity of mouse CNP cells induced by fibroblast growth factor 2 (FGF2, promoting neuronal differentiation. While GDNF leads to decreased proliferation of cultured cortical precursor cells, ablation of GFRα1 in glutamatergic cortical precursors enhances its proliferation. We show that GDNF treatment of CNPs promoted morphological differentiation even in the presence of the self-renewal-promoting factor, FGF2. Analysis of GFRα1-deficient mice shows an increase in the number of cycling cells during cortical development and a reduction in dendrite development of cortical GFRα1-expressing neurons. Together, these results indicate that GDNF/GFRα1 signaling plays an essential role in regulating the proliferative condition and the differentiation of cortical progenitors. : In this article, Ledda and colleagues show that GDNF acting through its receptor GFRα1 plays a critical role in the maturation of cortical progenitors by counteracting FGF2 self-renewal activity on neural stem cells and promoting neuronal differentiation. Keywords: GDNF, GFRα1, cortical precursors, proliferation, postmitotic neurons, neuronal differentiation

  6. Deconvolution using a neural network

    Energy Technology Data Exchange (ETDEWEB)

    Lehman, S.K.

    1990-11-15

    Viewing one dimensional deconvolution as a matrix inversion problem, we compare a neural network backpropagation matrix inverse with LMS, and pseudo-inverse. This is a largely an exercise in understanding how our neural network code works. 1 ref.

  7. Neural Networks in Control Applications

    DEFF Research Database (Denmark)

    Sørensen, O.

    The intention of this report is to make a systematic examination of the possibilities of applying neural networks in those technical areas, which are familiar to a control engineer. In other words, the potential of neural networks in control applications is given higher priority than a detailed...... study of the networks themselves. With this end in view the following restrictions have been made: - Amongst numerous neural network structures, only the Multi Layer Perceptron (a feed-forward network) is applied. - Amongst numerous training algorithms, only four algorithms are examined, all...... in a recursive form (sample updating). The simplest is the Back Probagation Error Algorithm, and the most complex is the recursive Prediction Error Method using a Gauss-Newton search direction. - Over-fitting is often considered to be a serious problem when training neural networks. This problem is specifically...

  8. Cooperating attackers in neural cryptography.

    Science.gov (United States)

    Shacham, Lanir N; Klein, Einat; Mislovaty, Rachel; Kanter, Ido; Kinzel, Wolfgang

    2004-06-01

    A successful attack strategy in neural cryptography is presented. The neural cryptosystem, based on synchronization of neural networks by mutual learning, has been recently shown to be secure under different attack strategies. The success of the advanced attacker presented here, called the "majority-flipping attacker," does not decay with the parameters of the model. This attacker's outstanding success is due to its using a group of attackers which cooperate throughout the synchronization process, unlike any other attack strategy known. An analytical description of this attack is also presented, and fits the results of simulations.

  9. The Laplacian spectrum of neural networks

    Science.gov (United States)

    de Lange, Siemon C.; de Reus, Marcel A.; van den Heuvel, Martijn P.

    2014-01-01

    The brain is a complex network of neural interactions, both at the microscopic and macroscopic level. Graph theory is well suited to examine the global network architecture of these neural networks. Many popular graph metrics, however, encode average properties of individual network elements. Complementing these “conventional” graph metrics, the eigenvalue spectrum of the normalized Laplacian describes a network's structure directly at a systems level, without referring to individual nodes or connections. In this paper, the Laplacian spectra of the macroscopic anatomical neuronal networks of the macaque and cat, and the microscopic network of the Caenorhabditis elegans were examined. Consistent with conventional graph metrics, analysis of the Laplacian spectra revealed an integrative community structure in neural brain networks. Extending previous findings of overlap of network attributes across species, similarity of the Laplacian spectra across the cat, macaque and C. elegans neural networks suggests a certain level of consistency in the overall architecture of the anatomical neural networks of these species. Our results further suggest a specific network class for neural networks, distinct from conceptual small-world and scale-free models as well as several empirical networks. PMID:24454286

  10. Decentralized neural control application to robotics

    CERN Document Server

    Garcia-Hernandez, Ramon; Sanchez, Edgar N; Alanis, Alma y; Ruz-Hernandez, Jose A

    2017-01-01

    This book provides a decentralized approach for the identification and control of robotics systems. It also presents recent research in decentralized neural control and includes applications to robotics. Decentralized control is free from difficulties due to complexity in design, debugging, data gathering and storage requirements, making it preferable for interconnected systems. Furthermore, as opposed to the centralized approach, it can be implemented with parallel processors. This approach deals with four decentralized control schemes, which are able to identify the robot dynamics. The training of each neural network is performed on-line using an extended Kalman filter (EKF). The first indirect decentralized control scheme applies the discrete-time block control approach, to formulate a nonlinear sliding manifold. The second direct decentralized neural control scheme is based on the backstepping technique, approximated by a high order neural network. The third control scheme applies a decentralized neural i...

  11. Genetic tracing of the gustatory and trigeminal neural pathways originating from T1R3-expressing taste receptor cells and solitary chemoreceptor cells.

    Science.gov (United States)

    Ohmoto, Makoto; Matsumoto, Ichiro; Yasuoka, Akihito; Yoshihara, Yoshihiro; Abe, Keiko

    2008-08-01

    We established transgenic mouse lines expressing a transneuronal tracer, wheat germ agglutinin (WGA), under the control of mouse T1R3 gene promoter/enhancer. In the taste buds, WGA transgene was faithfully expressed in T1R3-positive sweet/umami taste receptor cells. WGA protein was transferred not laterally to the synapse-bearing, sour-responsive type III cells in the taste buds but directly to a subset of neurons in the geniculate and nodose/petrosal ganglia, and further conveyed to a rostro-central region of the nucleus of solitary tract. In addition, WGA was expressed in solitary chemoreceptor cells in the nasal epithelium and transferred along the trigeminal sensory pathway to the brainstem neurons. The solitary chemoreceptor cells endogenously expressed T1R3 together with bitter taste receptors T2Rs. This result shows an exceptional signature of receptor expression. Thus, the t1r3-WGA transgenic mice revealed the sweet/umami gustatory pathways from taste receptor cells and the trigeminal neural pathway from solitary chemoreceptor cells.

  12. Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Sánchez-Martín

    Full Text Available Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb, an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD. Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons, and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents.

  13. Rybp, a polycomb complex-associated protein, is required for mouse eye development

    Directory of Open Access Journals (Sweden)

    Schreiber-Agus Nicole

    2007-04-01

    Full Text Available Abstract Background Rybp (Ring1 and YY1 binding protein is a zinc finger protein which interacts with the members of the mammalian polycomb complexes. Previously we have shown that Rybp is critical for early embryogenesis and that haploinsufficiency of Rybp in a subset of embryos causes failure of neural tube closure. Here we investigated the requirement for Rybp in ocular development using four in vivo mouse models which resulted in either the ablation or overexpression of Rybp. Results Our results demonstrate that loss of a single Rybp allele in conventional knockout mice often resulted in retinal coloboma, an incomplete closure of the optic fissure, characterized by perturbed localization of Pax6 but not of Pax2. In addition, about one half of Rybp-/- Rybp+/+ chimeric embryos also developed retinal colobomas and malformed lenses. Tissue-specific transgenic overexpression of Rybp in the lens resulted in abnormal fiber cell differentiation and severe lens opacification with increased levels of AP-2α and Sox2, and reduced levels of βA4-crystallin gene expression. Ubiquitous transgenic overexpression of Rybp in the entire eye caused abnormal retinal folds, corneal neovascularization, and lens opacification. Additional changes included defects in anterior eye development. Conclusion These studies establish Rybp as a novel gene that has been associated with coloboma. Other genes linked to coloboma encode various classes of transcription factors such as BCOR, CBP, Chx10, Pax2, Pax6, Six3, Ski, Vax1 and Vax2. We propose that the multiple functions for Rybp in regulating mouse retinal and lens development are mediated by genetic, epigenetic and physical interactions between these genes and proteins.

  14. Generation of Mouse Haploid Somatic Cells by Small Molecules for Genome-wide Genetic Screening

    Directory of Open Access Journals (Sweden)

    Zheng-Quan He

    2017-08-01

    Full Text Available The recent success of derivation of mammalian haploid embryonic stem cells (haESCs has provided a powerful tool for large-scale functional analysis of the mammalian genome. However, haESCs rapidly become diploidized after differentiation, posing challenges for genetic analysis. Here, we show that the spontaneous diploidization of haESCs happens in metaphase due to mitotic slippage. Diploidization can be suppressed by small-molecule-mediated inhibition of CDK1 and ROCK. Through ROCK inhibition, we can generate haploid somatic cells of all three germ layers from haESCs, including terminally differentiated neurons. Using piggyBac transposon-based insertional mutagenesis, we generated a haploid neural cell library harboring genome-wide mutations for genetic screening. As a proof of concept, we screened for Mn2+-mediated toxicity and identified the Park2 gene. Our findings expand the applications of mouse haploid cell technology to somatic cell types and may also shed light on the mechanisms of ploidy maintenance.

  15. Mouse embryonic stem cell culture for generation of three-dimensional retinal and cortical tissues.

    Science.gov (United States)

    Eiraku, Mototsugu; Sasai, Yoshiki

    2011-12-15

    Generation of compound tissues with complex structures is a major challenge in cell biology. In this article, we describe a protocol for mouse embryonic stem cell (ESC) culture for in vitro generation of three-dimensional retinal tissue, comparing it with the culture protocol for cortical tissue generation. Dissociated ESCs are reaggregated in a 96-well plate with reduced cell-plate adhesion and cultured as floating aggregates. Retinal epithelium is efficiently generated when ESC aggregates are cultured in serum-free medium containing extracellular matrix proteins, spontaneously forming hemispherical vesicles and then progressively transforming into a shape reminiscent of the embryonic optic cup in 9-10 d. In long-term culture, the ESC-derived optic cup generates a fully stratified retinal tissue consisting of all major neural retinal components. In contrast, the cortical differentiation culture can be started without exogenous extracellular matrix proteins, and it generates stratified cortical epithelia consisting of four distinct layers in 13 d.

  16. The Knockout of Secretin in Cerebellar Purkinje Cells Impairs Mouse Motor Coordination and Motor Learning

    Science.gov (United States)

    Zhang, Li; Chung, Sookja Kim; Chow, Billy Kwok Chong

    2014-01-01

    Secretin (SCT) was first considered to be a gut hormone regulating gastrointestinal functions when discovered. Recently, however, central actions of SCT have drawn intense research interest and are supported by the broad distribution of SCT in specific neuronal populations and by in vivo physiological studies regarding its role in water homeostasis and food intake. The direct action of SCT on a central neuron was first discovered in cerebellar Purkinje cells in which SCT from cerebellar Purkinje cells was found to potentiate GABAergic inhibitory transmission from presynaptic basket cells. Because Purkinje neurons have a major role in motor coordination and learning functions, we hypothesize a behavioral modulatory function for SCT. In this study, we successfully generated a mouse model in which the SCT gene was deleted specifically in Purkinje cells. This mouse line was tested together with SCT knockout and SCT receptor knockout mice in a full battery of behavioral tasks. We found that the knockout of SCT in Purkinje neurons did not affect general motor ability or the anxiety level in open field tests. However, knockout mice did exhibit impairments in neuromuscular strength, motor coordination, and motor learning abilities, as shown by wire hanging, vertical climbing, and rotarod tests. In addition, SCT knockout in Purkinje cells possibly led to the delayed development of motor neurons, as supported by the later occurrence of key neural reflexes. In summary, our data suggest a role in motor coordination and motor learning for SCT expressed in cerebellar Purkinje cells. PMID:24356714

  17. Significant improvement of mouse cloning technique by treatment with trichostatin A after somatic nuclear transfer

    International Nuclear Information System (INIS)

    Kishigami, Satoshi; Mizutani, Eiji; Ohta, Hiroshi; Hikichi, Takafusa; Thuan, Nguyen Van; Wakayama, Sayaka; Bui, Hong-Thuy; Wakayama, Teruhiko

    2006-01-01

    The low success rate of animal cloning by somatic cell nuclear transfer (SCNT) is believed to be associated with epigenetic errors including abnormal DNA hypermethylation. Recently, we elucidated by using round spermatids that, after nuclear transfer, treatment of zygotes with trichostatin A (TSA), an inhibitor of histone deacetylase, can remarkably reduce abnormal DNA hypermethylation depending on the origins of transferred nuclei and their genomic regions [S. Kishigami, N. Van Thuan, T. Hikichi, H. Ohta, S. Wakayama. E. Mizutani, T. Wakayama, Epigenetic abnormalities of the mouse paternal zygotic genome associated with microinsemination of round spermatids, Dev. Biol. (2005) in press]. Here, we found that 5-50 nM TSA-treatment for 10 h following oocyte activation resulted in more efficient in vitro development of somatic cloned embryos to the blastocyst stage from 2- to 5-fold depending on the donor cells including tail tip cells, spleen cells, neural stem cells, and cumulus cells. This TSA-treatment also led to more than 5-fold increase in success rate of mouse cloning from cumulus cells without obvious abnormality but failed to improve ES cloning success. Further, we succeeded in establishment of nuclear transfer-embryonic stem (NT-ES) cells from TSA-treated cloned blastocyst at a rate three times higher than those from untreated cloned blastocysts. Thus, our data indicate that TSA-treatment after SCNT in mice can dramatically improve the practical application of current cloning techniques

  18. Melatonin receptors: latest insights from mouse models

    Science.gov (United States)

    Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

    2014-01-01

    Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

  19. 22nd Italian Workshop on Neural Nets

    CERN Document Server

    Bassis, Simone; Esposito, Anna; Morabito, Francesco

    2013-01-01

    This volume collects a selection of contributions which has been presented at the 22nd Italian Workshop on Neural Networks, the yearly meeting of the Italian Society for Neural Networks (SIREN). The conference was held in Italy, Vietri sul Mare (Salerno), during May 17-19, 2012. The annual meeting of SIREN is sponsored by International Neural Network Society (INNS), European Neural Network Society (ENNS) and IEEE Computational Intelligence Society (CIS). The book – as well as the workshop-  is organized in three main components, two special sessions and a group of regular sessions featuring different aspects and point of views of artificial neural networks and natural intelligence, also including applications of present compelling interest.

  20. Adhesion modification of neural stem cells induced by nanoscale ripple patterns

    International Nuclear Information System (INIS)

    Pedraz, P; Casado, S; Rodriguez, V; Ayuso-Sacido, A; Gnecco, E; Giordano, M C; Mongeot, F Buatier de

    2016-01-01

    We have studied the influence of anisotropic nanopatterns (ripples) on the adhesion and morphology of mouse neural stem cells (C17.2) on glass substrates using cell viability assay, optical microscopy and atomic force microscopy. The ripples were produced by defocused ion beam sputtering with inert Ar ions, which physically remove atoms from the surface at the energy of 800 eV. The ripple periodicity (∼200 nm) is comparable to the thickness of the cytoplasmatic microspikes (filopodia) which link the stem cells to the substrate. All methods show that the cell adhesion is significantly lowered compared to the same type of cells on flat glass surfaces. Furthermore, the AFM analysis reveals that the filopodia tend to be trapped parallel or perpendicular to the ripples, which limits the spreading of the stem cell on the rippled substrate. This opens the perspective of controlling the micro-adhesion of stem cells and the orientation of their filopodia by tuning the anisotropic substrate morphology without chemical reactions occurring at the surface. (paper)

  1. Analysis of neural networks through base functions

    NARCIS (Netherlands)

    van der Zwaag, B.J.; Slump, Cornelis H.; Spaanenburg, L.

    Problem statement. Despite their success-story, neural networks have one major disadvantage compared to other techniques: the inability to explain comprehensively how a trained neural network reaches its output; neural networks are not only (incorrectly) seen as a "magic tool" but possibly even more

  2. Radioprotection by dipyridamole in the aging mouse. Effects on lipid peroxidation in mouse liver, spleen and brain after whole-body X-ray irradiation

    International Nuclear Information System (INIS)

    Seino, Noritaka

    1995-01-01

    To investigate the radioprotective effect of dipyridamole in the aging mouse, the lipid peroxide content in aging mouse liver, spleen and brain irradiated by X-ray were measured both before and after injection of dipyridamole. The lipid peroxide content increased with aging from 2 months old to 16 months old in the mouse liver, spleen and brain. The content of lipid peroxide in the liver and spleen of the aging mouse was significantly increased in 7 days after whole-body irradiation with 8 Gy, but was unchanged in the brain. Dipyridamole, given before irradiation, significantly inhibited the increase of lipid peroxide after irradiation. These results suggest that dipyridamole may have radioprotective effects on aging mouse liver and spleen as well as on young mouse, and that inhibition of lipid peroxidation is a possible factor in the radioprotective effect of dipyridamole. (author)

  3. Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab.

    Science.gov (United States)

    He, Xuzhi; Cruz, Jazmina L; Joseph, Shannon; Pett, Nicola; Chew, Hui Yi; Tuong, Zewen K; Okano, Satomi; Kelly, Gabrielle; Veitch, Margaret; Simpson, Fiona; Wells, James W

    2018-02-23

    The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be "mouse cetuximab" and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach.

  4. Introduction to neural networks

    International Nuclear Information System (INIS)

    Pavlopoulos, P.

    1996-01-01

    This lecture is a presentation of today's research in neural computation. Neural computation is inspired by knowledge from neuro-science. It draws its methods in large degree from statistical physics and its potential applications lie mainly in computer science and engineering. Neural networks models are algorithms for cognitive tasks, such as learning and optimization, which are based on concepts derived from research into the nature of the brain. The lecture first gives an historical presentation of neural networks development and interest in performing complex tasks. Then, an exhaustive overview of data management and networks computation methods is given: the supervised learning and the associative memory problem, the capacity of networks, the Perceptron networks, the functional link networks, the Madaline (Multiple Adalines) networks, the back-propagation networks, the reduced coulomb energy (RCE) networks, the unsupervised learning and the competitive learning and vector quantization. An example of application in high energy physics is given with the trigger systems and track recognition system (track parametrization, event selection and particle identification) developed for the CPLEAR experiment detectors from the LEAR at CERN. (J.S.). 56 refs., 20 figs., 1 tab., 1 appendix

  5. Neural Networks and Micromechanics

    Science.gov (United States)

    Kussul, Ernst; Baidyk, Tatiana; Wunsch, Donald C.

    The title of the book, "Neural Networks and Micromechanics," seems artificial. However, the scientific and technological developments in recent decades demonstrate a very close connection between the two different areas of neural networks and micromechanics. The purpose of this book is to demonstrate this connection. Some artificial intelligence (AI) methods, including neural networks, could be used to improve automation system performance in manufacturing processes. However, the implementation of these AI methods within industry is rather slow because of the high cost of conducting experiments using conventional manufacturing and AI systems. To lower the cost, we have developed special micromechanical equipment that is similar to conventional mechanical equipment but of much smaller size and therefore of lower cost. This equipment could be used to evaluate different AI methods in an easy and inexpensive way. The proved methods could be transferred to industry through appropriate scaling. In this book, we describe the prototypes of low cost microequipment for manufacturing processes and the implementation of some AI methods to increase precision, such as computer vision systems based on neural networks for microdevice assembly and genetic algorithms for microequipment characterization and the increase of microequipment precision.

  6. MEMBRAIN NEURAL NETWORK FOR VISUAL PATTERN RECOGNITION

    Directory of Open Access Journals (Sweden)

    Artur Popko

    2013-06-01

    Full Text Available Recognition of visual patterns is one of significant applications of Artificial Neural Networks, which partially emulate human thinking in the domain of artificial intelligence. In the paper, a simplified neural approach to recognition of visual patterns is portrayed and discussed. This paper is dedicated for investigators in visual patterns recognition, Artificial Neural Networking and related disciplines. The document describes also MemBrain application environment as a powerful and easy to use neural networks’ editor and simulator supporting ANN.

  7. Boolean Factor Analysis by Attractor Neural Network

    Czech Academy of Sciences Publication Activity Database

    Frolov, A. A.; Húsek, Dušan; Muraviev, I. P.; Polyakov, P.Y.

    2007-01-01

    Roč. 18, č. 3 (2007), s. 698-707 ISSN 1045-9227 R&D Projects: GA AV ČR 1ET100300419; GA ČR GA201/05/0079 Institutional research plan: CEZ:AV0Z10300504 Keywords : recurrent neural network * Hopfield-like neural network * associative memory * unsupervised learning * neural network architecture * neural network application * statistics * Boolean factor analysis * dimensionality reduction * features clustering * concepts search * information retrieval Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.769, year: 2007

  8. A report from the Sixth International Mouse Genome Conference

    Energy Technology Data Exchange (ETDEWEB)

    Brown, S. [Saint Mary`s Hospital Medical School, London (United Kingdom). Dept. of Biochemistry and Molecular Genetics

    1992-12-31

    The Sixth Annual Mouse Genome Conference was held in October, 1992 at Buffalo, USA. The mouse is one of the primary model organisms in the Human Genome Project. Through the use of gene targeting studies the mouse has become a powerful biological model for the study of gene function and, in addition, the comparison of the many homologous mutations identified in human and mouse have widened our understanding of the biology of these two organisms. A primary goal in the mouse genome program has been to create a genetic map of STSs of high resolution (<1cM) that would form the basis for the physical mapping of the whole mouse genome. Buffalo saw substantial new progress towards the goal of a very high density genetic map and the beginnings of substantive efforts towards physical mapping in chromosome regions with a high density of genetic markers.

  9. Enhanced casein kinase II activity during mouse embryogenesis. Identification of a 110-kDa phosphoprotein as the major phosphorylation product in mouse embryos and Krebs II mouse ascites tumor cells

    DEFF Research Database (Denmark)

    Schneider, H R; Reichert, G H; Issinger, O G

    1986-01-01

    Mouse embryos at various stages of development were used to study the relationship of protein kinase activities with normal embryogenesis. Casein kinase II (CKII) activity in developing mouse embryos shows a 3-4-fold activity increase at day 12 of gestation. Together with the CKII activity...... mouse tumour cells also show an enhanced CKII activity. Here too, a 110-kDa phosphoprotein was the major phosphoryl acceptor. Partial proteolytic digestion shows that both proteins are identical. Other protein kinases tested (cAMP- and cGMP-dependent protein kinases) only show a basal level of enzyme...

  10. Non-invasive neural stimulation

    Science.gov (United States)

    Tyler, William J.; Sanguinetti, Joseph L.; Fini, Maria; Hool, Nicholas

    2017-05-01

    Neurotechnologies for non-invasively interfacing with neural circuits have been evolving from those capable of sensing neural activity to those capable of restoring and enhancing human brain function. Generally referred to as non-invasive neural stimulation (NINS) methods, these neuromodulation approaches rely on electrical, magnetic, photonic, and acoustic or ultrasonic energy to influence nervous system activity, brain function, and behavior. Evidence that has been surmounting for decades shows that advanced neural engineering of NINS technologies will indeed transform the way humans treat diseases, interact with information, communicate, and learn. The physics underlying the ability of various NINS methods to modulate nervous system activity can be quite different from one another depending on the energy modality used as we briefly discuss. For members of commercial and defense industry sectors that have not traditionally engaged in neuroscience research and development, the science, engineering and technology required to advance NINS methods beyond the state-of-the-art presents tremendous opportunities. Within the past few years alone there have been large increases in global investments made by federal agencies, foundations, private investors and multinational corporations to develop advanced applications of NINS technologies. Driven by these efforts NINS methods and devices have recently been introduced to mass markets via the consumer electronics industry. Further, NINS continues to be explored in a growing number of defense applications focused on enhancing human dimensions. The present paper provides a brief introduction to the field of non-invasive neural stimulation by highlighting some of the more common methods in use or under current development today.

  11. Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients

    International Nuclear Information System (INIS)

    Wlodarczyk, Bogdan J.; Tang, Louisa S.; Triplett, Aleata; Aleman, Frank; Finnell, Richard H.

    2006-01-01

    Splotch (Sp/Sp) mice homozygous for a mutation in the Pax3 gene inevitably present with neural tube defects (NTDs), along with other associated congenital anomalies. The affected mutant embryos usually die by gestation days (E) 12-13. In the present study, the effect of modifier genes from a new genetic background (CXL-Sp) and periconceptional supplementation with selected micronutrients (folic acid, 5-formyltetrahydrofolate, 5-methyltetrahydrofolate, methionine, myoinositol, thiamine, thymidine, and α-tocopherol) was determined with respect to the incidence of NTDs. In order to explore how different exposure parameters (time, dose, and route of compound administration) modulate the beneficial effects of micronutrient supplementation, female mice received either short- or long-term nutrient supplements via enteral or parenteral routes. Embryos were collected on E12.5 and examined for the presence of anterior or posterior NTDs. Additionally, whole mount in situ hybridization studies were conducted in order to reveal/confirm normal expression patterns of the Pax3 gene during neurulation in the wild-type and Sp/Sp homozygous mutant mouse embryos utilized in this study. A strong Pax3 signal was demonstrated in CXL-Sp embryos during neural tube closure (E9.5 to E10.5). The intensity and spatial pattern of expression were similar to other Splotch mutant mice. Of all the micronutrients tested, only supplementation with folic acid or 5-methyltetrahydrofolate rescued the normal phenotype in Sp/Sp embryos. When the folate supplementation dose was increased to 200 mg/kg in the diet, the incidence of rescued splotch homozygotes reached 30%; however, this was accompanied by six-fold increased resorption rate

  12. Neural activation in stress-related exhaustion

    DEFF Research Database (Denmark)

    Gavelin, Hanna Malmberg; Neely, Anna Stigsdotter; Andersson, Micael

    2017-01-01

    The primary purpose of this study was to investigate the association between burnout and neural activation during working memory processing in patients with stress-related exhaustion. Additionally, we investigated the neural effects of cognitive training as part of stress rehabilitation. Fifty...... association between burnout level and working memory performance was found, however, our findings indicate that frontostriatal neural responses related to working memory were modulated by burnout severity. We suggest that patients with high levels of burnout need to recruit additional cognitive resources...... to uphold task performance. Following cognitive training, increased neural activation was observed during 3-back in working memory-related regions, including the striatum, however, low sample size limits any firm conclusions....

  13. Neural Networks for Optimal Control

    DEFF Research Database (Denmark)

    Sørensen, O.

    1995-01-01

    Two neural networks are trained to act as an observer and a controller, respectively, to control a non-linear, multi-variable process.......Two neural networks are trained to act as an observer and a controller, respectively, to control a non-linear, multi-variable process....

  14. Neural constructivism or self-organization?

    NARCIS (Netherlands)

    van der Maas, H.L.J.; Molenaar, P.C.M.

    2000-01-01

    Comments on the article by S. R. Quartz et al (see record 1998-00749-001) which discussed the constructivist perspective of interaction between cognition and neural processes during development and consequences for theories of learning. Three arguments are given to show that neural constructivism

  15. Program Helps Simulate Neural Networks

    Science.gov (United States)

    Villarreal, James; Mcintire, Gary

    1993-01-01

    Neural Network Environment on Transputer System (NNETS) computer program provides users high degree of flexibility in creating and manipulating wide variety of neural-network topologies at processing speeds not found in conventional computing environments. Supports back-propagation and back-propagation-related algorithms. Back-propagation algorithm used is implementation of Rumelhart's generalized delta rule. NNETS developed on INMOS Transputer(R). Predefines back-propagation network, Jordan network, and reinforcement network to assist users in learning and defining own networks. Also enables users to configure other neural-network paradigms from NNETS basic architecture. Small portion of software written in OCCAM(R) language.

  16. Prototype-Incorporated Emotional Neural Network.

    Science.gov (United States)

    Oyedotun, Oyebade K; Khashman, Adnan

    2017-08-15

    Artificial neural networks (ANNs) aim to simulate the biological neural activities. Interestingly, many ''engineering'' prospects in ANN have relied on motivations from cognition and psychology studies. So far, two important learning theories that have been subject of active research are the prototype and adaptive learning theories. The learning rules employed for ANNs can be related to adaptive learning theory, where several examples of the different classes in a task are supplied to the network for adjusting internal parameters. Conversely, the prototype-learning theory uses prototypes (representative examples); usually, one prototype per class of the different classes contained in the task. These prototypes are supplied for systematic matching with new examples so that class association can be achieved. In this paper, we propose and implement a novel neural network algorithm based on modifying the emotional neural network (EmNN) model to unify the prototype- and adaptive-learning theories. We refer to our new model as ``prototype-incorporated EmNN''. Furthermore, we apply the proposed model to two real-life challenging tasks, namely, static hand-gesture recognition and face recognition, and compare the result to those obtained using the popular back-propagation neural network (BPNN), emotional BPNN (EmNN), deep networks, an exemplar classification model, and k-nearest neighbor.

  17. The MAGIC Touch: Combining MAGIC-Pointing with a Touch-Sensitive Mouse

    Science.gov (United States)

    Drewes, Heiko; Schmidt, Albrecht

    In this paper, we show how to use the combination of eye-gaze and a touch-sensitive mouse to ease pointing tasks in graphical user interfaces. A touch of the mouse positions the mouse pointer at the current gaze position of the user. Thus, the pointer is always at the position where the user expects it on the screen. This approach changes the user experience in tasks that include frequent switching between keyboard and mouse input (e.g. working with spreadsheets). In a user study, we compared the touch-sensitive mouse with a traditional mouse and observed speed improvements for pointing tasks on complex backgrounds. For pointing task on plain backgrounds, performances with both devices were similar, but users perceived the gaze-sensitive interaction of the touch-sensitive mouse as being faster and more convenient. Our results show that using a touch-sensitive mouse that positions the pointer on the user’s gaze position reduces the need for mouse movements in pointing tasks enormously.

  18. Modular representation of layered neural networks.

    Science.gov (United States)

    Watanabe, Chihiro; Hiramatsu, Kaoru; Kashino, Kunio

    2018-01-01

    Layered neural networks have greatly improved the performance of various applications including image processing, speech recognition, natural language processing, and bioinformatics. However, it is still difficult to discover or interpret knowledge from the inference provided by a layered neural network, since its internal representation has many nonlinear and complex parameters embedded in hierarchical layers. Therefore, it becomes important to establish a new methodology by which layered neural networks can be understood. In this paper, we propose a new method for extracting a global and simplified structure from a layered neural network. Based on network analysis, the proposed method detects communities or clusters of units with similar connection patterns. We show its effectiveness by applying it to three use cases. (1) Network decomposition: it can decompose a trained neural network into multiple small independent networks thus dividing the problem and reducing the computation time. (2) Training assessment: the appropriateness of a trained result with a given hyperparameter or randomly chosen initial parameters can be evaluated by using a modularity index. And (3) data analysis: in practical data it reveals the community structure in the input, hidden, and output layers, which serves as a clue for discovering knowledge from a trained neural network. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. 38 CFR 17.149 - Sensori-neural aids.

    Science.gov (United States)

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Sensori-neural aids. 17... Prosthetic, Sensory, and Rehabilitative Aids § 17.149 Sensori-neural aids. (a) Notwithstanding any other provision of this part, VA will furnish needed sensori-neural aids (i.e., eyeglasses, contact lenses...

  20. Genetic Algorithm Optimized Neural Networks Ensemble as ...

    African Journals Online (AJOL)

    NJD

    Improvements in neural network calibration models by a novel approach using neural network ensemble (NNE) for the simultaneous ... process by training a number of neural networks. .... Matlab® version 6.1 was employed for building principal component ... provide a fair simulation of calibration data set with some degree.

  1. The Long-Term Outcome Comparison of Different Time-Delayed Kallikrein Treatments in a Mouse Cerebral Ischemic Model

    Directory of Open Access Journals (Sweden)

    Yaohui Ni

    2018-01-01

    Full Text Available Delayed administration of kallikrein after cerebral infarction can improve neurological function. However, the appropriate kallkrein treatment time after ischemic stroke has not been illuminated. In this study, we compared the long-term outcome among three kallikrein therapeutic regimens starting at different time points following mouse cerebral ischemia. Furthermore, the protective mechanisms involving neurogenesis, angiogenesis, and AKT-GSK3β-VEGF signaling pathway were analyzed. Human tissue kallikrein was injected through the tail vein daily starting at 8 h, 24 h, or 36 h after right middle cerebral artery occlusion (MCAO until the 28th day. Three therapeutic regimens all protected against neurological dysfunction, but kallikrein treatment starting at 8 h after MCAO had the best efficacy. Additionally, kallikrein treatment at 8 h after MCAO significantly enhanced cell proliferation including neural stem cell and induced differentiation of neural stem cell into mature neuron. Kallikrein treatment starting at 8 h also promoted more angiogenesis than other two treatment regimens, which was associated with AKT-GSK3β-VEGF signaling pathway. Thus, we confirm that three delayed kallikrein treatments provide protection against cerebral infarction and furthermore suggest that kallikrein treatment starting at 8 h had a better effect than that at 24 h and 36 h. These findings provide the experimental data contributing to better clinical application of exogenous kallikrein.

  2. Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions.

    Directory of Open Access Journals (Sweden)

    Vanessa Donega

    Full Text Available Intranasal treatment with C57BL/6 MSCs reduces lesion volume and improves motor and cognitive behavior in the neonatal hypoxic-ischemic (HI mouse model. In this study, we investigated the potential of human MSCs (hMSCs to treat HI brain injury in the neonatal mouse. Assessing the regenerative capacity of hMSCs is crucial for translation of our knowledge to the clinic. We determined the neuroregenerative potential of hMSCs in vitro and in vivo by intranasal administration 10 d post-HI in neonatal mice. HI was induced in P9 mouse pups. 1×10(6 or 2×10(6 hMSCs were administered intranasally 10 d post-HI. Motor behavior and lesion volume were measured 28 d post-HI. The in vitro capacity of hMSCs to induce differentiation of mouse neural stem cell (mNSC was determined using a transwell co-culture differentiation assay. To determine which chemotactic factors may play a role in mediating migration of MSCs to the lesion, we performed a PCR array on 84 chemotactic factors 10 days following sham-operation, and at 10 and 17 days post-HI. Our results show that 2×10(6 hMSCs decrease lesion volume, improve motor behavior, and reduce scar formation and microglia activity. Moreover, we demonstrate that the differentiation assay reflects the neuroregenerative potential of hMSCs in vivo, as hMSCs induce mNSCs to differentiate into neurons in vitro. We also provide evidence that the chemotactic factor CXCL10 may play an important role in hMSC migration to the lesion site. This is suggested by our finding that CXCL10 is significantly upregulated at 10 days following HI, but not at 17 days after HI, a time when MSCs no longer reach the lesion when given intranasally. The results described in this work also tempt us to contemplate hMSCs not only as a potential treatment option for neonatal encephalopathy, but also for a plethora of degenerative and traumatic injuries of the nervous system.

  3. Relationship between radiobiological hypoxia in a C3H mouse mammary carcinoma and osteopontin levels in mouse serum

    DEFF Research Database (Denmark)

    Lukácová, Slávka; Khalil, Azza Ahmed; Overgaard, Jens

    2005-01-01

    To investigate the possible relationship between radiobiological hypoxia in a C3H mouse mammary carcinoma and osteopontin (OPN) levels measured in mouse serum. MATERIAL AND METHODS: Experiments were performed in CDF1 mice that were either non-tumour bearing or with different sized tumours implanted...... in the right rear foot. Osteopontin levels in extracted mouse blood serum and tissue from the transplanted tumours were measured using an ELISA assay. The tumour oxygenation status was estimated using the Eppendorf Histograph and the fraction of oxygen partial pressure (pO2) values =5 mm Hg (HF5...

  4. Multiple POU-binding motifs, recognized by tissue-specific nuclear factors, are important for Dll1 gene expression in neural stem cells

    International Nuclear Information System (INIS)

    Nakayama, Kohzo; Nagase, Kazuko; Tokutake, Yuriko; Koh, Chang-Sung; Hiratochi, Masahiro; Ohkawara, Takeshi; Nakayama, Noriko

    2004-01-01

    We cloned the 5'-flanking region of the mouse homolog of the Delta gene (Dll1) and demonstrated that the sequence between nucleotide position -514 and -484 in the 5'-flanking region of Dll1 played a critical role in the regulation of its tissue-specific expression in neural stem cells (NSCs). Further, we showed that multiple POU-binding motifs, located within this short sequence of 30 bp, were essential for transcriptional activation of Dll1 and also that multiple tissue-specific nuclear factors recognized these POU-binding motifs in various combinations through differentiation of NSCs. Thus, POU-binding factors may play an important role in Dll1 expression in developing NSCs

  5. Fuzzy logic and neural networks basic concepts & application

    CERN Document Server

    Alavala, Chennakesava R

    2008-01-01

    About the Book: The primary purpose of this book is to provide the student with a comprehensive knowledge of basic concepts of fuzzy logic and neural networks. The hybridization of fuzzy logic and neural networks is also included. No previous knowledge of fuzzy logic and neural networks is required. Fuzzy logic and neural networks have been discussed in detail through illustrative examples, methods and generic applications. Extensive and carefully selected references is an invaluable resource for further study of fuzzy logic and neural networks. Each chapter is followed by a question bank

  6. Neural networks at the Tevatron

    International Nuclear Information System (INIS)

    Badgett, W.; Burkett, K.; Campbell, M.K.; Wu, D.Y.; Bianchin, S.; DeNardi, M.; Pauletta, G.; Santi, L.; Caner, A.; Denby, B.; Haggerty, H.; Lindsey, C.S.; Wainer, N.; Dall'Agata, M.; Johns, K.; Dickson, M.; Stanco, L.; Wyss, J.L.

    1992-10-01

    This paper summarizes neural network applications at the Fermilab Tevatron, including the first online hardware application in high energy physics (muon tracking): the CDF and DO neural network triggers; offline quark/gluon discrimination at CDF; ND a new tool for top to multijets recognition at CDF

  7. Nonequilibrium landscape theory of neural networks

    Science.gov (United States)

    Yan, Han; Zhao, Lei; Hu, Liang; Wang, Xidi; Wang, Erkang; Wang, Jin

    2013-01-01

    The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape–flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments. PMID:24145451

  8. Nonequilibrium landscape theory of neural networks.

    Science.gov (United States)

    Yan, Han; Zhao, Lei; Hu, Liang; Wang, Xidi; Wang, Erkang; Wang, Jin

    2013-11-05

    The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape-flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments.

  9. Application of neural network to CT

    International Nuclear Information System (INIS)

    Ma, Xiao-Feng; Takeda, Tatsuoki

    1999-01-01

    This paper presents a new method for two-dimensional image reconstruction by using a multilayer neural network. Multilayer neural networks are extensively investigated and practically applied to solution of various problems such as inverse problems or time series prediction problems. From learning an input-output mapping from a set of examples, neural networks can be regarded as synthesizing an approximation of multidimensional function (that is, solving the problem of hypersurface reconstruction, including smoothing and interpolation). From this viewpoint, neural networks are well suited to the solution of CT image reconstruction. Though a conventionally used object function of a neural network is composed of a sum of squared errors of the output data, we can define an object function composed of a sum of residue of an integral equation. By employing an appropriate line integral for this integral equation, we can construct a neural network that can be used for CT. We applied this method to some model problems and obtained satisfactory results. As it is not necessary to discretized the integral equation using this reconstruction method, therefore it is application to the problem of complicated geometrical shapes is also feasible. Moreover, in neural networks, interpolation is performed quite smoothly, as a result, inverse mapping can be achieved smoothly even in case of including experimental and numerical errors, However, use of conventional back propagation technique for optimization leads to an expensive computation cost. To overcome this drawback, 2nd order optimization methods or parallel computing will be applied in future. (J.P.N.)

  10. Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice.

    Directory of Open Access Journals (Sweden)

    Yosefu Arime

    Full Text Available Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days of either saline or PCP (10 mg/kg: (1 a discrete paired-trial variable-delay task in T-maze to assess working memory, and (2 brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2-3 of the prelimbic cortex, the number of working memory effort-elicited c-Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2-3 of the prelimbic cortex of the PFC.

  11. Wnt5a-treated midbrain neural stem cells improve dopamine cell replacement therapy in parkinsonian mice

    DEFF Research Database (Denmark)

    Parish, Clare L; Castelo-Branco, Gonçalo; Rawal, Nina

    2008-01-01

    have prevented their clinical application. We present here a method for generating large numbers of DA neurons based on expanding and differentiating ventral midbrain (VM) neural stem cells/progenitors in the presence of key signals necessary for VM DA neuron development. Mouse VM neurospheres (VMNs......Dopamine (DA) cell replacement therapy in Parkinson disease (PD) can be achieved using human fetal mesencephalic tissue; however, limited tissue availability has hindered further developments. Embryonic stem cells provide a promising alternative, but poor survival and risk of teratoma formation......) expanded with FGF2, differentiated with sonic hedgehog and FGF8, and transfected with Wnt5a (VMN-Wnt5a) generated 10-fold more DA neurons than did conventional FGF2-treated VMNs. VMN-Wnt5a cells exhibited the transcriptional and biochemical profiles and intrinsic electrophysiological properties of midbrain...

  12. Methodology of Neural Design: Applications in Microwave Engineering

    Directory of Open Access Journals (Sweden)

    Z. Raida

    2006-06-01

    Full Text Available In the paper, an original methodology for the automatic creation of neural models of microwave structures is proposed and verified. Following the methodology, neural models of the prescribed accuracy are built within the minimum CPU time. Validity of the proposed methodology is verified by developing neural models of selected microwave structures. Functionality of neural models is verified in a design - a neural model is joined with a genetic algorithm to find a global minimum of a formulated objective function. The objective function is minimized using different versions of genetic algorithms, and their mutual combinations. The verified methodology of the automated creation of accurate neural models of microwave structures, and their association with global optimization routines are the most important original features of the paper.

  13. Differentiation between non-neural and neural contributors to ankle joint stiffness in cerebral palsy.

    Science.gov (United States)

    de Gooijer-van de Groep, Karin L; de Vlugt, Erwin; de Groot, Jurriaan H; van der Heijden-Maessen, Hélène C M; Wielheesen, Dennis H M; van Wijlen-Hempel, Rietje M S; Arendzen, J Hans; Meskers, Carel G M

    2013-07-23

    Spastic paresis in cerebral palsy (CP) is characterized by increased joint stiffness that may be of neural origin, i.e. improper muscle activation caused by e.g. hyperreflexia or non-neural origin, i.e. altered tissue viscoelastic properties (clinically: "spasticity" vs. "contracture"). Differentiation between these components is hard to achieve by common manual tests. We applied an assessment instrument to obtain quantitative measures of neural and non-neural contributions to ankle joint stiffness in CP. Twenty-three adolescents with CP and eleven healthy subjects were seated with their foot fixated to an electrically powered single axis footplate. Passive ramp-and-hold rotations were applied over full ankle range of motion (RoM) at low and high velocities. Subject specific tissue stiffness, viscosity and reflexive torque were estimated from ankle angle, torque and triceps surae EMG activity using a neuromuscular model. In CP, triceps surae reflexive torque was on average 5.7 times larger (p = .002) and tissue stiffness 2.1 times larger (p = .018) compared to controls. High tissue stiffness was associated with reduced RoM (p therapy.

  14. Differentiation state determines neural effects on microvascular endothelial cells

    International Nuclear Information System (INIS)

    Muffley, Lara A.; Pan, Shin-Chen; Smith, Andria N.; Ga, Maricar; Hocking, Anne M.; Gibran, Nicole S.

    2012-01-01

    Growing evidence indicates that nerves and capillaries interact paracrinely in uninjured skin and cutaneous wounds. Although mature neurons are the predominant neural cell in the skin, neural progenitor cells have also been detected in uninjured adult skin. The aim of this study was to characterize differential paracrine effects of neural progenitor cells and mature sensory neurons on dermal microvascular endothelial cells. Our results suggest that neural progenitor cells and mature sensory neurons have unique secretory profiles and distinct effects on dermal microvascular endothelial cell proliferation, migration, and nitric oxide production. Neural progenitor cells and dorsal root ganglion neurons secrete different proteins related to angiogenesis. Specific to neural progenitor cells were dipeptidyl peptidase-4, IGFBP-2, pentraxin-3, serpin f1, TIMP-1, TIMP-4 and VEGF. In contrast, endostatin, FGF-1, MCP-1 and thrombospondin-2 were specific to dorsal root ganglion neurons. Microvascular endothelial cell proliferation was inhibited by dorsal root ganglion neurons but unaffected by neural progenitor cells. In contrast, microvascular endothelial cell migration in a scratch wound assay was inhibited by neural progenitor cells and unaffected by dorsal root ganglion neurons. In addition, nitric oxide production by microvascular endothelial cells was increased by dorsal root ganglion neurons but unaffected by neural progenitor cells. -- Highlights: ► Dorsal root ganglion neurons, not neural progenitor cells, regulate microvascular endothelial cell proliferation. ► Neural progenitor cells, not dorsal root ganglion neurons, regulate microvascular endothelial cell migration. ► Neural progenitor cells and dorsal root ganglion neurons do not effect microvascular endothelial tube formation. ► Dorsal root ganglion neurons, not neural progenitor cells, regulate microvascular endothelial cell production of nitric oxide. ► Neural progenitor cells and dorsal root

  15. Sequence and chromosomal localization of the mouse brevican gene

    DEFF Research Database (Denmark)

    Rauch, U; Meyer, H; Brakebusch, C

    1997-01-01

    Brevican is a brain-specific proteoglycan belonging to the aggrecan family. Phage clones containing the complete mouse brevican open reading frame of 2649 bp and the complete 3'-untranslated region of 341 bp were isolated from a mouse brain cDNA library, and cosmid clones containing the mouse...

  16. Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model

    International Nuclear Information System (INIS)

    Hill, Denise S.; Wlodarczyk, Bogdan J.; Mitchell, Laura E.; Finnell, Richard H.

    2009-01-01

    Background: Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals. Objectives: We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment. Methods: We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), L-methionine (L-Met), N-tert-Butyl-α-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects. Results: Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p = 0.0260). Arsenate caused NTDs (100%, p < 0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%. Conclusions: IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.

  17. The wobbler mouse, an ALS animal model

    DEFF Research Database (Denmark)

    Moser, Jakob Maximilian; Bigini, Paolo; Schmitt-John, Thomas

    2013-01-01

    This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking...

  18. Tuning Neural Phase Entrainment to Speech.

    Science.gov (United States)

    Falk, Simone; Lanzilotti, Cosima; Schön, Daniele

    2017-08-01

    Musical rhythm positively impacts on subsequent speech processing. However, the neural mechanisms underlying this phenomenon are so far unclear. We investigated whether carryover effects from a preceding musical cue to a speech stimulus result from a continuation of neural phase entrainment to periodicities that are present in both music and speech. Participants listened and memorized French metrical sentences that contained (quasi-)periodic recurrences of accents and syllables. Speech stimuli were preceded by a rhythmically regular or irregular musical cue. Our results show that the presence of a regular cue modulates neural response as estimated by EEG power spectral density, intertrial coherence, and source analyses at critical frequencies during speech processing compared with the irregular condition. Importantly, intertrial coherences for regular cues were indicative of the participants' success in memorizing the subsequent speech stimuli. These findings underscore the highly adaptive nature of neural phase entrainment across fundamentally different auditory stimuli. They also support current models of neural phase entrainment as a tool of predictive timing and attentional selection across cognitive domains.

  19. Kernel Temporal Differences for Neural Decoding

    Science.gov (United States)

    Bae, Jihye; Sanchez Giraldo, Luis G.; Pohlmeyer, Eric A.; Francis, Joseph T.; Sanchez, Justin C.; Príncipe, José C.

    2015-01-01

    We study the feasibility and capability of the kernel temporal difference (KTD)(λ) algorithm for neural decoding. KTD(λ) is an online, kernel-based learning algorithm, which has been introduced to estimate value functions in reinforcement learning. This algorithm combines kernel-based representations with the temporal difference approach to learning. One of our key observations is that by using strictly positive definite kernels, algorithm's convergence can be guaranteed for policy evaluation. The algorithm's nonlinear functional approximation capabilities are shown in both simulations of policy evaluation and neural decoding problems (policy improvement). KTD can handle high-dimensional neural states containing spatial-temporal information at a reasonable computational complexity allowing real-time applications. When the algorithm seeks a proper mapping between a monkey's neural states and desired positions of a computer cursor or a robot arm, in both open-loop and closed-loop experiments, it can effectively learn the neural state to action mapping. Finally, a visualization of the coadaptation process between the decoder and the subject shows the algorithm's capabilities in reinforcement learning brain machine interfaces. PMID:25866504

  20. Chemical Aspects of Lesser Mouse Deer Meat

    Directory of Open Access Journals (Sweden)

    Djalal Rosyidi

    2012-02-01

    Full Text Available An experiment aiming for studying chemical aspects of lesser mouse deer meat (Tragulus javanicus. This research explored the chemical aspects of lesser mouse deer meat (Tragulus javanicus. Eight lesser mouse deer (four female and four male were used in chemical aspects of lesser mouse deer meat. The parameters observed included proximate analysis, amino acid, fatty acid, cholesterol and EPA-DHA of the meat. The results showed that average meat chemical composition were content of water, protein, fat, ash and cholesterol were 76.33 %, 21.42 %, 0.51 %, 1.20% and 50.00 mg/100 g, respectively. Fatty acid consist of lauric acid, miristate, palmitate, stearic, oleic, linoleic, and linolenic were 1.04 % 3.09%, 30.97, 0.77%., 59.41%, 3.22% and 1.12%, respectively. The total EPA and DHA was 0.13% and 0.05%,   Keywords: amino acid, fatty acid, cholesterol and EPA-DHA

  1. A catalog of the mouse gut metagenome

    DEFF Research Database (Denmark)

    Xiao, Liang; Feng, Qiang; Liang, Suisha

    2015-01-01

    laboratories and fed either a low-fat or high-fat diet. Similar to the human gut microbiome, >99% of the cataloged genes are bacterial. We identified 541 metagenomic species and defined a core set of 26 metagenomic species found in 95% of the mice. The mouse gut microbiome is functionally similar to its human......We established a catalog of the mouse gut metagenome comprising ∼2.6 million nonredundant genes by sequencing DNA from fecal samples of 184 mice. To secure high microbiome diversity, we used mouse strains of diverse genetic backgrounds, from different providers, kept in different housing...... counterpart, with 95.2% of its Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous groups in common. However, only 4.0% of the mouse gut microbial genes were shared (95% identity, 90% coverage) with those of the human gut microbiome. This catalog provides a useful reference for future studies....

  2. Neural synchronization during face-to-face communication.

    Science.gov (United States)

    Jiang, Jing; Dai, Bohan; Peng, Danling; Zhu, Chaozhe; Liu, Li; Lu, Chunming

    2012-11-07

    Although the human brain may have evolutionarily adapted to face-to-face communication, other modes of communication, e.g., telephone and e-mail, increasingly dominate our modern daily life. This study examined the neural difference between face-to-face communication and other types of communication by simultaneously measuring two brains using a hyperscanning approach. The results showed a significant increase in the neural synchronization in the left inferior frontal cortex during a face-to-face dialog between partners but none during a back-to-back dialog, a face-to-face monologue, or a back-to-back monologue. Moreover, the neural synchronization between partners during the face-to-face dialog resulted primarily from the direct interactions between the partners, including multimodal sensory information integration and turn-taking behavior. The communicating behavior during the face-to-face dialog could be predicted accurately based on the neural synchronization level. These results suggest that face-to-face communication, particularly dialog, has special neural features that other types of communication do not have and that the neural synchronization between partners may underlie successful face-to-face communication.

  3. Single cell lineage analysis of mouse embryonic stem cells at the exit from pluripotency

    Directory of Open Access Journals (Sweden)

    Jamie Trott

    2013-08-01

    Understanding how interactions between extracellular signalling pathways and transcription factor networks influence cellular decision making will be crucial for understanding mammalian embryogenesis and for generating specialised cell types in vitro. To this end, pluripotent mouse Embryonic Stem (mES cells have proven to be a useful model system. However, understanding how transcription factors and signalling pathways affect decisions made by individual cells is confounded by the fact that measurements are generally made on groups of cells, whilst individual mES cells differentiate at different rates and towards different lineages, even in conditions that favour a particular lineage. Here we have used single-cell measurements of transcription factor expression and Wnt/β-catenin signalling activity to investigate their effects on lineage commitment decisions made by individual cells. We find that pluripotent mES cells exhibit differing degrees of heterogeneity in their expression of important regulators from pluripotency, depending on the signalling environment to which they are exposed. As mES cells differentiate, downregulation of Nanog and Oct4 primes cells for neural commitment, whilst loss of Sox2 expression primes cells for primitive streak commitment. Furthermore, we find that Wnt signalling acts through Nanog to direct cells towards a primitive streak fate, but that transcriptionally active β-catenin is associated with both neural and primitive streak commitment. These observations confirm and extend previous suggestions that pluripotency genes influence lineage commitment and demonstrate how their dynamic expression affects the direction of lineage commitment, whilst illustrating two ways in which the Wnt signalling pathway acts on this network during cell fate assignment.

  4. Neural principles of memory and a neural theory of analogical insight

    Science.gov (United States)

    Lawson, David I.; Lawson, Anton E.

    1993-12-01

    Grossberg's principles of neural modeling are reviewed and extended to provide a neural level theory to explain how analogies greatly increase the rate of learning and can, in fact, make learning and retention possible. In terms of memory, the key point is that the mind is able to recognize and recall when it is able to match sensory input from new objects, events, or situations with past memory records of similar objects, events, or situations. When a match occurs, an adaptive resonance is set up in which the synaptic strengths of neurons are increased; thus a long term record of the new input is formed in memory. Systems of neurons called outstars and instars are presumably the underlying units that enable this to occur. Analogies can greatly facilitate learning and retention because they activate the outstars (i.e., the cells that are sampling the to-be-learned pattern) and cause the neural activity to grow exponentially by forming feedback loops. This increased activity insures the boost in synaptic strengths of neurons, thus causing storage and retention in long-term memory (i.e., learning).

  5. Neural Network Based Load Frequency Control for Restructuring ...

    African Journals Online (AJOL)

    Neural Network Based Load Frequency Control for Restructuring Power Industry. ... an artificial neural network (ANN) application of load frequency control (LFC) of a Multi-Area power system by using a neural network controller is presented.

  6. Neural substrates of decision-making.

    Science.gov (United States)

    Broche-Pérez, Y; Herrera Jiménez, L F; Omar-Martínez, E

    2016-06-01

    Decision-making is the process of selecting a course of action from among 2 or more alternatives by considering the potential outcomes of selecting each option and estimating its consequences in the short, medium and long term. The prefrontal cortex (PFC) has traditionally been considered the key neural structure in decision-making process. However, new studies support the hypothesis that describes a complex neural network including both cortical and subcortical structures. The aim of this review is to summarise evidence on the anatomical structures underlying the decision-making process, considering new findings that support the existence of a complex neural network that gives rise to this complex neuropsychological process. Current evidence shows that the cortical structures involved in decision-making include the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). This process is assisted by subcortical structures including the amygdala, thalamus, and cerebellum. Findings to date show that both cortical and subcortical brain regions contribute to the decision-making process. The neural basis of decision-making is a complex neural network of cortico-cortical and cortico-subcortical connections which includes subareas of the PFC, limbic structures, and the cerebellum. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  7. Regional difference of radiosensitivity of neural cells in the fetal brain of mice on day 13 of gestation

    International Nuclear Information System (INIS)

    Hoshino, Kiyoshi; Kameyama, Yoshiro

    1986-01-01

    Pregnant Slc: ICR mice were exposed to a single whole-body X-irradiation at a dose of 12.5 R or 25 R on day 13 of gestation. After irradiation, fetuses were obtained from mothers at 1- or 3-hour intervals and coronal histological sections were made. Pyknotic cells were counted in the ventricular zone of brain mantle, hippocampal anlage and olfactory bulb. In the 25 R group, peak incidences of pyknotic cells in brain mantle, hippocampal anlage and olfactory bulb were 13.2 %, 6.9 % and 2.2 %, respectively. In the 12.5 R group, these were 6.0 %, 3.2 % and 1.7 %, respectively. This result indicates that neural cells in the ventricular zone of brain mantle are the most radiosensitive among the cerebral regions examined in day-13 mouse fetuses. (author)

  8. 10. international mouse genome conference

    Energy Technology Data Exchange (ETDEWEB)

    Meisler, M.H.

    1996-12-31

    Ten years after hosting the First International Mammalian Genome Conference in Paris in 1986, Dr. Jean-Louis Guenet presided over the Tenth Conference at the Pasteur Institute, October 7--10, 1996. The 1986 conference was a satellite to the Human Gene Mapping Workshop and had approximately 50 attendees. The 1996 meeting was attended by 300 scientists from around the world. In the interim, the number of mapped loci in the mouse increased from 1,000 to over 20,000. This report contains a listing of the program and its participants, and two articles that review the meeting and the role of the laboratory mouse in the Human Genome project. More than 200 papers were presented at the conference covering the following topics: International mouse chromosome committee meetings; Mutant generation and identification; Physical and genetic maps; New technology and resources; Chromatin structure and gene regulation; Rate and hamster genetic maps; Informatics and databases; and Quantitative trait analysis.

  9. Mouse Models of Gastric Cancer

    Science.gov (United States)

    Hayakawa, Yoku; Fox, James G.; Gonda, Tamas; Worthley, Daniel L.; Muthupalani, Sureshkumar; Wang, Timothy C.

    2013-01-01

    Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field. PMID:24216700

  10. Mouse models of Fanconi anemia

    International Nuclear Information System (INIS)

    Parmar, Kalindi; D'Andrea, Alan; Niedernhofer, Laura J.

    2009-01-01

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

  11. Mouse models of Fanconi anemia

    Energy Technology Data Exchange (ETDEWEB)

    Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

    2009-07-31

    Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

  12. Genetic algorithm for neural networks optimization

    Science.gov (United States)

    Setyawati, Bina R.; Creese, Robert C.; Sahirman, Sidharta

    2004-11-01

    This paper examines the forecasting performance of multi-layer feed forward neural networks in modeling a particular foreign exchange rates, i.e. Japanese Yen/US Dollar. The effects of two learning methods, Back Propagation and Genetic Algorithm, in which the neural network topology and other parameters fixed, were investigated. The early results indicate that the application of this hybrid system seems to be well suited for the forecasting of foreign exchange rates. The Neural Networks and Genetic Algorithm were programmed using MATLAB«.

  13. Neural network recognition of mammographic lesions

    International Nuclear Information System (INIS)

    Oldham, W.J.B.; Downes, P.T.; Hunter, V.

    1987-01-01

    A method for recognition of mammographic lesions through the use of neural networks is presented. Neural networks have exhibited the ability to learn the shape andinternal structure of patterns. Digitized mammograms containing circumscribed and stelate lesions were used to train a feedfoward synchronous neural network that self-organizes to stable attractor states. Encoding of data for submission to the network was accomplished by performing a fractal analysis of the digitized image. This results in scale invariant representation of the lesions. Results are discussed

  14. Optical-Correlator Neural Network Based On Neocognitron

    Science.gov (United States)

    Chao, Tien-Hsin; Stoner, William W.

    1994-01-01

    Multichannel optical correlator implements shift-invariant, high-discrimination pattern-recognizing neural network based on paradigm of neocognitron. Selected as basic building block of this neural network because invariance under shifts is inherent advantage of Fourier optics included in optical correlators in general. Neocognitron is conceptual electronic neural-network model for recognition of visual patterns. Multilayer processing achieved by iteratively feeding back output of feature correlator to input spatial light modulator and updating Fourier filters. Neural network trained by use of characteristic features extracted from target images. Multichannel implementation enables parallel processing of large number of selected features.

  15. Neutron spectrometry and dosimetry by means of Bonner spheres system and artificial neural networks applying robust design of artificial neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Martinez B, M.R.; Ortiz R, J.M.; Vega C, H.R. [UAZ, Av. Ramon Lopez Velarde No. 801, 98000 Zacatecas (Mexico)

    2006-07-01

    An Artificial Neural Network has been designed, trained and tested to unfold neutron spectra and simultaneously to calculate equivalent doses. A set of 187 neutron spectra compiled by the International Atomic Energy Agency and 13 equivalent doses were used in the artificial neural network designed, trained and tested. In order to design the neural network was used the robust design of artificial neural networks methodology, which assures that the quality of the neural networks takes into account from the design stage. Unless previous works, here, for first time a group of neural networks were designed and trained to unfold 187 neutron spectra and at the same time to calculate 13 equivalent doses, starting from the count rates coming from the Bonner spheres system by using a systematic and experimental strategy. (Author)

  16. Neutron spectrometry and dosimetry by means of Bonner spheres system and artificial neural networks applying robust design of artificial neural networks

    International Nuclear Information System (INIS)

    Martinez B, M.R.; Ortiz R, J.M.; Vega C, H.R.

    2006-01-01

    An Artificial Neural Network has been designed, trained and tested to unfold neutron spectra and simultaneously to calculate equivalent doses. A set of 187 neutron spectra compiled by the International Atomic Energy Agency and 13 equivalent doses were used in the artificial neural network designed, trained and tested. In order to design the neural network was used the robust design of artificial neural networks methodology, which assures that the quality of the neural networks takes into account from the design stage. Unless previous works, here, for first time a group of neural networks were designed and trained to unfold 187 neutron spectra and at the same time to calculate 13 equivalent doses, starting from the count rates coming from the Bonner spheres system by using a systematic and experimental strategy. (Author)

  17. PREDIKSI FOREX MENGGUNAKAN MODEL NEURAL NETWORK

    Directory of Open Access Journals (Sweden)

    R. Hadapiningradja Kusumodestoni

    2015-11-01

    Full Text Available ABSTRAK Prediksi adalah salah satu teknik yang paling penting dalam menjalankan bisnis forex. Keputusan dalam memprediksi adalah sangatlah penting, karena dengan prediksi dapat membantu mengetahui nilai forex di waktu tertentu kedepan sehingga dapat mengurangi resiko kerugian. Tujuan dari penelitian ini dimaksudkan memprediksi bisnis fores menggunakan model neural network dengan data time series per 1 menit untuk mengetahui nilai akurasi prediksi sehingga dapat mengurangi resiko dalam menjalankan bisnis forex. Metode penelitian pada penelitian ini meliputi metode pengumpulan data kemudian dilanjutkan ke metode training, learning, testing menggunakan neural network. Setelah di evaluasi hasil penelitian ini menunjukan bahwa penerapan algoritma Neural Network mampu untuk memprediksi forex dengan tingkat akurasi prediksi 0.431 +/- 0.096 sehingga dengan prediksi ini dapat membantu mengurangi resiko dalam menjalankan bisnis forex. Kata kunci: prediksi, forex, neural network.

  18. Artificial neural networks a practical course

    CERN Document Server

    da Silva, Ivan Nunes; Andrade Flauzino, Rogerio; Liboni, Luisa Helena Bartocci; dos Reis Alves, Silas Franco

    2017-01-01

    This book provides comprehensive coverage of neural networks, their evolution, their structure, the problems they can solve, and their applications. The first half of the book looks at theoretical investigations on artificial neural networks and addresses the key architectures that are capable of implementation in various application scenarios. The second half is designed specifically for the production of solutions using artificial neural networks to solve practical problems arising from different areas of knowledge. It also describes the various implementation details that were taken into account to achieve the reported results. These aspects contribute to the maturation and improvement of experimental techniques to specify the neural network architecture that is most appropriate for a particular application scope. The book is appropriate for students in graduate and upper undergraduate courses in addition to researchers and professionals.

  19. Distributed Recurrent Neural Forward Models with Neural Control for Complex Locomotion in Walking Robots

    DEFF Research Database (Denmark)

    Dasgupta, Sakyasingha; Goldschmidt, Dennis; Wörgötter, Florentin

    2015-01-01

    here, an artificial bio-inspired walking system which effectively combines biomechanics (in terms of the body and leg structures) with the underlying neural mechanisms. The neural mechanisms consist of (1) central pattern generator based control for generating basic rhythmic patterns and coordinated......Walking animals, like stick insects, cockroaches or ants, demonstrate a fascinating range of locomotive abilities and complex behaviors. The locomotive behaviors can consist of a variety of walking patterns along with adaptation that allow the animals to deal with changes in environmental...... conditions, like uneven terrains, gaps, obstacles etc. Biological study has revealed that such complex behaviors are a result of a combination of biomechanics and neural mechanism thus representing the true nature of embodied interactions. While the biomechanics helps maintain flexibility and sustain...

  20. In-vitro differentiation induction of neural stem cells

    NARCIS (Netherlands)

    Balasubramaniyan, Veerakumar

    2006-01-01

    Neurale stamcellen maken de drie belangrijkste celtypes van ons zenuwstelsel aan. Veerakumar Balasubramaniyan onderzocht hoe neurale stamcellen kunnen worden aangezet tot het aanmaken van specifieke neurale celtypes. Met behulp van genetische technieken lukte het hem oligodendrocyten te verkrijgen: