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Sample records for human neural crest-derived

  1. Intrastriatal transplantation of adult human neural crest-derived stem cells improves functional outcome in parkinsonian rats.

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    Müller, Janine; Ossig, Christiana; Greiner, Johannes F W; Hauser, Stefan; Fauser, Mareike; Widera, Darius; Kaltschmidt, Christian; Storch, Alexander; Kaltschmidt, Barbara

    2015-01-01

    Parkinson's disease (PD) is considered the second most frequent and one of the most severe neurodegenerative diseases, with dysfunctions of the motor system and with nonmotor symptoms such as depression and dementia. Compensation for the progressive loss of dopaminergic (DA) neurons during PD using current pharmacological treatment strategies is limited and remains challenging. Pluripotent stem cell-based regenerative medicine may offer a promising therapeutic alternative, although the medical application of human embryonic tissue and pluripotent stem cells is still a matter of ethical and practical debate. Addressing these challenges, the present study investigated the potential of adult human neural crest-derived stem cells derived from the inferior turbinate (ITSCs) transplanted into a parkinsonian rat model. Emphasizing their capability to give rise to nervous tissue, ITSCs isolated from the adult human nose efficiently differentiated into functional mature neurons in vitro. Additional successful dopaminergic differentiation of ITSCs was subsequently followed by their transplantation into a unilaterally lesioned 6-hydroxydopamine rat PD model. Transplantation of predifferentiated or undifferentiated ITSCs led to robust restoration of rotational behavior, accompanied by significant recovery of DA neurons within the substantia nigra. ITSCs were further shown to migrate extensively in loose streams primarily toward the posterior direction as far as to the midbrain region, at which point they were able to differentiate into DA neurons within the locus ceruleus. We demonstrate, for the first time, that adult human ITSCs are capable of functionally recovering a PD rat model. ©AlphaMed Press.

  2. Isolation and characterization of neural crest-derived stem cells from dental pulp of neonatal mice.

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    Kajohnkiart Janebodin

    Full Text Available Dental pulp stem cells (DPSCs are shown to reside within the tooth and play an important role in dentin regeneration. DPSCs were first isolated and characterized from human teeth and most studies have focused on using this adult stem cell for clinical applications. However, mouse DPSCs have not been well characterized and their origin(s have not yet been elucidated. Herein we examined if murine DPSCs are neural crest derived and determined their in vitro and in vivo capacity. DPSCs from neonatal murine tooth pulp expressed embryonic stem cell and neural crest related genes, but lacked expression of mesodermal genes. Cells isolated from the Wnt1-Cre/R26R-LacZ model, a reporter of neural crest-derived tissues, indicated that DPSCs were Wnt1-marked and therefore of neural crest origin. Clonal DPSCs showed multi-differentiation in neural crest lineage for odontoblasts, chondrocytes, adipocytes, neurons, and smooth muscles. Following in vivo subcutaneous transplantation with hydroxyapatite/tricalcium phosphate, based on tissue/cell morphology and specific antibody staining, the clones differentiated into odontoblast-like cells and produced dentin-like structure. Conversely, bone marrow stromal cells (BMSCs gave rise to osteoblast-like cells and generated bone-like structure. Interestingly, the capillary distribution in the DPSC transplants showed close proximity to odontoblasts whereas in the BMSC transplants bone condensations were distant to capillaries resembling dentinogenesis in the former vs. osteogenesis in the latter. Thus we demonstrate the existence of neural crest-derived DPSCs with differentiation capacity into cranial mesenchymal tissues and other neural crest-derived tissues. In turn, DPSCs hold promise as a source for regenerating cranial mesenchyme and other neural crest derived tissues.

  3. Isolation and Characterization of Neural Crest-Derived Stem Cells from Dental Pulp of Neonatal Mice

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    Janebodin, Kajohnkiart; Horst, Orapin V.; Ieronimakis, Nicholas; Balasundaram, Gayathri; Reesukumal, Kanit; Pratumvinit, Busadee; Reyes, Morayma

    2011-01-01

    Dental pulp stem cells (DPSCs) are shown to reside within the tooth and play an important role in dentin regeneration. DPSCs were first isolated and characterized from human teeth and most studies have focused on using this adult stem cell for clinical applications. However, mouse DPSCs have not been well characterized and their origin(s) have not yet been elucidated. Herein we examined if murine DPSCs are neural crest derived and determined their in vitro and in vivo capacity. DPSCs from neonatal murine tooth pulp expressed embryonic stem cell and neural crest related genes, but lacked expression of mesodermal genes. Cells isolated from the Wnt1-Cre/R26R-LacZ model, a reporter of neural crest-derived tissues, indicated that DPSCs were Wnt1-marked and therefore of neural crest origin. Clonal DPSCs showed multi-differentiation in neural crest lineage for odontoblasts, chondrocytes, adipocytes, neurons, and smooth muscles. Following in vivo subcutaneous transplantation with hydroxyapatite/tricalcium phosphate, based on tissue/cell morphology and specific antibody staining, the clones differentiated into odontoblast-like cells and produced dentin-like structure. Conversely, bone marrow stromal cells (BMSCs) gave rise to osteoblast-like cells and generated bone-like structure. Interestingly, the capillary distribution in the DPSC transplants showed close proximity to odontoblasts whereas in the BMSC transplants bone condensations were distant to capillaries resembling dentinogenesis in the former vs. osteogenesis in the latter. Thus we demonstrate the existence of neural crest-derived DPSCs with differentiation capacity into cranial mesenchymal tissues and other neural crest-derived tissues. In turn, DPSCs hold promise as a source for regenerating cranial mesenchyme and other neural crest derived tissues. PMID:22087335

  4. Regeneration of neural crest derivatives in the Xenopus tadpole tail

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    Slack Jonathan MW

    2007-05-01

    Full Text Available Abstract Background After amputation of the Xenopus tadpole tail, a functionally competent new tail is regenerated. It contains spinal cord, notochord and muscle, each of which has previously been shown to derive from the corresponding tissue in the stump. The regeneration of the neural crest derivatives has not previously been examined and is described in this paper. Results Labelling of the spinal cord by electroporation, or by orthotopic grafting of transgenic tissue expressing GFP, shows that no cells emigrate from the spinal cord in the course of regeneration. There is very limited regeneration of the spinal ganglia, but new neurons as well as fibre tracts do appear in the regenerated spinal cord and the regenerated tail also contains abundant peripheral innervation. The regenerated tail contains a normal density of melanophores. Cell labelling experiments show that melanophores do not arise from the spinal cord during regeneration, nor from the mesenchymal tissues of the skin, but they do arise by activation and proliferation of pre-existing melanophore precursors. If tails are prepared lacking melanophores, then the regenerates also lack them. Conclusion On regeneration there is no induction of a new neural crest similar to that seen in embryonic development. However there is some regeneration of neural crest derivatives. Abundant melanophores are regenerated from unpigmented precursors, and, although spinal ganglia are not regenerated, sufficient sensory systems are produced to enable essential functions to continue.

  5. [Phenotypic plasticity of neural crest-derived melanocytes and Schwann cells].

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    Dupin, Elisabeth

    2011-01-01

    -like progenitors. Altogether, these studies have shown that Schwann cells and pigment cells display an unstable status of differentiation, which can be disclosed if these differentiated cells are displaced out of their native tissue. When challenged with new environmental conditions in vitro, differentiated Schwann cells and pigment cells can reacquire stem cell properties of their neural crest ancestors. Notably, such reprogramming was achieved through the effect of a single exogenous factor and without the need of any induced genetic modification. Deciphering the cellular and molecular mechanisms that regulate the plasticity and maintenance of neural crest-derived differentiated cells is likely to be an important step towards the understanding of the neurocristopathies and cancers that target neural crest derivatives in humans. © Société de Biologie, 2011.

  6. Physiological Plasticity of Neural-Crest-Derived Stem Cells in the Adult Mammalian Carotid Body

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    Valentina Annese

    2017-04-01

    Full Text Available Adult stem cell plasticity, or the ability of somatic stem cells to cross boundaries and differentiate into unrelated cell types, has been a matter of debate in the last decade. Neural-crest-derived stem cells (NCSCs display a remarkable plasticity during development. Whether adult populations of NCSCs retain this plasticity is largely unknown. Herein, we describe that neural-crest-derived adult carotid body stem cells (CBSCs are able to undergo endothelial differentiation in addition to their reported role in neurogenesis, contributing to both neurogenic and angiogenic processes taking place in the organ during acclimatization to hypoxia. Moreover, CBSC conversion into vascular cell types is hypoxia inducible factor (HIF dependent and sensitive to hypoxia-released vascular cytokines such as erythropoietin. Our data highlight a remarkable physiological plasticity in an adult population of tissue-specific stem cells and could have impact on the use of these cells for cell therapy.

  7. Physiological Plasticity of Neural-Crest-Derived Stem Cells in the Adult Mammalian Carotid Body.

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    Annese, Valentina; Navarro-Guerrero, Elena; Rodríguez-Prieto, Ismael; Pardal, Ricardo

    2017-04-18

    Adult stem cell plasticity, or the ability of somatic stem cells to cross boundaries and differentiate into unrelated cell types, has been a matter of debate in the last decade. Neural-crest-derived stem cells (NCSCs) display a remarkable plasticity during development. Whether adult populations of NCSCs retain this plasticity is largely unknown. Herein, we describe that neural-crest-derived adult carotid body stem cells (CBSCs) are able to undergo endothelial differentiation in addition to their reported role in neurogenesis, contributing to both neurogenic and angiogenic processes taking place in the organ during acclimatization to hypoxia. Moreover, CBSC conversion into vascular cell types is hypoxia inducible factor (HIF) dependent and sensitive to hypoxia-released vascular cytokines such as erythropoietin. Our data highlight a remarkable physiological plasticity in an adult population of tissue-specific stem cells and could have impact on the use of these cells for cell therapy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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

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    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.

  9. Neural crest-derived mesenchymal cells require Wnt signaling for their development and drive invagination of the telencephalic midline.

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    Youngshik Choe

    Full Text Available Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of ß-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of ß-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized ß-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that ß-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that ß-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis.

  10. Enrichment and Schwann Cell Differentiation of Neural Crest-derived Dental Pulp Stem Cells.

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    Al-Zer, Heba; Apel, Christian; Heiland, Max; Friedrich, Reinhard E; Jung, Ole; Kroeger, Nadja; Eichhorn, Wolfgang; Smeets, Ralf

    2015-01-01

    As already described in previous studies, neural crest stem cells (NCSCs) can be found in adult human dental pulp. The present study investigated the methodology for enrichment and differentiation-induction of the above mentioned cells. Dental pulp was extracted from human wisdom teeth of four patients and subsequently cultured as explants on fibronectin-coated plates in neurobasal medium supplemented with B27, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin, l-glutamine and neuregulin-β1. The cells were then characterized by immunofluorescence, while their differentiation-potential was tested by the attempt to induce cells into different lineages, i.e. osteogenic, melanocytic and glial. The enriched cell population expressed nestin, CD271 and SOX10, which are well-known markers for NCSCs. Consequently, the cells were successfully induced to differentiate into osteoblasts, melanocytes and Schwann cells, expressing the corresponding differentiation markers. Human adult dental pulp contains a population of stem cells with neural crest ontogeny, which can thus be recruited for multiple regenerative therapies. Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  11. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

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    Myron S Ignatius

    Full Text Available The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382 mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382 mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382 mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382 defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  12. Epigenetic marks define the lineage and differentiation potential of two distinct neural crest-derived intermediate odontogenic progenitor populations.

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    Gopinathan, Gokul; Kolokythas, Antonia; Luan, Xianghong; Diekwisch, Thomas G H

    2013-06-15

    Epigenetic mechanisms, such as histone modifications, play an active role in the differentiation and lineage commitment of mesenchymal stem cells. In the present study, epigenetic states and differentiation profiles of two odontogenic neural crest-derived intermediate progenitor populations were compared: dental pulp (DP) and dental follicle (DF). ChIP on chip assays revealed substantial H3K27me3-mediated repression of odontoblast lineage genes DSPP and dentin matrix protein 1 (DMP1) in DF cells, but not in DP cells. Mineralization inductive conditions caused steep increases of mineralization and patterning gene expression levels in DP cells when compared to DF cells. In contrast, mineralization induction resulted in a highly dynamic histone modification response in DF cells, while there was only a subdued effect in DP cells. Both DF and DP progenitors featured H3K4me3-active marks on the promoters of early mineralization genes RUNX2, MSX2, and DLX5, while OSX, IBSP, and BGLAP promoters were enriched for H3K9me3 or H3K27me3. Compared to DF cells, DP cells expressed higher levels of three pluripotency-associated genes, OCT4, NANOG, and SOX2. Finally, gene ontology comparison of bivalent marks unique for DP and DF cells highlighted cell-cell attachment genes in DP cells and neurogenesis genes in DF cells. In conclusion, the present study indicates that the DF intermediate odontogenic neural crest lineage is distinguished from its DP counterpart by epigenetic repression of DSPP and DMP1 genes and through dynamic histone enrichment responses to mineralization induction. Findings presented here highlight the crucial role of epigenetic regulatory mechanisms in the terminal differentiation of odontogenic neural crest lineages.

  13. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

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    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.

  14. Neural crest-derived dental stem cells--where we are and where we are going.

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    Mayo, Vera; Sawatari, Yoh; Huang, C-Y Charles; Garcia-Godoy, Franklin

    2014-09-01

    There are five types of post-natal human dental stem cells that have been identified, isolated and characterized. Here, we review the information available on dental stem cells as well as their potential applications in dentistry, regenerative medicine and the development of other therapeutic approaches. Data pertinent to dental stem cells and their applications, published in peer-reviewed journals from 1982 to 2013 in English were reviewed. Sources were retrieved from PubMed databases as well as related references that the electronic search yielded. Manuscripts describing the origin, retrieval, characterization and application of dental stem cells were obtained and reviewed. Dental stem cell populations present properties similar to those of mesenchymal stem cells, such as the ability to self-renew and the potential for multilineage differentiation. While they have greater capacity to give rise to odontogenic cells and regenerate dental pulp and periodontal tissue, they have the capacity to differentiate into all three germ line cells, proving that a population of pluripotent stem cells exists in the dental tissues. Dental stem cells have the capacity to differentiate into endoderm, mesoderm and ectoderm tissues. Consequently they do not only have applications in dentistry, but also neurodegenerative and ischemic diseases, diabetes research, bone repair, and other applications in the field of tissue regeneration. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Neural crest-derived cells with stem cell features can be traced back to multiple lineages in the adult skin

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    C.E. Wong (Christine); S. Paratore (Sabrina); M.T. Dours-Zimmermann (María); T. Rochat (Thierry); T. Pietri (Thomas); U. Suter (Ueli); D. Zimmermann (Dieter); S. Dufour (Sylvie); J.P. Thiery (Joachim); D.N. Meijer (Dies); C. Beermann (Christopher); Y. Barrandon (Yann); L. Sommer (Lukas)

    2006-01-01

    textabstractGiven their accessibility, multipotent skin-derived cells might be useful for future cell replacement therapies. We describe the isolation of multipotent stem cell-like cells from the adult trunk skin of mice and humans that express the neural crest stem cell markers p75 and Sox10 and

  16. In vitro cementoblast-like differentiation of postmigratory neural crest-derived p75{sup +} stem cells with dental follicle cell conditioned medium

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    Wen, Xiujie; Liu, Luchuan; Deng, Manjing; Liu, Rui; Zhang, Li; Nie, Xin, E-mail: dr.xinnie@gmail.com

    2015-09-10

    Cranial neural crest-derived cells (CNCCs) play important role in epithelial–mesenchymal interactions during tooth morphogenesis. However, the heterogeneity of CNCCs and their tendency to spontaneously differentiate along smooth muscle or osteoblast lineages in vitro limit further understanding of their biological properties. We studied the differentiation properties of isolated rat embryonic postmigratory CNCCs, expressing p75 neurotrophin receptor (p75NTR). These p75NTR positive (p75{sup +}) CNCCs, isolated using fluorescence activated cell sorter, exhibited fibroblast-like morphology and characteristics of mesenchymal stem cells. Incubation of p75{sup +} CNCCs in dental follicle cell conditioned medium (DFCCM) combined with dentin non-collagenous proteins (dNCPs), altered their morphological features to cementoblast-like appearance. These cells also showed low proliferative activity, high ALP activity and significantly increased calcified nodule formation. Markers related to mineralization or specific to cementoblast lineage were highly expressed in dNCPs/DFCCM-treated p75{sup +} cells, suggesting their differentiation along cementoblast-like lineage. p75{sup +} stem cells selected from postmigratory CNCCs represent a pure stem cell population and could be used as a stem cell model for in vitro studies due to their intrinsic ability to differentiate to neuronal cells and transform from neuroectoderm to ectomesenchyme. They can provide a potential stem cell resource for tooth engineering studies and help to further investigate mechanisms of epithelial–mesenchymal interactions in tooth morphogenesis. - Highlights: • Cranial neural crest-derived cells (CNCCs) take part in tooth morphogenesis. • positive (p75{sup +}) CNCCs are fibroblast-like and resemble mesenchymal stem cells. • p75{sup +} CNCCs in dental follicle cell medium (DFCCM/dNCP) appear like cementoblasts. • DFCCM/dNCP-treated p75{sup +} cells express cementoblast specific mineralization

  17. Decreased proliferative, migrative and neuro-differentiative potential of postnatal rat enteric neural crest-derived cells during culture in vitro

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    Yu, Hui [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Pan, Wei-Kang; Zheng, Bai-Jun; Wang, Huai-Jie [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Chen, Xin-Lin; Liu, Yong [Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Gao, Ya, E-mail: ygao@mail.xjtu.edu.cn [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China)

    2016-05-01

    A growing body of evidence supports the potential use of enteric neural crest-derived cells (ENCCs) as a cell replacement therapy for Hirschsprung's disease. Based on previous observations of robust propagation of primary ENCCs, as opposed to their progeny, it is suggested that their therapeutic potential after in vitro expansion may be restricted. We therefore examined the growth and differentiation activities and phenotypic characteristics of continuous ENCC cultures. ENCCs were isolated from the intestines of postnatal rats and were identified using an immunocytochemical approach. During continuous ENCC culture expansion, proliferation, migration, apoptosis, and differentiation potentials were monitored. The Cell Counting Kit-8 was used for assessment of ENCC vitality, Transwell inserts for cell migration, immunocytochemistry for cell counts and identification, and flow cytometry for apoptosis. Over six continuous generations, ENCC proliferation potency was reduced and with prolonged culture, the ratio of migratory ENCCs was decreased. The percentage of apoptosis showed an upward trend with prolonged intragenerational culture, but showed a downward trend with prolonged culture of combined generations. Furthermore, the percentage of peripherin{sup +} cells decreased whilst the percentage of GFAP{sup +} cells increased with age. The results demonstrated that alterations in ENCC growth characteristics occur with increased culture time, which may partially account for the poor results of proposed cell therapies. - Highlights: • Differences were identified between primary and daughter ENCCs. • Daughter ENCCs had reduced proliferation, migration and differentiation. • Daughter ENCCs also had increased apoptosis. • These altered characteristics warrant further investigation.

  18. Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves

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    Jiao Jiao

    2016-08-01

    Full Text Available Individuals with bicuspid aortic valves (BAV are at a higher risk of developing thoracic aortic aneurysms (TAA than patients with trileaflet aortic valves (TAV. The aneurysms associated with BAV most commonly involve the ascending aorta and spare the descending aorta. Smooth muscle cells (SMCs in the ascending and descending aorta arise from neural crest (NC and paraxial mesoderm (PM, respectively. We hypothesized defective differentiation of the neural crest stem cells (NCSCs-derived SMCs but not paraxial mesoderm cells (PMCs-derived SMCs contributes to the aortopathy associated with BAV. When induced pluripotent stem cells (iPSCs from BAV/TAA patients were differentiated into NCSC-derived SMCs, these cells demonstrated significantly decreased expression of marker of SMC differentiation (MYH11 and impaired contraction compared to normal control. In contrast, the PMC-derived SMCs were similar to control cells in these aspects. The NCSC-SMCs from the BAV/TAA also showed decreased TGF-β signaling based on phosphorylation of SMAD2, and increased mTOR signaling. Inhibition of mTOR pathway using rapamycin rescued the aberrant differentiation. Our data demonstrates that decreased differentiation and contraction of patient's NCSC-derived SMCs may contribute to that aortopathy associated with BAV.

  19. Depletion of Neural Crest-Derived Cells Leads to Reduction in Plasma Noradrenaline and Alters B Lymphopoiesis.

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    Tsunokuma, Naoki; Yamane, Toshiyuki; Matsumoto, Chiaki; Tsuneto, Motokazu; Isono, Kana; Imanaka-Yoshida, Kyoko; Yamazaki, Hidetoshi

    2017-01-01

    Hematopoietic stem cells and their lymphoid progenitors are supported by the bone marrow (BM) microenvironmental niches composed of various stromal cells and Schwann cells and sympathetic nerve fibers. Although neural crest (NC) cells contribute to the development of all the three, their function in BM is not well understood. In this study, NC-derived cells were ablated with diphtheria toxin in double-transgenic mice expressing NC-specific Cre and Cre-driven diphtheria toxin receptor with yellow fluorescent protein reporter. We found that yellow fluorescent protein-expressing, NC-derived nonhematopoietic cells in BM expressed hematopoietic factors Cxcl12 and stem cell factor The ablation of NC-derived cells led to a significant decrease in B cell progenitors but not in hematopoietic stem cells or myeloid lineage cells in BM. Interestingly, plasma noradrenaline was markedly decreased in these mice. The i.p. administration of 6-hydroxydopamine, a known neurotoxin for noradrenergic neurons, led to a similar phenotype, whereas the administration of a noradrenaline precursor in NC-ablated mice partially rescued this phenotype. Additionally, the continuous administration of adrenergic receptor β antagonists partially decreased the number of B cell progenitors while preserving B lymphopoiesis in vitro. Taken together, our results indicate that NC-derived cell depletion leads to abnormal B lymphopoiesis partially through decreased plasma noradrenaline, suggesting this as a novel mechanism regulated by molecules released by the sympathetic neurons. Copyright © 2016 by The American Association of Immunologists, Inc.

  20. Combination of exogenous cell transplantation and 5-HT{sub 4} receptor agonism induce endogenous enteric neural crest-derived cells in a rat hypoganglionosis model

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    Yu, Hui [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Zheng, Bai-Jun; Pan, Wei-Kang; Wang, Huai-Jie; Xie, Chong; Zhao, Yu-Ying [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Chen, Xin-Lin; Liu, Yong [Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Gao, Ya, E-mail: ygao@mail.xjtu.edu.cn [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China)

    2017-02-01

    Enteric neural crest-derived cells (ENCCs) can migrate into endogenous ganglia and differentiate into progeny cells, and have even partially rescued bowel function; however, poor reliability and limited functional recovery after ENCC transplantation have yet to be addressed. Here, we investigated the induction of endogenous ENCCs by combining exogenous ENCC transplantation with a 5-HT{sub 4} receptor agonist mosapride in a rat model of hypoganglionosis, established by benzalkonium chloride treatment. ENCCs, isolated from the gut of newborn rats, were labeled with a lentiviral eGFP reporter. ENCCs and rats were treated with the 5-HT{sub 4} receptor agonist/antagonist. The labeled ENCCs were then transplanted into the muscular layer of benzalkonium chloride-treated colons. At given days post-intervention, colonic tissue samples were removed for histological analysis. ENCCs and neurons were detected by eGFP expression and immunoreactivity to p75{sup NTR} and peripherin, respectively. eGFP-positive ENCCs and neurons could survive and maintain levels of fluorescence after transplantation. With longer times post-intervention, the number of peripherin-positive cells gradually increased in all groups. Significantly more peripherin-positive cells were found following ENCCs plus mosapride treatment, compared with the other groups. These results show that exogenous ENCCs combined with the 5-HT{sub 4} receptor agonist effectively induced endogenous ENCCs proliferation and differentiation in a rat hypoganglionosis model. - Highlights: • Survival and differentiation of exogenous ENCCs in treated colons. • With longer times post-intervention, the number of ENCCs and their progeny cells gradually increased. • Exogenous ENCCs combined with the 5-HT4 receptor agonist ffectively induced ENCCs proliferation and differentiation.

  1. Cranial neural crest-derived mesenchymal proliferation is regulated by Msx1-mediated p19(INK4d) expression during odontogenesis.

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    Han, Jun; Ito, Yoshihiro; Yeo, Jae Yong; Sucov, Henry M; Maas, Richard; Chai, Yang

    2003-09-01

    Neural crest cells are multipotential progenitors that contribute to various cell and tissue types during embryogenesis. Here, we have investigated the molecular and cellular mechanism by which the fate of neural crest cell is regulated during tooth development. Using a two- component genetic system for indelibly marking the progeny of neural crest cells, we provide in vivo evidence of a deficiency of CNC-derived dental mesenchyme in Msx1 null mutant mouse embryos. The deficiency of the CNC results from an elevated CDK inhibitor p19(INK4d) activity and the disruption of cell proliferation. Interestingly, in the absence of Msx1, the CNC-derived dental mesenchyme misdifferentiates and possesses properties consistent with a neuronal fate, possibly through a default mechanism. Attenuation of p19(INK4d) in Msx1 null mutant mandibular explants restores mitotic activity in the dental mesenchyme, demonstrating the functional significance of Msx1-mediated p19(INK4d) expression in regulating CNC cell proliferation during odontogenesis. Collectively, our results demonstrate that homeobox gene Msx1 regulates the fate of CNC cells by controlling the progression of the cell cycle. Genetic mutation of Msx1 may alternatively instruct the fate of these progenitor cells during craniofacial development.

  2. Direct Genesis of Functional Rodent and Human Schwann Cells from Skin Mesenchymal Precursors

    Directory of Open Access Journals (Sweden)

    Matthew P. Krause

    2014-07-01

    Full Text Available Recent reports of directed reprogramming have raised questions about the stability of cell lineages. Here, we have addressed this issue, focusing upon skin-derived precursors (SKPs, a dermally derived precursor cell. We show by lineage tracing that murine SKPs from dorsal skin originate from mesenchymal and not neural crest-derived cells. These mesenchymally derived SKPs can, without genetic manipulation, generate functional Schwann cells, a neural crest cell type, and are highly similar at the transcriptional level to Schwann cells isolated from the peripheral nerve. This is not a mouse-specific phenomenon, since human SKPs that are highly similar at the transcriptome level can be made from neural crest-derived facial and mesodermally derived foreskin dermis and the foreskin SKPs can make myelinating Schwann cells. Thus, nonneural crest-derived mesenchymal precursors can differentiate into bona fide peripheral glia in the absence of genetic manipulation, suggesting that developmentally defined lineage boundaries are more flexible than widely thought.

  3. Sphere-Derived Multipotent Progenitor Cells Obtained From Human Oral Mucosa Are Enriched in Neural Crest Cells.

    Science.gov (United States)

    Abe, Shigehiro; Yamaguchi, Satoshi; Sato, Yutaka; Harada, Kiyoshi

    2016-01-01

    : Although isolation of oral mucosal stromal stem cells has been previously reported, complex isolation methods are not suitable for clinical application. The neurosphere culture technique is a convenient method for the isolation of neural stem cells and neural crest stem cells (NCSCs); neurosphere generation is a phenotype of NCSCs. However, the molecular details underlying the isolation and characterization of human oral mucosa stromal cells (OMSCs) by neurosphere culture are not understood. The purpose of the present study was to isolate NCSCs from oral mucosa using the neurosphere technique and to establish effective in vivo bone tissue regeneration methods. Human OMSCs were isolated from excised human oral mucosa; these cells formed spheres in neurosphere culture conditions. Oral mucosa sphere-forming cells (OMSFCs) were characterized by biological analyses of stem cells. Additionally, composites of OMSFCs and multiporous polylactic acid scaffolds were implanted subcutaneously into immunocompromised mice. OMSFCs had the capacity for self-renewal and expressed neural crest-related markers (e.g., nestin, CD44, slug, snail, and MSX1). Furthermore, upregulated expression of neural crest-related genes (EDNRA, Hes1, and Sox9) was observed in OMSFCs, which are thought to contain an enriched population of neural crest-derived cells. The expression pattern of α2-integrin (CD49b) in OMSFCs also differed from that in OMSCs. Finally, OMSFCs were capable of differentiating into neural crest lineages in vitro and generating ectopic bone tissues even in the subcutaneous region. The results of the present study suggest that OMSFCs are an ideal source of cells for the neural crest lineage and hard tissue regeneration. The sphere culture technique is a convenient method for isolating stem cells. However, the isolation and characterization of human oral mucosa stromal cells (OMSCs) using the sphere culture system are not fully understood. The present study describes the

  4. Human Neural Cell-Based Biosensor

    Science.gov (United States)

    2013-05-28

    Orlando R, Stice SL. Membrane proteomic signatures of karyotypically normal and abnormal human embryonic stem cell lines and derivatives. Proteomics. 2011...format (96-,384-well) assays, 2) grow as adherent monolayers, and 3) possess a stable karyotype for multiple (>10) passages with a doubling time of ~36...derived neural progenitor cell line working stock has been amplified, characterized for karyotype and evaluated for the expression of neural progenitor

  5. Stage-specific control of neural crest stem cell proliferation by the small rho GTPases Cdc42 and Rac1

    DEFF Research Database (Denmark)

    Fuchs, Sebastian; Herzog, Dominik; Sumara, Grzegorz

    2009-01-01

    The neural crest (NC) generates a variety of neural and non-neural tissues during vertebrate development. Both migratory NC cells and their target structures contain cells with stem cell features. Here we show that these populations of neural crest-derived stem cells (NCSCs) are differentially re...

  6. Neural networks of human nature and nurture

    Directory of Open Access Journals (Sweden)

    Daniel S. Levine

    2009-11-01

    Full Text Available Neural network methods have facilitated the unification of several unfortunate splits in psychology, including nature versus nurture. We review the contributions of this methodology and then discuss tentative network theories of caring behavior, of uncaring behavior, and of how the frontal lobes are involved in the choices between them. The implications of our theory are optimistic about the prospects of society to encourage the human potential for caring.

  7. Pax7 lineage contributions to the mammalian neural crest.

    Directory of Open Access Journals (Sweden)

    Barbara Murdoch

    Full Text Available Neural crest cells are vertebrate-specific multipotent cells that contribute to a variety of tissues including the peripheral nervous system, melanocytes, and craniofacial bones and cartilage. Abnormal development of the neural crest is associated with several human maladies including cleft/lip palate, aggressive cancers such as melanoma and neuroblastoma, and rare syndromes, like Waardenburg syndrome, a complex disorder involving hearing loss and pigment defects. We previously identified the transcription factor Pax7 as an early marker, and required component for neural crest development in chick embryos. In mammals, Pax7 is also thought to play a role in neural crest development, yet the precise contribution of Pax7 progenitors to the neural crest lineage has not been determined.Here we use Cre/loxP technology in double transgenic mice to fate map the Pax7 lineage in neural crest derivates. We find that Pax7 descendants contribute to multiple tissues including the cranial, cardiac and trunk neural crest, which in the cranial cartilage form a distinct regional pattern. The Pax7 lineage, like the Pax3 lineage, is additionally detected in some non-neural crest tissues, including a subset of the epithelial cells in specific organs.These results demonstrate a previously unappreciated widespread distribution of Pax7 descendants within and beyond the neural crest. They shed light regarding the regionally distinct phenotypes observed in Pax3 and Pax7 mutants, and provide a unique perspective into the potential roles of Pax7 during disease and development.

  8. Adipose stromal cells contain phenotypically distinct adipogenic progenitors derived from neural crest.

    Directory of Open Access Journals (Sweden)

    Yoshihiro Sowa

    Full Text Available Recent studies have shown that adipose-derived stromal/stem cells (ASCs contain phenotypically and functionally heterogeneous subpopulations of cells, but their developmental origin and their relative differentiation potential remain elusive. In the present study, we aimed at investigating how and to what extent the neural crest contributes to ASCs using Cre-loxP-mediated fate mapping. ASCs harvested from subcutaneous fat depots of either adult P0-Cre/or Wnt1-Cre/Floxed-reporter mice contained a few neural crest-derived ASCs (NCDASCs. This subpopulation of cells was successfully expanded in vitro under standard culture conditions and their growth rate was comparable to non-neural crest derivatives. Although NCDASCs were positive for several mesenchymal stem cell markers as non-neural crest derivatives, they exhibited a unique bipolar or multipolar morphology with higher expression of markers for both neural crest progenitors (p75NTR, Nestin, and Sox2 and preadipocytes (CD24, CD34, S100, Pref-1, GATA2, and C/EBP-delta. NCDASCs were able to differentiate into adipocytes with high efficiency but their osteogenic and chondrogenic potential was markedly attenuated, indicating their commitment to adipogenesis. In vivo, a very small proportion of adipocytes were originated from the neural crest. In addition, p75NTR-positive neural crest-derived cells were identified along the vessels within the subcutaneous adipose tissue, but they were negative for mural and endothelial markers. These results demonstrate that ASCs contain neural crest-derived adipocyte-restricted progenitors whose phenotype is distinct from that of non-neural crest derivatives.

  9. Neural Crest Stem Cells from Dental Tissues: A New Hope for Dental and Neural Regeneration

    Directory of Open Access Journals (Sweden)

    Gaskon Ibarretxe

    2012-01-01

    Full Text Available Several stem cell sources persist in the adult human body, which opens the doors to both allogeneic and autologous cell therapies. Tooth tissues have proven to be a surprisingly rich and accessible source of neural crest-derived ectomesenchymal stem cells (EMSCs, which may be employed to repair disease-affected oral tissues in advanced regenerative dentistry. Additionally, one area of medicine that demands intensive research on new sources of stem cells is nervous system regeneration, since this constitutes a therapeutic hope for patients affected by highly invalidating conditions such as spinal cord injury, stroke, or neurodegenerative diseases. However, endogenous adult sources of neural stem cells present major drawbacks, such as their scarcity and complicated obtention. In this context, EMSCs from dental tissues emerge as good alternative candidates, since they are preserved in adult human individuals, and retain both high proliferation ability and a neural-like phenotype in vitro. In this paper, we discuss some important aspects of tissue regeneration by cell therapy and point out some advantages that EMSCs provide for dental and neural regeneration. We will finally review some of the latest research featuring experimental approaches and benefits of dental stem cell therapy.

  10. The neural basis of human tool use

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    Guy A Orban

    2014-04-01

    Full Text Available In this review, we propose that the neural basis for the spontaneous, diversified human tool use is an area devoted to the execution and observation of tool actions, located in the left anterior supramarginal gyrus (aSMG. The aSMG activation elicited by observing tool use is typical of human subjects, as macaques show no similar activation, even after an extensive training to use tools. The execution of tool actions, as well as their observation, requires the convergence upon aSMG of inputs from different parts of the dorsal and ventral visual streams. Non semantic features of the target object may be provided by the posterior parietal cortex (PPC for tool-object interaction, paralleling the well-known PPC input to AIP for hand-object interaction. Semantic information regarding tool identity, and knowledge of the typical manner of handling the tool, could be provided by inferior and middle regions of the temporal lobe. Somatosensory feedback and technical reasoning, as well as motor and intentional constraints also play roles during the planning of tool actions and consequently their signals likewise converge upon aSMG.We further propose that aSMG may have arisen though duplication of monkey AIP and invasion of the duplicate area by afferents from PPC providing distinct signals depending on the kinematics of the manipulative action. This duplication may have occurred when Homo Habilis or Homo Erectus emerged, generating the Oldowan or Acheulean Industrial complexes respectively. Hence tool use may have emerged during hominid evolution between bipedalism and language.We conclude that humans have two parietal systems involved in tool behavior: a biological circuit for grasping objects, including tools, and an artifactual system devoted specifically to tool use. Only the latter allows humans to understand the causal relationship between tool use and obtaining the goal, and is likely to be the basis of all technological developments.

  11. Human Parsing with Contextualized Convolutional Neural Network.

    Science.gov (United States)

    Liang, Xiaodan; Xu, Chunyan; Shen, Xiaohui; Yang, Jianchao; Tang, Jinhui; Lin, Liang; Yan, Shuicheng

    2016-03-02

    In this work, we address the human parsing task with a novel Contextualized Convolutional Neural Network (Co-CNN) architecture, which well integrates the cross-layer context, global image-level context, semantic edge context, within-super-pixel context and cross-super-pixel neighborhood context into a unified network. Given an input human image, Co-CNN produces the pixel-wise categorization in an end-to-end way. First, the cross-layer context is captured by our basic local-to-global-to-local structure, which hierarchically combines the global semantic information and the local fine details across different convolutional layers. Second, the global image-level label prediction is used as an auxiliary objective in the intermediate layer of the Co-CNN, and its outputs are further used for guiding the feature learning in subsequent convolutional layers to leverage the global imagelevel context. Third, semantic edge context is further incorporated into Co-CNN, where the high-level semantic boundaries are leveraged to guide pixel-wise labeling. Finally, to further utilize the local super-pixel contexts, the within-super-pixel smoothing and cross-super-pixel neighbourhood voting are formulated as natural sub-components of the Co-CNN to achieve the local label consistency in both training and testing process. Comprehensive evaluations on two public datasets well demonstrate the significant superiority of our Co-CNN over other state-of-the-arts for human parsing. In particular, the F-1 score on the large dataset [1] reaches 81:72% by Co-CNN, significantly higher than 62:81% and 64:38% by the state-of-the-art algorithms, MCNN [2] and ATR [1], respectively. By utilizing our newly collected large dataset for training, our Co-CNN can achieve 85:36% in F-1 score.

  12. Harmine stimulates proliferation of human neural progenitors

    Directory of Open Access Journals (Sweden)

    Vanja Dakic

    2016-12-01

    Full Text Available Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A, which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY, and an irreversible selective inhibitor of monoamine oxidase (MAO but not DYRK1A (pargyline. INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo.

  13. Neural networks for perception human and machine perception

    CERN Document Server

    Wechsler, Harry

    1991-01-01

    Neural Networks for Perception, Volume 1: Human and Machine Perception focuses on models for understanding human perception in terms of distributed computation and examples of PDP models for machine perception. This book addresses both theoretical and practical issues related to the feasibility of both explaining human perception and implementing machine perception in terms of neural network models. The book is organized into two parts. The first part focuses on human perception. Topics on network model ofobject recognition in human vision, the self-organization of functional architecture in t

  14. 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.

  15. Human Face Recognition Using Convolutional Neural Networks

    Directory of Open Access Journals (Sweden)

    Răzvan-Daniel Albu

    2009-10-01

    Full Text Available In this paper, I present a novel hybrid face recognition approach based on a convolutional neural architecture, designed to robustly detect highly variable face patterns. The convolutional network extracts successively larger features in a hierarchical set of layers. With the weights of the trained neural networks there are created kernel windows used for feature extraction in a 3-stage algorithm. I present experimental results illustrating the efficiency of the proposed approach. I use a database of 796 images of 159 individuals from Reims University which contains quite a high degree of variability in expression, pose, and facial details.

  16. High Accuracy Human Activity Monitoring using Neural network

    OpenAIRE

    Sharma, Annapurna; Lee, Young-Dong; Chung, Wan-Young

    2011-01-01

    This paper presents the designing of a neural network for the classification of Human activity. A Triaxial accelerometer sensor, housed in a chest worn sensor unit, has been used for capturing the acceleration of the movements associated. All the three axis acceleration data were collected at a base station PC via a CC2420 2.4GHz ISM band radio (zigbee wireless compliant), processed and classified using MATLAB. A neural network approach for classification was used with an eye on theoretical a...

  17. Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention.

    Science.gov (United States)

    Heuckeroth, Robert O; Schäfer, Karl-Herbert

    2016-09-15

    Intestinal function is primarily controlled by an intrinsic nervous system of the bowel called the enteric nervous system (ENS). The cells of the ENS are neural crest derivatives that migrate into and through the bowel during early stages of organogenesis before differentiating into a wide variety of neurons and glia. Although genetic factors critically underlie ENS development, it is now clear that many non-genetic factors may influence the number of enteric neurons, types of enteric neurons, and ratio of neurons to glia. These non-genetic influences include dietary nutrients and medicines that may impact ENS structure and function before or after birth. This review summarizes current data about gene-environment interactions that affect ENS development and suggests that these factors may contribute to human intestinal motility disorders like Hirschsprung disease or irritable bowel syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Gene-environment interactions and the enteric nervous system: Neural plasticity and Hirschsprung disease prevention

    Science.gov (United States)

    Heuckeroth, Robert O.; Schäfer, Karl-Herbert

    2016-01-01

    Intestinal function is primarily controlled by an intrinsic nervous system of the bowel called the enteric nervous system (ENS). The cells of the ENS are neural crest derivatives that migrate into and through the bowel during early stages of organogenesis before differentiating into a wide variety of neurons and glia. Although genetic factors critically underlie ENS development, it is now clear that many non-genetic factors may influence the number of enteric neurons, types of enteric neurons, and ratio of neurons to glia. These non-genetic influences include dietary nutrients and medicines that may impact ENS structure and function before or after birth. This review summarizes current data about gene-environment interactions that affect ENS development and suggests that these factors may contribute to human intestinal motility disorders like Hirschsprung disease or irritable bowel syndrome. PMID:26997034

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

    Directory of Open Access Journals (Sweden)

    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.

  20. A cultured human neural network operates a robotic actuator.

    Science.gov (United States)

    Pizzi, R M R; Rossetti, D; Cino, G; Marino, D; A L Vescovi; Baer, W

    2009-02-01

    The development of bio-electronic prostheses, hybrid human-electronics devices and bionic robots has been the aim of many researchers. Although neurophysiologic processes have been widely investigated and bio-electronics has developed rapidly, the dynamics of a biological neuronal network that receive sensory inputs, store and control information is not yet understood. Toward this end, we have taken an interdisciplinary approach to study the learning and response of biological neural networks to complex stimulation patterns. This paper describes the design, execution, and results of several experiments performed in order to investigate the behavior of complex interconnected structures found in biological neural networks. The experimental design consisted of biological human neurons stimulated by parallel signal patterns intended to simulate complex perceptions. The response patterns were analyzed with an innovative artificial neural network (ANN), called ITSOM (Inductive Tracing Self Organizing Map). This system allowed us to decode the complex neural responses from a mixture of different stimulations and learned memory patterns inherent in the cell colonies. In the experiment described in this work, neurons derived from human neural stem cells were connected to a robotic actuator through the ANN analyzer to demonstrate our ability to produce useful control from simulated perceptions stimulating the cells. Preliminary results showed that in vitro human neuron colonies can learn to reply selectively to different stimulation patterns and that response signals can effectively be decoded to operate a minirobot. Lastly the fascinating performance of the hybrid system is evaluated quantitatively and potential future work is discussed.

  1. ARTIFICIAL NEURAL NETWORK FOR MODELS OF HUMAN OPERATOR

    Directory of Open Access Journals (Sweden)

    Martin Ruzek

    2017-12-01

    Full Text Available This paper presents a new approach to mental functions modeling with the use of artificial neural networks. The artificial neural networks seems to be a promising method for the modeling of a human operator because the architecture of the ANN is directly inspired by the biological neuron. On the other hand, the classical paradigms of artificial neural networks are not suitable because they simplify too much the real processes in biological neural network. The search for a compromise between the complexity of biological neural network and the practical feasibility of the artificial network led to a new learning algorithm. This algorithm is based on the classical multilayered neural network; however, the learning rule is different. The neurons are updating their parameters in a way that is similar to real biological processes. The basic idea is that the neurons are competing for resources and the criterion to decide which neuron will survive is the usefulness of the neuron to the whole neural network. The neuron is not using "teacher" or any kind of superior system, the neuron receives only the information that is present in the biological system. The learning process can be seen as searching of some equilibrium point that is equal to a state with maximal importance of the neuron for the neural network. This position can change if the environment changes. The name of this type of learning, the homeostatic artificial neural network, originates from this idea, as it is similar to the process of homeostasis known in any living cell. The simulation results suggest that this type of learning can be useful also in other tasks of artificial learning and recognition.

  2. Estimating Neural Signal Dynamics in the Human Brain

    Directory of Open Access Journals (Sweden)

    Christopher W Tyler

    2011-06-01

    Full Text Available Although brain imaging methods are highly effective for localizing the effects of neural activation throughout the human brain in terms of the blood oxygenation level dependent (BOLD response, there is currently no way to estimate the underlying neural signal dynamics in generating the BOLD response in each local activation region (except for processes slower than the BOLD time course. Knowledge of the neural signal is critical information if spatial mapping is to progress to the analysis of dynamic information flow through the cortical networks as the brain performs its tasks. We introduce an analytic approach that provides a new level of conceptualization and specificity in the study of brain processing by noninvasive methods. This technique allows us to use brain imaging methods to determine the dynamics of local neural population responses to their native temporal resolution throughout the human brain, with relatively narrow confidence intervals on many response properties. The ability to characterize local neural dynamics in the human brain represents a significant enhancement of brain imaging capabilities, with potential application from general cognitive studies to assessment of neuropathologies.

  3. Human Immunodeficiency Virus Type 1 Infection of Neural Xenografts

    Science.gov (United States)

    Cvetkovich, Therese A.; Lazar, Eliot; Blumberg, Benjamin M.; Saito, Yoshihiro; Eskin, Thomas A.; Reichman, Richard; Baram, David A.; del Cerro, Coca; Gendelman, Howard E.; del Cerro, Manuel; Epstein, Leon G.

    1992-06-01

    Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. To study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11 to 17.5 weeks) human fetal brain or neural retina is transplanted to the anterior chamber of the eye of immunosuppressed adult rats. The human xenografts vascularized, formed a blood-brain barrier, and differentiated, forming neurons and glia. The xenografts were infected with cell-free HIV-1 or with HIV-1-infected human monocytes. Analysis by polymerase chain reaction revealed HIV-1 sequences in DNA from xenograft tissue exposed to HIV-1 virions, and in situ hybridization demonstrated HIV-1 mRNA localized in macrophages and multinucleated giant cells. Pathological damage was observed only in neural xenografts containing HIV-1-infected human monocytes, supporting the hypothesis that these cells mediate neurotoxicity. This small animal model allows the study of direct and indirect effects of HIV-1 infection on developing human fetal neural tissues, and it should prove useful in evaluating antiviral therapies, which must ultimately target HIV-1 infection of the brain.

  4. Human Face Identification using KL Transform and Neural Networks

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yong Joo [LG Electronics Inc. Multimedia Research Lab. (Korea, Republic of); Ji, Seung Hwan [Mi Re Industry Inc. (Korea, Republic of); Yoo, Jae Hyung; Kim, Jung Hwan; Park, Min Yong [Yonsei University (Korea, Republic of)

    1999-01-01

    Machine recognition of faces from still and video images is emerging as an active research area spanning several disciplines such as image processing, pattern recognition, computer vision and neural networks. In addition, human face identification has numerous applications such as human interface based systems and real-time video systems of surveillance and security. In this paper, we propose an algorithm that can identify a particular individual face. We consider human face identification system in color space, which hasn`t often considered in conventional methods. In order to make the algorithm insensitive to luminance, we convert the conventional RGB coordinates into normalized CIE coordinates. The normalized-CIE-based facial images are KL-transformed. The transformed data are used as used as the input of multi-layered neural network and the network are trained using error-backpropagation methods. Finally, we verify the system performance of the proposed algorithm by experiments. (author). 12 refs., 7 figs., 3 tabs.

  5. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity.

    Science.gov (United States)

    Schwartz, Michael P; Hou, Zhonggang; Propson, Nicholas E; Zhang, Jue; Engstrom, Collin J; Santos Costa, Vitor; Jiang, Peng; Nguyen, Bao Kim; Bolin, Jennifer M; Daly, William; Wang, Yu; Stewart, Ron; Page, C David; Murphy, William L; Thomson, James A

    2015-10-06

    Human pluripotent stem cell-based in vitro models that reflect human physiology have the potential to reduce the number of drug failures in clinical trials and offer a cost-effective approach for assessing chemical safety. Here, human embryonic stem (ES) cell-derived neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursors were combined on chemically defined polyethylene glycol hydrogels and cultured in serum-free medium to model cellular interactions within the developing brain. The precursors self-assembled into 3D neural constructs with diverse neuronal and glial populations, interconnected vascular networks, and ramified microglia. Replicate constructs were reproducible by RNA sequencing (RNA-Seq) and expressed neurogenesis, vasculature development, and microglia genes. Linear support vector machines were used to construct a predictive model from RNA-Seq data for 240 neural constructs treated with 34 toxic and 26 nontoxic chemicals. The predictive model was evaluated using two standard hold-out testing methods: a nearly unbiased leave-one-out cross-validation for the 60 training compounds and an unbiased blinded trial using a single hold-out set of 10 additional chemicals. The linear support vector produced an estimate for future data of 0.91 in the cross-validation experiment and correctly classified 9 of 10 chemicals in the blinded trial.

  6. Enhanced expression of FNDC5 in human embryonic stem cell-derived neural cells along with relevant embryonic neural tissues.

    Science.gov (United States)

    Ghahrizjani, Fatemeh Ahmadi; Ghaedi, Kamran; Salamian, Ahmad; Tanhaei, Somayeh; Nejati, Alireza Shoaraye; Salehi, Hossein; Nabiuni, Mohammad; Baharvand, Hossein; Nasr-Esfahani, Mohammad Hossein

    2015-02-25

    Availability of human embryonic stem cells (hESCs) has enhanced the capability of basic and clinical research in the context of human neural differentiation. Derivation of neural progenitor (NP) cells from hESCs facilitates the process of human embryonic development through the generation of neuronal subtypes. We have recently indicated that fibronectin type III domain containing 5 protein (FNDC5) expression is required for appropriate neural differentiation of mouse embryonic stem cells (mESCs). Bioinformatics analyses have shown the presence of three isoforms for human FNDC5 mRNA. To differentiate which isoform of FNDC5 is involved in the process of human neural differentiation, we have used hESCs as an in vitro model for neural differentiation by retinoic acid (RA) induction. The hESC line, Royan H5, was differentiated into a neural lineage in defined adherent culture treated by RA and basic fibroblast growth factor (bFGF). We collected all cell types that included hESCs, rosette structures, and neural cells in an attempt to assess the expression of FNDC5 isoforms. There was a contiguous increase in all three FNDC5 isoforms during the neural differentiation process. Furthermore, the highest level of expression of the isoforms was significantly observed in neural cells compared to hESCs and the rosette structures known as neural precursor cells (NPCs). High expression levels of FNDC5 in human fetal brain and spinal cord tissues have suggested the involvement of this gene in neural tube development. Additional research is necessary to determine the major function of FDNC5 in this process. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Neural correlate of human reciprocity in social interactions

    Directory of Open Access Journals (Sweden)

    Shiro eSakaiya

    2013-12-01

    Full Text Available Reciprocity plays a key role maintaining cooperation in society. However, little is known about the neural process that underpins human reciprocity during social interactions. Our neuroimaging study manipulated partner identity (computer, human and strategy (random, tit-for-tat in repeated prisoner’s dilemma games and investigated the neural correlate of reciprocal interaction with humans. Reciprocal cooperation with humans but exploitation of computers by defection was associated with activation in the left amygdala. Amygdala activation was also positively and negatively correlated with a preference change for human partners following tit-for-tat and random strategies, respectively. The correlated activation represented the intensity of positive feeling toward reciprocal and negative feeling toward non-reciprocal partners, and so reflected reciprocity in social interaction. Reciprocity in social interaction, however, might plausibly be misinterpreted and so we also examined the neural coding of insight into the reciprocity of partners. Those with and without insight revealed differential brain activation across the reward-related circuitry (i.e., the right middle dorsolateral prefrontal cortex and dorsal caudate and theory of mind (ToM regions (i.e., ventromedial prefrontal cortex [VMPFC] and precuneus. Among differential activations, activation in the precuneus, which accompanied deactivation of the VMPFC, was specific to those without insight into human partners who were engaged in a tit-for-tat strategy. This asymmetric (deactivation might involve specific contributions of ToM regions to the human search for reciprocity. Consequently, the intensity of emotion attached to human reciprocity was represented in the amygdala, whereas insight into the reciprocity of others was reflected in activation across the reward-related and ToM regions. This suggests the critical role of mentalizing, which was not equated with reward expectation during

  8. Neural correlate of human reciprocity in social interactions.

    Science.gov (United States)

    Sakaiya, Shiro; Shiraito, Yuki; Kato, Junko; Ide, Hiroko; Okada, Kensuke; Takano, Kouji; Kansaku, Kenji

    2013-01-01

    Reciprocity plays a key role maintaining cooperation in society. However, little is known about the neural process that underpins human reciprocity during social interactions. Our neuroimaging study manipulated partner identity (computer, human) and strategy (random, tit-for-tat) in repeated prisoner's dilemma games and investigated the neural correlate of reciprocal interaction with humans. Reciprocal cooperation with humans but exploitation of computers by defection was associated with activation in the left amygdala. Amygdala activation was also positively and negatively correlated with a preference change for human partners following tit-for-tat and random strategies, respectively. The correlated activation represented the intensity of positive feeling toward reciprocal and negative feeling toward non-reciprocal partners, and so reflected reciprocity in social interaction. Reciprocity in social interaction, however, might plausibly be misinterpreted and so we also examined the neural coding of insight into the reciprocity of partners. Those with and without insight revealed differential brain activation across the reward-related circuitry (i.e., the right middle dorsolateral prefrontal cortex and dorsal caudate) and theory of mind (ToM) regions [i.e., ventromedial prefrontal cortex (VMPFC) and precuneus]. Among differential activations, activation in the precuneus, which accompanied deactivation of the VMPFC, was specific to those without insight into human partners who were engaged in a tit-for-tat strategy. This asymmetric (de)activation might involve specific contributions of ToM regions to the human search for reciprocity. Consequently, the intensity of emotion attached to human reciprocity was represented in the amygdala, whereas insight into the reciprocity of others was reflected in activation across the reward-related and ToM regions. This suggests the critical role of mentalizing, which was not equated with reward expectation during social interactions.

  9. Rapid Functional Reorganization in Human Cortex Following Neural Perturbation

    OpenAIRE

    Zanto, Theodore P.; Chadick, James Z.; Satris, Gabriela; Gazzaley, Adam

    2013-01-01

    Despite the human brain's ability to rapidly reorganize neuronal activity patterns in response to interactions with the environment (e.g., learning), it remains unclear whether compensatory mechanisms occur, on a similar time scale, in response to exogenous cortical perturbations. To investigate this, we disrupted normal neural function via repetitive transcranial magnetic stimulation and assessed, using fMRI, activity changes associated with performance on a working memory task. Although tra...

  10. Establishment of Human Neural Progenitor Cells from Human Induced Pluripotent Stem Cells with Diverse Tissue Origins

    Directory of Open Access Journals (Sweden)

    Hayato Fukusumi

    2016-01-01

    Full Text Available Human neural progenitor cells (hNPCs have previously been generated from limited numbers of human induced pluripotent stem cell (hiPSC clones. Here, 21 hiPSC clones derived from human dermal fibroblasts, cord blood cells, and peripheral blood mononuclear cells were differentiated using two neural induction methods, an embryoid body (EB formation-based method and an EB formation method using dual SMAD inhibitors (dSMADi. Our results showed that expandable hNPCs could be generated from hiPSC clones with diverse somatic tissue origins. The established hNPCs exhibited a mid/hindbrain-type neural identity and uniform expression of neural progenitor genes.

  11. The neural basis of human dance.

    Science.gov (United States)

    Brown, Steven; Martinez, Michael J; Parsons, Lawrence M

    2006-08-01

    Human dance was investigated with positron emission tomography to identify its systems-level organization. Three core aspects of dance were examined: entrainment, meter and patterned movement. Amateur dancers performed small-scale, cyclically repeated tango steps on an inclined surface to the beat of tango music, without visual guidance. Entrainment of dance steps to music, compared to self-pacing of movement, was supported by anterior cerebellar vermis. Movement to a regular, metric rhythm, compared to movement to an irregular rhythm, implicated the right putamen in the voluntary control of metric motion. Spatial navigation of leg movement during dance, when controlling for muscle contraction, activated the medial superior parietal lobule, reflecting proprioceptive and somatosensory contributions to spatial cognition in dance. Finally, additional cortical, subcortical and cerebellar regions were active at the systems level. Consistent with recent work on simpler, rhythmic, motor-sensory behaviors, these data reveal the interacting network of brain areas active during spatially patterned, bipedal, rhythmic movements that are integrated in dance.

  12. 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.

  13. Infrared neural stimulation of human spinal nerve roots in vivo.

    Science.gov (United States)

    Cayce, Jonathan M; Wells, Jonathon D; Malphrus, Jonathan D; Kao, Chris; Thomsen, Sharon; Tulipan, Noel B; Konrad, Peter E; Jansen, E Duco; Mahadevan-Jansen, Anita

    2015-01-01

    Infrared neural stimulation (INS) is a neurostimulation modality that uses pulsed infrared light to evoke artifact-free, spatially precise neural activity with a noncontact interface; however, the technique has not been demonstrated in humans. The objective of this study is to demonstrate the safety and efficacy of INS in humans in vivo. The feasibility of INS in humans was assessed in patients ([Formula: see text]) undergoing selective dorsal root rhizotomy, where hyperactive dorsal roots, identified for transection, were stimulated in vivo with INS on two to three sites per nerve with electromyogram recordings acquired throughout the stimulation. The stimulated dorsal root was removed and histology was performed to determine thermal damage thresholds of INS. Threshold activation of human dorsal rootlets occurred in 63% of nerves for radiant exposures between 0.53 and [Formula: see text]. In all cases, only one or two monitored muscle groups were activated from INS stimulation of a hyperactive spinal root identified by electrical stimulation. Thermal damage was first noted at [Formula: see text] and a [Formula: see text] safety ratio was identified. These findings demonstrate the success of INS as a fresh approach for activating human nerves in vivo and providing the necessary safety data needed to pursue clinically driven therapeutic and diagnostic applications of INS in humans.

  14. Neural mechanisms of discourse comprehension: a human lesion study.

    Science.gov (United States)

    Barbey, Aron K; Colom, Roberto; Grafman, Jordan

    2014-01-01

    Discourse comprehension is a hallmark of human social behaviour and refers to the act of interpreting a written or spoken message by constructing mental representations that integrate incoming language with prior knowledge and experience. Here, we report a human lesion study (n = 145) that investigates the neural mechanisms underlying discourse comprehension (measured by the Discourse Comprehension Test) and systematically examine its relation to a broad range of psychological factors, including psychometric intelligence (measured by the Wechsler Adult Intelligence Scale), emotional intelligence (measured by the Mayer, Salovey, Caruso Emotional Intelligence Test), and personality traits (measured by the Neuroticism-Extraversion-Openness Personality Inventory). Scores obtained from these factors were submitted to voxel-based lesion-symptom mapping to elucidate their neural substrates. Stepwise regression analyses revealed that working memory and extraversion reliably predict individual differences in discourse comprehension: higher working memory scores and lower extraversion levels predict better discourse comprehension performance. Lesion mapping results indicated that these convergent variables depend on a shared network of frontal and parietal regions, including white matter association tracts that bind these areas into a coordinated system. The observed findings motivate an integrative framework for understanding the neural foundations of discourse comprehension, suggesting that core elements of discourse processing emerge from a distributed network of brain regions that support specific competencies for executive and social function.

  15. CHARGEd with neural crest defects.

    Science.gov (United States)

    Pauli, Silke; Bajpai, Ruchi; Borchers, Annette

    2017-10-30

    Neural crest cells are highly migratory pluripotent cells that give rise to diverse derivatives including cartilage, bone, smooth muscle, pigment, and endocrine cells as well as neurons and glia. Abnormalities in neural crest-derived tissues contribute to the etiology of CHARGE syndrome, a complex malformation disorder that encompasses clinical symptoms like coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. Mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene are causative of CHARGE syndrome and loss-of-function data in different model systems have firmly established a role of CHD7 in neural crest development. Here, we will summarize our current understanding of the function of CHD7 in neural crest development and discuss possible links of CHARGE syndrome to other developmental disorders. © 2017 Wiley Periodicals, Inc.

  16. Structural Analysis of Three-dimensional Human Neural Tissue derived from Induced Pluripotent Stem Cells

    DEFF Research Database (Denmark)

    Terrence Brooks, Patrick; Rasmussen, Mikkel Aabech; Hyttel, Poul

    2016-01-01

    Objective: The present study aimed at establishing a method for production of a three-dimensional (3D) human neural tissue derived from induced pluripotent stem cells (iPSCs) and analyzing the outcome by a combination of tissue ultrastructure and expression of neural markers. Methods: A two......-step cell culture procedure was implemented by subjecting human iPSCs to a 3D scaffoldbased neural differentiation protocol. First, neural fate-inducing small molecules were used to create a neuroepithelial monolayer. Second, the monolayer was trypsinized into single cells and seeded into a porous...... polystyrene scaffold and further cultured to produce a 3D neural tissue. The neural tissue was characterized by a combination of immunohistochemistry and transmission electron microscopy (TEM). Results: iPSCs developed into a 3D neural tissue expressing markers for neural progenitor cells, early neural...

  17. Neural, cognitive, and evolutionary foundations of human altruism.

    Science.gov (United States)

    Marsh, Abigail A

    2016-01-01

    This article considers three forms of altruism from both a psychological and a neural perspective, with an emphasis on homologies that can be observed across species and potentially illuminate altruism's evolutionary origins. Kin-based altruism benefits biological relatives and, according to the theory of inclusive fitness, is ultimately beneficial to the altruist from a genetic standpoint. Kin selection adequately explains some altruistic behavior, but it is not applicable to much human altruism. Little is known about the neural processes that support it, but they may include cortical regions involved in processing autobiographical memory and the identities of familiar others. Reciprocity-based altruism is performed in expectation of future rewards and is supported by dopaminergic cortico-striatal networks that guide behavior according to anticipated rewards. Care-based altruism is aimed at improving the well-being of distressed and vulnerable individuals and is closely linked to empathic concern. This form of altruism is thought to rely on the subcortical neural systems that support parental care, particularly structures densely populated with receptors for the hormones oxytocin and vasopressin, including the amygdala, stria terminalis, and striatum. The amygdala may be a particularly important convergence point for care-based altruism because of its dual role in responding both to cues that signal infantile vulnerability and those that signal distress. Research on altruism continues to converge across disciplines, but more research linking molecular-level neural processes to altruistic behavior in humans and other species is needed, as is research on how various forms of altruism intersect. For further resources related to this article, please visit the WIREs website. © 2015 Wiley Periodicals, Inc.

  18. Human induced pluripotent stem cell-derived models to investigate human cytomegalovirus infection in neural cells.

    Directory of Open Access Journals (Sweden)

    Leonardo D'Aiuto

    Full Text Available Human cytomegalovirus (HCMV infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs, neural progenitor cells (NPCs and neurons suggests that (i iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii Neural stem cells have impaired differentiation when infected by HCMV; (iii NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv most iPS-derived neurons are not permissive to HCMV infection; and (v infected neurons have impaired calcium influx in response to glutamate.

  19. A developmental perspective on the neural bases of human empathy.

    Science.gov (United States)

    Tousignant, Béatrice; Eugène, Fanny; Jackson, Philip L

    2017-08-01

    While empathy has been widely studied in philosophical and psychological literatures, recent advances in social neuroscience have shed light on the neural correlates of this complex interpersonal phenomenon. In this review, we provide an overview of brain imaging studies that have investigated the neural substrates of human empathy. Based on existing models of the functional architecture of empathy, we review evidence of the neural underpinnings of each main component, as well as their development from infancy. Although early precursors of affective sharing and self-other distinction appear to be present from birth, recent findings also suggest that even higher-order components of empathy such as perspective-taking and emotion regulation demonstrate signs of development during infancy. This merging of developmental and social neuroscience literature thus supports the view that ontogenic development of empathy is rooted in early infancy, well before the emergence of verbal abilities. With age, the refinement of top-down mechanisms may foster more appropriate empathic responses, thus promoting greater altruistic motivation and prosocial behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Realistic animation of human figures using artificial neural networks.

    Science.gov (United States)

    Taha, Z; Brown, R; Wright, D

    1996-12-01

    We describe a new approach to the animation of human figures which can produce realistic animation and based on artificial neural networks (ANN). A fully connected ANN is trained with inputs and outputs of key frames obtained from image analysis and key postures and parameters of standing, walking and running. A behaviour index is introduced as an input to the ANN. Each index is unique to each behaviour. Other inputs include speed, cycle history and subsystem index. The subsystem index refers to the different subsystem of the human figure e.g. the right leg is a subsystem referred to by an index. The outputs are the joints displacements. The ANN is trained using the back propagation method. The ANN was able to generate realistic animations of walking and running and could merge three different behaviours, standing, walking and running. The proposed method should enable design evaluations, human factors analysis, task simulation and motion understanding easier for non-animation experts.

  1. Pig Induced Pluripotent Stem Cell-Derived Neural Rosettes Developmentally Mimic Human Pluripotent Stem Cell Neural Differentiation.

    Science.gov (United States)

    Gallegos-Cárdenas, Amalia; Webb, Robin; Jordan, Erin; West, Rachel; West, Franklin D; Yang, Jeong-Yeh; Wang, Kai; Stice, Steven L

    2015-08-15

    For diseases of the brain, the pig (Sus scrofa) is increasingly being used as a model organism that shares many anatomical and biological similarities with humans. We report that pig induced pluripotent stem cells (iPSC) can recapitulate events in early mammalian neural development. Pig iPSC line (POU5F1(high)/SSEA4(low)) had a higher potential to form neural rosettes (NR) containing neuroepithelial cells than either POU5F1(low)/SSEA4(low) or POU5F1(low)/SSEA4(high) lines. Thus, POU5F1 and SSEA4 pluripotency marker profiles in starting porcine iPSC populations can predict their propensity to form more robust NR populations in culture. The NR were isolated and expanded in vitro, retaining their NR morphology and neuroepithelial molecular properties. These cells expressed anterior central nervous system fate markers OTX2 and GBX2 through at least seven passages, and responded to retinoic acid, promoting a more posterior fate (HOXB4+, OTX2-, and GBX2-). These findings offer insight into pig iPSC development, which parallels the human iPSC in both anterior and posterior neural cell fates. These in vitro similarities in early neural differentiation processes support the use of pig iPSC and differentiated neural cells as a cell therapy in allogeneic porcine neural injury and degeneration models, providing relevant translational data for eventual human neural cell therapies.

  2. Signs of noise-induced neural degeneration in humans

    DEFF Research Database (Denmark)

    Holtegaard, Pernille; Olsen, Steen Østergaard

    2015-01-01

    of background noise, while leaving the processing of low-level stimuli unaffected. The purpose of this study was to investigate if signs of such primary neural damage from noise-exposure could also be found in noiseexposed human individuals. It was investigated: (1) if noise-exposed listeners with hearing...... thresholds within the “normal” range perform poorer, in terms of their speech recognition threshold in noise (SRTN), and (2) if auditory brainstem responses (ABR) reveal lower amplitude of wave I in the noise-exposed listeners. A test group of noise/music-exposed individuals and a control group were...

  3. 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.

  4. Zebrafish zic2 controls formation of periocular neural crest and choroid fissure morphogenesis.

    Science.gov (United States)

    Sedykh, Irina; Yoon, Baul; Roberson, Laura; Moskvin, Oleg; Dewey, Colin N; Grinblat, Yevgenya

    2017-09-01

    The vertebrate retina develops in close proximity to the forebrain and neural crest-derived cartilages of the face and jaw. Coloboma, a congenital eye malformation, is associated with aberrant forebrain development (holoprosencephaly) and with craniofacial defects (frontonasal dysplasia) in humans, suggesting a critical role for cross-lineage interactions during retinal morphogenesis. ZIC2, a zinc-finger transcription factor, is linked to human holoprosencephaly. We have previously used morpholino assays to show zebrafish zic2 functions in the developing forebrain, retina and craniofacial cartilage. We now report that zebrafish with genetic lesions in zebrafish zic2 orthologs, zic2a and zic2b, develop with retinal coloboma and craniofacial anomalies. We demonstrate a requirement for zic2 in restricting pax2a expression and show evidence that zic2 function limits Hh signaling. RNA-seq transcriptome analysis identified an early requirement for zic2 in periocular neural crest as an activator of alx1, a transcription factor with essential roles in craniofacial and ocular morphogenesis in human and zebrafish. Collectively, these data establish zic2 mutant zebrafish as a powerful new genetic model for in-depth dissection of cell interactions and genetic controls during craniofacial complex development. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Translocation of latex beads after laser ablation of the avian neural crest.

    Science.gov (United States)

    Coulombe, J N; Bronner-Fraser, M

    1984-11-01

    Previous studies from this laboratory (M.E. Bronner-Fraser, 1982, Dev. Biol. 91, 50-63) have demonstrated that latex beads translocate ventrally after injection into avian embryos during the phase of neural crest migration, to settle in the vicinity of neural-crest-derived structures. In order to examine the role of host neural crest cells in the ventral translocation of implanted beads, latex beads have been injected into regions of embryos from which the neural crest cells have been ablated using a laser microbeam. Prior to their migratory phase, neural crest cells reside in the dorsal portion of the neural tube. Laser irradiation of the dorsal neural tube was used to reproducibly achieve either partial or complete ablation of neural crest cells from the irradiated regions. The effectiveness of the ablation was assessed by the degree of reduction in dorsal root ganglia, a neural crest derivative. Because of the rapidity and precision of this technique, it was possible to selectively remove neural crest cells without significantly altering other embryonic structures. The results indicate that, after injection of latex beads into the somites of embryos whose neural crest cells were removed by laser irradiation, the beads translocate ventrally in the absence of the endogenous neural crest.

  6. 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.

  7. Neural contributions to the motivational control of appetite in humans.

    Science.gov (United States)

    Hinton, Elanor C; Parkinson, John A; Holland, Anthony J; Arana, F Sergio; Roberts, Angela C; Owen, Adrian M

    2004-09-01

    The motivation to eat in humans is a complex process influenced by intrinsic mechanisms relating to the hunger and satiety cascade, and extrinsic mechanisms based on the appetitive incentive value of individual foods, which can themselves induce desire. This study was designed to investigate the neural basis of these two factors contributing to the control of motivation to eat within the same experimental design using positron emission tomography. Using a novel counterbalanced approach, participants were scanned in two separate sessions, once after fasting and once after food intake, in which they imagined themselves in a restaurant and considered a number of items on a menu, and were asked to choose their most preferred. All items were tailored to each individual and varied in their incentive value. No actual foods were presented. In response to a hungry state, increased activation was shown in the hypothalamus, amygdala and insula cortex as predicted, as well as the medulla, striatum and anterior cingulate cortex. Satiety, in contrast, was associated with increased activation in the lateral orbitofrontal and temporal cortex. Only activity in the vicinity of the amygdala and orbitofrontal cortex was observed in response to the processing of extrinsic appetitive incentive information. These results suggest that the contributions of intrinsic homeostatic influences, and extrinsic incentive factors to the motivation to eat, are somewhat dissociable neurally, with areas of convergence in the amygdala and orbitofrontal cortex. The findings of this study have implications for research into the underlying mechanisms of eating disorders.

  8. Neural decoding of expressive human movement from scalp electroencephalography (EEG

    Directory of Open Access Journals (Sweden)

    Zachery Ryan Hernandez

    2014-04-01

    Full Text Available Although efforts to characterize human movement through EEG have revealed neural activities unique to limb control that can be used to infer movement kinematics, it is still unknown the extent to which EEG can be used to discern the expressive qualities that influence such movements. In this study we used EEG and inertial sensors to record brain activity and movement of five skilled and certified Laban Movement Analysis (LMA dancers. Each dancer performed whole body functional movements of three Action types: movements devoid of expressive qualities ('Neutral', non-expressive movements while thinking about specific expressive qualities ('Think’, and enacted expressive movements ('Do'. The expressive movement qualities that were used in the 'Think' and 'Do' actions consisted of a sequence of eight Laban Efforts as defined by LMA - a notation system and language for describing, visualizing, interpreting and documenting all varieties of human movement. We used delta band (0.2 – 4 Hz EEG as input to a machine learning algorithm that computed locality-preserving Fisher’s discriminant analysis (LFDA for dimensionality reduction followed by Gaussian mixture models (GMMs to decode the type of Action. We also trained our LFDA-GMM models to classify all the possible combinations of Action Type and Laban Effort (giving a total of 17 classes. Classification accuracy rates were 59.4 ± 0.6% for Action Type and 88.2 ± 0.7% for Laban Effort Type. Ancillary analyses of the potential relations between the EEG and movement kinematics of the dancer's body, indicated that motion-related artifacts did not significantly influence our classification results. In summary, this research demonstrates that EEG has valuable information about the expressive qualities of movement. These results may have applications for advancing the understanding of the neural basis of expressive movements and for the development of neuroprosthetics to restore movements.

  9. Neural decoding of expressive human movement from scalp electroencephalography (EEG)

    Science.gov (United States)

    Cruz-Garza, Jesus G.; Hernandez, Zachery R.; Nepaul, Sargoon; Bradley, Karen K.; Contreras-Vidal, Jose L.

    2014-01-01

    Although efforts to characterize human movement through electroencephalography (EEG) have revealed neural activities unique to limb control that can be used to infer movement kinematics, it is still unknown the extent to which EEG can be used to discern the expressive qualities that influence such movements. In this study we used EEG and inertial sensors to record brain activity and movement of five skilled and certified Laban Movement Analysis (LMA) dancers. Each dancer performed whole body movements of three Action types: movements devoid of expressive qualities (“Neutral”), non-expressive movements while thinking about specific expressive qualities (“Think”), and enacted expressive movements (“Do”). The expressive movement qualities that were used in the “Think” and “Do” actions consisted of a sequence of eight Laban Effort qualities as defined by LMA—a notation system and language for describing, visualizing, interpreting and documenting all varieties of human movement. We used delta band (0.2–4 Hz) EEG as input to a machine learning algorithm that computed locality-preserving Fisher's discriminant analysis (LFDA) for dimensionality reduction followed by Gaussian mixture models (GMMs) to decode the type of Action. We also trained our LFDA-GMM models to classify all the possible combinations of Action Type and Laban Effort quality (giving a total of 17 classes). Classification accuracy rates were 59.4 ± 0.6% for Action Type and 88.2 ± 0.7% for Laban Effort quality Type. Ancillary analyses of the potential relations between the EEG and movement kinematics of the dancer's body, indicated that motion-related artifacts did not significantly influence our classification results. In summary, this research demonstrates that EEG has valuable information about the expressive qualities of movement. These results may have applications for advancing the understanding of the neural basis of expressive movements and for the development of

  10. Neural decoding of expressive human movement from scalp electroencephalography (EEG).

    Science.gov (United States)

    Cruz-Garza, Jesus G; Hernandez, Zachery R; Nepaul, Sargoon; Bradley, Karen K; Contreras-Vidal, Jose L

    2014-01-01

    Although efforts to characterize human movement through electroencephalography (EEG) have revealed neural activities unique to limb control that can be used to infer movement kinematics, it is still unknown the extent to which EEG can be used to discern the expressive qualities that influence such movements. In this study we used EEG and inertial sensors to record brain activity and movement of five skilled and certified Laban Movement Analysis (LMA) dancers. Each dancer performed whole body movements of three Action types: movements devoid of expressive qualities ("Neutral"), non-expressive movements while thinking about specific expressive qualities ("Think"), and enacted expressive movements ("Do"). The expressive movement qualities that were used in the "Think" and "Do" actions consisted of a sequence of eight Laban Effort qualities as defined by LMA-a notation system and language for describing, visualizing, interpreting and documenting all varieties of human movement. We used delta band (0.2-4 Hz) EEG as input to a machine learning algorithm that computed locality-preserving Fisher's discriminant analysis (LFDA) for dimensionality reduction followed by Gaussian mixture models (GMMs) to decode the type of Action. We also trained our LFDA-GMM models to classify all the possible combinations of Action Type and Laban Effort quality (giving a total of 17 classes). Classification accuracy rates were 59.4 ± 0.6% for Action Type and 88.2 ± 0.7% for Laban Effort quality Type. Ancillary analyses of the potential relations between the EEG and movement kinematics of the dancer's body, indicated that motion-related artifacts did not significantly influence our classification results. In summary, this research demonstrates that EEG has valuable information about the expressive qualities of movement. These results may have applications for advancing the understanding of the neural basis of expressive movements and for the development of neuroprosthetics to restore

  11. Secretome analysis of human oligodendrocytes derived from neural stem cells.

    Directory of Open Access Journals (Sweden)

    Woo Kyung Kim

    Full Text Available In this study, we investigated the secretome of human oligodendrocytes (F3.Olig2 cells generated from human neural stem cells by transduction with the gene encoding the Olig2 transcription factor. Using mRNA sequencing and protein cytokine arrays, we identified a number of biologically important secretory proteins whose expression has not been previously reported in oligodendrocytes. We found that F3.Olig2 cells secrete IL-6, PDGF-AA, GRO, GM-CSF, and M-CSF, and showed prominent expression of their corresponding receptors. Co-expression of ligands and receptors suggests that autocrine signaling loops may play important roles in both differentiation and maintenance of oligodendrocytes. We also found that F3.Olig2 cells secrete matrix metalloproteinases and matrix metalloproteinase-associated proteins associated with functional competence of oligodendrocytes. The results of our secretome analysis provide insights into the functional and molecular details of human oligodendrocytes. To the best of our knowledge, this is the first systematic analysis of the secretome of oligodendrocytes.

  12. Comparison of 2D and 3D neural induction methods for the generation of neural progenitor cells from human induced pluripotent stem cells

    DEFF Research Database (Denmark)

    Chandrasekaran, Abinaya; Avci, Hasan; Ochalek, Anna

    2017-01-01

    Neural progenitor cells (NPCs) from human induced pluripotent stem cells (hiPSCs) are frequently induced using 3D culture methodologies however, it is unknown whether spheroid-based (3D) neural induction is actually superior to monolayer (2D) neural induction. Our aim was to compare the efficiency...

  13. Neural coding of movement direction in the healthy human brain.

    Directory of Open Access Journals (Sweden)

    Christopher D Cowper-Smith

    2010-10-01

    Full Text Available Neurophysiological studies in monkeys show that activity of neurons in primary cortex (M1, pre-motor cortex (PMC, and cerebellum varies systematically with the direction of reaching movements. These neurons exhibit preferred direction tuning, where the level of neural activity is highest when movements are made in the preferred direction (PD, and gets progressively lower as movements are made at increasing degrees of offset from the PD. Using a functional magnetic resonance imaging adaptation (fMRI-A paradigm, we show that PD coding does exist in regions of the human motor system that are homologous to those observed in non-human primates. Consistent with predictions of the PD model, we show adaptation (i.e., a lower level of the blood oxygen level dependent (BOLD time-course signal in M1, PMC, SMA, and cerebellum when consecutive wrist movements were made in the same direction (0° offset relative to movements offset by 90° or 180°. The BOLD signal in dorsolateral prefrontal cortex adapted equally in all movement offset conditions, mitigating against the possibility that the present results are the consequence of differential task complexity or attention to action in each movement offset condition.

  14. Neural Signature of Value-Based Sensorimotor Prioritization in Humans.

    Science.gov (United States)

    Blangero, Annabelle; Kelly, Simon P

    2017-11-01

    value biases in sensorimotor decision making have been widely studied, little is known about the neural processes that set these biases in place beforehand. Here, we report the discovery of a transient, spatially selective neural signal in humans that encodes the relative value of competing decision alternatives and strongly predicts behavioral value biases in decisions made ∼500 ms later. Follow-up manipulations of value differential, reward valence, response modality, sensory features, and time constraints establish that the signal reflects an active, feature- and effector-general preparatory mechanism for value-based prioritization. Copyright © 2017 the authors 0270-6474/17/3710725-13$15.00/0.

  15. Culture-sensitive neural substrates of human cognition: a transcultural neuroimaging approach.

    Science.gov (United States)

    Han, Shihui; Northoff, Georg

    2008-08-01

    Our brains and minds are shaped by our experiences, which mainly occur in the context of the culture in which we develop and live. Although psychologists have provided abundant evidence for diversity of human cognition and behaviour across cultures, the question of whether the neural correlates of human cognition are also culture-dependent is often not considered by neuroscientists. However, recent transcultural neuroimaging studies have demonstrated that one's cultural background can influence the neural activity that underlies both high- and low-level cognitive functions. The findings provide a novel approach by which to distinguish culture-sensitive from culture-invariant neural mechanisms of human cognition.

  16. Human Embryonic Stem Cells: A Model for the Study of Neural Development and Neurological Diseases

    Directory of Open Access Journals (Sweden)

    Piya Prajumwongs

    2016-01-01

    Full Text Available Although the mechanism of neurogenesis has been well documented in other organisms, there might be fundamental differences between human and those species referring to species-specific context. Based on principles learned from other systems, it is found that the signaling pathways required for neural induction and specification of human embryonic stem cells (hESCs recapitulated those in the early embryo development in vivo at certain degree. This underscores the usefulness of hESCs in understanding early human neural development and reinforces the need to integrate the principles of developmental biology and hESC biology for an efficient neural differentiation.

  17. Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells.

    Science.gov (United States)

    Lange, Christian; Mix, Eilhard; Frahm, Jana; Glass, Anne; Müller, Jana; Schmitt, Oliver; Schmöle, Anne-Caroline; Klemm, Kristin; Ortinau, Stefanie; Hübner, Rayk; Frech, Moritz J; Wree, Andreas; Rolfs, Arndt

    2011-01-13

    Human neural progenitor cells provide a source for cell replacement therapy to treat neurodegenerative diseases. Therefore, there is great interest in mechanisms and tools to direct the fate of multipotent progenitor cells during their differentiation to increase the yield of a desired cell type. We tested small molecule inhibitors of glycogen synthase kinase-3 (GSK-3) for their functionality and their influence on neurogenesis using the human neural progenitor cell line ReNcell VM. Here we report the enhancement of neurogenesis of human neural progenitor cells by treatment with GSK-3 inhibitors. We tested different small molecule inhibitors of GSK-3 i.e. LiCl, sodium-valproate, kenpaullone, indirubin-3-monoxime and SB-216763 for their ability to inhibit GSK-3 in human neural progenitor cells. The highest in situ GSK-3 inhibitory effect of the drugs was found for kenpaullone and SB-216763. Accordingly, kenpaullone and SB-216763 were the only drugs tested in this study to stimulate the Wnt/β-catenin pathway that is antagonized by GSK-3. Analysis of human neural progenitor differentiation revealed an augmentation of neurogenesis by SB-216763 and kenpaullone, without changing cell cycle exit or cell survival. Small molecule inhibitors of GSK-3 enhance neurogenesis of human neural progenitor cells and may be used to direct the differentiation of neural stem and progenitor cells in therapeutic applications. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

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

    NARCIS (Netherlands)

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

    2017-01-01

    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

  19. Neural correlates of human somatosensory integration in tinnitus

    NARCIS (Netherlands)

    Lanting, C. P.; de Kleine, E.; Eppinga, R. N.; van Dijk, P.

    2010-01-01

    Possible neural correlates of somatosensory modulation of tinnitus were assessed. Functional magnetic resonance imaging (fMRI) was used to investigate differences in neural activity between subjects that can modulate their tinnitus by jaw protrusion and normal hearing controls. We measured responses

  20. Evidence for neural encoding of Bayesian surprise in human somatosensation.

    Science.gov (United States)

    Ostwald, Dirk; Spitzer, Bernhard; Guggenmos, Matthias; Schmidt, Timo T; Kiebel, Stefan J; Blankenburg, Felix

    2012-08-01

    Accumulating empirical evidence suggests a role of Bayesian inference and learning for shaping neural responses in auditory and visual perception. However, its relevance for somatosensory processing is unclear. In the present study we test the hypothesis that cortical somatosensory processing exhibits dynamics that are consistent with Bayesian accounts of brain function. Specifically, we investigate the cortical encoding of Bayesian surprise, a recently proposed marker of Bayesian perceptual learning, using EEG data recorded from 15 subjects. Capitalizing on a somatosensory mismatch roving paradigm, we performed computational single-trial modeling of evoked somatosensory potentials for the entire peri-stimulus time period in source space. By means of Bayesian model selection, we find that, at 140 ms post-stimulus onset, secondary somatosensory cortex represents Bayesian surprise rather than stimulus change, which is the conventional marker of EEG mismatch responses. In contrast, at 250 ms, right inferior frontal cortex indexes stimulus change. Finally, at 360 ms, our analyses indicate additional perceptual learning attributable to medial cingulate cortex. In summary, the present study provides novel evidence for anatomical-temporal/functional segregation in human somatosensory processing that is consistent with the Bayesian brain hypothesis. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Highly Efficient Neural Conversion of Human Pluripotent Stem Cells in Adherent and Animal-Free Conditions.

    Science.gov (United States)

    Lukovic, Dunja; Diez Lloret, Andrea; Stojkovic, Petra; Rodríguez-Martínez, Daniel; Perez Arago, Maria Amparo; Rodriguez-Jimenez, Francisco Javier; González-Rodríguez, Patricia; López-Barneo, José; Sykova, Eva; Jendelova, Pavla; Kostic, Jelena; Moreno-Manzano, Victoria; Stojkovic, Miodrag; Bhattacharya, Shomi S; Erceg, Slaven

    2017-04-01

    Neural differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) can produce a valuable and robust source of human neural cell subtypes, holding great promise for the study of neurogenesis and development, and for treating neurological diseases. However, current hESCs and hiPSCs neural differentiation protocols require either animal factors or embryoid body formation, which decreases efficiency and yield, and strongly limits medical applications. Here we develop a simple, animal-free protocol for neural conversion of both hESCs and hiPSCs in adherent culture conditions. A simple medium formula including insulin induces the direct conversion of >98% of hESCs and hiPSCs into expandable, transplantable, and functional neural progenitors with neural rosette characteristics. Further differentiation of neural progenitors into dopaminergic and spinal motoneurons as well as astrocytes and oligodendrocytes indicates that these neural progenitors retain responsiveness to instructive cues revealing the robust applicability of the protocol in the treatment of different neurodegenerative diseases. The fact that this protocol includes animal-free medium and human extracellular matrix components avoiding embryoid bodies makes this protocol suitable for the use in clinic. Stem Cells Translational Medicine 2017;6:1217-1226. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  2. Methods for Derivation of Multipotent Neural Crest Cells Derived from Human Pluripotent Stem Cells.

    Science.gov (United States)

    Avery, John; Dalton, Stephen

    2016-01-01

    Multipotent, neural crest cells (NCCs) produce a wide range of cell types during embryonic development. This includes melanocytes, peripheral neurons, smooth muscle cells, osteocytes, chondrocytes, and adipocytes. The protocol described here allows for highly efficient differentiation of human pluripotent stem cells to a neural crest fate within 15 days. This is accomplished under feeder-free conditions, using chemically defined medium supplemented with two small molecule inhibitors that block glycogen synthase kinase 3 (GSK3) and bone morphogenic protein (BMP) signaling. This technology is well suited as a platform to understand in greater detail the pathogenesis of human disease associated with impaired neural crest development/migration.

  3. The human factor: behavioral and neural correlates of humanized perception in moral decision making.

    Directory of Open Access Journals (Sweden)

    Jasminka Majdandžić

    Full Text Available The extent to which people regard others as full-blown individuals with mental states ("humanization" seems crucial for their prosocial motivation towards them. Previous research has shown that decisions about moral dilemmas in which one person can be sacrificed to save multiple others do not consistently follow utilitarian principles. We hypothesized that this behavior can be explained by the potential victim's perceived humanness and an ensuing increase in vicarious emotions and emotional conflict during decision making. Using fMRI, we assessed neural activity underlying moral decisions that affected fictitious persons that had or had not been experimentally humanized. In implicit priming trials, participants either engaged in mentalizing about these persons (Humanized condition or not (Neutral condition. In subsequent moral dilemmas, participants had to decide about sacrificing these persons' lives in order to save the lives of numerous others. Humanized persons were sacrificed less often, and the activation pattern during decisions about them indicated increased negative affect, emotional conflict, vicarious emotions, and behavioral control (pgACC/mOFC, anterior insula/IFG, aMCC and precuneus/PCC. Besides, we found enhanced effective connectivity between aMCC and anterior insula, which suggests increased emotion regulation during decisions affecting humanized victims. These findings highlight the importance of others' perceived humanness for prosocial behavior - with aversive affect and other-related concern when imagining harming more "human-like" persons acting against purely utilitarian decisions.

  4. Neural Markers of Responsiveness to the Environment in Human Sleep

    DEFF Research Database (Denmark)

    Andrillon, Thomas; Poulsen, Andreas Trier; Hansen, Lars Kai

    2016-01-01

    Sleep is characterized by a loss of behavioral responsiveness. However, recent research has shown that the sleeping brain is not completely disconnected from its environment. How neural activity constrains the ability to process sensory information while asleep is yet unclear. Here, we instructed...... by Lempel-Ziv complexity (LZc), a measure shown to track arousal in sleep and anesthesia. Neural activity related to the semantic content of stimuli was conserved in light non-rapid eye movement (NREM) sleep. However, these processes were suppressed in deep NREM sleep and, importantly, also in REM sleep......, despite the recovery of wake-like neural activity in the latter. In NREM sleep, sensory activations were counterbalanced by evoked down states, which, when present, blocked further processing of external information. In addition, responsiveness markers correlated positively with baseline complexity, which...

  5. The human infant brain: A neural architecture able to learn language.

    Science.gov (United States)

    Dehaene-Lambertz, Ghislaine

    2017-02-01

    To understand the type of neural computations that may explain how human infants acquire their native language in only a few months, the study of their neural architecture is necessary. The development of brain imaging techniques has opened the possibilities of studying human infants without discomfort, and although these studies are still sparse, several characteristics are noticeable in the human infant's brain: first, parallel and hierarchical processing pathways are observed before intense exposure to speech with an efficient temporal coding in the left hemisphere and, second, frontal regions are involved from the start in infants' cognition. These observations are certainly not sufficient to explain language acquisition but illustrate a new approach that relies on a better description of infants' brain activity during linguistic tasks, which is compared to results in animals and human adults to clarify the neural bases of language in humans.

  6. Wnt/Yes-Associated Protein Interactions During Neural Tissue Patterning of Human Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Bejoy, Julie; Song, Liqing; Zhou, Yi; Li, Yan

    2017-08-31

    Human induced pluripotent stem cells (hiPSCs) have special ability to self-assemble into neural spheroids or mini-brain-like structures. During the self-assembly process, Wnt signaling plays an important role in regional patterning and establishing positional identity of hiPSC-derived neural progenitors. Recently, the role of Wnt signaling in regulating Yes-associated protein (YAP) expression (nuclear or cytoplasmic), the pivotal regulator during organ growth and tissue generation, has attracted increasing interests. However, the interactions between Wnt and YAP expression for neural lineage commitment of hiPSCs remain poorly explored. The objective of this study is to investigate the effects of Wnt signaling and YAP expression on the cellular population in three-dimensional (3D) neural spheroids derived from hiPSCs. In this study, Wnt signaling was activated using CHIR99021 for 3D neural spheroids derived from human iPSK3 cells through embryoid body formation. Our results indicate that Wnt activation induces nuclear localization of YAP and upregulates the expression of HOXB4, the marker for hindbrain/spinal cord. By contrast, the cells exhibit more rostral forebrain neural identity (expression of TBR1) without Wnt activation. Cytochalasin D was then used to induce cytoplasmic YAP and the results showed the decreased HOXB4 expression. In addition, the incorporation of microparticles in the neural spheroids was investigated for the perturbation of neural patterning. This study may indicate the bidirectional interactions of Wnt signaling and YAP expression during neural tissue patterning, which have the significance in neurological disease modeling, drug screening, and neural tissue regeneration.

  7. A Neural Basis of Facial Action Recognition in Humans.

    Science.gov (United States)

    Srinivasan, Ramprakash; Golomb, Julie D; Martinez, Aleix M

    2016-04-20

    By combining different facial muscle actions, called action units, humans can produce an extraordinarily large number of facial expressions. Computational models and studies in cognitive science and social psychology have long hypothesized that the brain needs to visually interpret these action units to understand other people's actions and intentions. Surprisingly, no studies have identified the neural basis of the visual recognition of these action units. Here, using functional magnetic resonance imaging and an innovative machine learning analysis approach, we identify a consistent and differential coding of action units in the brain. Crucially, in a brain region thought to be responsible for the processing of changeable aspects of the face, multivoxel pattern analysis could decode the presence of specific action units in an image. This coding was found to be consistent across people, facilitating the estimation of the perceived action units on participants not used to train the multivoxel decoder. Furthermore, this coding of action units was identified when participants attended to the emotion category of the facial expression, suggesting an interaction between the visual analysis of action units and emotion categorization as predicted by the computational models mentioned above. These results provide the first evidence for a representation of action units in the brain and suggest a mechanism for the analysis of large numbers of facial actions and a loss of this capacity in psychopathologies. Computational models and studies in cognitive and social psychology propound that visual recognition of facial expressions requires an intermediate step to identify visible facial changes caused by the movement of specific facial muscles. Because facial expressions are indeed created by moving one's facial muscles, it is logical to assume that our visual system solves this inverse problem. Here, using an innovative machine learning method and neuroimaging data, we identify

  8. Neural Progenitor Cells Derived from Human Embryonic Stem Cells as an Origin of Dopaminergic Neurons

    Directory of Open Access Journals (Sweden)

    Parinya Noisa

    2015-01-01

    Full Text Available Human embryonic stem cells (hESCs are able to proliferate in vitro indefinitely without losing their ability to differentiate into multiple cell types upon exposure to appropriate signals. Particularly, the ability of hESCs to differentiate into neuronal subtypes is fundamental to develop cell-based therapies for several neurodegenerative disorders, such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. In this study, we differentiated hESCs to dopaminergic neurons via an intermediate stage, neural progenitor cells (NPCs. hESCs were induced to neural progenitor cells by Dorsomorphin, a small molecule that inhibits BMP signalling. The resulting neural progenitor cells exhibited neural bipolarity with high expression of neural progenitor genes and possessed multipotential differentiation ability. CBF1 and bFGF responsiveness of these hES-NP cells suggested their similarity to embryonic neural progenitor cells. A substantial number of dopaminergic neurons were derived from hES-NP cells upon supplementation of FGF8 and SHH, key dopaminergic neuron inducers. Importantly, multiple markers of midbrain neurons were detected, including NURR1, PITX3, and EN1, suggesting that hESC-derived dopaminergic neurons attained the midbrain identity. Altogether, this work underscored the generation of neural progenitor cells that retain the properties of embryonic neural progenitor cells. These cells will serve as an unlimited source for the derivation of dopaminergic neurons, which might be applicable for treating patients with Parkinson’s disease.

  9. Differentiation of reprogrammed human adipose mesenchymal stem cells toward neural cells with defined transcription factors.

    Science.gov (United States)

    Qu, Xinjian; Liu, Tianqing; Song, Kedong; Li, Xiangqin; Ge, Dan

    2013-10-04

    Somatic cell reprogramming may become a powerful approach to generate specific human cell types for cell-fate determination studies and potential transplantation therapies of neurological diseases. Here we report a reprogramming methodology with which human adipose stem cells (hADSCs) can be differentiated into neural cells. After being reprogrammed with polycistronic plasmid carrying defined factor OCT3/4, SOX2, KLF4 and c-MYC, and further treated with neural induce medium, the hADSCs switched to differentiate toward neural cell lineages. The generated cells had normal karyotypes and exogenous vector sequences were not inserted in the genomes. Therefore, this cell lineage conversion methodology bypasses the risk of mutation and gene instability, and provides a novel strategy to obtain patient-specific neural cells for basic research and therapeutic application. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Neural correlates of human wayfinding in stroke patients.

    NARCIS (Netherlands)

    Asselen, M. van; Kessels, R.P.C.; Kappelle, L.J.; Neggers, S.F.W.; Frijns, C.J.M.; Postma, A.

    2006-01-01

    Wayfinding is a complex cognitive function involving different types of information, such as knowledge about landmarks and direction information. This variety of processes suggest that multiple neural mechanisms are involved, e.g., the hippocampal system, the posterior parietal and temporal cortical

  11. Generation and properties of a new human ventral mesencephalic neural stem cell line

    DEFF Research Database (Denmark)

    Villa, Ana; Liste, Isabel; Courtois, Elise T

    2009-01-01

    Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson's disease. Several epigenetic and genetic strategies have been tested for long-term maintenance and expansion of these cells in vitro....... Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon (hVM1) based on v-myc immortalization. The cells expressed neural stem cell and radial glia markers like nestin, vimentin and 3CB2 under proliferation conditions. After withdrawal...

  12. Human neural progenitors express functional lysophospholipid receptors that regulate cell growth and morphology

    Directory of Open Access Journals (Sweden)

    Callihan Phillip

    2008-12-01

    Full Text Available Abstract Background Lysophospholipids regulate the morphology and growth of neurons, neural cell lines, and neural progenitors. A stable human neural progenitor cell line is not currently available in which to study the role of lysophospholipids in human neural development. We recently established a stable, adherent human embryonic stem cell-derived neuroepithelial (hES-NEP cell line which recapitulates morphological and phenotypic features of neural progenitor cells isolated from fetal tissue. The goal of this study was to determine if hES-NEP cells express functional lysophospholipid receptors, and if activation of these receptors mediates cellular responses critical for neural development. Results Our results demonstrate that Lysophosphatidic Acid (LPA and Sphingosine-1-phosphate (S1P receptors are functionally expressed in hES-NEP cells and are coupled to multiple cellular signaling pathways. We have shown that transcript levels for S1P1 receptor increased significantly in the transition from embryonic stem cell to hES-NEP. hES-NEP cells express LPA and S1P receptors coupled to Gi/o G-proteins that inhibit adenylyl cyclase and to Gq-like phospholipase C activity. LPA and S1P also induce p44/42 ERK MAP kinase phosphorylation in these cells and stimulate cell proliferation via Gi/o coupled receptors in an Epidermal Growth Factor Receptor (EGFR- and ERK-dependent pathway. In contrast, LPA and S1P stimulate transient cell rounding and aggregation that is independent of EGFR and ERK, but dependent on the Rho effector p160 ROCK. Conclusion Thus, lysophospholipids regulate neural progenitor growth and morphology through distinct mechanisms. These findings establish human ES cell-derived NEP cells as a model system for studying the role of lysophospholipids in neural progenitors.

  13. Comparison of 2D and 3D neural induction methods for the generation of neural progenitor cells from human induced pluripotent stem cells

    DEFF Research Database (Denmark)

    Chandrasekaran, Abinaya; Avci, Hasan; Ochalek, Anna

    2017-01-01

    Neural progenitor cells (NPCs) from human induced pluripotent stem cells (hiPSCs) are frequently induced using 3D culture methodologies however, it is unknown whether spheroid-based (3D) neural induction is actually superior to monolayer (2D) neural induction. Our aim was to compare the efficiency......), cortical layer (TBR1, CUX1) and glial markers (SOX9, GFAP, AQP4). Electron microscopy demonstrated that both methods resulted in morphologically similar neural rosettes. However, quantification of NPCs derived from 3D neural induction exhibited an increase in the number of PAX6/NESTIN double positive cells...... and the derived neurons exhibited longer neurites. In contrast, 2D neural induction resulted in more SOX1 positive cells. While 2D monolayer induction resulted in slightly less mature neurons, at an early stage of differentiation, the patch clamp analysis failed to reveal any significant differences between...

  14. Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans.

    NARCIS (Netherlands)

    Hermans, E.J.; Ramsey, N.F.; Honk, J van

    2008-01-01

    BACKGROUND: In a range of species, the androgen steroid testosterone is known to potentiate neural circuits involved in intraspecific aggression. Disorders of impulsive aggression in humans have likewise been associated with high testosterone levels, but human evidence for the link between

  15. Neural Activity Patterns in the Human Brain Reflect Tactile Stickiness Perception

    Science.gov (United States)

    Kim, Junsuk; Yeon, Jiwon; Ryu, Jaekyun; Park, Jang-Yeon; Chung, Soon-Cheol; Kim, Sung-Phil

    2017-01-01

    Our previous human fMRI study found brain activations correlated with tactile stickiness perception using the uni-variate general linear model (GLM) (Yeon et al., 2017). Here, we conducted an in-depth investigation on neural correlates of sticky sensations by employing a multivoxel pattern analysis (MVPA) on the same dataset. In particular, we statistically compared multi-variate neural activities in response to the three groups of sticky stimuli: A supra-threshold group including a set of sticky stimuli that evoked vivid sticky perception; an infra-threshold group including another set of sticky stimuli that barely evoked sticky perception; and a sham group including acrylic stimuli with no physically sticky property. Searchlight MVPAs were performed to search for local activity patterns carrying neural information of stickiness perception. Similar to the uni-variate GLM results, significant multi-variate neural activity patterns were identified in postcentral gyrus, subcortical (basal ganglia and thalamus), and insula areas (insula and adjacent areas). Moreover, MVPAs revealed that activity patterns in posterior parietal cortex discriminated the perceptual intensities of stickiness, which was not present in the uni-variate analysis. Next, we applied a principal component analysis (PCA) to the voxel response patterns within identified clusters so as to find low-dimensional neural representations of stickiness intensities. Follow-up clustering analyses clearly showed separate neural grouping configurations between the Supra- and Infra-threshold groups. Interestingly, this neural categorization was in line with the perceptual grouping pattern obtained from the psychophysical data. Our findings thus suggest that different stickiness intensities would elicit distinct neural activity patterns in the human brain and may provide a neural basis for the perception and categorization of tactile stickiness. PMID:28936171

  16. Eye tracking using artificial neural networks for human computer interaction.

    Science.gov (United States)

    Demjén, E; Aboši, V; Tomori, Z

    2011-01-01

    This paper describes an ongoing project that has the aim to develop a low cost application to replace a computer mouse for people with physical impairment. The application is based on an eye tracking algorithm and assumes that the camera and the head position are fixed. Color tracking and template matching methods are used for pupil detection. Calibration is provided by neural networks as well as by parametric interpolation methods. Neural networks use back-propagation for learning and bipolar sigmoid function is chosen as the activation function. The user's eye is scanned with a simple web camera with backlight compensation which is attached to a head fixation device. Neural networks significantly outperform parametric interpolation techniques: 1) the calibration procedure is faster as they require less calibration marks and 2) cursor control is more precise. The system in its current stage of development is able to distinguish regions at least on the level of desktop icons. The main limitation of the proposed method is the lack of head-pose invariance and its relative sensitivity to illumination (especially to incidental pupil reflections).

  17. Capacity of Human Dental Follicle Cells to Differentiate into Neural Cells In Vitro

    Directory of Open Access Journals (Sweden)

    Shingo Kanao

    2017-01-01

    Full Text Available The dental follicle is an ectomesenchymal tissue surrounding the developing tooth germ. Human dental follicle cells (hDFCs have the capacity to commit to differentiation into multiple cell types. Here we investigated the capacity of hDFCs to differentiate into neural cells and the efficiency of a two-step strategy involving floating neurosphere-like bodies for neural differentiation. Undifferentiated hDFCs showed a spindle-like morphology and were positive for neural markers such as nestin, β-III-tubulin, and S100β. The cellular morphology of several cells was neuronal-like including branched dendrite-like processes and neurites. Next, hDFCs were used for neurosphere formation in serum-free medium containing basic fibroblast growth factor, epidermal growth factor, and B27 supplement. The number of cells with neuronal-like morphology and that were strongly positive for neural markers increased with sphere formation. Gene expression of neural markers also increased in hDFCs with sphere formation. Next, gene expression of neural markers was examined in hDFCs during neuronal differentiation after sphere formation. Expression of Musashi-1 and Musashi-2, MAP2, GFAP, MBP, and SOX10 was upregulated in hDFCs undergoing neuronal differentiation via neurospheres, whereas expression of nestin and β-III-tubulin was downregulated. In conclusion, hDFCs may be another optimal source of neural/glial cells for cell-based therapies to treat neurological diseases.

  18. Protection of neurons derived from human neural progenitor cells by veratridine.

    Science.gov (United States)

    Morgan, Peter J; Ortinau, Stefanie; Frahm, Jana; Krüger, Norman; Rolfs, Arndt; Frech, Moritz J

    2009-08-26

    The survival of developing dopaminergic neurons has been shown to be modulated by voltage-dependent mechanisms. Manipulation of these mechanisms in human neural progenitor cell cultures could improve the survival of immature dopaminergic neurons, and therefore aid research into pharmacological and cell replacement therapies for Parkinson's disease. Here, we examined the effect of the Na+ channel agonist veratridine on the human fetal neural progenitor ReNcell VM cell line. Neuronal differentiation was determined by immunocytochemistry, whereas patch clamp recordings showed the expression of functional voltage-gated sodium channels. Our results show that veratridine is neuroprotective in human fetal neural progenitor cells, which may benefit studies investigating neuronal development by reducing premature death amongst developing neurons.

  19. PRELIMINARY MODELING OF AN INDUSTRIAL RECOMBINANT HUMAN ERYTHROPOIETIN PURIFICATION PROCESS BY ARTIFICIAL NEURAL NETWORKS

    Directory of Open Access Journals (Sweden)

    R. H. R. Garcel1

    2015-09-01

    Full Text Available AbstractIn the present study a preliminary neural network modelling to improve our understanding of Recombinant Human Erythropoietin purification process in a plant was explored. A three layer feed-forward back propagation neural network was constructed for predicting the efficiency of the purification section comprising four chromatographic steps as a function of eleven operational variables. The neural network model performed very well in the training and validation phases. Using the connection weight method the predictor variables were ranked based on their estimated explanatory importance in the neural network and five input variables were found to be predominant over the others. These results provided useful information showing that the first chromatographic step and the third chromatographic step are decisive to achieve high efficiencies in the purification section, thus enriching the control strategy of the plant.

  20. Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (PhosphoProteomic Profiling

    Directory of Open Access Journals (Sweden)

    Ilyas Singec

    2016-09-01

    Full Text Available Controlled differentiation of human embryonic stem cells (hESCs can be utilized for precise analysis of cell type identities during early development. We established a highly efficient neural induction strategy and an improved analytical platform, and determined proteomic and phosphoproteomic profiles of hESCs and their specified multipotent neural stem cell derivatives (hNSCs. This quantitative dataset (nearly 13,000 proteins and 60,000 phosphorylation sites provides unique molecular insights into pluripotency and neural lineage entry. Systems-level comparative analysis of proteins (e.g., transcription factors, epigenetic regulators, kinase families, phosphorylation sites, and numerous biological pathways allowed the identification of distinct signatures in pluripotent and multipotent cells. Furthermore, as predicted by the dataset, we functionally validated an autocrine/paracrine mechanism by demonstrating that the secreted protein midkine is a regulator of neural specification. This resource is freely available to the scientific community, including a searchable website, PluriProt.

  1. Classification of Human Emotions from EEG Signals using Statistical Features and Neural Network

    OpenAIRE

    Chai Tong Yuen; Woo San San; Tan Ching Seong; Mohamed Rizon

    2009-01-01

    A statistical based system for human emotions classification by using electroencephalogram (EEG) is proposed in this paper. The data used in this study is acquired using EEG and the emotions are elicited from six human subjects under the effect of emotion stimuli. This paper also proposed an emotion stimulation experiment using visual stimuli. From the EEG data, a total of six statistical features are computed and back-propagation neural network is applied for the classification of human emot...

  2. The role of microRNAs in human neural stem cells, neuronal differentiation and subtype specification.

    Science.gov (United States)

    Stappert, Laura; Roese-Koerner, Beate; Brüstle, Oliver

    2015-01-01

    The impressive neuronal diversity found within the nervous system emerges from a limited pool of neural progenitor cells that proceed through different gene expression programs to acquire distinct cell fates. Here, we review recent evidence indicating that microRNAs (miRNAs) are critically involved in conferring neural cell identities during neural induction, neuronal differentiation and subtype specification. Several studies have shown that miRNAs act in concert with other gene regulatory factors and genetic switches to regulate the spatial and temporal expression profiles of important cell fate determinants. So far, most studies addressing the role of miRNAs during neurogenesis were conducted using animal models. With the advent of human pluripotent stem cells and the possibility to differentiate these into neural stem cells, we now have the opportunity to study miRNAs in a human context. More insight into the impact of miRNA-based regulation during neural fate choice could in the end be exploited to develop new strategies for the generation of distinct human neuronal cell types.

  3. Neural markers of inhibition in human memory retrieval.

    Science.gov (United States)

    Wimber, Maria; Bäuml, Karl-Heinz; Bergström, Zara; Markopoulos, Gerasimos; Heinze, Hans-Jochen; Richardson-Klavehn, Alan

    2008-12-10

    Retrieving particular information from memory facilitates the later retrieval of that information, but also impairs the later retrieval of related, interfering information. It has been theorized that this retrieval-induced forgetting reflects inhibition of interfering memory representations. We used event-related fMRI to investigate the functional neuroanatomy of this impaired retrieval, at the time the impairment is observed. Neural activity differences between impaired and facilitated information occurred in left ventrolateral prefrontal cortex (VLPFC, BA 45 and 47), precuneus (BA 7), and right inferior parietal lobule (IPL, BA 40). Activity in left anterior VLPFC (BA 47) and left posterior temporal cortex (BA 22), regions implicated in the controlled retrieval of weak semantic memory representations, predicted the degree of retrieval-induced forgetting. In contrast, activity in precuneus and right IPL predicted the degree of retrieval-induced facilitation. Our findings demonstrate that impairment of interfering memories and facilitation of practiced memories involve distinct neural processes, and suggest that the impairment reflects inhibition that weakens interfering memory representations.

  4. Application of structured support vector machine backpropagation to a convolutional neural network for human pose estimation.

    Science.gov (United States)

    Witoonchart, Peerajak; Chongstitvatana, Prabhas

    2017-08-01

    In this study, for the first time, we show how to formulate a structured support vector machine (SSVM) as two layers in a convolutional neural network, where the top layer is a loss augmented inference layer and the bottom layer is the normal convolutional layer. We show that a deformable part model can be learned with the proposed structured SVM neural network by backpropagating the error of the deformable part model to the convolutional neural network. The forward propagation calculates the loss augmented inference and the backpropagation calculates the gradient from the loss augmented inference layer to the convolutional layer. Thus, we obtain a new type of convolutional neural network called an Structured SVM convolutional neural network, which we applied to the human pose estimation problem. This new neural network can be used as the final layers in deep learning. Our method jointly learns the structural model parameters and the appearance model parameters. We implemented our method as a new layer in the existing Caffe library. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Evolution of Neural Computations: Mantis Shrimp and Human Color Decoding

    Directory of Open Access Journals (Sweden)

    Qasim Zaidi

    2014-10-01

    Full Text Available Mantis shrimp and primates both possess good color vision, but the neural implementation in the two species is very different, a reflection of the largely unrelated evolutionary lineages of these creatures. Mantis shrimp have scanning compound eyes with 12 classes of photoreceptors, and have evolved a system to decode color information at the front-end of the sensory stream. Primates have image-focusing eyes with three classes of cones, and decode color further along the visual-processing hierarchy. Despite these differences, we report a fascinating parallel between the computational strategies at the color-decoding stage in the brains of stomatopods and primates. Both species appear to use narrowly tuned cells that support interval decoding color identification.

  6. Engineering three dimensional micro nerve tissue using postnatal stem cells from human dental apical papilla.

    Science.gov (United States)

    Kim, Byung-Chul; Jun, Sung-Min; Kim, So Yeon; Kwon, Yong-Dae; Choe, Sung Chul; Kim, Eun-Chul; Lee, Jae-Hyung; Kim, Jinseok; Suh, Jun-Kyo Francis; Hwang, Yu-Shik

    2017-04-01

    The in vitro generation of cell-based three dimensional (3D) nerve tissue is an attractive subject to improve graft survival and integration into host tissue for neural tissue regeneration or to model biological events in stem cell differentiation. Although 3D organotypic culture strategies are well established for 3D nerve tissue formation of pluripotent stem cells to study underlying biology in nerve development, cell-based nerve tissues have not been developed using human postnatal stem cells with therapeutic potential. Here, we established a culture strategy for the generation of in vitro cell-based 3D nerve tissue from postnatal stem cells from apical papilla (SCAPs) of teeth, which originate from neural crest-derived ectomesenchyme cells. A stem cell population capable of differentiating into neural cell lineages was generated during the ex vivo expansion of SCAPs in the presence of EGF and bFGF, and SCAPs differentiated into neural cells, showing neural cell lineage-related molecular and gene expression profiles, morphological changes and electrophysical property under neural-inductive culture conditions. Moreover, we showed the first evidence that 3D cell-based nerve-like tissue with axons and myelin structures could be generated from SCAPs via 3D organotypic culture using an integrated bioprocess composed of polyethylene glycol (PEG) microwell-mediated cell spheroid formation and subsequent dynamic culture in a high aspect ratio vessel (HARV) bioreactor. In conclusion, the culture strategy in our study provides a novel approach to develop in vitro engineered nerve tissue using SCAPs and a foundation to study biological events in the neural differentiation of postnatal stem cells. Biotechnol. Bioeng. 2017;114: 903-914. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. Human Emotion Recognition with Electroencephalographic Multidimensional Features by Hybrid Deep Neural Networks

    Directory of Open Access Journals (Sweden)

    Youjun Li

    2017-10-01

    Full Text Available The aim of this study is to recognize human emotions by electroencephalographic (EEG signals. The innovation of our research methods involves two aspects: First, we integrate the spatial characteristics, frequency domain, and temporal characteristics of the EEG signals, and map them to a two-dimensional image. With these images, we build a series of EEG Multidimensional Feature Image (EEG MFI sequences to represent the emotion variation with EEG signals. Second, we construct a hybrid deep neural network to deal with the EEG MFI sequences to recognize human emotional states where the hybrid deep neural network combined the Convolution Neural Networks (CNN and Long Short-Term-Memory (LSTM Recurrent Neural Networks (RNN. Empirical research is carried out with the open-source dataset DEAP (a Dataset for Emotion Analysis using EEG, Physiological, and video signals using our method, and the results demonstrate the significant improvements over current state-of-the-art approaches in this field. The average emotion classification accuracy of each subject with CLRNN (the hybrid neural networks that we proposed in this study is 75.21%.

  8. Reward Motivation Accelerates the Onset of Neural Novelty Signals in Humans to 85 Milliseconds

    National Research Council Canada - National Science Library

    Bunzeck, Nico; Doeller, Christian F; Fuentemilla, Lluis; Dolan, Raymond J; Duzel, Emrah

    2009-01-01

    ... are rewarded [8] . In human recognition memory studies, on the other hand, reward is not used to motivate the detection of novel or familiar items. Remarkably, the possibility that the timing of neural novelty signals might be affected if the discrimination of novel and familiar items is rewarded has not yet been tested. Indeed, novelty proces...

  9. Point-and-Click Cursor Control With an Intracortical Neural Interface System by Humans With Tetraplegia

    Science.gov (United States)

    Kim, Sung-Phil; Simeral, John D.; Hochberg, Leigh R.; Donoghue, John P.; Friehs, Gerhard M.; Black, Michael J.

    2012-01-01

    We present a point-and-click intracortical neural interface system (NIS) that enables humans with tetraplegia to volitionally move a 2-D computer cursor in any desired direction on a computer screen, hold it still, and click on the area of interest. This direct brain–computer interface extracts both discrete (click) and continuous (cursor velocity) signals from a single small population of neurons in human motor cortex. A key component of this system is a multi-state probabilistic decoding algorithm that simultaneously decodes neural spiking activity of a small population of neurons and outputs either a click signal or the velocity of the cursor. The algorithm combines a linear classifier, which determines whether the user is intending to click or move the cursor, with a Kalman filter that translates the neural population activity into cursor velocity. We present a paradigm for training the multi-state decoding algorithm using neural activity observed during imagined actions. Two human participants with tetraplegia (paralysis of the four limbs) performed a closed-loop radial target acquisition task using the point-and-click NIS over multiple sessions. We quantified point-and-click performance using various human-computer interaction measurements for pointing devices. We found that participants could control the cursor motion and click on specified targets with a small error rate (click 2-D cursor control of a personal computer. PMID:21278024

  10. Neural population dynamics in human motor cortex during movements in people with ALS.

    Science.gov (United States)

    Pandarinath, Chethan; Gilja, Vikash; Blabe, Christine H; Nuyujukian, Paul; Sarma, Anish A; Sorice, Brittany L; Eskandar, Emad N; Hochberg, Leigh R; Henderson, Jaimie M; Shenoy, Krishna V

    2015-06-23

    The prevailing view of motor cortex holds that motor cortical neural activity represents muscle or movement parameters. However, recent studies in non-human primates have shown that neural activity does not simply represent muscle or movement parameters; instead, its temporal structure is well-described by a dynamical system where activity during movement evolves lawfully from an initial pre-movement state. In this study, we analyze neuronal ensemble activity in motor cortex in two clinical trial participants diagnosed with Amyotrophic Lateral Sclerosis (ALS). We find that activity in human motor cortex has similar dynamical structure to that of non-human primates, indicating that human motor cortex contains a similar underlying dynamical system for movement generation.

  11. Characterization of human neural differentiation from pluripotent stem cells using proteomics/PTMomics

    DEFF Research Database (Denmark)

    Braga, Marcella Nunes de Melo; Meyer, Morten; Zeng, Xianmin

    2015-01-01

    , neurological disease as well as contributing to clinical research. The neural differentiation process is associated with changes at protein and their post-translational modifications (PTMs). PTMs are important regulators of proteins physicochemical properties, function, activity, and interaction with other...... the understanding of molecular processes in cells. Substantial advances in PTM enrichment methods and mass spectrometry has allowed the characterization of a subset of PTMs in large-scale studies. This review focuses on the current state-of-the-art of proteomic, as well as PTMomic studies related to human neural...

  12. Neural correlates of gesture processing across human development.

    Science.gov (United States)

    Wakefield, Elizabeth M; James, Thomas W; James, Karin H

    2013-01-01

    Co-speech gesture facilitates learning to a greater degree in children than in adults, suggesting that the mechanisms underlying the processing of co-speech gesture differ as a function of development. We suggest that this may be partially due to children's lack of experience producing gesture, leading to differences in the recruitment of sensorimotor networks when comparing adults to children. Here, we investigated the neural substrates of gesture processing in a cross-sectional sample of 5-, 7.5-, and 10-year-old children and adults and focused on relative recruitment of a sensorimotor system that included the precentral gyrus (PCG) and the posterior middle temporal gyrus (pMTG). Children and adults were presented with videos in which communication occurred through different combinations of speech and gesture during a functional magnetic resonance imaging (fMRI) session. Results demonstrated that the PCG and pMTG were recruited to different extents in the two populations. We interpret these novel findings as supporting the idea that gesture perception (pMTG) is affected by a history of gesture production (PCG), revealing the importance of considering gesture processing as a sensorimotor process.

  13. Common neural correlates of emotion perception in humans.

    Science.gov (United States)

    Jastorff, Jan; Huang, Yun-An; Giese, Martin A; Vandenbulcke, Mathieu

    2015-10-01

    Whether neuroimaging findings support discriminable neural correlates of emotion categories is a longstanding controversy. Two recent meta-analyses arrived at opposite conclusions, with one supporting (Vytal and Hamann []: J Cogn Neurosci 22:2864-2885) and the other opposing this proposition (Lindquist et al. []: Behav Brain Sci 35:121-143). To obtain direct evidence regarding this issue, we compared activations for four emotions within a single fMRI design. Angry, happy, fearful, sad and neutral stimuli were presented as dynamic body expressions. In addition, observers categorized motion morphs between neutral and emotional stimuli in a behavioral experiment to determine their relative sensitivities. Brain-behavior correlations revealed a large brain network that was identical for all four tested emotions. This network consisted predominantly of regions located within the default mode network and the salience network. Despite showing brain-behavior correlations for all emotions, muli-voxel pattern analyses indicated that several nodes of this emotion general network contained information capable of discriminating between individual emotions. However, significant discrimination was not limited to the emotional network, but was also observed in several regions within the action observation network. Taken together, our results favor the position that one common emotional brain network supports the visual processing and discrimination of emotional stimuli. © 2015 Wiley Periodicals, Inc.

  14. Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

    Directory of Open Access Journals (Sweden)

    Paige Snider

    2007-01-01

    Full Text Available Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken and Xenopus embryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement (i.e., gap junctions, cadherins, and noncanonical Wnt1 pathway regulators. Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick and Xenopus premigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest

  15. Dopaminergic differentiation of human neural stem cells mediated by co-cultured rat striatal brain slices

    DEFF Research Database (Denmark)

    Anwar, Mohammad Raffaqat; Andreasen, Christian Maaløv; Lippert, Solvej Kølvraa

    2008-01-01

    differentiation, we co-cultured cells from a human neural forebrain-derived stem cell line (hNS1) with rat striatal brain slices. In brief, coronal slices of neonatal rat striatum were cultured on semiporous membrane inserts placed in six-well trays overlying monolayers of hNS1 cells. After 12 days of co......Properly committed neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. To establish a setting for identification of secreted neural compounds promoting dopaminergic......-culture, large numbers of tyrosine hydroxylase (TH)-immunoreactive, catecholaminergic cells could be found underneath individual striatal slices. Cell counting revealed that up to 25.3% (average 16.1%) of the total number of cells in these areas were TH-positive, contrasting a few TH-positive cells (

  16. Neural Crest Cells Isolated from the Bone Marrow of Transgenic Mice Express JCV T-Antigen.

    Directory of Open Access Journals (Sweden)

    Jennifer Gordon

    Full Text Available JC virus (JCV, a common human polyomavirus, is the etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML. In addition to its role in PML, studies have demonstrated the transforming ability of the JCV early protein, T-antigen, and its association with some human cancers. JCV infection occurs in childhood and latent virus is thought to be maintained within the bone marrow, which harbors cells of hematopoietic and non-hematopoietic lineages. Here we show that non-hematopoietic mesenchymal stem cells (MSCs isolated from the bone marrow of JCV T-antigen transgenic mice give rise to JCV T-antigen positive cells when cultured under neural conditions. JCV T-antigen positive cells exhibited neural crest characteristics and demonstrated p75, SOX-10 and nestin positivity. When cultured in conditions typical for mesenchymal cells, a population of T-antigen negative cells, which did not express neural crest markers arose from the MSCs. JCV T-antigen positive cells could be cultured long-term while maintaining their neural crest characteristics. When these cells were induced to differentiate into neural crest derivatives, JCV T-antigen was downregulated in cells differentiating into bone and maintained in glial cells expressing GFAP and S100. We conclude that JCV T-antigen can be stably expressed within a fraction of bone marrow cells differentiating along the neural crest/glial lineage when cultured in vitro. These findings identify a cell population within the bone marrow permissible for JCV early gene expression suggesting the possibility that these cells could support persistent viral infection and thus provide clues toward understanding the role of the bone marrow in JCV latency and reactivation. Further, our data provides an excellent experimental model system for studying the cell-type specificity of JCV T-antigen expression, the role of bone marrow-derived stem cells in the pathogenesis of JCV-related diseases

  17. Decoding of Human Movements Based on Deep Brain Local Field Potentials Using Ensemble Neural Networks

    Directory of Open Access Journals (Sweden)

    Mohammad S. Islam

    2017-01-01

    Full Text Available Decoding neural activities related to voluntary and involuntary movements is fundamental to understanding human brain motor circuits and neuromotor disorders and can lead to the development of neuromotor prosthetic devices for neurorehabilitation. This study explores using recorded deep brain local field potentials (LFPs for robust movement decoding of Parkinson’s disease (PD and Dystonia patients. The LFP data from voluntary movement activities such as left and right hand index finger clicking were recorded from patients who underwent surgeries for implantation of deep brain stimulation electrodes. Movement-related LFP signal features were extracted by computing instantaneous power related to motor response in different neural frequency bands. An innovative neural network ensemble classifier has been proposed and developed for accurate prediction of finger movement and its forthcoming laterality. The ensemble classifier contains three base neural network classifiers, namely, feedforward, radial basis, and probabilistic neural networks. The majority voting rule is used to fuse the decisions of the three base classifiers to generate the final decision of the ensemble classifier. The overall decoding performance reaches a level of agreement (kappa value at about 0.729±0.16 for decoding movement from the resting state and about 0.671±0.14 for decoding left and right visually cued movements.

  18. Neural speech recognition: continuous phoneme decoding using spatiotemporal representations of human cortical activity

    Science.gov (United States)

    Moses, David A.; Mesgarani, Nima; Leonard, Matthew K.; Chang, Edward F.

    2016-10-01

    Objective. The superior temporal gyrus (STG) and neighboring brain regions play a key role in human language processing. Previous studies have attempted to reconstruct speech information from brain activity in the STG, but few of them incorporate the probabilistic framework and engineering methodology used in modern speech recognition systems. In this work, we describe the initial efforts toward the design of a neural speech recognition (NSR) system that performs continuous phoneme recognition on English stimuli with arbitrary vocabulary sizes using the high gamma band power of local field potentials in the STG and neighboring cortical areas obtained via electrocorticography. Approach. The system implements a Viterbi decoder that incorporates phoneme likelihood estimates from a linear discriminant analysis model and transition probabilities from an n-gram phonemic language model. Grid searches were used in an attempt to determine optimal parameterizations of the feature vectors and Viterbi decoder. Main results. The performance of the system was significantly improved by using spatiotemporal representations of the neural activity (as opposed to purely spatial representations) and by including language modeling and Viterbi decoding in the NSR system. Significance. These results emphasize the importance of modeling the temporal dynamics of neural responses when analyzing their variations with respect to varying stimuli and demonstrate that speech recognition techniques can be successfully leveraged when decoding speech from neural signals. Guided by the results detailed in this work, further development of the NSR system could have applications in the fields of automatic speech recognition and neural prosthetics.

  19. Neural-Competent Cells of Adult Human Dermis Belong to the Schwann Lineage

    Directory of Open Access Journals (Sweden)

    Usue Etxaniz

    2014-11-01

    Full Text Available Resident neural precursor cells (NPCs have been reported for a number of adult tissues. Understanding their physiological function or, alternatively, their activation after tissue damage or in vitro manipulation remains an unsolved issue. Here, we investigated the source of human dermal NPCs in adult tissue. By following an unbiased, comprehensive approach employing cell-surface marker screening, cell separation, transcriptomic characterization, and in vivo fate analyses, we found that p75NTR+ precursors of human foreskin can be ascribed to the Schwann (CD56+ and perivascular (CD56− cell lineages. Moreover, neural differentiation potential was restricted to the p75NTR+CD56+ Schwann cells and mediated by SOX2 expression levels. Double-positive NPCs were similarly obtained from human cardiospheres, indicating that this phenomenon might be widespread.

  20. Human Inspired Self-developmental Model of Neural Network (HIM): Introducing Content/Form Computing

    Science.gov (United States)

    Krajíček, Jiří

    This paper presents cross-disciplinary research between medical/psychological evidence on human abilities and informatics needs to update current models in computer science to support alternative methods for computation and communication. In [10] we have already proposed hypothesis introducing concept of human information model (HIM) as cooperative system. Here we continue on HIM design in detail. In our design, first we introduce Content/Form computing system which is new principle of present methods in evolutionary computing (genetic algorithms, genetic programming). Then we apply this system on HIM (type of artificial neural network) model as basic network self-developmental paradigm. Main inspiration of our natural/human design comes from well known concept of artificial neural networks, medical/psychological evidence and Sheldrake theory of "Nature as Alive" [22].

  1. Differential neural responses to child and sexual stimuli in human fathers and non-fathers and their hormonal correlates

    OpenAIRE

    Mascaro, Jennifer S.; Hackett, Patrick D.; Rilling, James K.

    2014-01-01

    Despite the well-documented importance of paternal caregiving for positive child development, little is known about the neural changes that accompany the transition to fatherhood in humans, or about how changes in hormone levels affect paternal brain function. We compared fathers of children aged 1–2 with non-fathers in terms of hormone levels (oxytocin and testosterone), neural responses to child picture stimuli, and neural responses to visual sexual stimuli. Compared to non-fathers, fathers...

  2. Differentiation of human neural progenitor cell-derived spiral ganglion-like neurons: a time-lapse video study.

    Science.gov (United States)

    Edin, Fredrik; Liu, Wei; Boström, Marja; Magnusson, Peetra U; Rask-Andersen, Helge

    2014-05-01

    Human neural progenitor cells can differentiate into spiral ganglion-like cells when exposed to inner ear-associated growth factors. The phenotype bears resemblance to human sphere-derived neurons. To establish an in vitro model for the human auditory nerve to replace and complement in vivo animal experiments and ultimately human in vivo transplantation. Human neural progenitors were differentiated under conditions developed for in vitro survival of human primary spiral ganglion culture with media containing growth factors associated with inner ear development. Differentiation was documented using time-lapse video microscopy. Time-dependent marker expression was evaluated using immunocytochemistry with fluorescence and laser confocal microscopy. Within 14 days of differentiation, neural progenitors adopted neural phenotype and expressed spiral ganglion-associated markers.

  3. On the nature and evolution of the neural bases of human language

    Science.gov (United States)

    Lieberman, Philip

    2002-01-01

    The traditional theory equating the brain bases of language with Broca's and Wernicke's neocortical areas is wrong. Neural circuits linking activity in anatomically segregated populations of neurons in subcortical structures and the neocortex throughout the human brain regulate complex behaviors such as walking, talking, and comprehending the meaning of sentences. When we hear or read a word, neural structures involved in the perception or real-world associations of the word are activated as well as posterior cortical regions adjacent to Wernicke's area. Many areas of the neocortex and subcortical structures support the cortical-striatal-cortical circuits that confer complex syntactic ability, speech production, and a large vocabulary. However, many of these structures also form part of the neural circuits regulating other aspects of behavior. For example, the basal ganglia, which regulate motor control, are also crucial elements in the circuits that confer human linguistic ability and abstract reasoning. The cerebellum, traditionally associated with motor control, is active in motor learning. The basal ganglia are also key elements in reward-based learning. Data from studies of Broca's aphasia, Parkinson's disease, hypoxia, focal brain damage, and a genetically transmitted brain anomaly (the putative "language gene," family KE), and from comparative studies of the brains and behavior of other species, demonstrate that the basal ganglia sequence the discrete elements that constitute a complete motor act, syntactic process, or thought process. Imaging studies of intact human subjects and electrophysiologic and tracer studies of the brains and behavior of other species confirm these findings. As Dobzansky put it, "Nothing in biology makes sense except in the light of evolution" (cited in Mayr, 1982). That applies with as much force to the human brain and the neural bases of language as it does to the human foot or jaw. The converse follows: the mark of evolution on

  4. A Grey Wolf Optimizer for Modular Granular Neural Networks for Human Recognition

    Directory of Open Access Journals (Sweden)

    Daniela Sánchez

    2017-01-01

    Full Text Available A grey wolf optimizer for modular neural network (MNN with a granular approach is proposed. The proposed method performs optimal granulation of data and design of modular neural networks architectures to perform human recognition, and to prove its effectiveness benchmark databases of ear, iris, and face biometric measures are used to perform tests and comparisons against other works. The design of a modular granular neural network (MGNN consists in finding optimal parameters of its architecture; these parameters are the number of subgranules, percentage of data for the training phase, learning algorithm, goal error, number of hidden layers, and their number of neurons. Nowadays, there is a great variety of approaches and new techniques within the evolutionary computing area, and these approaches and techniques have emerged to help find optimal solutions to problems or models and bioinspired algorithms are part of this area. In this work a grey wolf optimizer is proposed for the design of modular granular neural networks, and the results are compared against a genetic algorithm and a firefly algorithm in order to know which of these techniques provides better results when applied to human recognition.

  5. Mutations in the Motile Cilia Gene DNAAF1 Are Associated with Neural Tube Defects in Humans.

    Science.gov (United States)

    Miao, Chunyue; Jiang, Qian; Li, Huili; Zhang, Qin; Bai, Baoling; Bao, Yihua; Zhang, Ting

    2016-10-13

    Neural tube defects (NTDs) are severe malformations of the central nervous system caused by complex genetic and environmental factors. Among genes involved in NTD, cilia-related genes have been well defined and found to be essential for the completion of neural tube closure (NTC). We have carried out next-generation sequencing on target genes in 373 NTDs and 222 healthy controls, and discovered eight disease-specific rare mutations in cilia-related gene DNAAF1 DNAAF1 plays a central role in cytoplasmic preassembly of distinct dynein-arm complexes, and is expressed in some key tissues involved in neural system development, such as neural tube, floor plate, embryonic node, and brain ependyma epithelial cells in zebrafish and mouse. Therefore, we evaluated the expression and functions of mutations in DNAAF1 in transfected cells to analyze the potential correlation of these mutants to NTDs in humans. One rare frameshift mutation (p.Gln341Argfs*10) resulted in significantly diminished DNAAF1 protein expression, compared to the wild type. Another mutation, p.Lys231Gln, disrupted cytoplasmic preassembly of the dynein-arm complexes in cellular assay. Furthermore, results from NanoString assay on mRNA from NTD samples indicated that DNAAF1 mutants altered the expression level of NTC-related genes. Altogether, these findings suggest that the rare mutations in DNAAF1 may contribute to the susceptibility for NTDs in humans. Copyright © 2016 Miao et al.

  6. Mutations in the Motile Cilia Gene DNAAF1 Are Associated with Neural Tube Defects in Humans

    Directory of Open Access Journals (Sweden)

    Chunyue Miao

    2016-10-01

    Full Text Available Neural tube defects (NTDs are severe malformations of the central nervous system caused by complex genetic and environmental factors. Among genes involved in NTD, cilia-related genes have been well defined and found to be essential for the completion of neural tube closure (NTC. We have carried out next-generation sequencing on target genes in 373 NTDs and 222 healthy controls, and discovered eight disease-specific rare mutations in cilia-related gene DNAAF1. DNAAF1 plays a central role in cytoplasmic preassembly of distinct dynein-arm complexes, and is expressed in some key tissues involved in neural system development, such as neural tube, floor plate, embryonic node, and brain ependyma epithelial cells in zebrafish and mouse. Therefore, we evaluated the expression and functions of mutations in DNAAF1 in transfected cells to analyze the potential correlation of these mutants to NTDs in humans. One rare frameshift mutation (p.Gln341Argfs*10 resulted in significantly diminished DNAAF1 protein expression, compared to the wild type. Another mutation, p.Lys231Gln, disrupted cytoplasmic preassembly of the dynein-arm complexes in cellular assay. Furthermore, results from NanoString assay on mRNA from NTD samples indicated that DNAAF1 mutants altered the expression level of NTC-related genes. Altogether, these findings suggest that the rare mutations in DNAAF1 may contribute to the susceptibility for NTDs in humans.

  7. Development and function of human cerebral cortex neural networks from pluripotent stem cells in vitro.

    Science.gov (United States)

    Kirwan, Peter; Turner-Bridger, Benita; Peter, Manuel; Momoh, Ayiba; Arambepola, Devika; Robinson, Hugh P C; Livesey, Frederick J

    2015-09-15

    A key aspect of nervous system development, including that of the cerebral cortex, is the formation of higher-order neural networks. Developing neural networks undergo several phases with distinct activity patterns in vivo, which are thought to prune and fine-tune network connectivity. We report here that human pluripotent stem cell (hPSC)-derived cerebral cortex neurons form large-scale networks that reflect those found in the developing cerebral cortex in vivo. Synchronised oscillatory networks develop in a highly stereotyped pattern over several weeks in culture. An initial phase of increasing frequency of oscillations is followed by a phase of decreasing frequency, before giving rise to non-synchronous, ordered activity patterns. hPSC-derived cortical neural networks are excitatory, driven by activation of AMPA- and NMDA-type glutamate receptors, and can undergo NMDA-receptor-mediated plasticity. Investigating single neuron connectivity within PSC-derived cultures, using rabies-based trans-synaptic tracing, we found two broad classes of neuronal connectivity: most neurons have small numbers (40). These data demonstrate that the formation of hPSC-derived cortical networks mimics in vivo cortical network development and function, demonstrating the utility of in vitro systems for mechanistic studies of human forebrain neural network biology. © 2015. Published by The Company of Biologists Ltd.

  8. A Grey Wolf Optimizer for Modular Granular Neural Networks for Human Recognition

    Science.gov (United States)

    Sánchez, Daniela; Melin, Patricia

    2017-01-01

    A grey wolf optimizer for modular neural network (MNN) with a granular approach is proposed. The proposed method performs optimal granulation of data and design of modular neural networks architectures to perform human recognition, and to prove its effectiveness benchmark databases of ear, iris, and face biometric measures are used to perform tests and comparisons against other works. The design of a modular granular neural network (MGNN) consists in finding optimal parameters of its architecture; these parameters are the number of subgranules, percentage of data for the training phase, learning algorithm, goal error, number of hidden layers, and their number of neurons. Nowadays, there is a great variety of approaches and new techniques within the evolutionary computing area, and these approaches and techniques have emerged to help find optimal solutions to problems or models and bioinspired algorithms are part of this area. In this work a grey wolf optimizer is proposed for the design of modular granular neural networks, and the results are compared against a genetic algorithm and a firefly algorithm in order to know which of these techniques provides better results when applied to human recognition. PMID:28894461

  9. Brief Report: Robo1 Regulates the Migration of Human Subventricular Zone Neural Progenitor Cells During Development.

    Science.gov (United States)

    Guerrero-Cazares, Hugo; Lavell, Emily; Chen, Linda; Schiapparelli, Paula; Lara-Velazquez, Montserrat; Capilla-Gonzalez, Vivian; Clements, Anna Christina; Drummond, Gabrielle; Noiman, Liron; Thaler, Katrina; Burke, Anne; Quiñones-Hinojosa, Alfredo

    2017-07-01

    Human neural progenitor cell (NPC) migration within the subventricular zone (SVZ) of the lateral ganglionic eminence is an active process throughout early brain development. The migration of human NPCs from the SVZ to the olfactory bulb during fetal stages resembles what occurs in adult rodents. As the human brain develops during infancy, this migratory stream is drastically reduced in cell number and becomes barely evident in adults. The mechanisms regulating human NPC migration are unknown. The Slit-Robo signaling pathway has been defined as a chemorepulsive cue involved in axon guidance and neuroblast migration in rodents. Slit and Robo proteins expressed in the rodent brain help guide neuroblast migration from the SVZ through the rostral migratory stream to the olfactory bulb. Here, we present the first study on the role that Slit and Robo proteins play in human-derived fetal neural progenitor cell migration (hfNPC). We describe that Robo1 and Robo2 isoforms are expressed in the human fetal SVZ. Furthermore, we demonstrate that Slit2 is able to induce a chemorepellent effect on the migration of hfNPCs derived from the human fetal SVZ. In addition, when Robo1 expression is inhibited, hfNPCs are unable to migrate to the olfactory bulb of mice when injected in the anterior SVZ. Our findings indicate that the migration of human NPCs from the SVZ is partially regulated by the Slit-Robo axis. This pathway could be regulated to direct the migration of NPCs in human endogenous neural cell therapy. Stem Cells 2017;35:1860-1865. © 2017 AlphaMed Press.

  10. Noncoding RNA in the Transcriptional Landscape of Human Neural Progenitor Cell Differentiation

    Directory of Open Access Journals (Sweden)

    Patrick eHecht

    2015-10-01

    Full Text Available Increasing evidence suggests that noncoding RNAs play key roles in cellular processes, particularly in the brain. The present study used RNA sequencing to identify the transcriptional landscape of two human neural progenitor cell lines, SK-N-SH and ReNcell CX, as they differentiate into human cortical projection neurons. Protein coding genes were found to account for 54.8% and 57.0% of expressed genes, respectively, and alignment of RNA sequencing reads revealed that only 25.5-28.1% mapped to exonic regions of the genome. Differential expression analysis in the two cell lines identified altered gene expression in both protein coding and noncoding RNAs as they undergo neural differentiation with 222 differentially expressed genes observed in SK-N-SH cells and 19 differentially expressed genes in ReNcell CX. Interestingly, genes showing differential expression in SK-N-SH cells are enriched in genes implicated in autism spectrum disorder, but not in gene sets related to cancer or Alzheimer’s disease. Weighted gene co-expression network analysis (WGCNA was used to detect modules of co-expressed protein coding and noncoding RNAs in SK-N-SH cells and found four modules to be associated with neural differentiation. These modules contain varying levels of noncoding RNAs ranging from 10.7% to 49.7% with gene ontology suggesting roles in numerous cellular processes important for differentiation. These results indicate that noncoding RNAs are highly expressed in human neural progenitor cells and likely hold key regulatory roles in gene networks underlying neural differentiation and neurodevelopmental disorders.

  11. Stem cells from human exfoliated deciduous tooth exhibit stromal-derived inducing activity and lead to generation of neural crest cells from human embryonic stem cells.

    Science.gov (United States)

    Karbalaie, Khadijeh; Tanhaei, Somayyeh; Rabiei, Farzaneh; Kiani-Esfahani, Abbas; Masoudi, Najmeh Sadat; Nasr-Esfahani, Mohammad Hossein; Baharvand, Hossein

    2015-01-01

    The neural crest is a transient structure of early vertebrate embryos that generates neural crest cells (NCCs). These cells can migrate throughout the body and produce a diverse array of mature tissue types. Due to the ethical and technical problems surrounding the isolation of these early human embryo cells, researchers have focused on in vitro studies to produce NCCs and increase their knowledge of neural crest development. In this experimental study, we cultured human embryonic stem cells (hESCs) on stromal stem cells from human exfoliated deciduous teeth (SHED) for a two-week period. We used different approaches to characterize these differentiated cells as neural precursor cells (NPCs) and NCCs. In the first co-culture week, hESCs appeared as crater-like structures with marginal rosettes. NPCs derived from these structures expressed the early neural crest marker p75 in addition to numerous other genes associated with neural crest induction such as SNAIL, SLUG, PTX3 and SOX9. Flow cytometry analysis showed 70% of the cells were AP2/P75 positive. Moreover, the cells were able to self-renew, sustain multipotent differentiation potential, and readily form neurospheres in suspension culture. SHED, as an adult stem cell with a neural crest origin, has stromal-derived inducing activity (SDIA) and can be used as an NCC inducer from hESCs. These cells provide an invaluable resource to study neural crest differentiation in both normal and disordered human neural crest development.

  12. Optimal Recognition Method of Human Activities Using Artificial Neural Networks

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    Oniga Stefan

    2015-12-01

    Full Text Available The aim of this research is an exhaustive analysis of the various factors that may influence the recognition rate of the human activity using wearable sensors data. We made a total of 1674 simulations on a publically released human activity database by a group of researcher from the University of California at Berkeley. In a previous research, we analyzed the influence of the number of sensors and their placement. In the present research we have examined the influence of the number of sensor nodes, the type of sensor node, preprocessing algorithms, type of classifier and its parameters. The final purpose is to find the optimal setup for best recognition rates with lowest hardware and software costs.

  13. Comparison of 2D and 3D neural induction methods for the generation of neural progenitor cells from human induced pluripotent stem cells.

    Science.gov (United States)

    Chandrasekaran, Abinaya; Avci, Hasan X; Ochalek, Anna; Rösingh, Lone N; Molnár, Kinga; László, Lajos; Bellák, Tamás; Téglási, Annamária; Pesti, Krisztina; Mike, Arpad; Phanthong, Phetcharat; Bíró, Orsolya; Hall, Vanessa; Kitiyanant, Narisorn; Krause, Karl-Heinz; Kobolák, Julianna; Dinnyés, András

    2017-12-01

    Neural progenitor cells (NPCs) from human induced pluripotent stem cells (hiPSCs) are frequently induced using 3D culture methodologies however, it is unknown whether spheroid-based (3D) neural induction is actually superior to monolayer (2D) neural induction. Our aim was to compare the efficiency of 2D induction with 3D induction method in their ability to generate NPCs, and subsequently neurons and astrocytes. Neural differentiation was analysed at the protein level qualitatively by immunocytochemistry and quantitatively by flow cytometry for NPC (SOX1, PAX6, NESTIN), neuronal (MAP2, TUBB3), cortical layer (TBR1, CUX1) and glial markers (SOX9, GFAP, AQP4). Electron microscopy demonstrated that both methods resulted in morphologically similar neural rosettes. However, quantification of NPCs derived from 3D neural induction exhibited an increase in the number of PAX6/NESTIN double positive cells and the derived neurons exhibited longer neurites. In contrast, 2D neural induction resulted in more SOX1 positive cells. While 2D monolayer induction resulted in slightly less mature neurons, at an early stage of differentiation, the patch clamp analysis failed to reveal any significant differences between the electrophysiological properties between the two induction methods. In conclusion, 3D neural induction increases the yield of PAX6+/NESTIN+ cells and gives rise to neurons with longer neurites, which might be an advantage for the production of forebrain cortical neurons, highlighting the potential of 3D neural induction, independent of iPSCs' genetic background. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Human-Derived Neurons and Neural Progenitor Cells in High Content Imaging Applications.

    Science.gov (United States)

    Harrill, Joshua A

    2018-01-01

    Due to advances in the fields of stem cell biology and cellular engineering, a variety of commercially available human-derived neurons and neural progenitor cells (NPCs) are now available for use in research applications, including small molecule efficacy or toxicity screening. The use of human-derived neural cells is anticipated to address some of the uncertainties associated with the use of nonhuman culture models or transformed cell lines derived from human tissues. Many of the human-derived neurons and NPCs currently available from commercial sources recapitulate critical process of nervous system development including NPC proliferation, neurite outgrowth, synaptogenesis, and calcium signaling, each of which can be evaluated using high content image analysis (HCA). Human-derived neurons and NPCs are also amenable to culture in multiwell plate formats and thus may be adapted for use in HCA-based screening applications. This article reviews various types of HCA-based assays that have been used in conjunction with human-derived neurons and NPC cultures. This article also highlights instances where lower throughput analysis of neurodevelopmental processes has been performed and which demonstrate a potential for adaptation to higher-throughout imaging methods. Finally, a generic protocol for evaluating neurite outgrowth in human-derived neurons using a combination of immunocytochemistry and HCA is presented. The information provided in this article is intended to serve as a resource for cell model and assay selection for those interested in evaluating neurodevelopmental processes in human-derived cells.

  15. Neural differentiation potential of human bone marrow-derived mesenchymal stromal cells: misleading marker gene expression

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    Montzka Katrin

    2009-03-01

    Full Text Available Abstract Background In contrast to pluripotent embryonic stem cells, adult stem cells have been considered to be multipotent, being somewhat more restricted in their differentiation capacity and only giving rise to cell types related to their tissue of origin. Several studies, however, have reported that bone marrow-derived mesenchymal stromal cells (MSCs are capable of transdifferentiating to neural cell types, effectively crossing normal lineage restriction boundaries. Such reports have been based on the detection of neural-related proteins by the differentiated MSCs. In order to assess the potential of human adult MSCs to undergo true differentiation to a neural lineage and to determine the degree of homogeneity between donor samples, we have used RT-PCR and immunocytochemistry to investigate the basal expression of a range of neural related mRNAs and proteins in populations of non-differentiated MSCs obtained from 4 donors. Results The expression analysis revealed that several of the commonly used marker genes from other studies like nestin, Enolase2 and microtubule associated protein 1b (MAP1b are already expressed by undifferentiated human MSCs. Furthermore, mRNA for some of the neural-related transcription factors, e.g. Engrailed-1 and Nurr1 were also strongly expressed. However, several other neural-related mRNAs (e.g. DRD2, enolase2, NFL and MBP could be identified, but not in all donor samples. Similarly, synaptic vesicle-related mRNA, STX1A could only be detected in 2 of the 4 undifferentiated donor hMSC samples. More significantly, each donor sample revealed a unique expression pattern, demonstrating a significant variation of marker expression. Conclusion The present study highlights the existence of an inter-donor variability of expression of neural-related markers in human MSC samples that has not previously been described. This donor-related heterogeneity might influence the reproducibility of transdifferentiation protocols as

  16. Borna disease virus infects human neural progenitor cells and impairs neurogenesis.

    Science.gov (United States)

    Brnic, Dragan; Stevanovic, Vladimir; Cochet, Marielle; Agier, Cécilia; Richardson, Jennifer; Montero-Menei, Claudia N; Milhavet, Ollivier; Eloit, Marc; Coulpier, Muriel

    2012-03-01

    Understanding the complex mechanisms by which infectious agents can disrupt behavior represents a major challenge. The Borna disease virus (BDV), a potential human pathogen, provides a unique model to study such mechanisms. Because BDV induces neurodegeneration in brain areas that are still undergoing maturation at the time of infection, we tested the hypothesis that BDV interferes with neurogenesis. We showed that human neural stem/progenitor cells are highly permissive to BDV, although infection does not alter their survival or undifferentiated phenotype. In contrast, upon the induction of differentiation, BDV is capable of severely impairing neurogenesis by interfering with the survival of newly generated neurons. Such impairment was specific to neurogenesis, since astrogliogenesis was unaltered. In conclusion, we demonstrate a new mechanism by which BDV might impair neural function and brain plasticity in infected individuals. These results may contribute to a better understanding of behavioral disorders associated with BDV infection.

  17. Expression of GD2 and GD3 Gangliosides in Human Embryonic Neural Stem Cells

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    Makoto Yanagisawa

    2011-03-01

    Full Text Available NSCs (neural stem cells are undifferentiated neural cells endowed with a high potential for proliferation and a capacity for self-renewal with retention of multipotency to differentiate into neurons and glial cells. It has been recently reported that GD3, a b-series ganglioside, is a marker molecule for identifying and isolating mouse NSCs. However, the expression of gangliosides in human NSCs is largely unknown. In the present study, we analysed the expression of gangliosides, GD2 and GD3, in human NSCs that were isolated from human brains at gestational week 17 in the form of neurospheres, which are floating clonal aggregates formed by NSCs in vitro. Employing immunocytochemistry, we found that human NSCs were strongly reactive to anti-GD2 antibody and relatively weakly reactive to anti-GD3 antibody. Treatment of these cells with an organic solvent such as 100% methanol, which selectively removes glycolipids from plasma membrane, abolished the immunoreactivity with those antibodies, indicating that the reactivity was due to GD2 and GD3, but not to GD2-/GD3-like glycoproteins or proteoglycans. The immunoreactivity of human NSCs to antibody against SSEA-1 (stage-specific embryonic antigen-1, a well-known carbohydrate antigen of NSCs, was not decreased by the treatment with 100% methanol, indicating that SSEA-1 is mainly carried by glycoproteins and/or proteoglycans in human NSCs. Our study suggests that GD2 and GD3 can be marker gangliosides for identifying human NSCs.

  18. Human dental follicle cells express embryonic, mesenchymal and neural stem cells markers.

    Science.gov (United States)

    Lima, Rodrigo Lopes; Holanda-Afonso, Rosenilde Carvalho; Moura-Neto, Vivaldo; Bolognese, Ana Maria; DosSantos, Marcos Fabio; Souza, Margareth Maria

    2017-01-01

    This study was conducted to identify and characterize dental follicle stem cells (DFSCs) by analyzing expression of embryonic, mesenchymal and neural stem cells surface markers. Design Dental follicle cells (DFCs) were evaluated by immunocytochemistry using embryonic stem cells markers (OCT4 and SOX2), mesenchmal stem cells (MSCs) markers (Notch1, active Notch1, STRO, CD44, HLA-ABC, CD90), neural stem cells markers (Nestin and β-III-tubulin), neural crest stem cells (NCSCs) markers (p75 and HNK1) and a glial cells marker (GFAP). RT-PCR was performed to identify the expression of OCT4 and NANOG in DFCs and dental follicle tissue. Immunocytochemistry and RT-PCR analysis revealed that a significant proportion of the DFCs evaluated expressed human embryonic stem cells marker OCT4 (75%) whereas NANOG was weakly expressed. A considerable amount of MSCs (90%) expressed Notch1, STRO, CD44 and HLA-ABC. However, they were weakly positive for CD90. Moreover, it was possible to demonstrate that dental follicle contains a significant proportion of neural stem/progenitors cells, expressing β-III-tubulin (90%) and nestin (70%). Interestingly, immunocytochemistry showed DFCs positive for p75 (50%), HNK1 (cells. This is the first study reporting the presence of NCSCs and glial-like cells in the dental follicle. The results of the present study suggest the occurrence of heterogeneous populations of stem cells, particularly neural stem/progenitor cells, in the dental follicle, Therefore, the human dental follicle might be a promising source of adult stem cells for regenerative purposes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Neural Plasticity following Abacus Training in Humans: A Review and Future Directions

    OpenAIRE

    Yongxin Li; Feiyan Chen; Wenhua Huang

    2016-01-01

    The human brain has an enormous capacity to adapt to a broad variety of environmental demands. Previous studies in the field of abacus training have shown that this training can induce specific changes in the brain. However, the neural mechanism underlying these changes remains elusive. Here, we reviewed the behavioral and imaging findings of comparisons between abacus experts and average control subjects and focused on changes in activation patterns and changes in brain structure. Finally, w...

  20. Differential development of neuronal physiological responsiveness in two human neural stem cell lines

    OpenAIRE

    Patel Sara; Pollock Kenneth; Aouabdi Sihem; Hines Susan J; Miljan Erik A; Donato Roberta; Edwards Frances A; Sinden John D

    2007-01-01

    Abstract Background Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to neurodegenerative disease. Overexpression of the myc family transcription factors in human primary cells from developing cortex and mesencephalon has produced two stable multipotential NSC lines (ReNcell VM and CX) that can be continuously expanded in monolayer culture. Results In the undifferentiated state, both ReNcell VM and CX are nestin positive and have resting memb...

  1. Deep Recurrent Neural Network for Mobile Human Activity Recognition with High Throughput

    OpenAIRE

    Inoue, Masaya; Inoue, Sozo; Nishida, Takeshi

    2016-01-01

    In this paper, we propose a method of human activity recognition with high throughput from raw accelerometer data applying a deep recurrent neural network (DRNN), and investigate various architectures and its combination to find the best parameter values. The "high throughput" refers to short time at a time of recognition. We investigated various parameters and architectures of the DRNN by using the training dataset of 432 trials with 6 activity classes from 7 people. The maximum recognition ...

  2. Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells.

    Science.gov (United States)

    Ghezzi, Silvia; Cooper, Lynsay; Rubio, Alicia; Pagani, Isabel; Capobianchi, Maria Rosaria; Ippolito, Giuseppe; Pelletier, Julien; Meneghetti, Maria Cecilia Z; Lima, Marcelo A; Skidmore, Mark A; Broccoli, Vania; Yates, Edwin A; Vicenzi, Elisa

    2017-04-01

    The recent Zika virus (ZIKV) outbreak, which mainly affected Brazil and neighbouring states, demonstrated the paucity of information concerning the epidemiology of several flaviruses, but also highlighted the lack of available agents with which to treat such emerging diseases. Here, we show that heparin, a widely used anticoagulant, while exerting a modest inhibitory effect on Zika Virus replication, fully prevents virus-induced cell death of human neural progenitor cells (NPCs). Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Point-and-click cursor control with an intracortical neural interface system by humans with tetraplegia.

    Science.gov (United States)

    Kim, Sung-Phil; Simeral, John D; Hochberg, Leigh R; Donoghue, John P; Friehs, Gerhard M; Black, Michael J

    2011-04-01

    We present a point-and-click intracortical neural interface system (NIS) that enables humans with tetraplegia to volitionally move a 2-D computer cursor in any desired direction on a computer screen, hold it still, and click on the area of interest. This direct brain-computer interface extracts both discrete (click) and continuous (cursor velocity) signals from a single small population of neurons in human motor cortex. A key component of this system is a multi-state probabilistic decoding algorithm that simultaneously decodes neural spiking activity of a small population of neurons and outputs either a click signal or the velocity of the cursor. The algorithm combines a linear classifier, which determines whether the user is intending to click or move the cursor, with a Kalman filter that translates the neural population activity into cursor velocity. We present a paradigm for training the multi-state decoding algorithm using neural activity observed during imagined actions. Two human participants with tetraplegia (paralysis of the four limbs) performed a closed-loop radial target acquisition task using the point-and-click NIS over multiple sessions. We quantified point-and-click performance using various human-computer interaction measurements for pointing devices. We found that participants could control the cursor motion and click on specified targets with a small error rate (one participant). This study suggests that signals from a small ensemble of motor cortical neurons (∼40) can be used for natural point-and-click 2-D cursor control of a personal computer.

  4. Differentiation of Human Embryonic Stem Cells to Regional Specific Neural Precursors in Chemically Defined Medium Conditions

    Science.gov (United States)

    Erceg, Slaven; Laínez, Sergio; Ronaghi, Mohammad; Stojkovic, Petra; Pérez-Aragó, Maria Amparo; Moreno-Manzano, Victoria; Moreno-Palanques, Rubén; Planells-Cases, Rosa; Stojkovic, Miodrag

    2008-01-01

    Background Human embryonic stem cells (hESC) provide a unique model to study early events in human development. The hESC-derived cells can potentially be used to replace or restore different tissues including neuronal that have been damaged by disease or injury. Methodology and Principal Findings The cells of two different hESC lines were converted to neural rosettes using adherent and chemically defined conditions. The progenitor cells were exposed to retinoic acid (RA) or to human recombinant basic fibroblast growth factor (bFGF) in the late phase of the rosette formation. Exposing the progenitor cells to RA suppressed differentiation to rostral forebrain dopamine neural lineage and promoted that of spinal neural tissue including motor neurons. The functional characteristics of these differentiated neuronal precursors under both, rostral (bFGF) and caudalizing (RA) signals were confirmed by patch clamp analysis. Conclusions/Significance These findings suggest that our differentiation protocol has the capacity to generate region-specific and electrophysiologically active neurons under in vitro conditions without embryoid body formation, co-culture with stromal cells and without presence of cells of mesodermal or endodermal lineages. PMID:18461168

  5. Differentiation of human embryonic stem cells to regional specific neural precursors in chemically defined medium conditions.

    Directory of Open Access Journals (Sweden)

    Slaven Erceg

    Full Text Available BACKGROUND: Human embryonic stem cells (hESC provide a unique model to study early events in human development. The hESC-derived cells can potentially be used to replace or restore different tissues including neuronal that have been damaged by disease or injury. METHODOLOGY AND PRINCIPAL FINDINGS: The cells of two different hESC lines were converted to neural rosettes using adherent and chemically defined conditions. The progenitor cells were exposed to retinoic acid (RA or to human recombinant basic fibroblast growth factor (bFGF in the late phase of the rosette formation. Exposing the progenitor cells to RA suppressed differentiation to rostral forebrain dopamine neural lineage and promoted that of spinal neural tissue including motor neurons. The functional characteristics of these differentiated neuronal precursors under both, rostral (bFGF and caudalizing (RA signals were confirmed by patch clamp analysis. CONCLUSIONS/SIGNIFICANCE: These findings suggest that our differentiation protocol has the capacity to generate region-specific and electrophysiologically active neurons under in vitro conditions without embryoid body formation, co-culture with stromal cells and without presence of cells of mesodermal or endodermal lineages.

  6. Hydrogel scaffolds promote neural gene expression and structural reorganization in human astrocyte cultures

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    V. Bleu Knight

    2017-01-01

    Full Text Available Biomaterial scaffolds have the potential to enhance neuronal development and regeneration. Understanding the genetic responses of astrocytes and neurons to biomaterials could facilitate the development of synthetic environments that enable the specification of neural tissue organization with engineered scaffolds. In this study, we used high throughput transcriptomic and imaging methods to determine the impact of a hydrogel, PuraMatrix™, on human glial cells in vitro. Parallel studies were undertaken with cells grown in a monolayer environment on tissue culture polystyrene. When the Normal Human Astrocyte (NHA cell line is grown in a hydrogel matrix environment, the glial cells adopt a structural organization that resembles that of neuronal-glial cocultures, where neurons form clusters that are distinct from the surrounding glia. Statistical analysis of next generation RNA sequencing data uncovered a set of genes that are differentially expressed in the monolayer and matrix hydrogel environments. Functional analysis demonstrated that hydrogel-upregulated genes can be grouped into three broad categories: neuronal differentiation and/or neural plasticity, response to neural insult, and sensory perception. Our results demonstrate that hydrogel biomaterials have the potential to transform human glial cell identity, and may have applications in the repair of damaged brain tissue.

  7. Delineating Neural Structures of Developmental Human Brains with Diffusion Tensor Imaging

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    Hao Huang

    2010-01-01

    Full Text Available The human brain anatomy is characterized by dramatic structural changes during fetal development. It is extraordinarily complex and yet its origin is a simple tubular structure. Revealing detailed anatomy at different stages of brain development not only aids in understanding this highly ordered process, but also provides clues to detect abnormalities caused by genetic or environmental factors. However, anatomical studies of human brain development during the fetal period are surprisingly scarce and histology-based atlases have become available only recently. Diffusion tensor imaging (DTI measures water diffusion to delineate the underlying neural structures. The high contrasts derived from DTI can be used to establish the brain atlas. With DTI tractography, coherent neural structures, such as white matter tracts, can be three-dimensionally reconstructed. The primary eigenvector of the diffusion tensor can be further explored to characterize microstructures in the cerebral wall of the developmental brains. In this mini-review, the application of DTI in order to reveal the structures of developmental fetal brains has been reviewed in the above-mentioned aspects. The fetal brain DTI provides a unique insight for delineating the neural structures in both macroscopic and microscopic levels. The resultant DTI database will provide structural guidance for the developmental study of human fetal brains in basic neuroscience, and reference standards for diagnostic radiology of premature newborns.

  8. Morphometric study of the neural ossification centers of the atlas and axis in the human fetus.

    Science.gov (United States)

    Baumgart, Mariusz; Wiśniewski, Marcin; Grzonkowska, Magdalena; Małkowski, Bogdan; Badura, Mateusz; Szpinda, Michał

    2016-12-01

    The knowledge of the developing cervical spine and its individual vertebrae, including their neural processes may be useful in the diagnostics of congenital vertebral malformations. This study was performed to quantitatively examine the neural ossification centers of the atlas and axis with respect to their linear, planar and volumetric parameters. Using the methods of CT, digital-image analysis and statistics, the size of neural ossification centers in the atlas and axis in 55 spontaneously aborted human fetuses aged 17-30 weeks was studied. Without any male-female and right-left significant differences, the best fit growth dynamics for the neural ossification centers of the atlas and axis were, respectively, modelled by the following functions: for length: y = -13.461 + 6.140 × ln(age) ± 0.570 and y = -15.683 + 6.882 × ln(age) ± 0.503, for width: y = -4.006 + 1.930 × ln(age) ± 0.178 and y = -3.054 + 1.648 × ln(age) ± 0.178, for cross-sectional area: y = -7.362 + 0.780 × age ± 1.700 and y = -9.930 + 0.869 × age ± 1.911, and for volume: y = -6.417 + 0.836 × age ± 1.924 and y = -11.592 + 1.087 × age ± 2.509. The size of neural ossification centers of the atlas and axis shows neither sexual nor bilateral differences. The neural ossification centers of the atlas and axis grow logarithmically in both length and width and linearly in both cross-sectional area and volume. The numerical data relating to the size of neural ossification centers of the atlas and axis derived from the CT and digital-image analysis are considered specific-age reference values of potential relevance in both the ultrasound monitoring and the early detection of spinal abnormalities relating to the neural processes of the first two cervical vertebrae in the fetus.

  9. Environmental layout complexity affects neural activity during navigation in humans.

    Science.gov (United States)

    Slone, Edward; Burles, Ford; Iaria, Giuseppe

    2016-05-01

    Navigating large-scale surroundings is a fundamental ability. In humans, it is commonly assumed that navigational performance is affected by individual differences, such as age, sex, and cognitive strategies adopted for orientation. We recently showed that the layout of the environment itself also influences how well people are able to find their way within it, yet it remains unclear whether differences in environmental complexity are associated with changes in brain activity during navigation. We used functional magnetic resonance imaging to investigate how the brain responds to a change in environmental complexity by asking participants to perform a navigation task in two large-scale virtual environments that differed solely in interconnection density, a measure of complexity defined as the average number of directional choices at decision points. The results showed that navigation in the simpler, less interconnected environment was faster and more accurate relative to the complex environment, and such performance was associated with increased activity in a number of brain areas (i.e. precuneus, retrosplenial cortex, and hippocampus) known to be involved in mental imagery, navigation, and memory. These findings provide novel evidence that environmental complexity not only affects navigational behaviour, but also modulates activity in brain regions that are important for successful orientation and navigation. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  10. Infants' somatotopic neural responses to seeing human actions: I've got you under my skin.

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    Joni N Saby

    Full Text Available Human infants rapidly learn new skills and customs via imitation, but the neural linkages between action perception and production are not well understood. Neuroscience studies in adults suggest that a key component of imitation-identifying the corresponding body part used in the acts of self and other-has an organized neural signature. In adults, perceiving someone using a specific body part (e.g., hand vs. foot is associated with activation of the corresponding area of the sensory and/or motor strip in the observer's brain-a phenomenon called neural somatotopy. Here we examine whether preverbal infants also exhibit somatotopic neural responses during the observation of others' actions. 14-month-old infants were randomly assigned to watch an adult reach towards and touch an object using either her hand or her foot. The scalp electroencephalogram (EEG was recorded and event-related changes in the sensorimotor mu rhythm were analyzed. Mu rhythm desynchronization was greater over hand areas of sensorimotor cortex during observation of hand actions and was greater over the foot area for observation of foot actions. This provides the first evidence that infants' observation of someone else using a particular body part activates the corresponding areas of sensorimotor cortex. We hypothesize that this somatotopic organization in the developing brain supports imitation and cultural learning. The findings connect developmental cognitive neuroscience, adult neuroscience, action representation, and behavioral imitation.

  11. Menstrual cycle-dependent neural plasticity in the adult human brain is hormone, task, and region specific.

    NARCIS (Netherlands)

    Fernandez, G.S.E.; Weis, S.; Stoffel-Wagner, B.; Tendolkar, I.; Reuber, M.; Beyenburg, S.; Klaver, P.; Fell, J.; Greiff, A. de; Ruhlmann, J.; Reul, J.; Elger, C.E.

    2003-01-01

    In rodents, cyclically fluctuating levels of gonadal steroid hormones modulate neural plasticity by altering synaptic transmission and synaptogenesis. Alterations of mood and cognition observed during the menstrual cycle suggest that steroid-related plasticity also occurs in humans. Cycle

  12. Xenotransplantation of human neural progenitor cells to the subretinal space of nonimmunosuppressed pigs

    DEFF Research Database (Denmark)

    Warfvinge, Karin; Schwartz, Philip H; Kiilgaard, Jens Folke

    2011-01-01

    To investigate the feasibility of transplanting human neural progenitor cells (hNPCs) to the retina of nonimmunosuppressed pigs, cultured hNPCs were injected into the subretinal space of 5 adult pigs after laser burns were applied to promote donor cell integration. Postoperatively, the retinal...... vessels appeared normal without signs of exudation, bleeding, or subretinal elevation. Eyes were harvested at 10-28 days. H&E consistently showed mild retinal vasculitis, depigmentation of the RPE, and marked mononuclear cell infiltrate in the choroid adjacent to the site of transplantation. Human...

  13. Impact of Ethnic Group on Human Emotion Recognition Using Backpropagation Neural Network

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    Nabil M. Hewahi

    2011-12-01

    Full Text Available We claim that knowing the ethnic group of human would increase the accuracy of the emotion recognition. This is due to the difference between the face appearances and expressions of
    various ethnic groups. To test our claim, we developed an approach based on Artificial Neural Networks (ANN using backpropgation algorithm to recognize the human emotion through facial expressions. Our approach has been tested by using MSDEF dataset, and we found that, there is a positive effect on the accuracy of the recognition of emotion if we consider the ethnic group as input factor while building the recognition model. We achieved 8% improvement rate.

  14. Efficient and Fast Differentiation of Human Neural Stem Cells from Human Embryonic Stem Cells for Cell Therapy

    Directory of Open Access Journals (Sweden)

    Xinxin Han

    2017-01-01

    Full Text Available Stem cell-based therapies have been used for repairing damaged brain tissue and helping functional recovery after brain injury. Aberrance neurogenesis is related with brain injury, and multipotential neural stem cells from human embryonic stem (hES cells provide a great promise for cell replacement therapies. Optimized protocols for neural differentiation are necessary to produce functional human neural stem cells (hNSCs for cell therapy. However, the qualified procedure is scarce and detailed features of hNSCs originated from hES cells are still unclear. In this study, we developed a method to obtain hNSCs from hES cells, by which we could harvest abundant hNSCs in a relatively short time. Then, we examined the expression of pluripotent and multipotent marker genes through immunostaining and confirmed differentiation potential of the differentiated hNSCs. Furthermore, we analyzed the mitotic activity of these hNSCs. In this report, we provided comprehensive features of hNSCs and delivered the knowledge about how to obtain more high-quality hNSCs from hES cells which may help to accelerate the NSC-based therapies in brain injury treatment.

  15. Survivin Improves Reprogramming Efficiency of Human Neural Progenitors by Single Molecule OCT4

    Directory of Open Access Journals (Sweden)

    Shixin Zhou

    2016-01-01

    Full Text Available Induced pluripotent stem (iPS cells have been generated from human somatic cells by ectopic expression of four Yamanaka factors. Here, we report that Survivin, an apoptosis inhibitor, can enhance iPS cells generation from human neural progenitor cells (NPCs together with one factor OCT4 (1F-OCT4-Survivin. Compared with 1F-OCT4, Survivin accelerates the process of reprogramming from human NPCs. The neurocyte-originated induced pluripotent stem (NiPS cells generated from 1F-OCT4-Survivin resemble human embryonic stem (hES cells in morphology, surface markers, global gene expression profiling, and epigenetic status. Survivin keeps high expression in both iPS and ES cells. During the process of NiPS cell to neural cell differentiation, the expression of Survivin is rapidly decreased in protein level. The mechanism of Survivin promotion of reprogramming efficiency from NPCs may be associated with stabilization of β-catenin in WNT signaling pathway. This hypothesis is supported by experiments of RT-PCR, chromatin immune-precipitation, and Western blot in human ES cells. Our results showed overexpression of Survivin could improve the efficiency of reprogramming from NPCs to iPS cells by one factor OCT4 through stabilization of the key molecule, β-catenin.

  16. Plasmid-based generation of induced neural stem cells from adult human fibroblasts

    Directory of Open Access Journals (Sweden)

    Philipp Capetian

    2016-10-01

    Full Text Available Direct reprogramming from somatic to neural cell types has become an alternative to induced pluripotent stem cells. Most protocols employ viral expression systems, posing the risk of random genomic integration. Recent developments led to plasmid-based protocols, lowering this risk. However, these protocols either relied on continuous presence of a variety of small molecules or were only able to reprogram murine cells. We therefore established a reprogramming protocol based on vectors containing the Epstein-Barr virus (EBV-derived oriP/EBNA1 as well as the defined expression factors Oct3/4, Sox2, Klf4, L-myc, Lin28, and a small hairpin directed against p53. We employed a defined neural medium in combination with the neurotrophins bFGF, EGF and FGF4 for cultivation without the addition of small molecules. After reprogramming, cells demonstrated a temporary increase in the expression of endogenous Oct3/4. We obtained induced neural stem cells (iNSC 30 days after transfection. In contrast to previous results, plasmid vectors as well as a residual expression of reprogramming factors remained detectable in all cell lines. Cells showed a robust differentiation into neuronal (72% and glial cells (9% astrocytes, 6% oligodendrocytes. Despite the temporary increase of pluripotency-associated Oct3/4 expression during reprogramming, we did not detect pluripotent stem cells or non-neural cells in culture (except occasional residual fibroblasts. Neurons showed electrical activity and functional glutamatergic synapses. Our results demonstrate that reprogramming adult human fibroblasts to iNSC by plasmid vectors and basic neural medium without small molecules is possible and feasible. However, a full set of pluripotency-associated transcription factors may indeed result in the acquisition of a transient (at least partial pluripotent intermediate during reprogramming. In contrast to previous reports, the EBV-based plasmid system remained present and active inside

  17. A wireless transmission neural interface system for unconstrained non-human primates

    Science.gov (United States)

    Fernandez-Leon, Jose A.; Parajuli, Arun; Franklin, Robert; Sorenson, Michael; Felleman, Daniel J.; Hansen, Bryan J.; Hu, Ming; Dragoi, Valentin

    2015-10-01

    Objective. Studying the brain in large animal models in a restrained laboratory rig severely limits our capacity to examine brain circuits in experimental and clinical applications. Approach. To overcome these limitations, we developed a high-fidelity 96-channel wireless system to record extracellular spikes and local field potentials from the neocortex. A removable, external case of the wireless device is attached to a titanium pedestal placed in the animal skull. Broadband neural signals are amplified, multiplexed, and continuously transmitted as TCP/IP data at a sustained rate of 24 Mbps. A Xilinx Spartan 6 FPGA assembles the digital signals into serial data frames for transmission at 20 kHz though an 802.11n wireless data link on a frequency-shift key-modulated signal at 5.7-5.8 GHz to a receiver up to 10 m away. The system is powered by two CR123A, 3 V batteries for 2 h of operation. Main results. We implanted a multi-electrode array in visual area V4 of one anesthetized monkey (Macaca fascicularis) and in the dorsolateral prefrontal cortex (dlPFC) of a freely moving monkey (Macaca mulatta). The implanted recording arrays were electrically stable and delivered broadband neural data over a year of testing. For the first time, we compared dlPFC neuronal responses to the same set of stimuli (food reward) in restrained and freely moving conditions. Although we did not find differences in neuronal responses as a function of reward type in the restrained and unrestrained conditions, there were significant differences in correlated activity. This demonstrates that measuring neural responses in freely moving animals can capture phenomena that are absent in the traditional head-fixed paradigm. Significance. We implemented a wireless neural interface for multi-electrode recordings in freely moving non-human primates, which can potentially move systems neuroscience to a new direction by allowing one to record neural signals while animals interact with their environment.

  18. Generation and properties of a new human ventral mesencephalic neural stem cell line

    Energy Technology Data Exchange (ETDEWEB)

    Villa, Ana; Liste, Isabel; Courtois, Elise T.; Seiz, Emma G.; Ramos, Milagros [Center of Molecular Biology ' Severo Ochoa' , Autonomous University of Madrid-C.S.I.C., Campus Cantoblanco 28049-Madrid (Spain); Meyer, Morten [Department of Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, Winslowparken 21,st, DK-500, Odense C (Denmark); Juliusson, Bengt; Kusk, Philip [NsGene A/S, Ballerup (Denmark); Martinez-Serrano, Alberto, E-mail: amserrano@cbm.uam.es [Center of Molecular Biology ' Severo Ochoa' , Autonomous University of Madrid-C.S.I.C., Campus Cantoblanco 28049-Madrid (Spain)

    2009-07-01

    Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson's disease. Several epigenetic and genetic strategies have been tested for long-term maintenance and expansion of these cells in vitro. Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon (hVM1) based on v-myc immortalization. The cells expressed neural stem cell and radial glia markers like nestin, vimentin and 3CB2 under proliferation conditions. After withdrawal of growth factors, proliferation and expression of v-myc were dramatically reduced and the cells differentiated into astrocytes, oligodendrocytes and neurons. hVM1 cells yield a large number of dopaminergic neurons (about 12% of total cells are TH{sup +}) after differentiation, which also produce dopamine. In addition to proneural genes (NGN2, MASH1), differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as: LMX1A, LMX1B, GIRK2, ADH2, NURR1, PITX3, VMAT2 and DAT, indicating that they retain their regional identity. Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro, and to develop tools for Parkinson's disease cell replacement preclinical research and drug testing.

  19. Effects of Chronic Low-Dose Radiation on Human Neural Progenitor Cells

    Science.gov (United States)

    Katsura, Mari; Cyou-Nakamine, Hiromasa; Zen, Qin; Zen, Yang; Nansai, Hiroko; Amagasa, Shota; Kanki, Yasuharu; Inoue, Tsuyoshi; Kaneki, Kiyomi; Taguchi, Akashi; Kobayashi, Mika; Kaji, Toshiyuki; Kodama, Tatsuhiko; Miyagawa, Kiyoshi; Wada, Youichiro; Akimitsu, Nobuyoshi; Sone, Hideko

    2016-01-01

    The effects of chronic low-dose radiation on human health have not been well established. Recent studies have revealed that neural progenitor cells are present not only in the fetal brain but also in the adult brain. Since immature cells are generally more radiosensitive, here we investigated the effects of chronic low-dose radiation on cultured human neural progenitor cells (hNPCs) derived from embryonic stem cells. Radiation at low doses of 31, 124 and 496 mGy per 72 h was administered to hNPCs. The effects were estimated by gene expression profiling with microarray analysis as well as morphological analysis. Gene expression was dose-dependently changed by radiation. By thirty-one mGy of radiation, inflammatory pathways involving interferon signaling and cell junctions were altered. DNA repair and cell adhesion molecules were affected by 124 mGy of radiation while DNA synthesis, apoptosis, metabolism, and neural differentiation were all affected by 496 mGy of radiation. These in vitro results suggest that 496 mGy radiation affects the development of neuronal progenitor cells while altered gene expression was observed at a radiation dose lower than 100 mGy. This study would contribute to the elucidation of the clinical and subclinical phenotypes of impaired neuronal development induced by chronic low-dose radiation.

  20. A Chronically Implantable Bidirectional Neural Interface for Non-human Primates

    Directory of Open Access Journals (Sweden)

    Misako Komatsu

    2017-09-01

    Full Text Available Optogenetics has potential applications in the study of epilepsy and neuroprostheses, and for studies on neural circuit dynamics. However, to achieve translation to clinical usage, optogenetic interfaces that are capable of chronic stimulation and monitoring with minimal brain trauma are required. We aimed to develop a chronically implantable device for photostimulation of the brain of non-human primates. We used a micro-light-emitting diode (LED array with a flexible polyimide film. The array was combined with a whole-cortex electrocorticographic (ECoG electrode array for simultaneous photostimulation and recording. Channelrhodopsin-2 (ChR2 was virally transduced into the cerebral cortex of common marmosets, and then the device was epidurally implanted into their brains. We recorded the neural activity during photostimulation of the awake monkeys for 4 months. The neural responses gradually increased after the virus injection for ~8 weeks and remained constant for another 8 weeks. The micro-LED and ECoG arrays allowed semi-invasive simultaneous stimulation and recording during long-term implantation in the brains of non-human primates. The development of this device represents substantial progress in the field of optogenetic applications.

  1. Generation of retinal pigment epithelial cells from human embryonic stem cell-derived spherical neural masses.

    Science.gov (United States)

    Cho, Myung Soo; Kim, Sang Jin; Ku, Seung-Yup; Park, Jung Hyun; Lee, Haksup; Yoo, Dae Hoon; Park, Un Chul; Song, Seul Ae; Choi, Young Min; Yu, Hyeong Gon

    2012-09-01

    Dysfunction and loss of retinal pigment epithelium (RPE) are major pathologic changes observed in various retinal degenerative diseases such as aged-related macular degeneration. RPE generated from human pluripotent stem cells can be a good candidate for RPE replacement therapy. Here, we show the differentiation of human embryonic stem cells (hESCs) toward RPE with the generation of spherical neural masses (SNMs), which are pure masses of hESCs-derived neural precursors. During the early passaging of SNMs, cystic structures arising from opened neural tube-like structures showed pigmented epithelial morphology. These pigmented cells were differentiated into functional RPE by neuroectodermal induction and mechanical purification. Most of the differentiated cells showed typical RPE morphologies, such as a polygonal-shaped epithelial monolayer, and transmission electron microscopy revealed apical microvilli, pigment granules, and tight junctions. These cells also expressed molecular markers of RPE, including Mitf, ZO-1, RPE65, CRALBP, and bestrophin. The generated RPE also showed phagocytosis of isolated bovine photoreceptor outer segment and secreting pigment epithelium-derived factor and vascular endothelial growth factor. Functional RPE could be generated from SNM in our method. Because SNMs have several advantages, including the capability of expansion for long periods without loss of differentiation capability, easy storage and thawing, and no need for feeder cells, our method for RPE differentiation may be used as an efficient strategy for generating functional RPE cells for retinal regeneration therapy. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. Taurine enhances the growth of neural precursors derived from fetal human brain and promotes neuronal specification.

    Science.gov (United States)

    Hernández-Benítez, Reyna; Vangipuram, Sharada D; Ramos-Mandujano, Gerardo; Lyman, William D; Pasantes-Morales, Herminia

    2013-01-01

    Taurine is present at high concentrations in the fetal brain and is required for optimal brain development. Recent studies have reported that taurine causes increased proliferation of neural stem/progenitor neural cells (neural precursor cells, NPCs) obtained from embryonic and adult rodent brain. The present study is the first to show that taurine markedly increases cell numbers in cultures and neuronal generation from human NPCs (hNPCs). hNPCs obtained from 3 fetal brains (14-15 weeks of gestation) were cultured and expanded as neurospheres, which contained 76.3% nestin-positive cells. Taurine (5-20 mM) increased the number of hNPCs in culture, with maximal effect found at 10 mM and 4 days of culture. The taurine-induced increase ranged from 57 to 188% in the 3 brains examined. Taurine significantly enhanced the percentage of neurons formed from hNPCs under differentiating conditions, with increases ranging from 172 to 480% over controls without taurine. Taurine also increased the cell number and neuronal generation in cultures of the immortalized human cell line ReNcell VM. These results suggest that taurine has a positive influence on hNPC growth and neuronal formation. Copyright © 2013 S. Karger AG, Basel.

  3. Stem Cell Bioprinting: Functional 3D Neural Mini-Tissues from Printed Gel-Based Bioink and Human Neural Stem Cells (Adv. Healthcare Mater. 12/2016).

    Science.gov (United States)

    Gu, Qi; Tomaskovic-Crook, Eva; Lozano, Rodrigo; Chen, Yu; Kapsa, Robert M; Zhou, Qi; Wallace, Gordon G; Crook, Jeremy M

    2016-06-01

    On page 1429 G. G. Wallace, J. M. Crook, and co-workers report the first example of fabricating neural tissue by 3D bioprinting human neural stem cells. A novel polysaccharide based bioink preserves stem cell viability and function within the printed construct, enabling self-renewal and differentiation to neurons and supporting neuroglia. Neurons are predominantly GABAergic, establish networks, are spontaneously active, and show a bicuculline induced increased calcium response. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Neural Plasticity following Abacus Training in Humans: A Review and Future Directions.

    Science.gov (United States)

    Li, Yongxin; Chen, Feiyan; Huang, Wenhua

    2016-01-01

    The human brain has an enormous capacity to adapt to a broad variety of environmental demands. Previous studies in the field of abacus training have shown that this training can induce specific changes in the brain. However, the neural mechanism underlying these changes remains elusive. Here, we reviewed the behavioral and imaging findings of comparisons between abacus experts and average control subjects and focused on changes in activation patterns and changes in brain structure. Finally, we noted the limitations and the future directions of this field. We concluded that although current studies have provided us with information about the mechanisms of abacus training, more research on abacus training is needed to understand its neural impact.

  5. Expression of Pluripotency Markers in Nonpluripotent Human Neural Stem and Progenitor Cells

    DEFF Research Database (Denmark)

    Vincent, P.; Benedikz, Eirikur; Uhlén, Per

    2017-01-01

    cells (CD133+/CD24lo), the capacity of sphere formation, or high cell proliferation rates. The rate of cell death among NPCs expressing pluripotency-associated genes was also similar to that of other NPCs. Live cell imaging showed that NANOG- and REX1-expressing NPCs continuously changed morphology......Nonpluripotent neural progenitor cells (NPCs) derived from the human fetal central nervous system were found to express a number of messenger RNA (mRNA) species associated with pluripotency, such as NANOG, REX1, and OCT4. The expression was restricted to small subpopulations of NPCs. In contrast...... to pluripotent stem cells, there was no coexpression of the pluripotency-associated genes studied. Although the expression of these genes rapidly declined during the in vitro differentiation of NPCs, we found no evidence that the discrete expression was associated with the markers of multipotent neural stem...

  6. Neural Plasticity following Abacus Training in Humans: A Review and Future Directions

    Directory of Open Access Journals (Sweden)

    Yongxin Li

    2016-01-01

    Full Text Available The human brain has an enormous capacity to adapt to a broad variety of environmental demands. Previous studies in the field of abacus training have shown that this training can induce specific changes in the brain. However, the neural mechanism underlying these changes remains elusive. Here, we reviewed the behavioral and imaging findings of comparisons between abacus experts and average control subjects and focused on changes in activation patterns and changes in brain structure. Finally, we noted the limitations and the future directions of this field. We concluded that although current studies have provided us with information about the mechanisms of abacus training, more research on abacus training is needed to understand its neural impact.

  7. Imaging of human differentiated 3D neural aggregates using light sheet fluorescence microscopy.

    Science.gov (United States)

    Gualda, Emilio J; Simão, Daniel; Pinto, Catarina; Alves, Paula M; Brito, Catarina

    2014-01-01

    The development of three dimensional (3D) cell cultures represents a big step for the better understanding of cell behavior and disease in a more natural like environment, providing not only single but multiple cell type interactions in a complex 3D matrix, highly resembling physiological conditions. Light sheet fluorescence microscopy (LSFM) is becoming an excellent tool for fast imaging of such 3D biological structures. We demonstrate the potential of this technique for the imaging of human differentiated 3D neural aggregates in fixed and live samples, namely calcium imaging and cell death processes, showing the power of imaging modality compared with traditional microscopy. The combination of light sheet microscopy and 3D neural cultures will open the door to more challenging experiments involving drug testing at large scale as well as a better understanding of relevant biological processes in a more realistic environment.

  8. Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans

    Directory of Open Access Journals (Sweden)

    Jinah Han

    2015-02-01

    Full Text Available Neural stem cells (NSCs continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs, VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.

  9. Statistical control chart and neural network classification for improving human fall detection

    KAUST Repository

    Harrou, Fouzi

    2017-01-05

    This paper proposes a statistical approach to detect and classify human falls based on both visual data from camera and accelerometric data captured by accelerometer. Specifically, we first use a Shewhart control chart to detect the presence of potential falls by using accelerometric data. Unfortunately, this chart cannot distinguish real falls from fall-like actions, such as lying down. To bypass this difficulty, a neural network classifier is then applied only on the detected cases through visual data. To assess the performance of the proposed method, experiments are conducted on the publicly available fall detection databases: the University of Rzeszow\\'s fall detection (URFD) dataset. Results demonstrate that the detection phase play a key role in reducing the number of sequences used as input into the neural network classifier for classification, significantly reducing computational burden and achieving better accuracy.

  10. Accelerometer signal-based human activity recognition using augmented autoregressive model coefficients and artificial neural nets.

    Science.gov (United States)

    Khan, A M; Lee, Y K; Kim, T S

    2008-01-01

    Automatic recognition of human activities is one of the important and challenging research areas in proactive and ubiquitous computing. In this work, we present some preliminary results of recognizing human activities using augmented features extracted from the activity signals measured using a single triaxial accelerometer sensor and artificial neural nets. The features include autoregressive (AR) modeling coefficients of activity signals, signal magnitude areas (SMA), and title angles (TA). We have recognized four human activities using AR coefficients (ARC) only, ARC with SMA, and ARC with SMA and TA. With the last augmented features, we have achieved the recognition rate above 99% for all four activities including lying, standing, walking, and running. With our proposed technique, real time recognition of some human activities is possible.

  11. Rejuvenation of MPTP-induced human neural precursor cell senescence by activating autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Liang [East Hospital, Tongji University School of Medicine, Shanghai (China); Dong, Chuanming [East Hospital, Tongji University School of Medicine, Shanghai (China); Department of Anatomy and Neurobiology, The Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong (China); Sun, Chenxi; Ma, Rongjie; Yang, Danjing [East Hospital, Tongji University School of Medicine, Shanghai (China); Zhu, Hongwen, E-mail: hongwen_zhu@hotmail.com [Tianjin Hospital, Tianjin Academy of Integrative Medicine, Tianjin (China); Xu, Jun, E-mail: xunymc2000@yahoo.com [East Hospital, Tongji University School of Medicine, Shanghai (China)

    2015-08-21

    Aging of neural stem cell, which can affect brain homeostasis, may be caused by many cellular mechanisms. Autophagy dysfunction was found in aged and neurodegenerative brains. However, little is known about the relationship between autophagy and human neural stem cell (hNSC) aging. The present study used 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to treat neural precursor cells (NPCs) derived from human embryonic stem cell (hESC) line H9 and investigate related molecular mechanisms involved in this process. MPTP-treated NPCs were found to undergo premature senescence [determined by increased senescence-associated-β-galactosidase (SA-β-gal) activity, elevated intracellular reactive oxygen species level, and decreased proliferation] and were associated with impaired autophagy. Additionally, the cellular senescence phenotypes were manifested at the molecular level by a significant increase in p21 and p53 expression, a decrease in SOD2 expression, and a decrease in expression of some key autophagy-related genes such as Atg5, Atg7, Atg12, and Beclin 1. Furthermore, we found that the senescence-like phenotype of MPTP-treated hNPCs was rejuvenated through treatment with a well-known autophagy enhancer rapamycin, which was blocked by suppression of essential autophagy gene Beclin 1. Taken together, these findings reveal the critical role of autophagy in the process of hNSC aging, and this process can be reversed by activating autophagy. - Highlights: • We successfully establish hESC-derived neural precursor cells. • MPTP treatment induced senescence-like state in hESC-derived NPCs. • MPTP treatment induced impaired autophagy of hESC-derived NPCs. • MPTP-induced hESC-derived NPC senescence was rejuvenated by activating autophagy.

  12. In vivo transplantation of fetal human gut-derived enteric neural crest cells.

    Science.gov (United States)

    Cooper, J E; Natarajan, D; McCann, C J; Choudhury, S; Godwin, H; Burns, A J; Thapar, N

    2017-01-01

    The prospect of using neural cell replacement for the treatment of severe enteric neuropathies has seen significant progress in the last decade. The ability to harvest and transplant enteric neural crest cells (ENCCs) that functionally integrate within recipient intestine has recently been confirmed by in vivo murine studies. Although similar cells can be harvested from human fetal and postnatal gut, no studies have as yet verified their functional viability upon in vivo transplantation. We sought to determine whether ENCCs harvested from human fetal bowel are capable of engraftment and functional integration within recipient intestine following in vivo transplantation into postnatal murine colon. Enteric neural crest cells selected and harvested from fetal human gut using the neurotrophin receptor p75(NTR) were lentivirally labeled with either GFP or calcium-sensitive GCaMP and transplanted into the hindgut of Rag2(-) /γc(-) /C5(-) -immunodeficient mice at postnatal day 21. Transplanted intestines were assessed immunohistochemically for engraftment and differentiation of donor cells. Functional viability and integration with host neuromusculature was assessed using calcium imaging. Transplanted human fetal gut-derived ENCC showed engraftment within the recipient postnatal colon in 8/15 mice (53.3%). At 4 weeks posttransplantation, donor cells had spread from the site of transplantation and extended projections over distances of 1.2 ± 0.6 mm (n = 5), and differentiated into enteric nervous system (ENS) appropriate neurons and glia. These cells formed branching networks located with the myenteric plexus. Calcium transients (change in intensity F/F0 = 1.25 ± 0.03; 15 cells) were recorded in transplanted cells upon stimulation of the recipient endogenous ENS demonstrating their viability and establishment of functional connections. © 2016 The Authors. Neurogastroenterology & Motility Published by John Wiley & Sons Ltd.

  13. Neural Correlates of the Binaural Masking Level Difference in Human Frequency-Following Responses.

    Science.gov (United States)

    Clinard, Christopher G; Hodgson, Sarah L; Scherer, Mary Ellen

    2017-04-01

    The binaural masking level difference (BMLD) is an auditory phenomenon where binaural tone-in-noise detection is improved when the phase of either signal or noise is inverted in one of the ears (SπNo or SoNπ, respectively), relative to detection when signal and noise are in identical phase at each ear (SoNo). Processing related to BMLDs and interaural time differences has been confirmed in the auditory brainstem of non-human mammals; in the human auditory brainstem, phase-locked neural responses elicited by BMLD stimuli have not been systematically examined across signal-to-noise ratio. Behavioral and physiological testing was performed in three binaural stimulus conditions: SoNo, SπNo, and SoNπ. BMLDs at 500 Hz were obtained from 14 young, normal-hearing adults (ages 21-26). Physiological BMLDs used the frequency-following response (FFR), a scalp-recorded auditory evoked potential dependent on sustained phase-locked neural activity; FFR tone-in-noise detection thresholds were used to calculate physiological BMLDs. FFR BMLDs were significantly smaller (poorer) than behavioral BMLDs, and FFR BMLDs did not reflect a physiological release from masking, on average. Raw FFR amplitude showed substantial reductions in the SπNo condition relative to SoNo and SoNπ conditions, consistent with negative effects of phase summation from left and right ear FFRs. FFR amplitude differences between stimulus conditions (e.g., SoNo amplitude-SπNo amplitude) were significantly predictive of behavioral SπNo BMLDs; individuals with larger amplitude differences had larger (better) behavioral B MLDs and individuals with smaller amplitude differences had smaller (poorer) behavioral B MLDs. These data indicate a role for sustained phase-locked neural activity in BMLDs of humans and are the first to show predictive relationships between behavioral BMLDs and human brainstem responses.

  14. Continuous Timescale Long-Short Term Memory Neural Network for Human Intent Understanding

    Directory of Open Access Journals (Sweden)

    Zhibin Yu

    2017-08-01

    Full Text Available Understanding of human intention by observing a series of human actions has been a challenging task. In order to do so, we need to analyze longer sequences of human actions related with intentions and extract the context from the dynamic features. The multiple timescales recurrent neural network (MTRNN model, which is believed to be a kind of solution, is a useful tool for recording and regenerating a continuous signal for dynamic tasks. However, the conventional MTRNN suffers from the vanishing gradient problem which renders it impossible to be used for longer sequence understanding. To address this problem, we propose a new model named Continuous Timescale Long-Short Term Memory (CTLSTM in which we inherit the multiple timescales concept into the Long-Short Term Memory (LSTM recurrent neural network (RNN that addresses the vanishing gradient problem. We design an additional recurrent connection in the LSTM cell outputs to produce a time-delay in order to capture the slow context. Our experiments show that the proposed model exhibits better context modeling ability and captures the dynamic features on multiple large dataset classification tasks. The results illustrate that the multiple timescales concept enhances the ability of our model to handle longer sequences related with human intentions and hence proving to be more suitable for complex tasks, such as intention recognition.

  15. Highly efficient differentiation of neural precursors from human embryonic stem cells and benefits of transplantation after ischemic stroke in mice.

    Science.gov (United States)

    Drury-Stewart, Danielle; Song, Mingke; Mohamad, Osama; Guo, Ying; Gu, Xiaohuan; Chen, Dongdong; Wei, Ling

    2013-08-08

    Ischemic stroke is a leading cause of death and disability, but treatment options are severely limited. Cell therapy offers an attractive strategy for regenerating lost tissues and enhancing the endogenous healing process. In this study, we investigated the use of human embryonic stem cell-derived neural precursors as a cell therapy in a murine stroke model. Neural precursors were derived from human embryonic stem cells by using a fully adherent SMAD inhibition protocol employing small molecules. The efficiency of neural induction and the ability of these cells to further differentiate into neurons were assessed by using immunocytochemistry. Whole-cell patch-clamp recording was used to demonstrate the electrophysiological activity of human embryonic stem cell-derived neurons. Neural precursors were transplanted into the core and penumbra regions of a focal ischemic stroke in the barrel cortex of mice. Animals received injections of bromodeoxyuridine to track regeneration. Neural differentiation of the transplanted cells and regenerative markers were measured by using immunohistochemistry. The adhesive removal test was used to determine functional improvement after stroke and intervention. After 11 days of neural induction by using the small-molecule protocol, over 95% of human embryonic stem-derived cells expressed at least one neural marker. Further in vitro differentiation yielded cells that stained for mature neuronal markers and exhibited high-amplitude, repetitive action potentials in response to depolarization. Neuronal differentiation also occurred after transplantation into the ischemic cortex. A greater level of bromodeoxyuridine co-localization with neurons was observed in the penumbra region of animals receiving cell transplantation. Transplantation also improved sensory recovery in transplant animals over that in control animals. Human embryonic stem cell-derived neural precursors derived by using a highly efficient small-molecule SMAD inhibition

  16. Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors

    Energy Technology Data Exchange (ETDEWEB)

    Manceur, Aziza P. [Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto, Ontario (Canada); Donnelly Centre, University of Toronto, Toronto, Ontario (Canada); Tseng, Michael [Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Ontario (Canada); Department of Psychiatry, University of Toronto, Toronto, ON (Canada); Institute of Medical Science, University of Toronto, Toronto, ON (Canada); Holowacz, Tamara [Donnelly Centre, University of Toronto, Toronto, Ontario (Canada); Witterick, Ian [Institute of Medical Science, University of Toronto, Toronto, ON (Canada); Department of Otolaryngology, Head and Neck Surgery, University of Toronto, ON (Canada); Weksberg, Rosanna [Institute of Medical Science, University of Toronto, Toronto, ON (Canada); The Hospital for Sick Children, Research Institute, Program in Genetics and Genomic Biology, Toronto, Ontario Canada (Canada); McCurdy, Richard D. [The Hospital for Sick Children, Research Institute, Program in Genetics and Genomic Biology, Toronto, Ontario Canada (Canada); Warsh, Jerry J. [Laboratory of Cellular and Molecular Pathophysiology, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Ontario (Canada); Department of Psychiatry, University of Toronto, Toronto, ON (Canada); Institute of Medical Science, University of Toronto, Toronto, ON (Canada); Audet, Julie, E-mail: julie.audet@utoronto.ca [Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto, Ontario (Canada); Donnelly Centre, University of Toronto, Toronto, Ontario (Canada)

    2011-09-10

    The olfactory epithelium (OE) contains neural precursor cells which can be easily harvested from a minimally invasive nasal biopsy, making them a valuable cell source to study human neural cell lineages in health and disease. Glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology and treatment of neuropsychiatric disorders and also in the regulation of murine neural precursor cell fate in vitro and in vivo. In this study, we examined the impact of decreased GSK-3 activity on the fate of adult human OE neural precursors in vitro. GSK-3 inhibition was achieved using ATP-competitive (6-bromoindirubin-3'-oxime and CHIR99021) or substrate-competitive (TAT-eIF2B) inhibitors to eliminate potential confounding effects on cell fate due to off-target kinase inhibition. GSK-3 inhibitors decreased the number of neural precursor cells in OE cell cultures through a reduction in proliferation. Decreased proliferation was not associated with a reduction in cell survival but was accompanied by a reduction in nestin expression and a substantial increase in the expression of the neuronal differentiation markers MAP1B and neurofilament (NF-M) after 10 days in culture. Taken together, these results suggest that GSK-3 inhibition promotes the early stages of neuronal differentiation in cultures of adult human neural precursors and provide insights into the mechanisms by which alterations in GSK-3 signaling affect adult human neurogenesis, a cellular process strongly suspected to play a role in the etiology of neuropsychiatric disorders.

  17. Neural Conversion and Patterning of Human Pluripotent Stem Cells: A Developmental Perspective

    Directory of Open Access Journals (Sweden)

    Alexandra Zirra

    2016-01-01

    Full Text Available Since the reprogramming of adult human terminally differentiated somatic cells into induced pluripotent stem cells (hiPSCs became a reality in 2007, only eight years have passed. Yet over this relatively short period, myriad experiments have revolutionized previous stem cell dogmata. The tremendous promise of hiPSC technology for regenerative medicine has fuelled rising expectations from both the public and scientific communities alike. In order to effectively harness hiPSCs to uncover fundamental mechanisms of disease, it is imperative to first understand the developmental neurobiology underpinning their lineage restriction choices in order to predictably manipulate cell fate to desired derivatives. Significant progress in developmental biology provides an invaluable resource for rationalising directed differentiation of hiPSCs to cellular derivatives of the nervous system. In this paper we begin by reviewing core developmental concepts underlying neural induction in order to provide context for how such insights have guided reductionist in vitro models of neural conversion from hiPSCs. We then discuss early factors relevant in neural patterning, again drawing upon crucial knowledge gained from developmental neurobiological studies. We conclude by discussing open questions relating to these concepts and how their resolution might serve to strengthen the promise of pluripotent stem cells in regenerative medicine.

  18. Lifelong learning of human actions with deep neural network self-organization.

    Science.gov (United States)

    Parisi, German I; Tani, Jun; Weber, Cornelius; Wermter, Stefan

    2017-12-01

    Lifelong learning is fundamental in autonomous robotics for the acquisition and fine-tuning of knowledge through experience. However, conventional deep neural models for action recognition from videos do not account for lifelong learning but rather learn a batch of training data with a predefined number of action classes and samples. Thus, there is the need to develop learning systems with the ability to incrementally process available perceptual cues and to adapt their responses over time. We propose a self-organizing neural architecture for incrementally learning to classify human actions from video sequences. The architecture comprises growing self-organizing networks equipped with recurrent neurons for processing time-varying patterns. We use a set of hierarchically arranged recurrent networks for the unsupervised learning of action representations with increasingly large spatiotemporal receptive fields. Lifelong learning is achieved in terms of prediction-driven neural dynamics in which the growth and the adaptation of the recurrent networks are driven by their capability to reconstruct temporally ordered input sequences. Experimental results on a classification task using two action benchmark datasets show that our model is competitive with state-of-the-art methods for batch learning also when a significant number of sample labels are missing or corrupted during training sessions. Additional experiments show the ability of our model to adapt to non-stationary input avoiding catastrophic interference. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  19. Is avoiding an aversive outcome rewarding? Neural substrates of avoidance learning in the human brain.

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    Hackjin Kim

    2006-07-01

    Full Text Available Avoidance learning poses a challenge for reinforcement-based theories of instrumental conditioning, because once an aversive outcome is successfully avoided an individual may no longer experience extrinsic reinforcement for their behavior. One possible account for this is to propose that avoiding an aversive outcome is in itself a reward, and thus avoidance behavior is positively reinforced on each trial when the aversive outcome is successfully avoided. In the present study we aimed to test this possibility by determining whether avoidance of an aversive outcome recruits the same neural circuitry as that elicited by a reward itself. We scanned 16 human participants with functional MRI while they performed an instrumental choice task, in which on each trial they chose from one of two actions in order to either win money or else avoid losing money. Neural activity in a region previously implicated in encoding stimulus reward value, the medial orbitofrontal cortex, was found to increase, not only following receipt of reward, but also following successful avoidance of an aversive outcome. This neural signal may itself act as an intrinsic reward, thereby serving to reinforce actions during instrumental avoidance.

  20. Neural dynamics of reward probability coding: a Magnetoencephalographic study in humans

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    Julie eThomas

    2013-11-01

    Full Text Available Prediction of future rewards and discrepancy between actual and expected outcomes (prediction error are crucial signals for adaptive behavior. In humans, a number of fMRI studies demonstrated that reward probability modulates these two signals in a large brain network. Yet, the spatio-temporal dynamics underlying the neural coding of reward probability remains unknown. Here, using magnetoencephalography, we investigated the neural dynamics of prediction and reward prediction error computations while subjects learned to associate cues of slot machines with monetary rewards with different probabilities. We showed that event-related magnetic fields (ERFs arising from the visual cortex coded the expected reward value 155 ms after the cue, demonstrating that reward value signals emerge early in the visual stream. Moreover, a prediction error was reflected in ERF peaking 300 ms after the rewarded outcome and showing decreasing amplitude with higher reward probability. This prediction error signal was generated in a network including the anterior and posterior cingulate cortex. These findings pinpoint the spatio-temporal characteristics underlying reward probability coding. Together, our results provide insights into the neural dynamics underlying the ability to learn probabilistic stimuli-reward contingencies.

  1. Human Age Recognition by Electrocardiogram Signal Based on Artificial Neural Network

    Science.gov (United States)

    Dasgupta, Hirak

    2016-12-01

    The objective of this work is to make a neural network function approximation model to detect human age from the electrocardiogram (ECG) signal. The input vectors of the neural network are the Katz fractal dimension of the ECG signal, frequencies in the QRS complex, male or female (represented by numeric constant) and the average of successive R-R peak distance of a particular ECG signal. The QRS complex has been detected by short time Fourier transform algorithm. The successive R peak has been detected by, first cutting the signal into periods by auto-correlation method and then finding the absolute of the highest point in each period. The neural network used in this problem consists of two layers, with Sigmoid neuron in the input and linear neuron in the output layer. The result shows the mean of errors as -0.49, 1.03, 0.79 years and the standard deviation of errors as 1.81, 1.77, 2.70 years during training, cross validation and testing with unknown data sets, respectively.

  2. 3D Normal Human Neural Progenitor Tissue-Like Assemblies: A Model of Persistent VZV Infection

    Science.gov (United States)

    Goodwin, Thomas J.

    2013-01-01

    Varicella-zoster virus (VZV) is a neurotropic human alphaherpesvirus that causes varicella upon primary infection, establishes latency in multiple ganglionic neurons, and can reactivate to cause zoster. Live attenuated VZV vaccines are available; however, they can also establish latent infections and reactivate. Studies of VZV latency have been limited to the analyses of human ganglia removed at autopsy, as the virus is strictly a human pathogen. Recently, terminally differentiated human neurons have received much attention as a means to study the interaction between VZV and human neurons; however, the short life-span of these cells in culture has limited their application. Herein, we describe the construction of a model of normal human neural progenitor cells (NHNP) in tissue-like assemblies (TLAs), which can be successfully maintained for at least 180 days in three-dimensional (3D) culture, and exhibit an expression profile similar to that of human trigeminal ganglia. Infection of NHNP TLAs with cell-free VZV resulted in a persistent infection that was maintained for three months, during which the virus genome remained stable. Immediate-early, early and late VZV genes were transcribed, and low-levels of infectious VZV were recurrently detected in the culture supernatant. Our data suggest that NHNP TLAs are an effective system to investigate long-term interactions of VZV with complex assemblies of human neuronal cells.

  3. Cross-sectional study of the neural ossification centers of vertebrae C1-S5 in the human fetus.

    Science.gov (United States)

    Szpinda, Michał; Baumgart, Mariusz; Szpinda, Anna; Woźniak, Alina; Mila-Kierzenkowska, Celestyna

    2013-10-01

    An understanding of the normal evolution of the spine is of great relevance in the prenatal detection of spinal abnormalities. This study was carried out to estimate the length, width, cross-sectional area and volume of the neural ossification centers of vertebrae C1-S5 in the human fetus. Using the methods of CT (Biograph mCT), digital-image analysis (Osirix 3.9) and statistics (the one-way ANOVA test for paired data, the Kolmogorov-Smirnov test, Levene's test, Student's t test, the one-way ANOVA test for unpaired data with post hoc RIR Tukey comparisons) the size for the neural ossification centers throughout the spine in 55 spontaneously aborted human fetuses (27 males, 28 females) at ages of 17-30 weeks was studied. The neural ossification centers were visualized in the whole pre-sacral spine, in 74.5 % for S1, in 61.8 % for S2, in 52.7 % for S3, and in 12.7 % for S4. Neither male-female nor right-left significant differences in the size of neural ossification centers were found. The neural ossification centers were the longest within the cervical spine. The maximum values referred to the axis on the right, and to C5 vertebra on the left. There was a gradual decrease in length for the neural ossification centers of T1-S4 vertebrae. The neural ossification centers were the widest within the proximal thoracic spine and narrowed bi-directionally. The growth dynamics for CSA of neural ossification centers were found to parallel that of volume. The largest CSAs and volumes of neural ossification centers were found in the C3 vertebra, and decreased in the distal direction. The neural ossification centers show neither male-female nor right-left differences. The neural ossification centers are characterized by the maximum length for C2-C6 vertebrae, the maximum width for the proximal thoracic spine, and both the maximum cross-sectional area and volume for C3 vertebra. There is a sharp decrease in size of the neural ossification centers along the sacral spine. A

  4. Derivation of Neural Progenitors and Retinal Pigment Epithelium from Common Marmoset and Human Pluripotent Stem Cells

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    Laughing Bear Torrez

    2012-01-01

    Full Text Available Embryonic and induced pluripotent stem cells (IPSCs derived from mammalian species are valuable tools for modeling human disease, including retinal degenerative eye diseases that result in visual loss. Restoration of vision has focused on transplantation of neural progenitor cells (NPCs and retinal pigmented epithelium (RPE to the retina. Here we used transgenic common marmoset (Callithrix jacchus and human pluripotent stem cells carrying the enhanced green fluorescent protein (eGFP reporter as a model system for retinal differentiation. Using suspension and subsequent adherent differentiation cultures, we observed spontaneous in vitro differentiation that included NPCs and cells with pigment granules characteristic of differentiated RPE. Retinal cells derived from human and common marmoset pluripotent stem cells provide potentially unlimited cell sources for testing safety and immune compatibility following autologous or allogeneic transplantation using nonhuman primates in early translational applications.

  5. A 3D human neural cell culture system for modeling Alzheimer’s disease

    Science.gov (United States)

    Kim, Young Hye; Choi, Se Hoon; D’Avanzo, Carla; Hebisch, Matthias; Sliwinski, Christopher; Bylykbashi, Enjana; Washicosky, Kevin J.; Klee, Justin B.; Brüstle, Oliver; Tanzi, Rudolph E.; Kim, Doo Yeon

    2015-01-01

    Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer’s disease (AD) because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel three-dimensional (3D) culture system that exhibits key events in AD pathogenesis, including extracellular aggregation of β-amyloid and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix, and the analysis of AD pathogenesis. The 3D culture generation takes 1–2 days. The aggregation of β-amyloid is observed after 6-weeks of differentiation followed by robust tau pathology after 10–14 weeks. PMID:26068894

  6. Neural control of computer cursor velocity by decoding motor cortical spiking activity in humans with tetraplegia

    Science.gov (United States)

    Kim, Sung-Phil; Simeral, John D.; Hochberg, Leigh R.; Donoghue, John P.; Black, Michael J.

    2008-12-01

    Computer-mediated connections between human motor cortical neurons and assistive devices promise to improve or restore lost function in people with paralysis. Recently, a pilot clinical study of an intracortical neural interface system demonstrated that a tetraplegic human was able to obtain continuous two-dimensional control of a computer cursor using neural activity recorded from his motor cortex. This control, however, was not sufficiently accurate for reliable use in many common computer control tasks. Here, we studied several central design choices for such a system including the kinematic representation for cursor movement, the decoding method that translates neuronal ensemble spiking activity into a control signal and the cursor control task used during training for optimizing the parameters of the decoding method. In two tetraplegic participants, we found that controlling a cursor's velocity resulted in more accurate closed-loop control than controlling its position directly and that cursor velocity control was achieved more rapidly than position control. Control quality was further improved over conventional linear filters by using a probabilistic method, the Kalman filter, to decode human motor cortical activity. Performance assessment based on standard metrics used for the evaluation of a wide range of pointing devices demonstrated significantly improved cursor control with velocity rather than position decoding. Disclosure. JPD is the Chief Scientific Officer and a director of Cyberkinetics Neurotechnology Systems (CYKN); he holds stock and receives compensation. JDS has been a consultant for CYKN. LRH receives clinical trial support from CYKN.

  7. Neural mechanisms underlying contextual dependency of subjective values: converging evidence from monkeys and humans.

    Science.gov (United States)

    Abitbol, Raphaëlle; Lebreton, Maël; Hollard, Guillaume; Richmond, Barry J; Bouret, Sébastien; Pessiglione, Mathias

    2015-02-04

    A major challenge for decision theory is to account for the instability of expressed preferences across time and context. Such variability could arise from specific properties of the brain system used to assign subjective values. Growing evidence has identified the ventromedial prefrontal cortex (VMPFC) as a key node of the human brain valuation system. Here, we first replicate this observation with an fMRI study in humans showing that subjective values of painting pictures, as expressed in explicit pleasantness ratings, are specifically encoded in the VMPFC. We then establish a bridge with monkey electrophysiology, by comparing single-unit activity evoked by visual cues between the VMPFC and the orbitofrontal cortex. At the neural population level, expected reward magnitude was only encoded in the VMPFC, which also reflected subjective cue values, as expressed in Pavlovian appetitive responses. In addition, we demonstrate in both species that the additive effect of prestimulus activity on evoked activity has a significant impact on subjective values. In monkeys, the factor dominating prestimulus VMPFC activity was trial number, which likely indexed variations in internal dispositions related to fatigue or satiety. In humans, prestimulus VMPFC activity was externally manipulated through changes in the musical context, which induced a systematic bias in subjective values. Thus, the apparent stochasticity of preferences might relate to the VMPFC automatically aggregating the values of contextual features, which would bias subsequent valuation because of temporal autocorrelation in neural activity. Copyright © 2015 the authors 0270-6474/15/352308-13$15.00/0.

  8. The experimental study of genetic engineering human neural stem cells mediated by lentivirus to express multigene.

    Science.gov (United States)

    Cai, Pei-qiang; Tang, Xun; Lin, Yue-qiu; Martin, Oudega; Sun, Guang-yun; Xu, Lin; Yang, Yun-kang; Zhou, Tian-hua

    2006-02-01

    To explore the feasibility to construct genetic engineering human neural stem cells (hNSCs) mediated by lentivirus to express multigene in order to provide a graft source for further studies of spinal cord injury (SCI). Human neural stem cells from the brain cortex of human abortus were isolated and cultured, then gene was modified by lentivirus to express both green fluorescence protein (GFP) and rat neurotrophin-3 (NT-3); the transgenic expression was detected by the methods of fluorescence microscope, dorsal root ganglion of fetal rats and slot blot. Genetic engineering hNSCs were successfully constructed. All of the genetic engineering hNSCs which expressed bright green fluorescence were observed under the fluorescence microscope. The conditioned medium of transgenic hNSCs could induce neurite flourishing outgrowth from dorsal root ganglion (DRG). The genetic engineering hNSCs expressed high level NT-3 which could be detected by using slot blot. Genetic engineering hNSCs mediated by lentivirus can be constructed to express multigene successfully.

  9. Distributed Neural Plasticity for Shape Learning in the Human Visual Cortex

    Science.gov (United States)

    Betts, Lisa R; Sarkheil, Pegah; Welchman, Andrew E

    2005-01-01

    Expertise in recognizing objects in cluttered scenes is a critical skill for our interactions in complex environments and is thought to develop with learning. However, the neural implementation of object learning across stages of visual analysis in the human brain remains largely unknown. Using combined psychophysics and functional magnetic resonance imaging (fMRI), we show a link between shape-specific learning in cluttered scenes and distributed neuronal plasticity in the human visual cortex. We report stronger fMRI responses for trained than untrained shapes across early and higher visual areas when observers learned to detect low-salience shapes in noisy backgrounds. However, training with high-salience pop-out targets resulted in lower fMRI responses for trained than untrained shapes in higher occipitotemporal areas. These findings suggest that learning of camouflaged shapes is mediated by increasing neural sensitivity across visual areas to bolster target segmentation and feature integration. In contrast, learning of prominent pop-out shapes is mediated by associations at higher occipitotemporal areas that support sparser coding of the critical features for target recognition. We propose that the human brain learns novel objects in complex scenes by reorganizing shape processing across visual areas, while taking advantage of natural image correlations that determine the distinctiveness of target shapes. PMID:15934786

  10. Direct Neural Conversion from Human Fibroblasts Using Self-Regulating and Nonintegrating Viral Vectors

    Directory of Open Access Journals (Sweden)

    Shong Lau

    2014-12-01

    Full Text Available Recent findings show that human fibroblasts can be directly programmed into functional neurons without passing via a proliferative stem cell intermediate. These findings open up the possibility of generating subtype-specific neurons of human origin for therapeutic use from fetal cell, from patients themselves, or from matched donors. In this study, we present an improved system for direct neural conversion of human fibroblasts. The neural reprogramming genes are regulated by the neuron-specific microRNA, miR-124, such that each cell turns off expression of the reprogramming genes once the cell has reached a stable neuronal fate. The regulated system can be combined with integrase-deficient vectors, providing a nonintegrative and self-regulated conversion system that rids problems associated with the integration of viral transgenes into the host genome. These modifications make the system suitable for clinical use and therefore represent a major step forward in the development of induced neurons for cell therapy.

  11. Integrating verbal and nonverbal communication in a dynamic neural field architecture for human-robot interaction

    Directory of Open Access Journals (Sweden)

    Estela Bicho

    2010-05-01

    Full Text Available How do humans coordinate their intentions, goals and motor behaviors when performing joint action tasks? Recent experimental evidence suggests that resonance processes in the observer's motor system are crucially involved in our ability to understand actions of others', to infer their goals and even to comprehend their action-related language. In this paper, we present a control architecture for human-robot collaboration that exploits this close perception-action linkage as a means to achieve more natural and efficient communication grounded in sensorimotor experiences. The architecture is formalized by a coupled system of dynamic neural fields representing a distributed network of neural populations that encode in their activation patterns goals, actions and shared task knowledge. We validate the verbal and non-verbal communication skills of the robot in a joint assembly task in which the human-robot team has to construct toy objects from their components. The experiments focus on the robot’s capacity to anticipate the user’s needs and to detect and communicate unexpected events that may occur during joint task execution.

  12. Expression of nestin by neural cells in the adult rat and human brain.

    Science.gov (United States)

    Hendrickson, Michael L; Rao, Abigail J; Demerdash, Omar N A; Kalil, Ronald E

    2011-04-07

    Neurons and glial cells in the developing brain arise from neural progenitor cells (NPCs). Nestin, an intermediate filament protein, is thought to be expressed exclusively by NPCs in the normal brain, and is replaced by the expression of proteins specific for neurons or glia in differentiated cells. Nestin expressing NPCs are found in the adult brain in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus. While significant attention has been paid to studying NPCs in the SVZ and SGZ in the adult brain, relatively little attention has been paid to determining whether nestin-expressing neural cells (NECs) exist outside of the SVZ and SGZ. We therefore stained sections immunocytochemically from the adult rat and human brain for NECs, observed four distinct classes of these cells, and present here the first comprehensive report on these cells. Class I cells are among the smallest neural cells in the brain and are widely distributed. Class II cells are located in the walls of the aqueduct and third ventricle. Class IV cells are found throughout the forebrain and typically reside immediately adjacent to a neuron. Class III cells are observed only in the basal forebrain and closely related areas such as the hippocampus and corpus striatum. Class III cells resemble neurons structurally and co-express markers associated exclusively with neurons. Cell proliferation experiments demonstrate that Class III cells are not recently born. Instead, these cells appear to be mature neurons in the adult brain that express nestin. Neurons that express nestin are not supposed to exist in the brain at any stage of development. That these unique neurons are found only in brain regions involved in higher order cognitive function suggests that they may be remodeling their cytoskeleton in supporting the neural plasticity required for these functions.

  13. Extensive neuronal differentiation of human neural stem cell grafts in adult rat spinal cord.

    Directory of Open Access Journals (Sweden)

    Jun Yan

    2007-02-01

    Full Text Available Effective treatments for degenerative and traumatic diseases of the nervous system are not currently available. The support or replacement of injured neurons with neural grafts, already an established approach in experimental therapeutics, has been recently invigorated with the addition of neural and embryonic stem-derived precursors as inexhaustible, self-propagating alternatives to fetal tissues. The adult spinal cord, i.e., the site of common devastating injuries and motor neuron disease, has been an especially challenging target for stem cell therapies. In most cases, neural stem cell (NSC transplants have shown either poor differentiation or a preferential choice of glial lineages.In the present investigation, we grafted NSCs from human fetal spinal cord grown in monolayer into the lumbar cord of normal or injured adult nude rats and observed large-scale differentiation of these cells into neurons that formed axons and synapses and established extensive contacts with host motor neurons. Spinal cord microenvironment appeared to influence fate choice, with centrally located cells taking on a predominant neuronal path, and cells located under the pia membrane persisting as NSCs or presenting with astrocytic phenotypes. Slightly fewer than one-tenth of grafted neurons differentiated into oligodendrocytes. The presence of lesions increased the frequency of astrocytic phenotypes in the white matter.NSC grafts can show substantial neuronal differentiation in the normal and injured adult spinal cord with good potential of integration into host neural circuits. In view of recent similar findings from other laboratories, the extent of neuronal differentiation observed here disputes the notion of a spinal cord that is constitutively unfavorable to neuronal repair. Restoration of spinal cord circuitry in traumatic and degenerative diseases may be more realistic than previously thought, although major challenges remain, especially with respect to the

  14. Three dimensional cellular microarray platform for human neural stem cell differentiation and toxicology

    Directory of Open Access Journals (Sweden)

    Luciana Meli

    2014-07-01

    Full Text Available We developed a three-dimensional (3D cellular microarray platform for the high-throughput (HT analysis of human neural stem cell (hNSC growth and differentiation. The growth of an immortalized hNSC line, ReNcell VM, was evaluated on a miniaturized cell culture chip consisting of 60 nl spots of cells encapsulated in alginate, and compared to standard 2D well plate culture conditions. Using a live/dead cell viability assay, we demonstrated that the hNSCs are able to expand on-chip, albeit with lower proliferation rates and viabilities than in conventional 2D culture platforms. Using an in-cell, on-chip immunofluorescence assay, which provides quantitative information on cellular levels of proteins involved in neural fate, we demonstrated that ReNcell VM can preserve its multipotent state during on-chip expansion. Moreover, differentiation of the hNSCs into glial progeny was achieved both off- and on-chip six days after growth factor removal, accompanied by a decrease in the neural progenitor markers. The versatility of the platform was further demonstrated by complementing the cell culture chip with a chamber system that allowed us to screen for differential toxicity of small molecules to hNSCs. Using this approach, we showed differential toxicity when evaluating three neurotoxic compounds and one antiproliferative compound, and the null effect of a non-toxic compound at relevant concentrations. Thus, our 3D high-throughput microarray platform may help predict, in vitro, which compounds pose an increased threat to neural development and should therefore be prioritized for further screening and evaluation.

  15. Glycogen synthase kinase-3beta regulates differentiation-induced apoptosis of human neural progenitor cells.

    Science.gov (United States)

    Jaeger, Alexandra; Baake, Jana; Weiss, Dieter G; Kriehuber, Ralf

    2013-02-01

    Glycogen synthase kinase-3beta is a multifunctional key regulator enzyme in neural developmental processes and a main component of the canonical Wnt signaling pathway. It is already known that the Wnt-driven differentiation of neural progenitor cells is accompanied by an increase of apoptosis at which the pro-apoptotic function of GSK-3beta is still discussed. The aim of the present study was to investigate whether the phosphorylation level of GSK-3beta at serine 9 is the primary regulatory mechanism of differentiation-induced apoptosis. Differentiating human neural ReNcell VM progenitor cells were treated with the specific GSK-3beta inhibitor SB216763 (10 μM) and analyzed in respect to the intrinsic apoptosis pathway regulation using microscopy and protein expression analysis. Differentiation of ReNcell VM cells was accompanied by cell morphological changes, cytoskeleton rearrangement and apoptosis increase. Treatment of differentiating cells with SB216763 induced a significant dephosphorylation of GSK-3beta at serine 9 accompanied by a significant decrease of apoptosis of about 0.7±0.03% and reduced activation of caspase-3 as well as BAX and PARP cleavage during the first 12h of differentiation compared to untreated, differentiating cells. Dephosphorylation of GSK-3beta at serine 9 appears not solely to be responsible for its pro-apoptotic function, because we observed a decrease of intrinsic apoptosis after treatment of the cells with the specific GSK-3beta inhibitor SB216763. We assume that GSK-3beta drives neural progenitor cell apoptosis by direct interaction with pro-apoptotic BAX or by indirect influence on the canonical Wnt/beta-catenin target gene transcription. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

  16. Three dimensional cellular microarray platform for human neural stem cell differentiation and toxicology.

    Science.gov (United States)

    Meli, Luciana; Barbosa, Hélder S C; Hickey, Anne Marie; Gasimli, Leyla; Nierode, Gregory; Diogo, Maria Margarida; Linhardt, Robert J; Cabral, Joaquim M S; Dordick, Jonathan S

    2014-07-01

    We developed a three-dimensional (3D) cellular microarray platform for the high-throughput (HT) analysis of human neural stem cell (hNSC) growth and differentiation. The growth of an immortalized hNSC line, ReNcell VM, was evaluated on a miniaturized cell culture chip consisting of 60nl spots of cells encapsulated in alginate, and compared to standard 2D well plate culture conditions. Using a live/dead cell viability assay, we demonstrated that the hNSCs are able to expand on-chip, albeit with lower proliferation rates and viabilities than in conventional 2D culture platforms. Using an in-cell, on-chip immunofluorescence assay, which provides quantitative information on cellular levels of proteins involved in neural fate, we demonstrated that ReNcell VM can preserve its multipotent state during on-chip expansion. Moreover, differentiation of the hNSCs into glial progeny was achieved both off- and on-chip six days after growth factor removal, accompanied by a decrease in the neural progenitor markers. The versatility of the platform was further demonstrated by complementing the cell culture chip with a chamber system that allowed us to screen for differential toxicity of small molecules to hNSCs. Using this approach, we showed differential toxicity when evaluating three neurotoxic compounds and one antiproliferative compound, and the null effect of a non-toxic compound at relevant concentrations. Thus, our 3D high-throughput microarray platform may help predict, in vitro, which compounds pose an increased threat to neural development and should therefore be prioritized for further screening and evaluation. Copyright © 2014. Published by Elsevier B.V.

  17. An "as soon as possible" effect in human intertemporal decision making: behavioral evidence and neural mechanisms.

    Science.gov (United States)

    Kable, Joseph W; Glimcher, Paul W

    2010-05-01

    Many decisions involve a trade-off between the quality of an outcome and the time at which that outcome is received. In psychology and behavioral economics, the most widely studied models hypothesize that the values of future gains decline as a roughly hyperbolic function of delay from the present. Recently, it has been proposed that this hyperbolic-like decline in value arises from the interaction of two separate neural systems: one specialized to value immediate rewards and the other specialized to value delayed rewards. Here we report behavioral and functional magnetic resonance imaging results that are inconsistent with both the standard behavioral models of discounting and the hypothesis that separate neural systems value immediate and delayed rewards. Behaviorally, we find that human subjects do not necessarily make the impulsive preference reversals predicted by hyperbolic-like discounting. We also find that blood oxygenation level dependent activity in ventral striatum, medial prefrontal, and posterior cingulate cortex does not track whether an immediate reward was present, as proposed by the separate neural systems hypothesis. Activity in these regions was correlated with the subjective value of both immediate and delayed rewards. Rather than encoding only the relative value of one reward compared with another, these values are represented on a more absolute scale. These data support an alternative behavioral-neural model (which we call "ASAP"), in which subjective value declines hyperbolically relative to the soonest currently available reward and a small number of valuation areas serve as a final common pathway through which these subjective values guide choice.

  18. BrainCrafter: An investigation into human-based neural network engineering

    DEFF Research Database (Denmark)

    Piskur, J.; Greve, P.; Togelius, J.

    2015-01-01

    This paper presents the online application Brain-Crafter, in which users can manually build artificial neural networks (ANNs) to control a robot in a maze environment. Users can either start to construct networks from scratch or elaborate on networks created by other users. In particular, Brain......Crafter was designed to study how good we as humans are at building ANNs for control problems and if collaborating with other users can facilitate this process. The results in this paper show that (1) some users were in fact able to successfully construct ANNs that solve the navigation tasks, (2) collaboration between...

  19. Three dimensional cellular microarray platform for human neural stem cell differentiation and toxicology

    OpenAIRE

    Luciana Meli; Hélder S.C. Barbosa; Anne Marie Hickey; Leyla Gasimli; Gregory Nierode; Maria Margarida Diogo; Linhardt, Robert J.; Joaquim M S Cabral; Dordick, Jonathan S.

    2014-01-01

    We developed a three-dimensional (3D) cellular microarray platform for the high-throughput (HT) analysis of human neural stem cell (hNSC) growth and differentiation. The growth of an immortalized hNSC line, ReNcell VM, was evaluated on a miniaturized cell culture chip consisting of 60 nl spots of cells encapsulated in alginate, and compared to standard 2D well plate culture conditions. Using a live/dead cell viability assay, we demonstrated that the hNSCs are able to expand on-chip, albeit wi...

  20. Three Dimensional Cellular Microarray Platform for Human Neural Stem Cell Differentiation and Toxicology

    OpenAIRE

    Meli, Luciana; Hélder S.C. Barbosa; Hickey, Anne Marie; Gasimli, Leyla; Nierode, Gregory; Diogo, Maria Margarida; Linhardt, Robert J.; Joaquim M S Cabral; Dordick, Jonathan S.

    2014-01-01

    We developed a three-dimensional (3D) cellular microarray platform for the high-throughput (HT) analysis of human neural stem cell (hNSC) growth and differentiation. The growth of an immortalized hNSC line, ReNcell VM, was evaluated on a miniaturized cell culture chip consisting of 60 nl spots of cells encapsulated in alginate, and compared to standard 2D well plate culture conditions. Using a live/dead cell viability assay, we demonstrated that the hNSCs are able to expand on-chip, albeit wi...

  1. Using convolutional neural networks for human activity classification on micro-Doppler radar spectrograms

    Science.gov (United States)

    Jordan, Tyler S.

    2016-05-01

    This paper presents the findings of using convolutional neural networks (CNNs) to classify human activity from micro-Doppler features. An emphasis on activities involving potential security threats such as holding a gun are explored. An automotive 24 GHz radar on chip was used to collect the data and a CNN (normally applied to image classification) was trained on the resulting spectrograms. The CNN achieves an error rate of 1.65 % on classifying running vs. walking, 17.3 % error on armed walking vs. unarmed walking, and 22 % on classifying six different actions.

  2. Xenotransplantation of human neural progenitor cells to the subretinal space of nonimmunosuppressed pigs

    DEFF Research Database (Denmark)

    Warfvinge, Karin; Schwartz, Philip H; Kiilgaard, Jens Folke

    2011-01-01

    To investigate the feasibility of transplanting human neural progenitor cells (hNPCs) to the retina of nonimmunosuppressed pigs, cultured hNPCs were injected into the subretinal space of 5 adult pigs after laser burns were applied to promote donor cell integration. Postoperatively, the retinal......-specific antibodies revealed donor cells in the subretinal space at 10-13 days and smaller numbers within the retina on days 12 and 13, with evidence suggesting a limited degree of morphological integration; however, no cells remained at 4 weeks. The strong mononuclear cell reaction and loss of donor cells indicate...

  3. Identification and classification of human neural stem cells by infrared spectroscopic imaging

    Science.gov (United States)

    Steiner, G.; Küchler, S.; Koch, E.; Salzer, R.; Schackert, G.; Kirsch, M.

    2009-02-01

    Human neural stem were cultivated and characterized using infrared spectroscopic imaging. A classification algorithm based on linear discriminate analysis was developed to distinguish the differentiation of the stem cells to neurons, astrocytes and stem cells without labeling. The classification is based upon spectral features which mainly arise from proteins, nucleic acids. A spectral training set was formed with spectra from cells which were identified by a subsequently staining according to a standard histological protocol. Differentiated cells could be classified with a high accuracy whereas not differentiated stem cells did exhibit some misclassifications

  4. Convolutional neural networks for segmentation and object detection of human semen

    DEFF Research Database (Denmark)

    Nissen, Malte Stær; Krause, Oswin; Almstrup, Kristian

    2017-01-01

    We compare a set of convolutional neural network (CNN) architectures for the task of segmenting and detecting human sperm cells in an image taken from a semen sample. In contrast to previous work, samples are not stained or washed to allow for full sperm quality analysis, making analysis harder due...... are found by using connected components on the CNN predictions. We investigate optimization of a threshold parameter on the size of detected components. Our best network achieves 93.87% precision and 91.89% recall on our test dataset after thresholding outperforming a classical image analysis approach....

  5. Mathematical Modeling and Evaluation of Human Motions in Physical Therapy Using Mixture Density Neural Networks

    Science.gov (United States)

    Vakanski, A; Ferguson, JM; Lee, S

    2016-01-01

    Objective The objective of the proposed research is to develop a methodology for modeling and evaluation of human motions, which will potentially benefit patients undertaking a physical rehabilitation therapy (e.g., following a stroke or due to other medical conditions). The ultimate aim is to allow patients to perform home-based rehabilitation exercises using a sensory system for capturing the motions, where an algorithm will retrieve the trajectories of a patient’s exercises, will perform data analysis by comparing the performed motions to a reference model of prescribed motions, and will send the analysis results to the patient’s physician with recommendations for improvement. Methods The modeling approach employs an artificial neural network, consisting of layers of recurrent neuron units and layers of neuron units for estimating a mixture density function over the spatio-temporal dependencies within the human motion sequences. Input data are sequences of motions related to a prescribed exercise by a physiotherapist to a patient, and recorded with a motion capture system. An autoencoder subnet is employed for reducing the dimensionality of captured sequences of human motions, complemented with a mixture density subnet for probabilistic modeling of the motion data using a mixture of Gaussian distributions. Results The proposed neural network architecture produced a model for sets of human motions represented with a mixture of Gaussian density functions. The mean log-likelihood of observed sequences was employed as a performance metric in evaluating the consistency of a subject’s performance relative to the reference dataset of motions. A publically available dataset of human motions captured with Microsoft Kinect was used for validation of the proposed method. Conclusion The article presents a novel approach for modeling and evaluation of human motions with a potential application in home-based physical therapy and rehabilitation. The described approach

  6. Mathematical Modeling and Evaluation of Human Motions in Physical Therapy Using Mixture Density Neural Networks.

    Science.gov (United States)

    Vakanski, A; Ferguson, J M; Lee, S

    2016-12-01

    The objective of the proposed research is to develop a methodology for modeling and evaluation of human motions, which will potentially benefit patients undertaking a physical rehabilitation therapy (e.g., following a stroke or due to other medical conditions). The ultimate aim is to allow patients to perform home-based rehabilitation exercises using a sensory system for capturing the motions, where an algorithm will retrieve the trajectories of a patient's exercises, will perform data analysis by comparing the performed motions to a reference model of prescribed motions, and will send the analysis results to the patient's physician with recommendations for improvement. The modeling approach employs an artificial neural network, consisting of layers of recurrent neuron units and layers of neuron units for estimating a mixture density function over the spatio-temporal dependencies within the human motion sequences. Input data are sequences of motions related to a prescribed exercise by a physiotherapist to a patient, and recorded with a motion capture system. An autoencoder subnet is employed for reducing the dimensionality of captured sequences of human motions, complemented with a mixture density subnet for probabilistic modeling of the motion data using a mixture of Gaussian distributions. The proposed neural network architecture produced a model for sets of human motions represented with a mixture of Gaussian density functions. The mean log-likelihood of observed sequences was employed as a performance metric in evaluating the consistency of a subject's performance relative to the reference dataset of motions. A publically available dataset of human motions captured with Microsoft Kinect was used for validation of the proposed method. The article presents a novel approach for modeling and evaluation of human motions with a potential application in home-based physical therapy and rehabilitation. The described approach employs the recent progress in the field of

  7. Classification of human activity on water through micro-Dopplers using deep convolutional neural networks

    Science.gov (United States)

    Kim, Youngwook; Moon, Taesup

    2016-05-01

    Detecting humans and classifying their activities on the water has significant applications for surveillance, border patrols, and rescue operations. When humans are illuminated by radar signal, they produce micro-Doppler signatures due to moving limbs. There has been a number of research into recognizing humans on land by their unique micro-Doppler signatures, but there is scant research into detecting humans on water. In this study, we investigate the micro-Doppler signatures of humans on water, including a swimming person, a swimming person pulling a floating object, and a rowing person in a small boat. The measured swimming styles were free stroke, backstroke, and breaststroke. Each activity was observed to have a unique micro-Doppler signature. Human activities were classified based on their micro-Doppler signatures. For the classification, we propose to apply deep convolutional neural networks (DCNN), a powerful deep learning technique. Rather than using conventional supervised learning that relies on handcrafted features, we present an alternative deep learning approach. We apply the DCNN, one of the most successful deep learning algorithms for image recognition, directly to a raw micro-Doppler spectrogram of humans on the water. Without extracting any explicit features from the micro-Dopplers, the DCNN can learn the necessary features and build classification boundaries using the training data. We show that the DCNN can achieve accuracy of more than 87.8% for activity classification using 5- fold cross validation.

  8. Perceptual and neural responses to sweet taste in humans and rodents.

    Science.gov (United States)

    Lemon, Christian H

    2015-08-01

    This mini-review discusses some of the parallels between rodent neurophysiological and human psychophysical data concerning temperature effects on sweet taste. "Sweet" is an innately rewarding taste sensation that is associated in part with foods that contain calories in the form of sugars. Humans and other mammals can show unconditioned preference for select sweet stimuli. Such preference is poised to influence diet selection and, in turn, nutritional status, which underscores the importance of delineating the physiological mechanisms for sweet taste with respect to their influence on human health. Advances in our knowledge of the biology of sweet taste in humans have arisen in part through studies on mechanisms of gustatory processing in rodent models. Along this line, recent work has revealed there are operational parallels in neural systems for sweet taste between mice and humans, as indexed by similarities in the effects of temperature on central neurophysiological and psychophysical responses to sucrose in these species. Such association strengthens the postulate that rodents can serve as effective models of particular mechanisms of appetitive taste processing. Data supporting this link are discussed here, as are rodent and human data that shed light on relationships between mechanisms for sweet taste and ingestive disorders, such as alcohol abuse. Rodent models have utility for understanding mechanisms of taste processing that may pertain to human flavor perception. Importantly, there are limitations to generalizing data from rodents, albeit parallels across species do exist.

  9. Scaling up a chemically-defined aggregate-based suspension culture system for neural commitment of human pluripotent stem cells.

    Science.gov (United States)

    Miranda, Cláudia C; Fernandes, Tiago G; Diogo, M Margarida; Cabral, Joaquim M S

    2016-12-01

    The demand of high cell numbers for applications in cellular therapies and drug screening requires the development of scalable platforms capable to generating highly pure populations of tissue-specific cells from human pluripotent stem cells. In this work, we describe the scaling-up of an aggregate-based culture system for neural induction of human induced pluripotent stem cells (hiPSCs) under chemically-defined conditions. A combination of non-enzymatic dissociation and rotary agitation was successfully used to produce homogeneous populations of hiPSC aggregates with an optimal (140 μm) and narrow distribution of diameters (coefficient of variation of 21.6%). Scalable neural commitment of hiPSCs as 3D aggregates was performed in 50 mL spinner flasks, and the process was optimized using a factorial design approach, involving parameters such as agitation rate and seeding density. We were able to produce neural progenitor cell cultures, that at the end of a 6-day neural induction process contained less than 3% of Oct4-positive cells and that, after replating, retained more than 60% of Pax6-positive neural cells. The results here presented should set the stage for the future generation of a clinically relevant number of human neural progenitors for transplantation and other biomedical applications using controlled, automated and reproducible large-scale bioreactor culture systems. Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice

    DEFF Research Database (Denmark)

    Wang, Yaoming; Zhao, Zhen; Rege, Sanket V

    2016-01-01

    profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate-receptor 1-Akt pathway, which suggests...

  11. Intermittent, low dose carbon monoxide exposure enhances survival and dopaminergic differentiation of human neural stem cells

    Science.gov (United States)

    Dreyer-Andersen, Nanna; Almeida, Ana Sofia; Jensen, Pia; Kamand, Morad; Okarmus, Justyna; Rosenberg, Tine; Friis, Stig Düring; Martínez Serrano, Alberto; Blaabjerg, Morten; Kristensen, Bjarne Winther; Skrydstrup, Troels; Gramsbergen, Jan Bert; Vieira, Helena L. A.

    2018-01-01

    Exploratory studies using human fetal tissue have suggested that intrastriatal transplantation of dopaminergic neurons may become a future treatment for patients with Parkinson’s disease. However, the use of human fetal tissue is compromised by ethical, regulatory and practical concerns. Human stem cells constitute an alternative source of cells for transplantation in Parkinson’s disease, but efficient protocols for controlled dopaminergic differentiation need to be developed. Short-term, low-level carbon monoxide (CO) exposure has been shown to affect signaling in several tissues, resulting in both protection and generation of reactive oxygen species. The present study investigated the effect of CO produced by a novel CO-releasing molecule on dopaminergic differentiation of human neural stem cells. Short-term exposure to 25 ppm CO at days 0 and 4 significantly increased the relative content of β-tubulin III-immunoreactive immature neurons and tyrosine hydroxylase expressing catecholaminergic neurons, as assessed 6 days after differentiation. Also the number of microtubule associated protein 2-positive mature neurons had increased significantly. Moreover, the content of apoptotic cells (Caspase3) was reduced, whereas the expression of a cell proliferation marker (Ki67) was left unchanged. Increased expression of hypoxia inducible factor-1α and production of reactive oxygen species (ROS) in cultures exposed to CO may suggest a mechanism involving mitochondrial alterations and generation of ROS. In conclusion, the present procedure using controlled, short-term CO exposure allows efficient dopaminergic differentiation of human neural stem cells at low cost and may as such be useful for derivation of cells for experimental studies and future development of donor cells for transplantation in Parkinson’s disease. PMID:29338033

  12. Classification of Human Emotion from Deap EEG Signal Using Hybrid Improved Neural Networks with Cuckoo Search

    Directory of Open Access Journals (Sweden)

    M. Sreeshakthy

    2016-01-01

    Full Text Available Department of Computer Science and Engineering,Anna University Regional Centre, Coimbatore, Indiam.sribtechit@gmail.comJ. PreethiDepartment of Computer Science and EngineeringAnna University Regional Centre, Coimbatore, Indiapreethi17j@yahoo.comEmotions are very important in human decision handling, interaction and cognitive process. In this paper describes that recognize the human emotions from DEAP EEG dataset with different kind of methods. Audio – video based stimuli is used to extract the emotions. EEG signal is divided into different bands using discrete wavelet transformation with db8 wavelet function for further process. Statistical and energy based features are extracted from the bands, based on the features emotions are classified with feed forward neural network with weight optimized algorithm like PSO. Before that the particular band has to be selected based on the training performance of neural networks and then the emotions are classified. In this experimental result describes that the gamma and alpha bands are provides the accurate classification result with average classification rate of 90.3% of using NNRBF, 90.325% of using PNN, 96.3% of using PSO trained NN, 98.1 of using Cuckoo trained NN. At last the emotions are classified into two different groups like valence and arousal. Based on that identifies the person normal and abnormal behavioral using classified emotion.

  13. A Method for Assessing the Retention of Trace Elements in Human Body Using Neural Network Technology.

    Science.gov (United States)

    Tunakova, Yulia; Novikova, Svetlana; Ragimov, Aligejdar; Faizullin, Rashat; Valiev, Vsevolod

    2017-01-01

    Models that describe the trace element status formation in the human organism are essential for a correction of micromineral (trace elements) deficiency. A direct trace element retention assessment in the body is difficult due to the many internal mechanisms. The trace element retention is determined by the amount and the ratio of incoming and excreted substance. So, the concentration of trace elements in drinking water characterizes the intake, whereas the element concentration in urine characterizes the excretion. This system can be interpreted as three interrelated elements that are in equilibrium. Since many relationships in the system are not known, the use of standard mathematical models is difficult. The artificial neural network use is suitable for constructing a model in the best way because it can take into account all dependencies in the system implicitly and process inaccurate and incomplete data. We created several neural network models to describe the retentions of trace elements in the human body. On the model basis, we can calculate the microelement levels in the body, knowing the trace element levels in drinking water and urine. These results can be used in health care to provide the population with safe drinking water.

  14. Unsupervised decoding of long-term, naturalistic human neural recordings with automated video and audio annotations

    Directory of Open Access Journals (Sweden)

    Nancy X.R. Wang

    2016-04-01

    Full Text Available Fully automated decoding of human activities and intentions from direct neural recordings is a tantalizing challenge in brain-computer interfacing. Implementing Brain Computer Interfaces (BCIs outside carefully controlled experiments in laboratory settings requires adaptive and scalable strategies with minimal supervision. Here we describe an unsupervised approach to decoding neural states from naturalistic human brain recordings. We analyzed continuous, long-term electrocorticography (ECoG data recorded over many days from the brain of subjects in a hospital room, with simultaneous audio and video recordings. We discovered coherent clusters in high-dimensional ECoG recordings using hierarchical clustering and automatically annotated them using speech and movement labels extracted from audio and video. To our knowledge, this represents the first time techniques from computer vision and speech processing have been used for natural ECoG decoding. Interpretable behaviors were decoded from ECoG data, including moving, speaking and resting; the results were assessed by comparison with manual annotation. Discovered clusters were projected back onto the brain revealing features consistent with known functional areas, opening the door to automated functional brain mapping in natural settings.

  15. Neural Correlates of Visual Spatial Attention in Electrocorticographic (ECoG Signals in Humans

    Directory of Open Access Journals (Sweden)

    Aysegul eGunduz

    2011-09-01

    Full Text Available Attention is a cognitive selection mechanism that allocates the limited processing resources of the brain to the sensory streams most relevant to our immediate goals, thereby enhancing responsiveness and behavioral performance. The underlying neural mechanisms of orienting attention are distributedacross a widespread cortical network. While aspects of this network have been extensively studied, details about the electrophysiological dynamics of this network are scarce. In this study, we investigated attentional networks using electrocorticographic (ECoG recordings from the surface ofthe brain, which combine broad spatial coverage with high temporal resolution, in five human subjects. ECoG was recorded when subjects covertly attended to a spatial location and responded to contrast changes in the presence of distractors in a modified Posner cueing task. ECoG amplitudes in the alpha, beta and gamma bands identified neural changes associated with covert attention and motor preparation/execution in the different stages of the task. The results show that attentional engagement was primarily associated with ECoG activity in the visual, prefrontal, premotor, and parietal cortices. Motor preparation/execution was associated with ECoG activity in premotor/sensorimotor cortices. In summary, our results illustrate rich and distributed cortical dynamics that are associated with orienting attention and the subsequent motor preparation and execution. These findings are largely consistent with and expand on primate studies using intracortical recordings and human functional neuroimaging studies.

  16. Slow moving neural source in the epileptic hippocampus can mimic progression of human seizures.

    Science.gov (United States)

    Chiang, Chia-Chu; Wei, Xile; Ananthakrishnan, Arvind Keshav; Shivacharan, Rajat S; Gonzalez-Reyes, Luis E; Zhang, Mingming; Durand, Dominique M

    2018-01-24

    Fast and slow neural waves have been observed to propagate in the human brain during seizures. Yet the nature of these waves is difficult to study in a surgical setting. Here, we report an observation of two different traveling waves propagating in the in-vitro epileptic hippocampus at speeds similar to those in the human brain. A fast traveling spike and a slow moving wave were recorded simultaneously with a genetically encoded voltage sensitive fluorescent protein (VSFP Butterfly 1.2) and a high speed camera. The results of this study indicate that the fast traveling spike is NMDA-sensitive but the slow moving wave is not. Image analysis and model simulation demonstrate that the slow moving wave is moving slowly, generating the fast traveling spike and is, therefore, a moving source of the epileptiform activity. This slow moving wave is associated with a propagating neural calcium wave detected with calcium dye (OGB-1) but is independent of NMDA receptors, not related to ATP release, and much faster than those previously recorded potassium waves. Computer modeling suggests that the slow moving wave can propagate by the ephaptic effect like epileptiform activity. These findings provide an alternative explanation for slow propagation seizure wavefronts associated with fast propagating spikes.

  17. Inverted Encoding Models of Human Population Response Conflate Noise and Neural Tuning Width.

    Science.gov (United States)

    Liu, Taosheng; Cable, Dylan; Gardner, Justin L

    2018-01-10

    Channel-encoding models offer the ability to bridge different scales of neuronal measurement by interpreting population responses, typically measured with BOLD imaging in humans, as linear sums of groups of neurons (channels) tuned for visual stimulus properties. Inverting these models to form predicted channel responses from population measurements in humans seemingly offers the potential to infer neuronal tuning properties. Here, we test the ability to make inferences about neural tuning width from inverted encoding models. We examined contrast invariance of orientation selectivity in human V1 (both sexes) and found that inverting the encoding model resulted in channel response functions that became broader with lower contrast, thus apparently violating contrast invariance. Simulations showed that this broadening could be explained by contrast-invariant single-unit tuning with the measured decrease in response amplitude at lower contrast. The decrease in response lowers the signal-to-noise ratio of population responses that results in poorer population representation of orientation. Simulations further showed that increasing signal to noise makes channel response functions less sensitive to underlying neural tuning width, and in the limit of zero noise will reconstruct the channel function assumed by the model regardless of the bandwidth of single units. We conclude that our data are consistent with contrast-invariant orientation tuning in human V1. More generally, our results demonstrate that population selectivity measures obtained by encoding models can deviate substantially from the behavior of single units because they conflate neural tuning width and noise and are therefore better used to estimate the uncertainty of decoded stimulus properties.SIGNIFICANCE STATEMENT It is widely recognized that perceptual experience arises from large populations of neurons, rather than a few single units. Yet, much theory and experiment have examined links between single

  18. A hybrid neural network system for prediction and recognition of promoter regions in human genome.

    Science.gov (United States)

    Chen, Chuan-Bo; Li, Tao

    2005-05-01

    This paper proposes a high specificity and sensitivity algorithm called PromPredictor for recognizing promoter regions in the human genome. PromPredictor extracts compositional features and CpG islands information from genomic sequence, feeding these features as input for a hybrid neural network system (HNN) and then applies the HNN for prediction. It combines a novel promoter recognition model, coding theory, feature selection and dimensionality reduction with machine learning algorithm. Evaluation on Human chromosome 22 was approximately 66% in sensitivity and approximately 48% in specificity. Comparison with two other systems revealed that our method had superior sensitivity and specificity in predicting promoter regions. PromPredictor is written in MATLAB and requires Matlab to run. PromPredictor is freely available at http://www.whtelecom.com/Prompredictor.htm.

  19. Neural plasticity and functional recovery of human central nervous system with special reference to spinal cord injury.

    Science.gov (United States)

    Wang, D; Sun, T

    2011-04-01

    Literature review. To study the progress that has been made in neural plasticity for the past few decades. United Kingdom/China. An electronic search of relevant publications through PubMed was conducted using two key words: 'axonal regeneration' and 'neural plasticity'. The search included publications of the past three decades of all languages and of both animal and human studies. After confirmation of immense increase of publications on neural plasticity, reviewing of neural plasticity alone was conducted. The review covered only the most important and clinically relevant publications. For convenience of reading by busy clinicians, discussions focused on cellular and functional levels, and only the most investigated molecules were mentioned. The size of references is also planned to be concise rather than comprehensive into three digits. Neural plasticity is about memory and learning. The entire process of neural plasticity is presented in the sequence of (1) lesion-induced plasticity, (2) clearance of debris, (3) collateral sprouting (4) potentiation. The recent discovery and understanding of the important role of Chondroitinase in clearance of debris is discussed in detail. Neural plasticity has enormous potentials in facilitating functional recovery. It is a realistic target than structural axonal regeneration at current level of neuroscience.

  20. Insights in spatio-temporal characterization of human fetal neural stem cells.

    Science.gov (United States)

    Martín-Ibáñez, Raquel; Guardia, Inés; Pardo, Mónica; Herranz, Cristina; Zietlow, Rike; Vinh, Ngoc-Nga; Rosser, Anne; Canals, Josep M

    2017-05-01

    Primary human fetal cells have been used in clinical trials of cell replacement therapy for the treatment of neurodegenerative disorders such as Huntington's disease (HD). However, human fetal primary cells are scarce and difficult to work with and so a renewable source of cells is sought. Human fetal neural stem cells (hfNSCs) can be generated from human fetal tissue, but little is known about the differences between hfNSCs obtained from different developmental stages and brain areas. In the present work we characterized hfNSCs, grown as neurospheres, obtained from three developmental stages: 4-5, 6-7 and 8-9weeks post conception (wpc) and four brain areas: forebrain, cortex, whole ganglionic eminence (WGE) and cerebellum. We observed that, as fetal brain development proceeds, the number of neural precursors is diminished and post-mitotic cells are increased. In turn, primary cells obtained from older embryos are more sensitive to the dissociation process, their viability is diminished and they present lower proliferation ratios compared to younger embryos. However, independently of the developmental stage of derivation proliferation ratios were very low in all cases. Improvements in the expansion rates were achieved by mechanical, instead of enzymatic, dissociation of neurospheres but not by changes in the seeding densities. Regardless of the developmental stage, neurosphere cultures presented large variability in the viability and proliferation rates during the initial 3-4 passages, but stabilized achieving significant expansion rates at passage 5 to 6. This was true also for all brain regions except cerebellar derived cultures that did not expand. Interestingly, the brain region of hfNSC derivation influences the expansion potential, being forebrain, cortex and WGE derived cells the most expandable compared to cerebellar. Short term expansion partially compromised the regional identity of cortical but not WGE cultures. Nevertheless, both expanded cultures were

  1. Impairment of human neural crest cell migration by prolonged exposure to interferon-beta.

    Science.gov (United States)

    Pallocca, Giorgia; Nyffeler, Johanna; Dolde, Xenia; Grinberg, Marianna; Gstraunthaler, Gerhard; Waldmann, Tanja; Rahnenführer, Jörg; Sachinidis, Agapios; Leist, Marcel

    2017-10-01

    Human cell-based toxicological assays have been used successfully to detect known toxicants, and to distinguish them from negative controls. However, there is at present little experience on how to deal with hits from screens of compounds with yet unknown hazard. As a case study to this issue, we characterized human interferon-beta (IFNβ) as potential developmental toxicant affecting neural crest cells (NCC). The protein was identified as a hit during a screen of clinically used drugs in the 'migration inhibition of neural crest' (MINC) assay. Concentration-response studies in the MINC combined with immunocytochemistry and mRNA quantification of cellular markers showed that IFNβ inhibited NCC migration at concentrations as low as 20 pM. The effective concentrations found here correspond to levels found in human plasma, and they were neither cytostatic nor cytotoxic nor did they did they affect the differentiation state and overall phenotype of NCC. Data from two other migration assays confirmed that picomolar concentration of IFNβ reduced the motility of NCC, while other interferons were less potent. The activation of JAK kinase by IFNβ, as suggested by bioinformatics analysis of the transcriptome changes, was confirmed by biochemical methods. The degree and duration of pathway activation correlated with the extent of migration inhibition, and pharmacological block of this signaling pathway before, or up to 6 h after exposure to the cytokine prevented the effects of IFNβ on migration. Thus, the reduction of vital functions of human NCC is a hitherto unknown potential hazard of endogenous or pharmacologically applied interferons.

  2. Dual origins of measured phase-amplitude coupling reveal distinct neural mechanisms underlying episodic memory in the human cortex.

    Science.gov (United States)

    Vaz, Alex P; Yaffe, Robert B; Wittig, John H; Inati, Sara K; Zaghloul, Kareem A

    2017-03-01

    Phase-amplitude coupling (PAC) is hypothesized to coordinate neural activity, but its role in successful memory formation in the human cortex is unknown. Measures of PAC are difficult to interpret, however. Both increases and decreases in PAC have been linked to memory encoding, and PAC may arise due to different neural mechanisms. Here, we use a waveform analysis to examine PAC in the human cortex as participants with intracranial electrodes performed a paired associates memory task. We found that successful memory formation exhibited significant decreases in left temporal lobe and prefrontal cortical PAC, and these two regions exhibited changes in PAC within different frequency bands. Two underlying neural mechanisms, nested oscillations and sharp waveforms, were responsible for the changes in these regions. Our data therefore suggest that decreases in measured cortical PAC during episodic memory reflect two distinct underlying mechanisms that are anatomically segregated in the human brain. Published by Elsevier Inc.

  3. Prospect of Human Pluripotent Stem Cell-Derived Neural Crest Stem Cells in Clinical Application

    Directory of Open Access Journals (Sweden)

    Qian Zhu

    2016-01-01

    Full Text Available Neural crest stem cells (NCSCs represent a transient and multipotent cell population that contributes to numerous anatomical structures such as peripheral nervous system, teeth, and cornea. NCSC maldevelopment is related to various human diseases including pigmentation abnormalities, disorders affecting autonomic nervous system, and malformations of teeth, eyes, and hearts. As human pluripotent stem cells including human embryonic stem cells (hESCs and human induced pluripotent stem cells (hiPSCs can serve as an unlimited cell source to generate NCSCs, hESC/hiPSC-derived NCSCs can be a valuable tool to study the underlying mechanisms of NCSC-associated diseases, which paves the way for future therapies for these abnormalities. In addition, hESC/hiPSC-derived NCSCs with the capability of differentiating to various cell types are highly promising for clinical organ repair and regeneration. In this review, we first discuss NCSC generation methods from human pluripotent stem cells and differentiation mechanism of NCSCs. Then we focus on the clinical application potential of hESC/hiPSC-derived NCSCs on peripheral nerve injuries, corneal blindness, tooth regeneration, pathological melanogenesis, Hirschsprung disease, and cardiac repair and regeneration.

  4. The influences and neural correlates of past and present during gambling in humans.

    Science.gov (United States)

    Sacré, Pierre; Subramanian, Sandya; Kerr, Matthew S D; Kahn, Kevin; Johnson, Matthew A; Bulacio, Juan; González-Martínez, Jorge A; Sarma, Sridevi V; Gale, John T

    2017-12-07

    During financial decision-making tasks, humans often make "rational" decisions, where they maximize expected reward. However, this rationality may compete with a bias that reflects past outcomes. That is, if one just lost money or won money, this may impact future decisions. It is unclear how past outcomes influence future decisions in humans, and how neural circuits encode present and past information. In this study, six human subjects performed a financial decision-making task while we recorded local field potentials from multiple brain structures. We constructed a model for each subject characterizing bets on each trial as a function of present and past information. The models suggest that some patients are more influenced by previous trial outcomes (i.e., previous return and risk) than others who stick to more fixed decision strategies. In addition, past return and present risk modulated with the activity in the cuneus; while present return and past risk modulated with the activity in the superior temporal gyrus and the angular gyrus, respectively. Our findings suggest that these structures play a role in decision-making beyond their classical functions by incorporating predictions and risks in humans' decision strategy, and provide new insight into how humans link their internal biases to decisions.

  5. γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation

    OpenAIRE

    D’Avanzo, Carla; Sliwinski, Christopher; Wagner, Steven L.; Tanzi, Rudolph E.; Kim, Doo Yeon; Kovacs, Dora M.

    2015-01-01

    Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ42). However, their effect on the physiologic functions of γ-secretase has not been tested in human model systems. γ-Secretase regulates fate determination of neural progenitor cells. Thus, we studied the impact of SGSMs on the neuronal differentiation of ReNcell VM (ReN) human neural progenitor cells (hNPCs). Quantitative PCR analysis showed that treatment of neurosphere-like ReN cell aggregate cultu...

  6. 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.

  7. STAT3 modulation to enhance motor neuron differentiation in human neural stem cells.

    Directory of Open Access Journals (Sweden)

    Rajalaxmi Natarajan

    Full Text Available Spinal cord injury or amyotrophic lateral sclerosis damages spinal motor neurons and forms a glial scar, which prevents neural regeneration. Signal transducer and activator of transcription 3 (STAT3 plays a critical role in astrogliogenesis and scar formation, and thus a fine modulation of STAT3 signaling may help to control the excessive gliogenic environment and enhance neural repair. The objective of this study was to determine the effect of STAT3 inhibition on human neural stem cells (hNSCs. In vitro hNSCs primed with fibroblast growth factor 2 (FGF2 exhibited a lower level of phosphorylated STAT3 than cells primed by epidermal growth factor (EGF, which correlated with a higher number of motor neurons differentiated from FGF2-primed hNSCs. Treatment with STAT3 inhibitors, Stattic and Niclosamide, enhanced motor neuron differentiation only in FGF2-primed hNSCs, as shown by increased homeobox gene Hb9 mRNA levels as well as HB9+ and microtubule-associated protein 2 (MAP2+ co-labeled cells. The increased motor neuron differentiation was accompanied by a decrease in the number of glial fibrillary acidic protein (GFAP-positive astrocytes. Interestingly, Stattic and Niclosamide did not affect the level of STAT3 phosphorylation; rather, they perturbed the nuclear translocation of phosphorylated STAT3. In summary, we demonstrate that FGF2 is required for motor neuron differentiation from hNSCs and that inhibition of STAT3 further increases motor neuron differentiation at the expense of astrogliogenesis. Our study thus suggests a potential benefit of targeting the STAT3 pathway for neurotrauma or neurodegenerative diseases.

  8. Local versus distal transplantation of human neural stem cells following chronic spinal cord injury.

    Science.gov (United States)

    Cheng, Ivan; Githens, Michael; Smith, Robert L; Johnston, Tyler R; Park, Don Y; Stauff, Michael P; Salari, Nima; Tileston, Kali R; Kharazi, Alexander I

    2016-06-01

    Previous studies have demonstrated functional recovery of rats with spinal cord contusions after transplantation of neural stem cells adjacent to the site of acute injury. The purpose of the study was to determine if the local or distal injection of neural stem cells can cause functional difference in recovery after chronic spinal cord injury. Twenty-four adult female Long-Evans hooded rats were randomized into four groups, with six animals in each group: two experimental and two control groups. Functional assessment was measured after injury and then weekly for 6 weeks using the Basso, Beattie, and Bresnahan locomotor rating score. Data were analyzed using two-sample t test and linear mixed-effects model analysis. Posterior exposure and laminectomy at the T10 level was used. Moderate spinal cord contusion was induced by the Multicenter Animal Spinal Cord Injury Study Impactor with 10-g weight dropped from a height of 25 mm. Experimental subjects received either a subdural injection of human neural stem cells (hNSCs) locally at the injury site or intrathecal injection of hNSCs through a separate distal laminotomy 4 weeks after injury. Controls received control media injection either locally or distally. A statistically significant functional improvement in subjects that received hNSCs injected distally to the site of injury was observed when compared with the control (p=.042). The difference between subjects that received hNSCs locally and the control did not reach statistical significance (p=.085). The transplantation of hNSCs into the contused spinal cord of a rat led to significant functional recovery of the spinal cord when injected distally but not locally to the site of chronic spinal cord injury. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Δ9-THC Disrupts Gamma (γ)-Band Neural Oscillations in Humans.

    Science.gov (United States)

    Cortes-Briones, Jose; Skosnik, Patrick D; Mathalon, Daniel; Cahill, John; Pittman, Brian; Williams, Ashley; Sewell, R Andrew; Ranganathan, Mohini; Roach, Brian; Ford, Judith; D'Souza, Deepak Cyril

    2015-08-01

    Gamma (γ)-band oscillations play a key role in perception, associative learning, and conscious awareness and have been shown to be disrupted by cannabinoids in animal studies. The goal of this study was to determine whether cannabinoids disrupt γ-oscillations in humans and whether these effects relate to their psychosis-relevant behavioral effects. The acute, dose-related effects of Δ-9-tetrahydrocannabinol (Δ(9)-THC) on the auditory steady-state response (ASSR) were studied in humans (n=20) who completed 3 test days during which they received intravenous Δ(9)-THC (placebo, 0.015, and 0.03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Electroencephalography (EEG) was recorded while subjects listened to auditory click trains presented at 20, 30, and 40 Hz. Psychosis-relevant effects were measured with the Positive and Negative Syndrome scale (PANSS). Δ(9)-THC (0.03 mg/kg) reduced intertrial coherence (ITC) in the 40 Hz condition compared with 0.015 mg/kg and placebo. No significant effects were detected for 30 and 20 Hz stimulation. Furthermore, there was a negative correlation between 40 Hz ITC and PANSS subscales and total scores under the influence of Δ(9)-THC. Δ(9)-THC (0.03 mg/kg) reduced evoked power during 40 Hz stimulation at a trend level. Recent users of cannabis showed blunted Δ(9)-THC effects on ITC and evoked power. We show for the first time in humans that cannabinoids disrupt γ-band neural oscillations. Furthermore, there is a relationship between disruption of γ-band neural oscillations and psychosis-relevant phenomena induced by cannabinoids. These findings add to a growing literature suggesting some overlap between the acute effects of cannabinoids and the behavioral and psychophysiological alterations observed in psychotic disorders.

  10. Identification of Nucleoside Analogs as Inducers of Neuronal Differentiation in a Human Reporter Cell Line and Adult Stem Cells.

    Science.gov (United States)

    Raasch, Katharina; Malecki, Edith; Siemann, Maria; Martinez, Malayko M; Heinisch, Jürgen J; Müller, Janine; Bakota, Lidia; Kaltschmidt, Christian; Kaltschmidt, Barbara; Rosemeyer, Helmut; Brandt, Roland

    2015-08-01

    Nucleoside analogs (NSAs) were among the first chemotherapeutic agents and could also be useful for the manipulation of cell fate. To investigate the potential of NSAs for the induction of neuronal differentiation, we developed a novel phenotypic assay based on a human neuron-committed teratocarcinoma cell line (NT2) as a model for neuronal progenitors and constructed a NT2-based reporter cell line that expressed eGFP under the control of a neuron-specific promoter. We tested 38 structurally related NSAs and determined their activity to induce neuronal differentiation by immunocytochemistry of neuronal marker proteins, live cell imaging, fluorometric detection and immunoblot analysis. We identified twelve NSAs, which induced neuronal differentiation to different extents. NSAs with highest activity carried a halogen substituent at their pyrimidine nucleobase and an unmodified or 2'-O-methyl substituted 2-deoxy-β-D-ribofuranosyl residue as glyconic moiety. Cladribine, a purine nucleoside with similar structural features and in use to treat leukemia and multiple sclerosis, induced also differentiation of adult human neural crest-derived stem cells. Our results suggest that NSAs could be useful for the manipulation of neuronal cell fate in cell replacement therapy or treatment of neurodegenerative disorders. The data on the structure and function relationship will help to design compounds with increased activity and low toxicity. © 2014 John Wiley & Sons A/S.

  11. Human conditionally immortalized neural stem cells improve locomotor function after spinal cord injury in the rat

    Science.gov (United States)

    2013-01-01

    Introduction A growing number of studies have highlighted the potential of stem cell and more-differentiated neural cell transplantation as intriguing therapeutic approaches for neural repair after spinal cord injury (SCI). Methods A conditionally immortalized neural stem cell line derived from human fetal spinal cord tissue (SPC-01) was used to treat a balloon-induced SCI. SPC-01 cells were implanted into the lesion 1 week after SCI. To determine the feasibility of tracking transplanted stem cells, a portion of the SPC-01 cells was labeled with poly-L-lysine-coated superparamagnetic iron-oxide nanoparticles, and the animals grafted with labeled cells underwent magnetic resonance imaging. Functional recovery was evaluated by using the BBB and plantar tests, and lesion morphology, endogenous axonal sprouting and graft survival, and differentiation were analyzed. Quantitative polymerase chain reaction (qPCR) was used to evaluate the effect of transplanted SPC-01 cells on endogenous regenerative processes. Results Transplanted animals displayed significant motor and sensory improvement 2 months after SCI, when the cells robustly survived in the lesion and partially filled the lesion cavity. qPCR revealed the increased expression of rat and human neurotrophin and motor neuron genes. The grafted cells were immunohistologically positive for glial fibrillary acidic protein (GFAP); however, we found 25% of the cells to be positive for Nkx6.1, an early motor neuron marker. Spared white matter and the robust sprouting of growth-associated protein 43 (GAP43)+ axons were found in the host tissue. Four months after SCI, the grafted cells matured into Islet2+ and choline acetyltransferase (ChAT)+ neurons, and the graft was grown through with endogenous neurons. Grafted cells labeled with poly-L-lysine-coated superparamagnetic nanoparticles before transplantation were detected in the lesion on T2-weighted images as hypointense spots that correlated with histologic staining for

  12. Expression of Pluripotency Markers in Nonpluripotent Human Neural Stem and Progenitor Cells.

    Science.gov (United States)

    Vincent, Per Henrik; Benedikz, Eirikur; Uhlén, Per; Hovatta, Outi; Sundström, Erik

    2017-06-15

    Nonpluripotent neural progenitor cells (NPCs) derived from the human fetal central nervous system were found to express a number of messenger RNA (mRNA) species associated with pluripotency, such as NANOG, REX1, and OCT4. The expression was restricted to small subpopulations of NPCs. In contrast to pluripotent stem cells, there was no coexpression of the pluripotency-associated genes studied. Although the expression of these genes rapidly declined during the in vitro differentiation of NPCs, we found no evidence that the discrete expression was associated with the markers of multipotent neural stem cells (CD133+/CD24lo), the capacity of sphere formation, or high cell proliferation rates. The rate of cell death among NPCs expressing pluripotency-associated genes was also similar to that of other NPCs. Live cell imaging showed that NANOG- and REX1-expressing NPCs continuously changed morphology, as did the nonexpressing cells. Depletion experiments showed that after the complete removal of the subpopulations of NANOG- and REX1-expressing NPCs, the expression of these genes appeared in other NPCs within a few days. The percentage of NANOG- and REX1-expressing cells returned to that observed before depletion. Our results are best explained by a model in which there is stochastic transient expression of pluripotency-associated genes in proliferating NPCs.

  13. Brightness in human rod vision depends on slow neural adaptation to quantum statistics of light.

    Science.gov (United States)

    Rudd, Michael E; Rieke, Fred

    2016-11-01

    In human rod-mediated vision, threshold for small, brief flashes rises in proportion to the square root of adapting luminance at all but the lowest and highest adapting intensities. A classical signal detection theory from Rose (1942, 1948) and de Vries (1943) attributed this rise to the perceptual masking of weak flashes by Poisson fluctuations in photon absorptions from the adapting field. However, previous work by Brown and Rudd (1998) demonstrated that the square-root law also holds for suprathreshold brightness judgments, a finding that supports an alternative explanation of the square-root sensitivity changes as a consequence of physiological adaptation (i.e., neural gain control). Here, we employ a dichoptic matching technique to investigate the properties of this brightness gain control. We show that the brightness gain control: 1) affects the brightness of high-intensity suprathreshold flashes for which assumptions of the de Vries-Rose theory are strongly violated; 2) exhibits a long time course of 100-200 s; and 3) is subject to modulation by temporal contrast noise when the mean adapting luminance is held constant. These findings are consistent with the hypothesis that the square-root law results from a slow neural adaptation to statistical noise in the rod pool. We suggest that such adaptation may function to reduce the probability of spurious ganglion cell spiking activity due to photon fluctuation noise as the ambient illumination level is increased.

  14. Functional plasticity before the cradle: a review of neural functional imaging in the human fetus.

    Science.gov (United States)

    Anderson, Amy L; Thomason, Moriah E

    2013-11-01

    The organization of the brain is highly plastic in fetal life. Establishment of healthy neural functional systems during the fetal period is essential to normal growth and development. Across the last several decades, remarkable progress has been made in understanding the development of human fetal functional brain systems. This is largely due to advances in imaging methodologies. Fetal neuroimaging began in the 1950-1970's with fetal electroencephalography (EEG) applied during labor. Later, in the 1980's, magnetoencephalography (MEG) emerged as an effective approach for investigating fetal brain function. Most recently, functional magnetic resonance imaging (fMRI) has arisen as an additional powerful approach for examining fetal brain function. This review will discuss major developmental findings from fetal imaging studies such as the maturation of prenatal sensory system functions, functional hemispheric asymmetry, and sensory-driven neurodevelopment. We describe how with improved imaging and analysis techniques, functional imaging of the fetus has the potential to assess the earliest point of neural maturation and provide insight into the patterning and sequence of normal and abnormal brain development. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Effects of halobenzoquinone and haloacetic acid water disinfection byproducts on human neural stem cells.

    Science.gov (United States)

    Fu, Katherine Z; Li, Jinhua; Vemula, Sai; Moe, Birget; Li, Xing-Fang

    2017-08-01

    Human neural stem cells (hNSCs) are a useful tool to assess the developmental effects of various environmental contaminants; however, the application of hNSCs to evaluate water disinfection byproducts (DBPs) is scarce. Comprehensive toxicological results are essential to the prioritization of DBPs for further testing and regulation. Therefore, this study examines the effects of DBPs on the proliferation and differentiation of hNSCs. Prior to DBP treatment, characteristic protein markers of hNSCs from passages 3 to 6 were carefully examined and it was determined that hNSCs passaged 3 or 4 times maintained stem cell characteristics and can be used for DBP analysis. Two regulated DBPs, monobromoacetic acid (BAA) and monochloroacetic acid (CAA), and two emerging DBPs, 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ) and 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), were chosen for hNSC treatment. Both 2,6-DBBQ and 2,6-DCBQ induced cell cycle arrest at S-phase at concentrations up to 1μmol/L. Comparatively, BAA and CAA at 0.5μmol/L affected neural differentiation. These results suggest DBP-dependent effects on hNSC proliferation and differentiation. The DBP-induced cell cycle arrest and inhibition of normal hNSC differentiation demonstrate the need to assess the developmental neurotoxicity of DBPs. Copyright © 2017. Published by Elsevier B.V.

  16. High-frequency oscillations in distributed neural networks reveal the dynamics of human decision making

    Directory of Open Access Journals (Sweden)

    Adrian G Guggisberg

    2008-03-01

    Full Text Available We examine the relative timing of numerous brain regions involved in human decisions that are based on external criteria, learned information, personal preferences, or unconstrained internal considerations. Using magnetoencephalography (MEG and advanced signal analysis techniques, we were able to non-invasively reconstruct oscillations of distributed neural networks in the high-gamma frequency band (60–150 Hz. The time course of the observed neural activity suggested that two-alternative forced choice tasks are processed in four overlapping stages: processing of sensory input, option evaluation, intention formation, and action execution. Visual areas are activated fi rst, and show recurring activations throughout the entire decision process. The temporo-occipital junction and the intraparietal sulcus are active during evaluation of external values of the options, 250–500 ms after stimulus presentation. Simultaneously, personal preference is mediated by cortical midline structures. Subsequently, the posterior parietal and superior occipital cortices appear to encode intention, with different subregions being responsible for different types of choice. The cerebellum and inferior parietal cortex are recruited for internal generation of decisions and actions, when all options have the same value. Action execution was accompanied by activation peaks in the contralateral motor cortex. These results suggest that high-gamma oscillations as recorded by MEG allow a reliable reconstruction of decision processes with excellent spatiotemporal resolution.

  17. Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses.

    Science.gov (United States)

    Yan, Yuanwei; Bejoy, Julie; Xia, Junfei; Guan, Jingjiao; Zhou, Yi; Li, Yan

    2016-09-15

    Appropriate neural patterning of human induced pluripotent stem cells (hiPSCs) is critical to generate specific neural cells/tissues and even mini-brains that are physiologically relevant to model neurological diseases. However, the capacity of signaling factors that regulate 3-D neural tissue patterning in vitro and differential responses of the resulting neural populations to various biomolecules have not yet been fully understood. By tuning neural patterning of hiPSCs with small molecules targeting sonic hedgehog (SHH) signaling, this study generated different 3-D neuronal cultures that were mainly comprised of either cortical glutamatergic neurons or motor neurons. Abundant glutamatergic neurons were observed following the treatment with an antagonist of SHH signaling, cyclopamine, while Islet-1 and HB9-expressing motor neurons were enriched by an SHH agonist, purmorphamine. In neurons derived with different neural patterning factors, whole-cell patch clamp recordings showed similar voltage-gated Na(+)/K(+) currents, depolarization-evoked action potentials and spontaneous excitatory post-synaptic currents. Moreover, these different neuronal populations exhibited differential responses to three classes of biomolecules, including (1) matrix metalloproteinase inhibitors that affect extracellular matrix remodeling; (2) N-methyl-d-aspartate that induces general neurotoxicity; and (3) amyloid β (1-42) oligomers that cause neuronal subtype-specific neurotoxicity. This study should advance our understanding of hiPSC self-organization and neural tissue development and provide a transformative approach to establish 3-D models for neurological disease modeling and drug discovery. Appropriate neural patterning of human induced pluripotent stem cells (hiPSCs) is critical to generate specific neural cells, tissues and even mini-brains that are physiologically relevant to model neurological diseases. However, the capability of sonic hedgehog-related small molecules to tune

  18. Human neural tuning estimated from compound action potentials in normal hearing human volunteers

    Science.gov (United States)

    Verschooten, Eric; Desloovere, Christian; Joris, Philip X.

    2015-12-01

    The sharpness of cochlear frequency tuning in humans is debated. Evoked otoacoustic emissions and psychophysical measurements suggest sharper tuning in humans than in laboratory animals [15], but this is disputed based on comparisons of behavioral and electrophysiological measurements across species [14]. Here we used evoked mass potentials to electrophysiologically quantify tuning (Q10) in humans. We combined a notched noise forward masking paradigm [9] with the recording of trans tympanic compound action potentials (CAP) from masked probe tones in awake human and anesthetized monkey (Macaca mulatta). We compare our results to data obtained with the same paradigm in cat and chinchilla [16], and find that CAP-Q10values in human are ˜1.6x higher than in cat and chinchilla and ˜1.3x higher than in monkey. To estimate frequency tuning of single auditory nerve fibers (ANFs) in humans, we derive conversion functions from ANFs in cat, chinchilla, and monkey and apply these to the human CAP measurements. The data suggest that sharp cochlear tuning is a feature of old-world primates.

  19. Convolutional Neural Network-Based Human Detection in Nighttime Images Using Visible Light Camera Sensors

    Directory of Open Access Journals (Sweden)

    Jong Hyun Kim

    2017-05-01

    Full Text Available Because intelligent surveillance systems have recently undergone rapid growth, research on accurately detecting humans in videos captured at a long distance is growing in importance. The existing research using visible light cameras has mainly focused on methods of human detection for daytime hours when there is outside light, but human detection during nighttime hours when there is no outside light is difficult. Thus, methods that employ additional near-infrared (NIR illuminators and NIR cameras or thermal cameras have been used. However, in the case of NIR illuminators, there are limitations in terms of the illumination angle and distance. There are also difficulties because the illuminator power must be adaptively adjusted depending on whether the object is close or far away. In the case of thermal cameras, their cost is still high, which makes it difficult to install and use them in a variety of places. Because of this, research has been conducted on nighttime human detection using visible light cameras, but this has focused on objects at a short distance in an indoor environment or the use of video-based methods to capture multiple images and process them, which causes problems related to the increase in the processing time. To resolve these problems, this paper presents a method that uses a single image captured at night on a visible light camera to detect humans in a variety of environments based on a convolutional neural network. Experimental results using a self-constructed Dongguk night-time human detection database (DNHD-DB1 and two open databases (Korea advanced institute of science and technology (KAIST and computer vision center (CVC databases, as well as high-accuracy human detection in a variety of environments, show that the method has excellent performance compared to existing methods.

  20. Convolutional Neural Network-Based Human Detection in Nighttime Images Using Visible Light Camera Sensors.

    Science.gov (United States)

    Kim, Jong Hyun; Hong, Hyung Gil; Park, Kang Ryoung

    2017-05-08

    Because intelligent surveillance systems have recently undergone rapid growth, research on accurately detecting humans in videos captured at a long distance is growing in importance. The existing research using visible light cameras has mainly focused on methods of human detection for daytime hours when there is outside light, but human detection during nighttime hours when there is no outside light is difficult. Thus, methods that employ additional near-infrared (NIR) illuminators and NIR cameras or thermal cameras have been used. However, in the case of NIR illuminators, there are limitations in terms of the illumination angle and distance. There are also difficulties because the illuminator power must be adaptively adjusted depending on whether the object is close or far away. In the case of thermal cameras, their cost is still high, which makes it difficult to install and use them in a variety of places. Because of this, research has been conducted on nighttime human detection using visible light cameras, but this has focused on objects at a short distance in an indoor environment or the use of video-based methods to capture multiple images and process them, which causes problems related to the increase in the processing time. To resolve these problems, this paper presents a method that uses a single image captured at night on a visible light camera to detect humans in a variety of environments based on a convolutional neural network. Experimental results using a self-constructed Dongguk night-time human detection database (DNHD-DB1) and two open databases (Korea advanced institute of science and technology (KAIST) and computer vision center (CVC) databases), as well as high-accuracy human detection in a variety of environments, show that the method has excellent performance compared to existing methods.

  1. Neural correlates of first-person perspective as one constituent of human self-consciousness.

    Science.gov (United States)

    Vogeley, K; May, M; Ritzl, A; Falkai, P; Zilles, K; Fink, G R

    2004-06-01

    Taking the first-person perspective (1PP) centered upon one's own body as opposed to the third-person perspective (3PP), which enables us to take the viewpoint of someone else, is constitutive for human self-consciousness. At the underlying representational or cognitive level, these operations are processed in an egocentric reference frame, where locations are represented centered around another person's (3PP) or one's own perspective (1PP). To study 3PP and 1PP, both operating in egocentric frames, a virtual scene with an avatar and red balls in a room was presented from different camera viewpoints to normal volunteers (n = 11) in a functional magnetic resonance imaging experiment. The task for the subjects was to count the objects as seen either from the avatar's perspective (3PP) or one's own perspective (1PP). The scene was presented either from a ground view (GV ) or an aerial view (AV ) to investigate the effect of view on perspective taking. The factors perspective (3PP vs. 1PP) and view (GV vs. AV ) were arranged in a two-factorial way. Reaction times were increased and percent correctness scores were decreased in 3PP as opposed to 1PP. To detect the neural mechanisms associated with perspective taking, functional magnetic resonance imaging was employed. Data were analyzed using SPM'99 in each subject and non-parametric statistics on the group level. Activations common to 3PP and 1PP (relative to baseline) were observed in a network of occipital, parietal, and prefrontal areas. Deactivations common to 3PP and 1PP (relative to baseline) were observed predominantly in mesial (i.e., parasagittal) cortical and lateral superior temporal areas bilaterally. Differential increases of neural activity were found in mesial superior parietal and right premotor cortex during 3PP (relative to 1PP), whereas differential increases during 1PP (relative to 3PP) were found in mesial prefrontal cortex, posterior cingulate cortex, and superior temporal cortex bilaterally. The

  2. Preservation of neuronal functions by exosomes derived from different human neural cell types under ischemic conditions.

    Science.gov (United States)

    Deng, Mingyang; Xiao, Han; Peng, Hongling; Yuan, Huan; Xu, Yunxiao; Zhang, Guangsen; Tang, Jianguang; Hu, Zhiping

    2017-11-27

    Stem cell-based therapies have been reported in protecting cerebral infarction-induced neuronal dysfunction and death. However, most studies used rat/mouse neuron as model cell when treated with stem cell or exosomes. Whether these findings can be translated from rodent to humans has been in doubt. Here, we used human embryonic stem cell-derived neurons to detect the protective potential of exosomes against ischemia. Neurons were treated with in vitro oxygen-glucose deprivation (OGD) for 1 h. For treatment group, different exosomes were derived from neuron, embryonic stem cell, neural progenitor cell and astrocyte differentiated from H9 human embryonic stem cell and added to culture medium 30 min after OGD (100 μg/mL). Western blotting was performed 12 h after OGD, while cell counting and electrophysiological recording were performed 48 h after OGD. We found that these exosomes attenuated OGD-induced neuronal death, Mammalian target of rapamycin (mTOR), pro-inflammatory and apoptotic signaling pathway changes, as well as basal spontaneous synaptic transmission inhibition in varying degrees. The results implicate the protective effect of exosomes on OGD-induced neuronal death and dysfunction in human embryonic stem cell-derived neurons, potentially through their modulation on mTOR, pro-inflammatory and apoptotic signaling pathways. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  3. Deep biomarkers of human aging: Application of deep neural networks to biomarker development.

    Science.gov (United States)

    Putin, Evgeny; Mamoshina, Polina; Aliper, Alexander; Korzinkin, Mikhail; Moskalev, Alexey; Kolosov, Alexey; Ostrovskiy, Alexander; Cantor, Charles; Vijg, Jan; Zhavoronkov, Alex

    2016-05-01

    One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. The best performing DNN in the ensemble demonstrated 81.5 % epsilon-accuracy r = 0.90 with R(2) = 0.80 and MAE = 6.07 years in predicting chronological age within a 10 year frame, while the entire ensemble achieved 83.5% epsilon-accuracy r = 0.91 with R(2) = 0.82 and MAE = 5.55 years. The ensemble also identified the 5 most important markers for predicting human chronological age: albumin, glucose, alkaline phosphatase, urea and erythrocytes. To allow for public testing and evaluate real-life performance of the predictor, we developed an online system available at http://www.aging.ai. The ensemble approach may facilitate integration of multi-modal data linked to chronological age and sex that may lead to simple, minimally invasive, and affordable methods of tracking integrated biomarkers of aging in humans and performing cross-species feature importance analysis.

  4. Expandable and Rapidly Differentiating Human Induced Neural Stem Cell Lines for Multiple Tissue Engineering Applications

    Directory of Open Access Journals (Sweden)

    Dana M. Cairns

    2016-09-01

    Full Text Available Limited availability of human neurons poses a significant barrier to progress in biological and preclinical studies of the human nervous system. Current stem cell-based approaches of neuron generation are still hindered by prolonged culture requirements, protocol complexity, and variability in neuronal differentiation. Here we establish stable human induced neural stem cell (hiNSC lines through the direct reprogramming of neonatal fibroblasts and adult adipose-derived stem cells. These hiNSCs can be passaged indefinitely and cryopreserved as colonies. Independently of media composition, hiNSCs robustly differentiate into TUJ1-positive neurons within 4 days, making them ideal for innervated co-cultures. In vivo, hiNSCs migrate, engraft, and contribute to both central and peripheral nervous systems. Lastly, we demonstrate utility of hiNSCs in a 3D human brain model. This method provides a valuable interdisciplinary tool that could be used to develop drug screening applications as well as patient-specific disease models related to disorders of innervation and the brain.

  5. Boundary cap neural crest stem cells homotopically implanted to the injured dorsal root transitional zone give rise to different types of neurons and glia in adult rodents

    OpenAIRE

    Trolle, Carl; Abrahamsson, Ninnie; König, Niclas; Vasylovska, Svitlana; Kozlova, Elena

    2014-01-01

    The boundary cap is a transient group of neural crest-derived cells located at the presumptive dorsal root transitional zone (DRTZ) when sensory axons enter the spinal cord during development. Later, these cells migrate to dorsal root ganglia and differentiate into subtypes of sensory neurons and glia. After birth when the DRTZ is established, sensory axons are no longer able to enter the spinal cord. Here we explored the fate of mouse bNCSCs implanted to the uninjured DRTZ after dorsal root ...

  6. Continuous Learning from Human Post-Edits for Neural Machine Translation

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    Turchi Marco

    2017-06-01

    Full Text Available Improving machine translation (MT by learning from human post-edits is a powerful solution that is still unexplored in the neural machine translation (NMT framework. Also in this scenario, effective techniques for the continuous tuning of an existing model to a stream of manual corrections would have several advantages over current batch methods. First, they would make it possible to adapt systems at run time to new users/domains; second, this would happen at a lower computational cost compared to NMT retraining from scratch or in batch mode. To attack the problem, we explore several online learning strategies to stepwise fine-tune an existing model to the incoming post-edits. Our evaluation on data from two language pairs and different target domains shows significant improvements over the use of static models.

  7. Brain Tumor Tropism of Transplanted Human Neural Stem Cells Is Induced by Vascular Endothelial Growth Factor

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    Nils Ole Schmidt

    2005-06-01

    Full Text Available The transplantation of neural stem cells (NSCs offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumorupregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.

  8. Human intracranial high-frequency activity during memory processing: neural oscillations or stochastic volatility?

    Science.gov (United States)

    Burke, John F; Ramayya, Ashwin G; Kahana, Michael J

    2015-04-01

    Intracranial high-frequency activity (HFA), which refers to fast fluctuations in electrophysiological recordings, increases during memory processing. Two views have emerged to explain this effect: (1) HFA reflects a synchronous signal, related to underlying gamma oscillations, that plays a mechanistic role in human memory and (2) HFA reflects an asynchronous signal that is a non-specific marker of brain activation. We review recent data supporting each of these views and conclude that HFA during memory processing is more consistent with an asynchronous signal. Memory-related HFA is therefore best conceptualized as a biomarker of neural activation that can functionally map memory with high spatial and temporal precision. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Convolutional neural networks for segmentation and object detection of human semen

    DEFF Research Database (Denmark)

    Nissen, Malte Stær; Krause, Oswin; Almstrup, Kristian

    2017-01-01

    We compare a set of convolutional neural network (CNN) architectures for the task of segmenting and detecting human sperm cells in an image taken from a semen sample. In contrast to previous work, samples are not stained or washed to allow for full sperm quality analysis, making analysis harder due...... are found by using connected components on the CNN predictions. We investigate optimization of a threshold parameter on the size of detected components. Our best network achieves 93.87% precision and 91.89% recall on our test dataset after thresholding outperforming a classical image analysis approach....... to clutter. Our results indicate that training on full images is superior to training on patches when class-skew is properly handled. Full image training including up-sampling during training proves to be beneficial in deep CNNs for pixel wise accuracy and detection performance. Predicted sperm cells...

  10. Cantorian Fractal Spacetime and Quantum-like Chaos in Neural Networks of the Human Brain

    CERN Document Server

    Selvam, A M

    1998-01-01

    The neural networks of the human brain act as very efficient parallel processing computers co-ordinating memory related responses to a multitude of input signals from sensory organs. Information storage, update and appropriate retrieval are controlled at the molecular level by the neuronal cytoskeleton which serves as the internal communication network within neurons. Information flow in the highly ordered parallel networks of the filamentous protein polymers which make up the cytoskeleton may be compared to atmospheric flows which exhibit long-range spatiotemporal correlations, i.e. long-term memory. Such long-range spatiotemporal correlations are ubiquitous to real world dynamical systems and is recently identified as signature of self-organized criticality or chaos. The signatures of self-organized criticality i.e. long-range temporal correlations have recently been identified in the electrical activity of the brain. A recently developed non-deterministic cell dynamical system model for atmospheric flows p...

  11. SOX10-Nano-Lantern Reporter Human iPS Cells; A Versatile Tool for Neural Crest Research.

    Directory of Open Access Journals (Sweden)

    Tomoko Horikiri

    Full Text Available The neural crest is a source to produce multipotent neural crest stem cells that have a potential to differentiate into diverse cell types. The transcription factor SOX10 is expressed through early neural crest progenitors and stem cells in vertebrates. Here we report the generation of SOX10-Nano-lantern (NL reporter human induced pluripotent stem cells (hiPS by using CRISPR/Cas9 systems, that are beneficial to investigate the generation and maintenance of neural crest progenitor cells. SOX10-NL positive cells are produced transiently from hiPS cells by treatment with TGFβ inhibitor SB431542 and GSK3 inhibitor CHIR99021. We found that all SOX10-NL-positive cells expressed an early neural crest marker NGFR, however SOX10-NL-positive cells purified from differentiated hiPS cells progressively attenuate their NL-expression under proliferation. We therefore attempted to maintain SOX10-NL-positive cells with additional signaling on the plane and sphere culture conditions. These SOX10-NL cells provide us to investigate mass culture with neural crest cells for stem cell research.

  12. Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation

    Science.gov (United States)

    Budi, Erine H.; Patterson, Larissa B.; Parichy, David M.

    2009-01-01

    SUMMARY Vertebrate pigment cells are derived from neural crest cells and are a useful system for studying neural crest-derived traits during post-embryonic development. In zebrafish, neural crest-derived melanophores differentiate during embryogenesis to produce stripes in the early larva. Dramatic changes to the pigment pattern occur subsequently during the larva-to-adult transformation, or metamorphosis. At this time, embryonic melanophores are replaced by newly differentiating metamorphic melanophores that form the adult stripes. Mutants with normal embryonic/early larval pigment patterns but defective adult patterns identify factors required uniquely to establish, maintain, or recruit the latent precursors to metamorphic melanophores. We show that one such mutant, picasso, lacks most metamorphic melanophores and results from mutations in the ErbB gene erbb3b, encoding an EGFR-like receptor tyrosine kinase. To identify critical periods for ErbB activities, we treated fish with pharmacological ErbB inhibitors and also knocked-down erbb3b by morpholino injection. These analyses reveal an embryonic critical period for ErbB signaling in promoting later pigment pattern metamorphosis, despite the normal patterning of embryonic/early larval melanophores. We further demonstrate a peak requirement during neural crest migration that correlates with early defects in neural crest pathfinding and peripheral ganglion formation. Finally, we show that erbb3b activities are both autonomous and non-autonomous to the metamorphic melanophore lineage. These data identify a very early, embryonic, requirement for erbb3b in the development of much later metamorphic melanophores, and suggest complex modes by which ErbB signals promote adult pigment pattern development. PMID:18508863

  13. Neural Correlates of Vocal Production and Motor Control in Human Heschl's Gyrus.

    Science.gov (United States)

    Behroozmand, Roozbeh; Oya, Hiroyuki; Nourski, Kirill V; Kawasaki, Hiroto; Larson, Charles R; Brugge, John F; Howard, Matthew A; Greenlee, Jeremy D W

    2016-02-17

    The present study investigated how pitch frequency, a perceptually relevant aspect of periodicity in natural human vocalizations, is encoded in Heschl's gyrus (HG), and how this information may be used to influence vocal pitch motor control. We recorded local field potentials from multicontact depth electrodes implanted in HG of 14 neurosurgical epilepsy patients as they vocalized vowel sounds and received brief (200 ms) pitch perturbations at 100 Cents in their auditory feedback. Event-related band power responses to vocalizations showed sustained frequency following responses that tracked voice fundamental frequency (F0) and were significantly enhanced in posteromedial HG during speaking compared with when subjects listened to the playback of their own voice. In addition to frequency following responses, a transient response component within the high gamma frequency band (75-150 Hz) was identified. When this response followed the onset of vocalization, the magnitude of the response was the same for the speaking and playback conditions. In contrast, when this response followed a pitch shift, its magnitude was significantly enhanced during speaking compared with playback. We also observed that, in anterolateral HG, the power of high gamma responses to pitch shifts correlated with the magnitude of compensatory vocal responses. These findings demonstrate a functional parcellation of HG with neural activity that encodes pitch in natural human voice, distinguishes between self-generated and passively heard vocalizations, detects discrepancies between the intended and heard vocalization, and contains information about the resulting behavioral vocal compensations in response to auditory feedback pitch perturbations. The present study is a significant contribution to our understanding of sensor-motor mechanisms of vocal production and motor control. The findings demonstrate distinct functional parcellation of core and noncore areas within human auditory cortex on Heschl

  14. Suppression of the SOX2 Neural Effector Gene by PRDM1 Promotes Human Germ Cell Fate in Embryonic Stem Cells

    Directory of Open Access Journals (Sweden)

    I-Ying Lin

    2014-02-01

    Full Text Available The mechanisms of transcriptional regulation underlying human primordial germ cell (PGC differentiation are largely unknown. The transcriptional repressor Prdm1/Blimp-1 is known to play a critical role in controlling germ cell specification in mice. Here, we show that PRDM1 is expressed in developing human gonads and contributes to the determination of germline versus neural fate in early development. We show that knockdown of PRDM1 in human embryonic stem cells (hESCs impairs germline potential and upregulates neural genes. Conversely, ectopic expression of PRDM1 in hESCs promotes the generation of cells that exhibit phenotypic and transcriptomic features of early PGCs. Furthermore, PRDM1 suppresses transcription of SOX2. Overexpression of SOX2 in hESCs under conditions favoring germline differentiation skews cell fate from the germline to the neural lineage. Collectively, our results demonstrate that PRDM1 serves as a molecular switch to modulate the divergence of neural or germline fates through repression of SOX2 during human development.

  15. The Pavlovian craver: Neural and experiential correlates of single trial naturalistic food conditioning in humans.

    Science.gov (United States)

    Blechert, J; Testa, G; Georgii, C; Klimesch, W; Wilhelm, F H

    2016-05-01

    Present-day environments are replete with tempting foods and the current obesity pandemic speaks to humans' inability to adjust to this. Pavlovian processes may be fundamental to such hedonic overeating. However, a lack of naturalistic Pavlovian paradigms in humans makes translational research difficult and important parameters such as implicitness and acquisition speed are unknown. Here we present a novel naturalistic conditioning task: an image of a neutral object was conditioned to marzipan taste in a single trial procedure by asking the participant to eat the 'object' (made from marzipan). Relative to control objects, results demonstrate robust pre- to post-conditioning changes of both subjective ratings and early as well as late event related brain potentials, suggesting contributions of implicit (attentional) and explicit (motivational) processes. Naturalistic single-trial taste-appetitive conditioning is potent in humans and shapes attentional and motivational neural processes that might challenge self-regulation during exposure to tempting foods. Thus, appetitive conditioning processes might contribute to overweight and obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Neural signatures of conscious and unconscious emotional face processing in human infants.

    Science.gov (United States)

    Jessen, Sarah; Grossmann, Tobias

    2015-03-01

    Human adults can process emotional information both with and without conscious awareness, and it has been suggested that the two processes rely on partly distinct brain mechanisms. However, the developmental origins of these brain processes are unknown. In the present event-related brain potential (ERP) study, we examined the brain responses of 7-month-old infants in response to subliminally (50 and 100 msec) and supraliminally (500 msec) presented happy and fearful facial expressions. Our results revealed that infants' brain responses (Pb and Nc) over central electrodes distinguished between emotions irrespective of stimulus duration, whereas the discrimination between emotions at occipital electrodes (N290 and P400) only occurred when faces were presented supraliminally (above threshold). This suggests that early in development the human brain not only discriminates between happy and fearful facial expressions irrespective of conscious perception, but also that, similar to adults, supraliminal and subliminal emotion processing relies on distinct neural processes. Our data further suggest that the processing of emotional facial expressions differs across infants depending on their behaviorally shown perceptual sensitivity. The current ERP findings suggest that distinct brain processes underpinning conscious and unconscious emotion perception emerge early in ontogeny and can therefore be seen as a key feature of human social functioning. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors

    DEFF Research Database (Denmark)

    Seminatore, Christine; Polentes, Jerome; Ellman, Ditte

    2010-01-01

    Risk of tumorigenesis is a major obstacle to human embryonic and induced pluripotent stem cell therapy. Likely linked to the stage of differentiation of the cells at the time of implantation, formation of teratoma/tumors can also be influenced by factors released by the host tissue. We have...... analyzed the relative effects of the stage of differentiation and the postischemic environment on the formation of adverse structures by transplanted human embryonic stem cell-derived neural progenitors....

  18. The neural basis of temporal individuation and its capacity limits in the human brain.

    Science.gov (United States)

    Naughtin, Claire K; Tamber-Rosenau, Benjamin J; Dux, Paul E

    2017-11-01

    Individuation refers to individuals' use of spatial and temporal properties to register objects as distinct perceptual events relative to other stimuli. Although behavioral studies have examined both spatial and temporal individuation, neuroimaging investigations have been restricted to the spatial domain and at relatively late stages of information processing. Here, we used univariate and multivoxel pattern analyses of functional MRI data to identify brain regions involved in individuating temporally distinct visual items and the neural consequences that arise when this process reaches its capacity limit (repetition blindness, RB). First, we found that regional patterns of blood-oxygen-level-dependent activity across the cortex discriminated between instances where repeated and nonrepeated stimuli were successfully individuated-conditions that placed differential demands on temporal individuation. These results could not be attributed to repetition suppression or other stimulus-related factors, task difficulty, regional activation differences, other capacity-limited processes, or artifacts in the data or analyses. Contrary to current theoretical models, this finding suggests that temporal individuation is supported by a distributed set of brain regions, rather than a single neural correlate. Second, conditions that reflect the capacity limit of individuation-instances of RB-lead to changes in the spatial patterns within this network, as well as amplitude changes in the left hemisphere premotor cortex, superior medial frontal cortex, anterior cingulate cortex, and bilateral parahippocampal place area. These findings could not be attributed to response conflict/ambiguity and likely reflect the core brain regions and mechanisms that underlie the capacity-limited process that gives rise to RB.NEW & NOTEWORTHY We present novel findings into the neural bases of temporal individuation and repetition blindness (RB)-the perceptual deficit that arises when this process

  19. Neural and non-neural control of skin blood flow during isometric handgrip exercise in the heat stressed human

    DEFF Research Database (Denmark)

    Shibasaki, M.; Rasmussen, P.; Secher, Niels H.

    2009-01-01

    as an absence of sweating and cutaneous vasodilatation during a whole-body heat stress. Upon this confirmation, adenosine was perfused through one of the microdialysis probes to increase skin blood flow similar to that of the unblocked site. After internal temperature increased approximately 0.7 degrees C......During heat stress, isometric handgrip (IHG) exercise causes cutaneous vasoconstriction, but it remains controversial whether neural mechanisms are responsible for this observation. The objective of this study was to test the hypothesis that cutaneous vasoconstriction during IHG exercise in heat......, subjects performed 2 min of IHG exercise at 35% of maximal voluntary contraction using the non-blocked arm. IHG exercise significantly decreased CVC at the unblocked site (82.3 +/- 5.7 to 70.9 +/- 5.4%max, P = 0.005, means +/- S.E.M.) and the adenosine treated site of the blocked arm (75.2 +/- 7.2 to 68...

  20. Neural coding of cooperative vs. affective human interactions: 150 ms to code the action's purpose.

    Directory of Open Access Journals (Sweden)

    Alice Mado Proverbio

    Full Text Available The timing and neural processing of the understanding of social interactions was investigated by presenting scenes in which 2 people performed cooperative or affective actions. While the role of the human mirror neuron system (MNS in understanding actions and intentions is widely accepted, little is known about the time course within which these aspects of visual information are automatically extracted. Event-Related Potentials were recorded in 35 university students perceiving 260 pictures of cooperative (e.g., 2 people dragging a box or affective (e.g., 2 people smiling and holding hands interactions. The action's goal was automatically discriminated at about 150-170 ms, as reflected by occipito/temporal N170 response. The swLORETA inverse solution revealed the strongest sources in the right posterior cingulate cortex (CC for affective actions and in the right pSTS for cooperative actions. It was found a right hemispheric asymmetry that involved the fusiform gyrus (BA37, the posterior CC, and the medial frontal gyrus (BA10/11 for the processing of affective interactions, particularly in the 155-175 ms time window. In a later time window (200-250 ms the processing of cooperative interactions activated the left post-central gyrus (BA3, the left parahippocampal gyrus, the left superior frontal gyrus (BA10, as well as the right premotor cortex (BA6. Women showed a greater response discriminative of the action's goal compared to men at P300 and anterior negativity level (220-500 ms. These findings might be related to a greater responsiveness of the female vs. male MNS. In addition, the discriminative effect was bilateral in women and was smaller and left-sided in men. Evidence was provided that perceptually similar social interactions are discriminated on the basis of the agents' intentions quite early in neural processing, differentially activating regions devoted to face/body/action coding, the limbic system and the MNS.

  1. The Neural Correlates of Chronic Symptoms of Vertigo Proneness in Humans.

    Directory of Open Access Journals (Sweden)

    Ola Alsalman

    Full Text Available Vestibular signals are of significant importance for variable functions including gaze stabilization, spatial perception, navigation, cognition, and bodily self-consciousness. The vestibular network governs functions that might be impaired in patients affected with vestibular dysfunction. It is currently unclear how different brain regions/networks process vestibular information and integrate the information into a unified spatial percept related to somatosensory awareness and whether people with recurrent balance complaints have a neural signature as a trait affecting their development of chronic symptoms of vertigo. Pivotal evidence points to a vestibular-related brain network in humans that is widely distributed in nature. By using resting state source localized electroencephalography in non-vertiginous state, electrophysiological changes in activity and functional connectivity of 23 patients with balance complaints where chronic symptoms of vertigo and dizziness are among the most common reported complaints are analyzed and compared to healthy subjects. The analyses showed increased alpha2 activity within the posterior cingulate cortex and the precuneues/cuneus and reduced beta3 and gamma activity within the pregenual and subgenual anterior cingulate cortex for the subjects with balance complaints. These electrophysiological variations were correlated with reported chronic symptoms of vertigo intensity. A region of interest analysis found reduced functional connectivity for gamma activity within the vestibular cortex, precuneus, frontal eye field, intra-parietal sulcus, orbitofrontal cortex, and the dorsal anterior cingulate cortex. In addition, there was a positive correlation between chronic symptoms of vertigo intensity and increased alpha-gamma nesting in the left frontal eye field. When compared to healthy subjects, there is evidence of electrophysiological changes in the brain of patients with balance complaints even outside chronic

  2. Interaction matters: A perceived social partner alters the neural processing of human speech.

    Science.gov (United States)

    Rice, Katherine; Redcay, Elizabeth

    2016-04-01

    Mounting evidence suggests that social interaction changes how communicative behaviors (e.g., spoken language, gaze) are processed, but the precise neural bases by which social-interactive context may alter communication remain unknown. Various perspectives suggest that live interactions are more rewarding, more attention-grabbing, or require increased mentalizing-thinking about the thoughts of others. Dissociating between these possibilities is difficult because most extant neuroimaging paradigms examining social interaction have not directly compared live paradigms to conventional "offline" (or recorded) paradigms. We developed a novel fMRI paradigm to assess whether and how an interactive context changes the processing of speech matched in content and vocal characteristics. Participants listened to short vignettes--which contained no reference to people or mental states--believing that some vignettes were prerecorded and that others were presented over a real-time audio-feed by a live social partner. In actuality, all speech was prerecorded. Simply believing that speech was live increased activation in each participant's own mentalizing regions, defined using a functional localizer. Contrasting live to recorded speech did not reveal significant differences in attention or reward regions. Further, higher levels of autistic-like traits were associated with altered neural specialization for live interaction. These results suggest that humans engage in ongoing mentalizing about social partners, even when such mentalizing is not explicitly required, illustrating how social context shapes social cognition. Understanding communication in social context has important implications for typical and atypical social processing, especially for disorders like autism where social difficulties are more acute in live interaction. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. False memory for face in short-term memory and neural activity in human amygdala.

    Science.gov (United States)

    Iidaka, Tetsuya; Harada, Tokiko; Sadato, Norihiro

    2014-12-03

    Human memory is often inaccurate. Similar to words and figures, new faces are often recognized as seen or studied items in long- and short-term memory tests; however, the neural mechanisms underlying this false memory remain elusive. In a previous fMRI study using morphed faces and a standard false memory paradigm, we found that there was a U-shaped response curve of the amygdala to old, new, and lure items. This indicates that the amygdala is more active in response to items that are salient (hit and correct rejection) compared to items that are less salient (false alarm), in terms of memory retrieval. In the present fMRI study, we determined whether the false memory for faces occurs within the short-term memory range (a few seconds), and assessed which neural correlates are involved in veridical and illusory memories. Nineteen healthy participants were scanned by 3T MRI during a short-term memory task using morphed faces. The behavioral results indicated that the occurrence of false memories was within the short-term range. We found that the amygdala displayed a U-shaped response curve to memory items, similar to those observed in our previous study. These results suggest that the amygdala plays a common role in both long- and short-term false memory for faces. We made the following conclusions: First, the amygdala is involved in detecting the saliency of items, in addition to fear, and supports goal-oriented behavior by modulating memory. Second, amygdala activity and response time might be related with a subject's response criterion for similar faces. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia.

    Science.gov (United States)

    Benson, Sven; Rebernik, Laura; Wegner, Alexander; Kleine-Borgmann, Julian; Engler, Harald; Schlamann, Marc; Forsting, Michael; Schedlowski, Manfred; Elsenbruch, Sigrid

    2015-08-01

    To elucidate the brain mechanisms underlying inflammation-induced visceral hyperalgesia in humans, in this functional magnetic resonance imaging (fMRI) study we tested if intravenous administration of lipopolysaccharide (LPS) involves altered central processing of visceral pain stimuli. In this randomized, double-blind, placebo-controlled fMRI study, 26 healthy male subjects received either an intravenous injection of low-dose LPS (N=14, 0.4 ng/kg body weight) or placebo (N=12, control group). Plasma cytokines (TNF-α, IL-6), body temperature, plasma cortisol and mood were assessed at baseline and up to 6 h post-injection. At baseline and 2 h post-injection (test), rectal pain thresholds and painful rectal distension-induced blood oxygen level-dependent (BOLD) responses in brain regions-of-interest were assessed. To address specificity for visceral pain, BOLD responses to non-painful rectal distensions and painful somatic stimuli (i.e., punctuate mechanical stimulation) were also analyzed as control stimuli. Compared to the control group, LPS-treated subjects demonstrated significant and transient increases in TNF-α, IL-6, body temperature and cortisol, along with impaired mood. In response to LPS, rectal pain thresholds decreased in trend, along with enhanced up-regulation of rectal pain-induced BOLD responses within the posterior insula, dorsolateral prefrontal (DLPFC), anterior midcingulate (aMCC) and somatosensory cortices (all FWE-corrected ppain-induced neural activation in DLPFC and aMCC. No significant LPS effects were observed on neural responses to non-painful rectal distensions or mechanical stimulation. These findings support that peripheral inflammatory processes affect visceral pain thresholds and the central processing of sensory-discriminative aspects of visceral pain. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles

    Directory of Open Access Journals (Sweden)

    Janet E. Baulch

    2015-08-01

    Full Text Available Exposure to the space radiation environment poses risks for a range of deleterious health effects due to the unique types of radiation encountered. Galactic cosmic rays are comprised of a spectrum of highly energetic nuclei that deposit densely ionizing tracks of damage along the particle trajectory. These tracks are distinct from those generated by the more sparsely ionizing terrestrial radiations, and define the geometric distribution of the complex cellular damage that results when charged particles traverse the tissues of the body. The exquisite radiosensitivity of multipotent neural stem and progenitor cells found within the neurogenic regions of the brain predispose the central nervous system to elevated risks for radiation induced sequelae. Here we show that human neural stem cells (hNSC exposed to different charged particles at space relevant fluences exhibit significant and persistent oxidative stress. Radiation induced oxidative stress was found to be most dependent on total dose rather than on the linear energy transfer of the incident particle. The use of redox sensitive fluorogenic dyes possessing relative specificity for hydroxyl radicals, peroxynitrite, nitric oxide (NO and mitochondrial superoxide confirmed that most irradiation paradigms elevated reactive oxygen and nitrogen species (ROS and RNS, respectively in hNSC over a 1 week interval following exposure. Nitric oxide synthase (NOS was not the major source of elevated nitric oxides, as the use of NOS inhibitors had little effect on NO dependent fluorescence. Our data provide extensive evidence for the capability of low doses of charged particles to elicit marked changes in the metabolic profile of irradiated hNSC. Radiation induced changes in redox state may render the brain more susceptible to the development of neurocognitive deficits that could affect an astronaut’s ability to perform complex tasks during extended missions in deep space.

  6. Determining the Neural Substrate for Encoding a Memory of Human Pain and the Influence of Anxiety.

    Science.gov (United States)

    Tseng, Ming-Tsung; Kong, Yazhuo; Eippert, Falk; Tracey, Irene

    2017-12-06

    To convert a painful stimulus into a briefly maintainable construct when the painful stimulus is no longer accessible is essential to guide human behavior and avoid dangerous situations. Because of the aversive nature of pain, this encoding process might be influenced by emotional aspects and could thus vary across individuals, but we have yet to understand both the basic underlying neural mechanisms as well as potential interindividual differences. Using fMRI in combination with a delayed-discrimination task in healthy volunteers of both sexes, we discovered that brain regions involved in this working memory encoding process were dissociable according to whether the to-be-remembered stimulus was painful or not, with the medial thalamus and the rostral anterior cingulate cortex encoding painful and the primary somatosensory cortex encoding nonpainful stimuli. Encoding of painful stimuli furthermore significantly enhanced functional connectivity between the thalamus and medial prefrontal cortex (mPFC). With regards to emotional aspects influencing encoding processes, we observed that more anxious participants showed significant performance advantages when encoding painful stimuli. Importantly, only during the encoding of pain, the interindividual differences in anxiety were associated with the strength of coupling between medial thalamus and mPFC, which was furthermore related to activity in the amygdala. These results indicate not only that there is a distinct signature for the encoding of a painful experience in humans, but also that this encoding process involves a strong affective component. SIGNIFICANCE STATEMENT To convert the sensation of pain into a briefly maintainable construct is essential to guide human behavior and avoid dangerous situations. Although this working memory encoding process is implicitly contained in the majority of studies, the underlying neural mechanisms remain unclear. Using fMRI in a delayed-discrimination task, we found that the

  7. Inhibition of Sirt1 promotes neural progenitors toward motoneuron differentiation from human embryonic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yun; Wang, Jing [Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China); Clinical Stem Cell Center, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China); Chen, Guian [Clinical Stem Cell Center, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China); Reproductive Medical Center, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China); Fan, Dongsheng, E-mail: dsfan@yahoo.cn [Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China); Clinical Stem Cell Center, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China); Deng, Min, E-mail: dengmin1706@yahoo.com.cn [Department of Neurology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China); Clinical Stem Cell Center, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191 (China)

    2011-01-14

    Research highlights: {yields} Nicotinamide inhibit Sirt1. {yields} MASH1 and Ngn2 activation. {yields} Increase the expression of HB9. {yields} Motoneurons formation increases significantly. -- Abstract: Several protocols direct human embryonic stem cells (hESCs) toward differentiation into functional motoneurons, but the efficiency of motoneuron generation varies based on the human ESC line used. We aimed to develop a novel protocol to increase the formation of motoneurons from human ESCs. In this study, we tested a nuclear histone deacetylase protein, Sirt1, to promote neural precursor cell (NPC) development during differentiation of human ESCs into motoneurons. A specific inhibitor of Sirt1, nicotinamide, dramatically increased motoneuron formation. We found that about 60% of the cells from the total NPCs expressed HB9 and {beta}III-tubulin, commonly used motoneuronal markers found in neurons derived from ESCs following nicotinamide treatment. Motoneurons derived from ESC expressed choline acetyltransferase (ChAT), a positive marker of mature motoneuron. Moreover, we also examined the transcript levels of Mash1, Ngn2, and HB9 mRNA in the differentiated NPCs treated with the Sirt1 activator resveratrol (50 {mu}M) or inhibitor nicotinamide (100 {mu}M). The levels of Mash1, Ngn2, and HB9 mRNA were significantly increased after nicotinamide treatment compared with control groups, which used the traditional protocol. These results suggested that increasing Mash1 and Ngn2 levels by inhibiting Sirt1 could elevate HB9 expression, which promotes motoneuron differentiation. This study provides an alternative method for the production of transplantable motoneurons, a key requirement in the development of hESC-based cell therapy in motoneuron disease.

  8. Left-Right Asymmetry of Maturation Rates in Human Embryonic Neural Development.

    Science.gov (United States)

    de Kovel, Carolien G F; Lisgo, Steven; Karlebach, Guy; Ju, Jia; Cheng, Gang; Fisher, Simon E; Francks, Clyde

    2017-08-01

    Left-right asymmetry is a fundamental organizing feature of the human brain, and neuropsychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks postconception, the majority of human fetuses move their right arms more than their left arms, but because nerve fiber tracts are still descending from the forebrain at this stage, spinal-muscular asymmetries are likely to play an important developmental role. We used RNA sequencing to measure gene expression levels in the left and right spinal cords, and the left and right hindbrains, of 18 postmortem human embryos aged 4 to 8 weeks postconception. Genes showing embryonic lateralization were tested for an enrichment of signals in genome-wide association data for schizophrenia. The left side of the embryonic spinal cord was found to mature faster than the right side. Both sides transitioned from transcriptional profiles associated with cell division and proliferation at earlier stages to neuronal differentiation and function at later stages, but the two sides were not in synchrony (p = 2.2 E-161). The hindbrain showed a left-right mirrored pattern compared with the spinal cord, consistent with the well-known crossing over of function between these two structures. Genes that showed lateralization in the embryonic spinal cord were enriched for association signals with schizophrenia (p = 4.3 E-05). These are the earliest stage left-right differences of human neural development ever reported. Disruption of the lateralized developmental program may play a role in the genetic susceptibility to schizophrenia. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  9. Not all about sex: neural and biobehavioral functions of human dance.

    Science.gov (United States)

    Christensen, Julia F; Cela-Conde, Camilo José; Gomila, Antoni

    2017-07-01

    This paper provides an integrative review of neuroscientific and biobehavioral evidence about the effects of dance on the individual across cultural differences. Dance moves us, and many derive aesthetic pleasure from it. However, in addition-and beyond aesthetics-we propose that dance has noteworthy, deeper neurobiological effects. We first summarize evidence that illustrates the centrality of dance to human life indirectly from archaeology, comparative psychology, developmental psychology, and cross-cultural psychology. Second, we review empirical evidence for six neural and biobehavioral functions of dance: (1) attentional focus/flow, (2) basic emotional experiences, (3) imagery, (4) communication, (5) self-intimation, and (6) social cohesion. We discuss the reviewed evidence in relation to current debates in the field of empirical enquiry into the functions of human dance, questioning the positions that dance is (1) just for pleasure, (2) all about sex, (3) just for mood management and well-being, and (4) for experts only. Being a young field, evidence is still piecemeal and inconclusive. This review aims to take a step toward a systematization of an emerging avenue of research: a neuro- and biobehavioral science of dance. © 2017 New York Academy of Sciences.

  10. Experience Shapes the Development of Neural Substrates of Face Processing in Human Ventral Temporal Cortex.

    Science.gov (United States)

    Golarai, Golijeh; Liberman, Alina; Grill-Spector, Kalanit

    2017-02-01

    In adult humans, the ventral temporal cortex (VTC) represents faces in a reproducible topology. However, it is unknown what role visual experience plays in the development of this topology. Using functional magnetic resonance imaging in children and adults, we found a sequential development, in which the topology of face-selective activations across the VTC was matured by age 7, but the spatial extent and degree of face selectivity continued to develop past age 7 into adulthood. Importantly, own- and other-age faces were differentially represented, both in the distributed multivoxel patterns across the VTC, and also in the magnitude of responses of face-selective regions. These results provide strong evidence that experience shapes cortical representations of faces during development from childhood to adulthood. Our findings have important implications for the role of experience and age in shaping the neural substrates of face processing in the human VTC. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Differential Responses of Human Fetal Brain Neural Stem Cells to Zika Virus Infection

    Directory of Open Access Journals (Sweden)

    Erica L. McGrath

    2017-03-01

    Full Text Available Zika virus (ZIKV infection causes microcephaly in a subset of infants born to infected pregnant mothers. It is unknown whether human individual differences contribute to differential susceptibility of ZIKV-related neuropathology. Here, we use an Asian-lineage ZIKV strain, isolated from the 2015 Mexican outbreak (Mex1-7, to infect primary human neural stem cells (hNSCs originally derived from three individual fetal brains. All three strains of hNSCs exhibited similar rates of Mex1-7 infection and reduced proliferation. However, Mex1-7 decreased neuronal differentiation in only two of the three stem cell strains. Correspondingly, ZIKA-mediated transcriptome alterations were similar in these two strains but significantly different from that of the third strain with no ZIKV-induced neuronal reduction. This study thus confirms that an Asian-lineage ZIKV strain infects primary hNSCs and demonstrates a cell-strain-dependent response of hNSCs to ZIKV infection.

  12. Differential Responses of Human Fetal Brain Neural Stem Cells to Zika Virus Infection.

    Science.gov (United States)

    McGrath, Erica L; Rossi, Shannan L; Gao, Junling; Widen, Steven G; Grant, Auston C; Dunn, Tiffany J; Azar, Sasha R; Roundy, Christopher M; Xiong, Ying; Prusak, Deborah J; Loucas, Bradford D; Wood, Thomas G; Yu, Yongjia; Fernández-Salas, Ildefonso; Weaver, Scott C; Vasilakis, Nikos; Wu, Ping

    2017-03-14

    Zika virus (ZIKV) infection causes microcephaly in a subset of infants born to infected pregnant mothers. It is unknown whether human individual differences contribute to differential susceptibility of ZIKV-related neuropathology. Here, we use an Asian-lineage ZIKV strain, isolated from the 2015 Mexican outbreak (Mex1-7), to infect primary human neural stem cells (hNSCs) originally derived from three individual fetal brains. All three strains of hNSCs exhibited similar rates of Mex1-7 infection and reduced proliferation. However, Mex1-7 decreased neuronal differentiation in only two of the three stem cell strains. Correspondingly, ZIKA-mediated transcriptome alterations were similar in these two strains but significantly different from that of the third strain with no ZIKV-induced neuronal reduction. This study thus confirms that an Asian-lineage ZIKV strain infects primary hNSCs and demonstrates a cell-strain-dependent response of hNSCs to ZIKV infection. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Putting the tritone paradox into context: insights from neural population decoding and human psychophysics.

    Science.gov (United States)

    Englitz, Bernhard; Akram, S; David, S V; Chambers, C; Pressnitzer, Daniel; Depireux, D; Fritz, J B; Shamma, Shihab A

    2013-01-01

    The context in which a stimulus occurs can influence its perception. We study contextual effects in audition using the tritone paradox, where a pair of complex (Shepard) tones separated by half an octave can be perceived as ascending or descending. While ambiguous in isolation, they are heard with a clear upward or downward change in pitch, when preceded by spectrally matched biasing sequences. We presented these biased Shepard pairs to awake ferrets and obtained neuronal responses from primary auditory cortex. Using dimensionality reduction from the neural population response, we decode the perceived pitch for each tone. The bias sequence is found to reliably shift the perceived pitch of the tones away from its central frequency. Using human psychophysics, we provide evidence that this shift in pitch is present in active human perception as well. These results are incompatible with the standard absolute distance decoder for Shepard tones, which would have predicted the bias to attract the tones. We propose a relative decoder that takes the stimulus history into account and is consistent with the present and other data sets.

  14. Neural and cortisol responses during play with human and computer partners in children with autism.

    Science.gov (United States)

    Edmiston, Elliot Kale; Merkle, Kristen; Corbett, Blythe A

    2015-08-01

    Children with autism spectrum disorder (ASD) exhibit impairment in reciprocal social interactions, including play, which can manifest as failure to show social preference or discrimination between social and nonsocial stimuli. To explore mechanisms underlying these deficits, we collected salivary cortisol from 42 children 8-12 years with ASD or typical development during a playground interaction with a confederate child. Participants underwent functional MRI during a prisoner's dilemma game requiring cooperation or defection with a human (confederate) or computer partner. Search region of interest analyses were based on previous research (e.g. insula, amygdala, temporal parietal junction-TPJ). There were significant group differences in neural activation based on partner and response pattern. When playing with a human partner, children with ASD showed limited engagement of a social salience brain circuit during defection. Reduced insula activation during defection in the ASD children relative to TD children, regardless of partner type, was also a prominent finding. Insula and TPJ BOLD during defection was also associated with stress responsivity and behavior in the ASD group under playground conditions. Children with ASD engage social salience networks less than TD children during conditions of social salience, supporting a fundamental disturbance of social engagement. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  15. Safety of human neural stem cell transplantation in chronic spinal cord injury.

    Science.gov (United States)

    Piltti, Katja M; Salazar, Desiree L; Uchida, Nobuko; Cummings, Brian J; Anderson, Aileen J

    2013-12-01

    The spinal cord injury (SCI) microenvironment undergoes dynamic changes over time, which could potentially affect survival or differentiation of cells in early versus delayed transplantation study designs. Accordingly, assessment of safety parameters, including cell survival, migration, fate, sensory fiber sprouting, and behavioral measures of pain sensitivity in animals receiving transplants during the chronic postinjury period is required for establishing a potential therapeutic window. The goal of the study was assessment of safety parameters for delayed transplantation of human central nervous system-derived neural stem cells (hCNS-SCns) by comparing hCNS-SCns transplantation in the subacute period, 9 days postinjury (DPI), versus the chronic period, 60 DPI, in contusion-injured athymic nude rats. Although the number of surviving human cells after chronic transplantation was lower, no changes in cell migration were detected between the 9 and 60 DPI cohorts; however, the data suggest chronic transplantation may have enhanced the generation of mature oligodendrocytes. The timing of transplantation did not induce changes in allodynia or hyperalgesia measures. Together, these data support the safety of hCNS-SCns transplantation in the chronic period post-SCI.

  16. Reducing the neural search space for hominid cognition: what distinguishes human and great ape brains from those of small apes?

    Science.gov (United States)

    Butler, David; Suddendorf, Thomas

    2014-06-01

    Differences in the psychological capacities of closely related species are likely due to differences in their brains. Here, we review neuroanatomical comparisons between hominids (i.e., great apes and humans) and their closest living relatives, the hylobatids (i.e., small apes). We report the differences in quantitative, as well as qualitative, neural characteristics on the basis of 19 comparative studies that each included representatives of all hominid genera and at least one genus of hylobatid. The current data are patchy, based on a small number of hylobatids and few neuroanatomical features. Yet a systematic interspecies comparison could help reduce the neuroanatomical search space for the neural correlates underlying psychological abilities restricted to hominids. We illustrate the potential power of this approach by discussing the neural features of visual self-recognition.

  17. Differential neural responses to child and sexual stimuli in human fathers and non-fathers and their hormonal correlates.

    Science.gov (United States)

    Mascaro, Jennifer S; Hackett, Patrick D; Rilling, James K

    2014-08-01

    Despite the well-documented importance of paternal caregiving for positive child development, little is known about the neural changes that accompany the transition to fatherhood in humans, or about how changes in hormone levels affect paternal brain function. We compared fathers of children aged 1-2 with non-fathers in terms of hormone levels (oxytocin and testosterone), neural responses to child picture stimuli, and neural responses to visual sexual stimuli. Compared to non-fathers, fathers had significantly higher levels of plasma oxytocin and lower levels of plasma testosterone. In response to child picture stimuli, fathers showed stronger activation than non-fathers within regions important for face emotion processing (caudal middle frontal gyrus [MFG]), mentalizing (temporo-parietal junction [TPJ]) and reward processing (medial orbitofrontal cortex [mOFC]). On the other hand, non-fathers had significantly stronger neural responses to sexually provocative images in regions important for reward and approach-related motivation (dorsal caudate and nucleus accumbens). Testosterone levels were negatively correlated with responses to child stimuli in the MFG. Surprisingly, neither testosterone nor oxytocin levels predicted neural responses to sexual stimuli. Our results suggest that the decline in testosterone that accompanies the transition to fatherhood may be important for augmenting empathy toward children. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors

    Energy Technology Data Exchange (ETDEWEB)

    Colleoni, Silvia, E-mail: silviacolleoni@avantea.it [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy); Galli, Cesare [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy); Dipartimento Clinico Veterinario, Universita di Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia (Italy); Giannelli, Serena G. [Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan (Italy); Armentero, Marie-Therese; Blandini, Fabio [Laboratory of Functional Neurochemistry, Interdepartmental Research Center for Parkinson' s Disease, Neurological Institute C. Mondino, Via Mondino 2, 27100 Pavia (Italy); Broccoli, Vania, E-mail: broccoli.vania@hsr.it [Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan (Italy); Lazzari, Giovanna, E-mail: giovannalazzari@avantea.it [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy)

    2010-04-15

    In this study we demonstrated that neural rosettes derived from human ES cells can give rise either to neural crest precursors, following expansion in presence of bFGF and EGF, or to dopaminergic precursors after exposure to ventralizing factors Shh and FGF8. Both regionalised precursors are capable of extensive proliferation and differentiation towards the corresponding terminally differentiated cell types. In particular, peripheral neurons, cartilage, bone, smooth muscle cells and also pigmented cells were obtained from neural crest precursors while tyrosine hydroxylase and Nurr1 positive dopaminergic neurons were derived from FGF8 and Shh primed rosette cells. Gene expression and immunocytochemistry analyses confirmed the expression of dorsal and neural crest genes such as Sox10, Slug, p75, FoxD3, Pax7 in neural precursors from bFGF-EGF exposed rosettes. By contrast, priming of rosettes with FGF8 and Shh induced the expression of dopaminergic markers Engrailed1, Pax2, Pitx3, floor plate marker FoxA2 and radial glia markers Blbp and Glast, the latter in agreement with the origin of dopaminergic precursors from floor plate radial glia. Moreover, in vivo transplant of proliferating Shh/FGF8 primed precursors in parkinsonian rats demonstrated engraftment and terminal dopaminergic differentiation. In conclusion, we demonstrated the derivation of long-term self-renewing precursors of selected regional identity as potential cell reservoirs for cell therapy applications, such as CNS degenerative diseases, or for the development of toxicological tests.

  19. Discrimination of human bodies from bones and teeth remains by Laser Induced Breakdown Spectroscopy and Neural Networks

    Energy Technology Data Exchange (ETDEWEB)

    Moncayo, S.; Manzoor, S.; Ugidos, T.; Navarro-Villoslada, F.; Caceres, J.O., E-mail: jcaceres@ucm.es

    2014-11-01

    A fast and minimally destructive method based on Laser Induced Breakdown Spectroscopy (LIBS) and Neural Networks (NN) has been developed and applied to the classification and discrimination of human bones and teeth fragments. The methodology can be useful in Disaster Victim Identification (DVI) tasks. The elemental compositions of bone and teeth samples provided enough information to achieve a correct discrimination and reassembling of different human remains. Individuals were classified with spectral correlation higher than 95%, regardless of the type of bone or tooth sample analyzed. No false positive or false negative was observed, demonstrating the high robustness and accuracy of the proposed methodology. - Highlights: • Classification and discrimination of human remains have been studied. • Remains were analyzed by Laser Induced Breakdown Spectroscopy (LIBS). • Neural Networks models (NN) were used. • Individuals were classified with spectral correlation higher than 95 %. • LIBS-NN showed the potential for rapid and cost-effective analysis.

  20. Generation of Regionally Specified Neural Progenitors and Functional Neurons from Human Embryonic Stem Cells under Defined Conditions

    Directory of Open Access Journals (Sweden)

    Agnete Kirkeby

    2012-06-01

    Full Text Available To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease.

  1. Neural mechanisms underlying catastrophic failure in human-machine interaction during aerial navigation

    Science.gov (United States)

    Saproo, Sameer; Shih, Victor; Jangraw, David C.; Sajda, Paul

    2016-12-01

    Objective. We investigated the neural correlates of workload buildup in a fine visuomotor task called the boundary avoidance task (BAT). The BAT has been known to induce naturally occurring failures of human-machine coupling in high performance aircraft that can potentially lead to a crash—these failures are termed pilot induced oscillations (PIOs). Approach. We recorded EEG and pupillometry data from human subjects engaged in a flight BAT simulated within a virtual 3D environment. Main results. We find that workload buildup in a BAT can be successfully decoded from oscillatory features in the electroencephalogram (EEG). Information in delta, theta, alpha, beta, and gamma spectral bands of the EEG all contribute to successful decoding, however gamma band activity with a lateralized somatosensory topography has the highest contribution, while theta band activity with a fronto-central topography has the most robust contribution in terms of real-world usability. We show that the output of the spectral decoder can be used to predict PIO susceptibility. We also find that workload buildup in the task induces pupil dilation, the magnitude of which is significantly correlated with the magnitude of the decoded EEG signals. These results suggest that PIOs may result from the dysregulation of cortical networks such as the locus coeruleus (LC)—anterior cingulate cortex (ACC) circuit. Significance. Our findings may generalize to similar control failures in other cases of tight man-machine coupling where gains and latencies in the control system must be inferred and compensated for by the human operators. A closed-loop intervention using neurophysiological decoding of workload buildup that targets the LC-ACC circuit may positively impact operator performance in such situations.

  2. Conversion of adult human peripheral blood mononuclear cells into induced neural stem cell by using episomal vectors

    Directory of Open Access Journals (Sweden)

    Xihe Tang

    2016-03-01

    Full Text Available Human neural stem cells (NSCs hold great promise for research and therapy in neural diseases. Many studies have shown direct induction of NSCs from human fibroblasts, which require an invasive skin biopsy and a prolonged period of expansion in cell culture prior to use. Peripheral blood (PB is routinely used in medical diagnoses, and represents a noninvasive and easily accessible source of cells. Here we show direct derivation of NSCs from adult human PB mononuclear cells (PB-MNCs by employing episomal vectors for transgene delivery. These induced NSCs (iNSCs can expand more than 60 passages, can exhibit NSC morphology, gene expression, differentiation potential, and self-renewing capability and can give rise to multiple functional neural subtypes and glial cells in vitro. Furthermore, the iNSCs carry a specific regional identity and have electrophysiological activity upon differentiation. Our findings provide an easily accessible approach for generating human iNSCs which will facilitate disease modeling, drug screening, and possibly regenerative medicine.

  3. Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla; O'Sullivan, Ursula; Harmer, Catherine J

    2007-01-01

    ) versus saline on the neural processing of happy and fearful faces in 23 healthy volunteers. Facial expression recognition was assessed outside the scanner. RESULTS: One week after administration, Epo reduced neural response to fearful versus neutral faces in the occipito-parietal cortex consistent...

  4. In vitro effects of Epidiferphane™ on adult human neural progenitor cells

    Science.gov (United States)

    Neural stem cells have the capacity to respond to their environment, migrate to the injury site and generate functional cell types, and thus they hold great promise for cell therapies. In addition to representing a source for central nervous system (CNS) repair, neural stem and progenitor cells als...

  5. Neural correlates of natural human echolocation in early and late blind echolocation experts.

    Directory of Open Access Journals (Sweden)

    Lore Thaler

    Full Text Available A small number of blind people are adept at echolocating silent objects simply by producing mouth clicks and listening to the returning echoes. Yet the neural architecture underlying this type of aid-free human echolocation has not been investigated. To tackle this question, we recruited echolocation experts, one early- and one late-blind, and measured functional brain activity in each of them while they listened to their own echolocation sounds.When we compared brain activity for sounds that contained both clicks and the returning echoes with brain activity for control sounds that did not contain the echoes, but were otherwise acoustically matched, we found activity in calcarine cortex in both individuals. Importantly, for the same comparison, we did not observe a difference in activity in auditory cortex. In the early-blind, but not the late-blind participant, we also found that the calcarine activity was greater for echoes reflected from surfaces located in contralateral space. Finally, in both individuals, we found activation in middle temporal and nearby cortical regions when they listened to echoes reflected from moving targets.These findings suggest that processing of click-echoes recruits brain regions typically devoted to vision rather than audition in both early and late blind echolocation experts.

  6. The uptake mechanism and biocompatibility of graphene quantum dots with human neural stem cells

    Science.gov (United States)

    Shang, Weihu; Zhang, Xiaoyan; Zhang, Mo; Fan, Zetan; Sun, Ying; Han, Mei; Fan, Louzhen

    2014-05-01

    Cellular imaging after transplantation may provide important information to determine the efficacy of stem cell therapy. We have reported that graphene quantum dots (GQDs) are a type of robust biological labeling agent for stem cells that demonstrate little cytotoxicity. In this study, we examined the interactions of GQDs on human neural stem cells (hNSCs) with the aim to investigate the uptake and biocompatibility of GQDs. We examined the mechanism of GQD uptake by hNSCs and investigated the effects of GQDs on the proliferation, metabolic activity, and differentiation potential of hNSCs. This information is critical to assess the suitability of GQDs for stem cell tracking. Our results indicated that GQDs were taken up into hNSCs in a concentration- and time-dependent manner via the endocytosis mechanism. Furthermore, no significant change was found in the viability, proliferation, metabolic activity, and differentiation potential of hNSCs after treatment with GQDs. Thus, these data open a promising avenue for labeling stem cells with GQDs and also offer a potential opportunity to develop GQDs for biomedical applications.

  7. Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Tingting Dou

    2016-01-01

    Full Text Available Compelling evidences have shown that diverse environmental insults arising during early life can either directly lead to a reduction in the number of dopaminergic neurons or cause an increased susceptibility to neurons degeneration with subsequent environmental insults or with aging alone. Oxidative stress is considered the main effect of neurotoxins exposure. In this study, we investigated the oxidative stress effect of Paraquat (PQ on immortalized human embryonic neural progenitor cells by treating them with various concentrations of PQ. We show that PQ can decrease the activity of SOD and CAT but increase MDA and LDH level. Furthermore, the activities of Cyc and caspase-9 were found increased significantly at 10 μM of PQ treatment. The cytoplasmic Nrf2 protein expressions were upregulated at 10 μM but fell back at 100 μM. The nuclear Nrf2 protein expressions were upregulated as well as the downstream mRNA expressions of HO-1 and NQO1 in a dose-dependent manner. In addition, the proteins expression of PKC and CKII was also increased significantly even at 1 μM. The results suggested that Nrf2/ARE pathway is involved in mild to moderate PQ-induced oxidative stress which is evident from dampened Nrf2 activity and low expression of antioxidant genes in PQ induced oxidative damage.

  8. BrainSegNet: a convolutional neural network architecture for automated segmentation of human brain structures.

    Science.gov (United States)

    Mehta, Raghav; Majumdar, Aabhas; Sivaswamy, Jayanthi

    2017-04-01

    Automated segmentation of cortical and noncortical human brain structures has been hitherto approached using nonrigid registration followed by label fusion. We propose an alternative approach for this using a convolutional neural network (CNN) which classifies a voxel into one of many structures. Four different kinds of two-dimensional and three-dimensional intensity patches are extracted for each voxel, providing local and global (context) information to the CNN. The proposed approach is evaluated on five different publicly available datasets which differ in the number of labels per volume. The obtained mean Dice coefficient varied according to the number of labels, for example, it is [Formula: see text] and [Formula: see text] for datasets with the least (32) and the most (134) number of labels, respectively. These figures are marginally better or on par with those obtained with the current state-of-the-art methods on nearly all datasets, at a reduced computational time. The consistently good performance of the proposed method across datasets and no requirement for registration make it attractive for many applications where reduced computational time is necessary.

  9. Neural differentiation of choroid plexus epithelial cells: role of human traumatic cerebrospinal fluid

    Directory of Open Access Journals (Sweden)

    Elham Hashemi

    2017-01-01

    Full Text Available As the key producer of cerebrospinal fluid (CSF, the choroid plexus (CP provides a unique protective system in the central nervous system. CSF components are not invariable and they can change based on the pathological conditions of the central nervous system. The purpose of the present study was to assess the effects of non-traumatic and traumatic CSF on the differentiation of multipotent stem-like cells of CP into the neural and/or glial cells. CP epithelial cells were isolated from adult male rats and treated with human non-traumatic and traumatic CSF. Alterations in mRNA expression of Nestin and microtubule-associated protein (MAP2, as the specific markers of neurogenesis, and astrocyte marker glial fibrillary acidic protein (GFAP in cultured CP epithelial cells were evaluated using quantitative real-time PCR. The data revealed that treatment with CSF (non-traumatic and traumatic led to increase in mRNA expression levels of MAP2 and GFAP. Moreover, the expression of Nestin decreased in CP epithelial cells treated with non-traumatic CSF, while treatment with traumatic CSF significantly increased its mRNA level compared to the cells cultured only in DMEM/F12 as control. It seems that CP epithelial cells contain multipotent stem-like cells which are inducible under pathological conditions including exposure to traumatic CSF because of its compositions.

  10. Near infrared laser stimulation of human neural stem cells into neurons on graphene nanomesh semiconductors.

    Science.gov (United States)

    Akhavan, Omid; Ghaderi, Elham; Shirazian, Soheil A

    2015-02-01

    Reduced graphene oxide nanomeshes (rGONMs), as p-type semiconductors with band-gap energy of ∼ 1 eV, were developed and applied in near infrared (NIR) laser stimulation of human neural stem cells (hNSCs) into neurons. The biocompatibility of the rGONMs in growth of hNSCs was found similar to that of the graphene oxide (GO) sheets. Proliferation of the hNSCs on the GONMs was assigned to the excess oxygen functional groups formed on edge defects of the GONMs, resulting in superhydrophilicity of the surface. Under NIR laser stimulation, the graphene layers (especially the rGONMs) exhibited significant cell differentiations, including more elongations of the cells and higher differentiation of neurons than glia. The higher hNSC differentiation on the rGONM than the reduced GO (rGO) was assigned to the stimulation effects of the low-energy photoexcited electrons injected from the rGONM semiconductors into the cells, while the high-energy photoelectrons of the rGO (as a zero band-gap semiconductor) could suppress the cell proliferation and/or even cause cell damages. Using conventional heating of the culture media up to ∼ 43 °C (the temperature typically reached under the laser irradiation), no significant differentiation was observed in dark. This further confirmed the role of photoelectrons in the hNSC differentiation. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Differentiation of human neural progenitor cells regulated by Wnt-3a.

    Science.gov (United States)

    Hübner, Rayk; Schmöle, Anne-Caroline; Liedmann, Andrea; Frech, Moritz J; Rolfs, Arndt; Luo, Jiankai

    2010-09-24

    Wnt ligands play pivotal roles in the control of cell growth and differentiation during central nervous system development via the Wnt signaling pathway. In this study, we investigated the effects of Wnt-3a and β-catenin on the differentiation of ReNcell VM human neural progenitor cells. After overexpression of Wnt-3a or mutant-stabilized β-catenin in ReNcell VM cells, their effects on TCF-mediated transcription, Wnt target gene expression and differentiation into neuronal and glial cells were investigated. Our results show that activation of Wnt/β-catenin signaling increases TCF-mediated transcription and the expression of the Wnt target genes Axin2, LEF1 and CyclinD1 in ReNcell VM cells. In contrast to mutant-stabilized β-catenin, Wnt-3a increases neurogenesis during the differentiation of ReNcell VM cells. Thus, our data suggest that neurogenesis induced by Wnt-3a is independent of the transcriptional activity of Wnt/β-catenin pathway in ReNcell VM cells. Copyright © 2010 Elsevier Inc. All rights reserved.

  12. Neural correlates of natural human echolocation in early and late blind echolocation experts.

    Science.gov (United States)

    Thaler, Lore; Arnott, Stephen R; Goodale, Melvyn A

    2011-01-01

    A small number of blind people are adept at echolocating silent objects simply by producing mouth clicks and listening to the returning echoes. Yet the neural architecture underlying this type of aid-free human echolocation has not been investigated. To tackle this question, we recruited echolocation experts, one early- and one late-blind, and measured functional brain activity in each of them while they listened to their own echolocation sounds. When we compared brain activity for sounds that contained both clicks and the returning echoes with brain activity for control sounds that did not contain the echoes, but were otherwise acoustically matched, we found activity in calcarine cortex in both individuals. Importantly, for the same comparison, we did not observe a difference in activity in auditory cortex. In the early-blind, but not the late-blind participant, we also found that the calcarine activity was greater for echoes reflected from surfaces located in contralateral space. Finally, in both individuals, we found activation in middle temporal and nearby cortical regions when they listened to echoes reflected from moving targets. These findings suggest that processing of click-echoes recruits brain regions typically devoted to vision rather than audition in both early and late blind echolocation experts.

  13. Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation.

    Science.gov (United States)

    Milosevic, Javorina; Schwarz, Sigrid C; Ogunlade, Vera; Meyer, Anne K; Storch, Alexander; Schwarz, Johannes

    2009-06-15

    Despite a comprehensive mapping of the Parkinson's disease (PD)-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2) in the mammalian brain, its physiological function in healthy individuals remains enigmatic. Based on its structural features and kinase properties, LRRK2 may interact with other proteins involved in signalling pathways. Here, we show a widespread LRRK2 mRNA and/or protein expression in expanded or differentiated human mesencephalic neural progenitor cells (hmNPCs) and in post-mortem substantia nigra PD patients. Using small interfering RNA duplexes targeting LRRK2 in hmNPCs following their differentiation into glia and neurons, we observed a reduced number of dopaminergic neurons due to apoptosis in LRRK2 knockdown samples. LRRK2-deficient hmNPCs exhibited elevated cell cycle- and cell death-related markers. In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle.

  14. Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation

    Directory of Open Access Journals (Sweden)

    Meyer Anne K

    2009-06-01

    Full Text Available Abstract Despite a comprehensive mapping of the Parkinson's disease (PD-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2 in the mammalian brain, its physiological function in healthy individuals remains enigmatic. Based on its structural features and kinase properties, LRRK2 may interact with other proteins involved in signalling pathways. Here, we show a widespread LRRK2 mRNA and/or protein expression in expanded or differentiated human mesencephalic neural progenitor cells (hmNPCs and in post-mortem substantia nigra PD patients. Using small interfering RNA duplexes targeting LRRK2 in hmNPCs following their differentiation into glia and neurons, we observed a reduced number of dopaminergic neurons due to apoptosis in LRRK2 knockdown samples. LRRK2-deficient hmNPCs exhibited elevated cell cycle- and cell death-related markers. In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle.

  15. The Promotion of Human Neural Stem Cells Adhesion Using Bioinspired Poly(norepinephrine Nanoscale Coating

    Directory of Open Access Journals (Sweden)

    Minah Park

    2014-01-01

    Full Text Available The establishment of versatile biomaterial interfaces that can facilitate cellular adhesion is crucial for elucidating the cellular processes that occur on biomaterial surfaces. Furthermore, biomaterial interfaces can provide physical or chemical cues that are capable of stimulating cellular behaviors by regulating intracellular signaling cascades. Herein, a method of creating a biomimetic functional biointerface was introduced to enhance human neural stem cell (hNSC adhesion. The hNSC-compatible biointerface was prepared by the oxidative polymerization of the neurotransmitter norepinephrine, which generates a nanoscale organic thin layer, termed poly(norepinephrine (pNE. Due to its adhesive property, pNE resulted in an adherent layer on various substrates, and pNE-coated biointerfaces provided a highly favorable microenvironment for hNSCs, with no observed cytotoxicity. Only a 2-hour incubation of hNSCs was required to firmly attach the stem cells, regardless of the type of substrate. Importantly, the adhesive properties of pNE interfaces led to micropatterns of cellular attachment, thereby demonstrating the ability of the interface to organize the stem cells. This highly facile surface-modification method using a biomimetic pNE thin layer can be applied to a number of suitable materials that were previously not compatible with hNSC technology.

  16. Hypoxia Epigenetically Confers Astrocytic Differentiation Potential on Human Pluripotent Cell-Derived Neural Precursor Cells

    Directory of Open Access Journals (Sweden)

    Tetsuro Yasui

    2017-06-01

    Full Text Available Human neural precursor cells (hNPCs derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia-inducible factor 1α and Notch signaling, accompanied by a reduction of DNA methylation level in the promoter region of a typical astrocyte-specific gene, Glial fibrillary acidic protein. Furthermore, we found that this hypoxic culture condition could be applied to rapid generation of astrocytes from Rett syndrome patient-derived hNPCs, and that these astrocytes impaired neuronal development. Thus, our findings shed further light on the molecular mechanisms regulating hNPC differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders.

  17. Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis

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    Lu Chen

    2014-06-01

    Full Text Available Using a viral model of the demyelinating disease multiple sclerosis (MS, we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination. Evidence indicates that the reduced neuroinflammation is correlated with an increased number of CD4+CD25+FOXP3+ regulatory T cells (Tregs within the spinal cords. Coculture of hNPCs with activated T cells resulted in reduced T cell proliferation and increased Treg numbers. The hNPCs acted, in part, through secretion of TGF-β1 and TGF-β2. These findings indicate that the transient presence of hNPCs transplanted in an animal model of MS has powerful immunomodulatory effects and mediates recovery. Further investigation of the restorative effects of hNPC transplantation may aid in the development of clinically relevant MS treatments.

  18. Injury to the Spinal Cord Niche Alters the Engraftment Dynamics of Human Neural Stem Cells

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    Christopher J. Sontag

    2014-05-01

    Full Text Available The microenvironment is a critical mediator of stem cell survival, proliferation, migration, and differentiation. The majority of preclinical studies involving transplantation of neural stem cells (NSCs into the CNS have focused on injured or degenerating microenvironments, leaving a dearth of information as to how NSCs differentially respond to intact versus damaged CNS. Furthermore, single, terminal histological endpoints predominate, providing limited insight into the spatiotemporal dynamics of NSC engraftment and migration. We investigated the early and long-term engraftment dynamics of human CNS stem cells propagated as neurospheres (hCNS-SCns following transplantation into uninjured versus subacutely injured spinal cords of immunodeficient NOD-scid mice. We stereologically quantified engraftment, survival, proliferation, migration, and differentiation at 1, 7, 14, 28, and 98 days posttransplantation, and identified injury-dependent alterations. Notably, the injured microenvironment decreased hCNS-SCns survival, delayed and altered the location of proliferation, influenced both total and fate-specific migration, and promoted oligodendrocyte maturation.

  19. Chitosan scaffolds induce human dental pulp stem cells to neural differentiation: potential roles for spinal cord injury therapy.

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    Zhang, Jinlong; Lu, Xiaohui; Feng, Guijuan; Gu, Zhifeng; Sun, Yuyu; Bao, Guofeng; Xu, Guanhua; Lu, Yuanzhou; Chen, Jiajia; Xu, Lingfeng; Feng, Xingmei; Cui, Zhiming

    2016-10-01

    Cell-based transplantation strategies hold great potential for spinal cord injury (SCI) repair. Chitosan scaffolds have therapeutic benefits for spinal cord regeneration. Human dental pulp stem cells (DPSCs) are abundant available stem cells with low immunological incompatibility and can be considered for cell replacement therapy. The purpose of this study is to investigate the role of chitosan scaffolds in the neural differentiation of DPSCs in vitro and to assess the supportive effects of chitosan scaffolds in an animal model of SCI. DPSCs were incubated with chitosan scaffolds. Cell viability and the secretion of neurotrophic factors were analyzed. DPSCs incubated with chitosan scaffolds were treated with neural differentiation medium for 14 days and then neural genes and protein markers were analyzed by Western blot and reverse transcription plus the polymerase chain reaction. Our study revealed a higher cell viability and neural differentiation in the DPSC/chitosan-scaffold group. Compared with the control group, the levels of BDNF, GDNF, b-NGF, and NT-3 were significantly increased in the DPSC/chitosan-scaffold group. The Wnt/β-catenin signaling pathway played a key role in the neural differentiation of DPSCs combined with chitosan scaffolds. Transplantation of DPSCs together with chitosan scaffolds into an SCI rat model resulted in the marked recovery of hind limb locomotor functions. Thus, chitosan scaffolds were non-cytotoxic and provided a conducive and favorable microenvironment for the survival and neural differentiation of DPSCs. Transplantation of DPSCs might therefore be a suitable candidate for treating SCI and other neuronal degenerative diseases.

  20. Self-Organizing Neural Integration of Pose-Motion Features for Human Action Recognition

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    German Ignacio Parisi

    2015-06-01

    Full Text Available The visual recognition of complex, articulated human movements is fundamental for a wide range of artificial systems oriented towards human-robot communication, action classification, and action-driven perception. These challenging tasks may generally involve the processing of a huge amount of visual information and learning-based mechanisms for generalizing a set of training actions and classifying new samples. To operate in natural environments, a crucial property is the efficient and robust recognition of actions, also under noisy conditions caused by, for instance, systematic sensor errors and temporarily occluded persons. Studies of the mammalian visual system and its outperforming ability to process biological motion information suggest separate neural pathways for the distinct processing of pose and motion features at multiple levels and the subsequent integration of these visual cues for action perception. We present a neurobiologically-motivated approach to achieve noise-tolerant action recognition in real time. Our model consists of self-organizing Growing When Required (GWR networks that obtain progressively generalized representations of sensory inputs and learn inherent spatiotemporal dependencies. During the training, the GWR networks dynamically change their topological structure to better match the input space. We first extract pose and motion features from video sequences and then cluster actions in terms of prototypical pose-motion trajectories. Multi-cue trajectories from matching action frames are subsequently combined to provide action dynamics in the joint feature space. Reported experiments show that our approach outperforms previous results on a dataset of full-body actions captured with a depth sensor, and ranks among the best 21 results for a public benchmark of domestic daily actions.

  1. Gold- and silver nanoparticles affect the growth characteristics of human embryonic neural precursor cells.

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    Erika Söderstjerna

    Full Text Available Rapid development of nanotechnologies and their applications in clinical research have raised concerns about the adverse effects of nanoparticles (NPs on human health and environment. NPs can be directly taken up by organs exposed, but also translocated to secondary organs, such as the central nervous system (CNS after systemic- or subcutaneous administration, or via the olfactory system. The CNS is particularly vulnerable during development and recent reports describe transport of NPs across the placenta and even into brain tissue using in vitro and in vivo experimental systems. Here, we investigated whether well-characterized commercial 20 and 80 nm Au- and AgNPs have an effect on human embryonic neural precursor cell (HNPC growth. After two weeks of NP exposure, uptake of NPs, morphological features and the amount of viable and dead cells, proliferative cells (Ki67 immunostaining and apoptotic cells (TUNEL assay, respectively, were studied. We demonstrate uptake of both 20 and 80 nm Au- and AgNPs respectively, by HNPCs during proliferation. A significant effect on the sphere size- and morphology was found for all cultures exposed to Au- and AgNPs. AgNPs of both sizes caused a significant increase in numbers of proliferating and apoptotic HNPCs. In contrast, only the highest dose of 20 nm AuNPs significantly affected proliferation, whereas no effect was seen on apoptotic cell death. Our data demonstrates that both Au- and AgNPs interfere with the growth profile of HNPCs, indicating the need of further detailed studies on the adverse effects of NPs on the developing CNS.

  2. Effects of Polyamidoamine Dendrimers on a 3-D Neurosphere System Using Human Neural Progenitor Cells.

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    Zeng, Yang; Kurokawa, Yoshika; Zeng, Qin; Win-Shwe, Tin-Tin; Nansai, Hiroko; Zhang, Zhenya; Sone, Hideko

    2016-07-01

    The practical application of engineered nanomaterials or nanoparticles like polyamidoamine (PAMAM) dendrimers has been promoted in medical devices or industrial uses. The safety of PAMAM dendrimers needs to be assessed when used as a drug carrier to treat brain disease. However, the effects of PAMAM on the human nervous system remain unknown. In this study, human neural progenitor cells cultured as a 3D neurosphere model were used to study the effects of PAMAM dendrimers on the nervous system. Neurospheres were exposed to different G4-PAMAM dendrimers for 72 h at concentrations of 0.3, 1, 3, and 10 μg/ml. The biodistribution was investigated using fluorescence-labeled PAMAM dendrimers, and gene expression was evaluated using microarray analysis followed by pathway and network analysis. Results showed that PAMAM dendrimer nanoparticles can penetrate into neurospheres via superficial cells on them. PAMAM-NH2 but not PAMAM-SC can inhibit neurosphere growth. A reduced number of MAP2-positive cells in flare regions were inhibited after 10 days of differentiation, indicating an inhibitory effect of PAMAM-NH2 on cell proliferation and neuronal migration. A microarray assay showed 32 dendrimer toxicity-related genes, with network analysis showing 3 independent networks of the selected gene targets. Inducible immediate early gene early growth response gene 1 (Egr1), insulin-like growth factor-binding protein 3 (IGFBP3), tissue factor pathway inhibitor (TFPI2), and adrenomedullin (ADM) were the key genes in each network, and the expression of these genes was significantly down regulated. These findings suggest that exposure of neurospheres to PAMAM-NH2 dendrimers affects cell proliferation and migration through pathways regulated by Egr1, IGFBP3, TFPI2, and ADM. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. The neural dynamics of reward value and risk coding in the human orbitofrontal cortex.

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    Li, Yansong; Vanni-Mercier, Giovanna; Isnard, Jean; Mauguière, François; Dreher, Jean-Claude

    2016-04-01

    The orbitofrontal cortex is known to carry information regarding expected reward, risk and experienced outcome. Yet, due to inherent limitations in lesion and neuroimaging methods, the neural dynamics of these computations has remained elusive in humans. Here, taking advantage of the high temporal definition of intracranial recordings, we characterize the neurophysiological signatures of the intact orbitofrontal cortex in processing information relevant for risky decisions. Local field potentials were recorded from the intact orbitofrontal cortex of patients suffering from drug-refractory partial epilepsy with implanted depth electrodes as they performed a probabilistic reward learning task that required them to associate visual cues with distinct reward probabilities. We observed three successive signals: (i) around 400 ms after cue presentation, the amplitudes of the local field potentials increased with reward probability; (ii) a risk signal emerged during the late phase of reward anticipation and during the outcome phase; and (iii) an experienced value signal appeared at the time of reward delivery. Both the medial and lateral orbitofrontal cortex encoded risk and reward probability while the lateral orbitofrontal cortex played a dominant role in coding experienced value. The present study provides the first evidence from intracranial recordings that the human orbitofrontal cortex codes reward risk both during late reward anticipation and during the outcome phase at a time scale of milliseconds. Our findings offer insights into the rapid mechanisms underlying the ability to learn structural relationships from the environment. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Neurogenin-2-transduced human neural progenitor cells attenuate neonatal hypoxic-ischemic brain injury.

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    Lee, Il-Shin; Koo, Kyo Yeon; Jung, Kwangsoo; Kim, Miri; Kim, Il-Sun; Hwang, Kyujin; Yun, Seokhwan; Lee, Haejin; Shin, Jeong Eun; Park, Kook In

    2017-05-01

    Neonatal hypoxic-ischemic (HI) brain injury leads to high mortality and neurodevelopmental disabilities. Multipotent neural progenitor cells (NPCs) with self-renewing capacity have the potential to reduce neuronal loss and improve the compromised environment in the HI brain injury. However, the therapeutic efficacy of neuronal-committed progenitor cells and the underlying mechanisms of recovery are not yet fully understood. Therefore, this study investigated the regenerative ability and action mechanisms of neuronally committed human NPCs (hNPCs) transduced with neurogenin-2 (NEUROG2) in neonatal HI brain injury. NEUROG2- or green fluorescent protein (GFP)-encoding adenoviral vector-transduced hNPCs (NEUROG2- or GFP-NPCs) were transplanted into neonatal mouse brains with HI injury. Grafted NEUROG2-NPCs showed robust dispersion and engraftment, prolonged survival, and neuronal differentiation in HI brain injury. NEUROG2-NPCs significantly improved neurological behaviors, decreased cellular apoptosis, and increased the neurite outgrowth and axonal sprouting in HI brain injury. In contrast, GFP-NPC grafts moderately enhanced axonal extension with limited behavioral recovery. Notably, NEUROG2-NPCs showed increased secretion of multiple factors, such as nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 (NTF3), fibroblast growth factor 9 (FGF9), ciliary neurotrophic factor (CNTF), and thrombospondins 1 and 2 (THBS 1/2), which promoted SH-SY5Y neuroblastoma cell survival and neurite outgrowth. Thus, we postulate that NEUROG2-expressing human NPCs facilitate functional recovery after neonatal HI brain injury via their ability to secrete multiple factors that enhance neuronal survival and neuroplasticity. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation.

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    Acharya, Munjal M; Christie, Lori-Ann; Hazel, Thomas G; Johe, Karl K; Limoli, Charles L

    2014-01-01

    Treatment of central nervous system (CNS) malignancies typically involves radiotherapy to forestall tumor growth and recurrence following surgical resection. Despite the many benefits of cranial radiotherapy, survivors often suffer from a wide range of debilitating and progressive cognitive deficits. Thus, while patients afflicted with primary and secondary malignancies of the CNS now experience longer local regional control and progression-free survival, there remains no clinical recourse for the unintended neurocognitive sequelae associated with their cancer treatments. Multiple mechanisms contribute to disrupted cognition following irradiation, including the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. We have explored the potential of using intrahippocampal transplantation of human stem cells to ameliorate radiation-induced cognitive dysfunction. Past studies demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4 months after cranial irradiation. The present study employed an FDA-approved fetal-derived hNSC line capable of large scale-up under good manufacturing practice (GMP). Animals receiving cranial transplantation of these cells 1 month following irradiation showed improved hippocampal spatial memory and contextual fear conditioning performance compared to irradiated, sham surgery controls. Significant newly born (doublecortin positive) neurons and a smaller fraction of glial subtypes were observed within and nearby the transplantation core. Engrafted cells migrated and differentiated into neuronal and glial subtypes throughout the CA1 and CA3 subfields of the host hippocampus. These studies expand our prior findings to demonstrate that transplantation of fetal-derived hNSCs improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks.

  6. A study on the possible involvement of the PAX3 gene in human neural tube defects

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    Hol, F.A.; Hamel, B.C.J.; Geurds, M.P.A. [University Hospital Nijmegen (Netherlands)] [and others

    1994-09-01

    Neural tube defects (NTD) are congenital malformations of the central nervous system which are generally attributed to a combination of environmental and genetic factors. Recently, the molecular defect responsible for the phenotype of the Splotch mouse, a monogenic model system for NTD, was determined. A mutation disrupts the homeodomain of the gene for Pax3. In humans, mutations in the cognate gene for PAX3 can cause Waardenburg syndrome (WS), which is associated with NTD. Based on these findings, PAX3 can be regarded as a candidate gene for human NTD. To test this hypothesis we have screened the DNA of 39 familial and 70 sporadic NTD patients for mutations in the coding exons and flanking intron sequences of the PAX3 gene. SSC analysis revealed abnormal bands in exon 2, exon 5, exon 6 and exon 7 in different patients. A missense mutation was identified in exon 6 downstream from the homeodomain in several patients resulting in an amino acid substitution (Thr315Lys) in the protein. However, the same substitution was detected in unaffected controls suggesting no biological significance. Above shifts most likely represent polymorphisms that are irrelevant for NTD. A conspicuous SSC-band shift was observed in exon 5 of one familial patient with spina bifida. Sequencing revealed that the patient was heterozygous for a 5 bp deletion upstream of the homeodomain. The deletion causes a frameshift, which leads to premature termination of translation. Mild characteristics of WS were detected in several members of the family including the index patient. DNA analysis showed co-segregation of the mutation with these symptoms. Although PAX3 mutations can increase the penetrance of NTD in families with WS, our results show that their presence is not sufficient to cause NTD.

  7. High-frequency neural activity and human cognition: past, present and possible future of intracranial EEG research

    Science.gov (United States)

    Lachaux, Jean-Philippe; Axmacher, Nikolai; Mormann, Florian; Halgren, Eric; Crone, Nathan E.

    2013-01-01

    Human intracranial EEG (iEEG) recordings are primarily performed in epileptic patients for presurgical mapping. When patients perform cognitive tasks, iEEG signals reveal high-frequency neural activities (HFA, between around 40 Hz and 150 Hz) with exquisite anatomical, functional and temporal specificity. Such HFA were originally interpreted in the context of perceptual or motor binding, in line with animal studies on gamma-band (‘40Hz’) neural synchronization. Today, our understanding of HFA has evolved into a more general index of cortical processing: task-induced HFA reveals, with excellent spatial and time resolution, the participation of local neural ensembles in the task-at-hand, and perhaps the neural communication mechanisms allowing them to do so. This review promotes the claim that studying HFA with iEEG provides insights into the neural bases of cognition that cannot be derived as easily from other approaches, such as fMRI. We provide a series of examples supporting that claim, drawn from studies on memory, language and default-mode networks, and successful attempts of real-time functional mapping. These examples are followed by several guidelines for HFA research, intended for new groups interested by this approach. Overall, iEEG research on HFA should play an increasing role in cognitive neuroscience in humans, because it can be explicitly linked to basic research in animals. We conclude by discussing the future evolution of this field, which might expand that role even further, for instance through the use of multi-scale electrodes and the fusion of iEEG with MEG and fMRI. PMID:22750156

  8. An externally head-mounted wireless neural recording device for laboratory animal research and possible human clinical use.

    Science.gov (United States)

    Yin, Ming; Li, Hao; Bull, Christopher; Borton, David A; Aceros, Juan; Larson, Lawrence; Nurmikko, Arto V

    2013-01-01

    In this paper we present a new type of head-mounted wireless neural recording device in a highly compact package, dedicated for untethered laboratory animal research and designed for future mobile human clinical use. The device, which takes its input from an array of intracortical microelectrode arrays (MEA) has ninety-seven broadband parallel neural recording channels and was integrated on to two custom designed printed circuit boards. These house several low power, custom integrated circuits, including a preamplifier ASIC, a controller ASIC, plus two SAR ADCs, a 3-axis accelerometer, a 48MHz clock source, and a Manchester encoder. Another ultralow power RF chip supports an OOK transmitter with the center frequency tunable from 3GHz to 4GHz, mounted on a separate low loss dielectric board together with a 3V LDO, with output fed to a UWB chip antenna. The IC boards were interconnected and packaged in a polyether ether ketone (PEEK) enclosure which is compatible with both animal and human use (e.g. sterilizable). The entire system consumes 17mA from a 1.2Ahr 3.6V Li-SOCl2 1/2AA battery, which operates the device for more than 2 days. The overall system includes a custom RF receiver electronics which are designed to directly interface with any number of commercial (or custom) neural signal processors for multi-channel broadband neural recording. Bench-top measurements and in vivo testing of the device in rhesus macaques are presented to demonstrate the performance of the wireless neural interface.

  9. Characterization of Apoptosis Signaling Cascades During the Differentiation Process of Human Neural ReNcell VM Progenitor Cells In Vitro.

    Science.gov (United States)

    Jaeger, Alexandra; Fröhlich, Michael; Klum, Susanne; Lantow, Margareta; Viergutz, Torsten; Weiss, Dieter G; Kriehuber, Ralf

    2015-11-01

    Apoptosis is an essential physiological process accompanying the development of the central nervous system and human neurogenesis. However, the time scale and the underlying molecular mechanisms are yet poorly understood. Due to this fact, we investigated the functionality and general inducibility of apoptosis in the human neural ReNcell VM progenitor cell line during differentiation and also after exposure to staurosporine (STS) and ultraviolet B (UVB) irradiation. Transmission light microscopy, flow cytometry, and Western-/Immunoblot analysis were performed to compare proliferating and differentiating, in addition to STS- and UVB-treated cells. In particular, from 24 to 72 h post-initiation of differentiation, G0/G1 cell cycle arrest, increased loss of apoptotic cells, activation of pro-apoptotic BAX, Caspase-3, and cleavage of its substrate PARP were observed during cell differentiation and, to a higher extent, after treatment with STS and UVB. We conclude that redundant or defective cells are eliminated by apoptosis, while otherwise fully differentiated cells were less responsive to apoptosis induction by STS than proliferating cells, likely as a result of reduced APAF-1 expression, and increased levels of BCL-2. These data provide the evidence that apoptotic mechanisms in the neural ReNcell VM progenitor cell line are not only functional, but also inducible by external stimuli like growth factor withdrawal or treatment with STS and UVB, which marks this cell line as a suitable model to investigate apoptosis signaling pathways in respect to the differentiation processes of human neural progenitor cells in vitro.

  10. Quantitative and kinetic profile of Wnt/β-catenin signaling components during human neural progenitor cell differentiation.

    Science.gov (United States)

    Mazemondet, Orianne; Hubner, Rayk; Frahm, Jana; Koczan, Dirk; Bader, Benjamin M; Weiss, Dieter G; Uhrmacher, Adelinde M; Frech, Moritz J; Rolfs, Arndt; Luo, Jiankai

    2011-12-01

    ReNcell VM is an immortalized human neural progenitor cell line with the ability to differentiate in vitro into astrocytes and neurons, in which the Wnt/β-catenin pathway is known to be involved. However, little is known about kinetic changes of this pathway in human neural progenitor cell differentiation. In the present study, we provide a quantitative profile of Wnt/β-catenin pathway dynamics showing its spatio-temporal regulation during ReNcell VM cell differentiation. We show first that T-cell factor dependent transcription can be activated by stabilized β-catenin. Furthermore, endogenous Wnt ligands, pathway receptors and signaling molecules are temporally controlled, demonstrating changes related to differentiation stages. During the first three hours of differentiation the signaling molecules LRP6, Dvl2 and β-catenin are spatio-temporally regulated between distinct cellular compartments. From 24 h onward, components of the Wnt/β-catenin pathway are strongly activated and regulated as shown by mRNA up-regulation of Wnt ligands (Wnt5a and Wnt7a), receptors including Frizzled-2, -3, -6, -7, and -9, and co-receptors, and target genes including Axin2. This detailed temporal profile of the Wnt/β-catenin pathway is a first step to understand, control and to orientate, in vitro, human neural progenitor cell differentiation.

  11. Electromagnetic fields induce neural differentiation of human bone marrow derived mesenchymal stem cells via ROS mediated EGFR activation.

    Science.gov (United States)

    Park, Jeong-Eun; Seo, Young-Kwon; Yoon, Hee-Hoon; Kim, Chan-Wha; Park, Jung-Keug; Jeon, Songhee

    2013-03-01

    Even though the inducing effect of electromagnetic fields (EMF) on the neural differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) is a distinctive, the underlying mechanism of differentiation remains unclear. To find out the signaling pathways involved in the neural differentiation of BM-MSCs by EMF, we examined the CREB phosphorylation and Akt or ERK activation as an upstream of CREB. In hBM-MSCs treated with ELF-EMF (50 Hz, 1 mT), the expression of neural markers such as NF-L, MAP2, and NeuroD1 increased at 6 days and phosphorylation of Akt and CREB but not ERK increased at 90 min in BM-MSCs. Moreover, EMF increased phosphorylation of epidermal growth factor receptor (EGFR) as an upstream receptor tyrosine kinase of PI3K/Akt at 90 min. It has been well documented that ELF-MF exposure may alter cellular processes by increasing intracellular reactive oxygen species (ROS) concentrations. Thus, we examined EMF-induced ROS production in BM-MSCs. Moreover, pretreatment with a ROS scavenger, N-acetylcystein, and an EGFR inhibitor, AG-1478, prevented the phosphorylation of EGFR and downstream molecules. These results suggest that EMF induce neural differentiation through activation of EGFR signaling and mild generation of ROS. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. A computational model incorporating neural stem cell dynamics reproduces glioma incidence across the lifespan in the human population.

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    Roman Bauer

    Full Text Available Glioma is the most common form of primary brain tumor. Demographically, the risk of occurrence increases until old age. Here we present a novel computational model to reproduce the probability of glioma incidence across the lifespan. Previous mathematical models explaining glioma incidence are framed in a rather abstract way, and do not directly relate to empirical findings. To decrease this gap between theory and experimental observations, we incorporate recent data on cellular and molecular factors underlying gliomagenesis. Since evidence implicates the adult neural stem cell as the likely cell-of-origin of glioma, we have incorporated empirically-determined estimates of neural stem cell number, cell division rate, mutation rate and oncogenic potential into our model. We demonstrate that our model yields results which match actual demographic data in the human population. In particular, this model accounts for the observed peak incidence of glioma at approximately 80 years of age, without the need to assert differential susceptibility throughout the population. Overall, our model supports the hypothesis that glioma is caused by randomly-occurring oncogenic mutations within the neural stem cell population. Based on this model, we assess the influence of the (experimentally indicated decrease in the number of neural stem cells and increase of cell division rate during aging. Our model provides multiple testable predictions, and suggests that different temporal sequences of oncogenic mutations can lead to tumorigenesis. Finally, we conclude that four or five oncogenic mutations are sufficient for the formation of glioma.

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

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    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.

  14. Discrimination of human bodies from bones and teeth remains by Laser Induced Breakdown Spectroscopy and Neural Networks

    Science.gov (United States)

    Moncayo, S.; Manzoor, S.; Ugidos, T.; Navarro-Villoslada, F.; Caceres, J. O.

    2014-11-01

    A fast and minimally destructive method based on Laser Induced Breakdown Spectroscopy (LIBS) and Neural Networks (NN) has been developed and applied to the classification and discrimination of human bones and teeth fragments. The methodology can be useful in Disaster Victim Identification (DVI) tasks. The elemental compositions of bone and teeth samples provided enough information to achieve a correct discrimination and reassembling of different human remains. Individuals were classified with spectral correlation higher than 95%, regardless of the type of bone or tooth sample analyzed. No false positive or false negative was observed, demonstrating the high robustness and accuracy of the proposed methodology.

  15. Neural tuning for face wholes and parts in human fusiform gyrus revealed by FMRI adaptation.

    Science.gov (United States)

    Harris, Alison; Aguirre, Geoffrey Karl

    2010-07-01

    Although the right fusiform face area (FFA) is often linked to holistic processing, new data suggest this region also encodes part-based face representations. We examined this question by assessing the metric of neural similarity for faces using a continuous carryover functional MRI (fMRI) design. Using faces varying along dimensions of eye and mouth identity, we tested whether these axes are coded independently by separate part-tuned neural populations or conjointly by a single population of holistically tuned neurons. Consistent with prior results, we found a subadditive adaptation response in the right FFA, as predicted for holistic processing. However, when holistic processing was disrupted by misaligning the halves of the face, the right FFA continued to show significant adaptation, but in an additive pattern indicative of part-based neural tuning. Thus this region seems to contain neural populations capable of representing both individual parts and their integration into a face gestalt. A third experiment, which varied the asymmetry of changes in the eye and mouth identity dimensions, also showed part-based tuning from the right FFA. In contrast to the right FFA, the left FFA consistently showed a part-based pattern of neural tuning across all experiments. Together, these data support the existence of both part-based and holistic neural tuning within the right FFA, further suggesting that such tuning is surprisingly flexible and dynamic.

  16. Zika virus infection dysregulates human neural stem cell growth and inhibits differentiation into neuroprogenitor cells

    Science.gov (United States)

    Devhare, Pradip; Meyer, Keith; Steele, Robert; Ray, Ratna B; Ray, Ranjit

    2017-01-01

    The current outbreak of Zika virus-associated diseases in South America and its threat to spread to other parts of the world has emerged as a global health emergency. A strong link between Zika virus and microcephaly exists, and the potential mechanisms associated with microcephaly are under intense investigation. In this study, we evaluated the effect of Zika virus infection of Asian and African lineages (PRVABC59 and MR766) in human neural stem cells (hNSCs). These two Zika virus strains displayed distinct infection pattern and growth rates in hNSCs. Zika virus MR766 strain increased serine 139 phosphorylation of histone H2AX (γH2AX), a known early cellular response proteins to DNA damage. On the other hand, PRVABC59 strain upregulated serine 15 phosphorylation of p53, p21 and PUMA expression. MR766-infected cells displayed poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavage. Interestingly, infection of hNSCs by both strains of Zika virus for 24 h, followed by incubation in astrocyte differentiation medium, induced rounding and cell death. However, astrocytes generated from hNSCs by incubation in differentiation medium when infected with Zika virus displayed minimal cytopathic effect at an early time point. Infected hNSCs incubated in astrocyte differentiating medium displayed PARP cleavage within 24–36 h. Together, these results showed that two distinct strains of Zika virus potentiate hNSC growth inhibition by different mechanisms, but both viruses strongly induce death in early differentiating neuroprogenitor cells even at a very low multiplicity of infection. Our observations demonstrate further mechanistic insights for impaired neuronal homeostasis during active Zika virus infection. PMID:29022904

  17. Ago2 immunoprecipitation identifies predicted microRNAs in human embryonic stem cells and neural precursors.

    Directory of Open Access Journals (Sweden)

    Loyal A Goff

    2009-09-01

    Full Text Available MicroRNAs are required for maintenance of pluripotency as well as differentiation, but since more microRNAs have been computationally predicted in genome than have been found, there are likely to be undiscovered microRNAs expressed early in stem cell differentiation.SOLiD ultra-deep sequencing identified >10(7 unique small RNAs from human embryonic stem cells (hESC and neural-restricted precursors that were fit to a model of microRNA biogenesis to computationally predict 818 new microRNA genes. These predicted genomic loci are associated with chromatin patterns of modified histones that are predictive of regulated gene expression. 146 of the predicted microRNAs were enriched in Ago2-containing complexes along with 609 known microRNAs, demonstrating association with a functional RISC complex. This Ago2 IP-selected subset was consistently expressed in four independent hESC lines and exhibited complex patterns of regulation over development similar to previously-known microRNAs, including pluripotency-specific expression in both hESC and iPS cells. More than 30% of the Ago2 IP-enriched predicted microRNAs are new members of existing families since they share seed sequences with known microRNAs.Extending the classic definition of microRNAs, this large number of new microRNA genes, the majority of which are less conserved than their canonical counterparts, likely represent evolutionarily recent regulators of early differentiation. The enrichment in Ago2 containing complexes, the presence of chromatin marks indicative of regulated gene expression, and differential expression over development all support the identification of 146 new microRNAs active during early hESC differentiation.

  18. Is this a brain which I see before me? Modeling human neural development with pluripotent stem cells.

    Science.gov (United States)

    Suzuki, Ikuo K; Vanderhaeghen, Pierre

    2015-09-15

    The human brain is arguably the most complex structure among living organisms. However, the specific mechanisms leading to this complexity remain incompletely understood, primarily because of the poor experimental accessibility of the human embryonic brain. Over recent years, technologies based on pluripotent stem cells (PSCs) have been developed to generate neural cells of various types. While the translational potential of PSC technologies for disease modeling and/or cell replacement therapies is usually put forward as a rationale for their utility, they are also opening novel windows for direct observation and experimentation of the basic mechanisms of human brain development. PSC-based studies have revealed that a number of cardinal features of neural ontogenesis are remarkably conserved in human models, which can be studied in a reductionist fashion. They have also revealed species-specific features, which constitute attractive lines of investigation to elucidate the mechanisms underlying the development of the human brain, and its link with evolution. © 2015. Published by The Company of Biologists Ltd.

  19. Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

    Science.gov (United States)

    Zheng, Jialin; Ghorpade, Anuja; Niemann, Douglas; Cotter, Robin L.; Thylin, Michael R.; Epstein, Leon; Swartz, Jennifer M.; Shepard, Robin B.; Liu, Xiaojuan; Nukuna, Adeline; Gendelman, Howard E.

    1999-01-01

    Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis. PMID:10482576

  20. Dual small-molecule targeting of SMAD signaling stimulates human induced pluripotent stem cells toward neural lineages.

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    Methichit Wattanapanitch

    Full Text Available Incurable neurological disorders such as Parkinson's disease (PD, Huntington's disease (HD, and Alzheimer's disease (AD are very common and can be life-threatening because of their progressive disease symptoms with limited treatment options. To provide an alternative renewable cell source for cell-based transplantation and as study models for neurological diseases, we generated induced pluripotent stem cells (iPSCs from human dermal fibroblasts (HDFs and then differentiated them into neural progenitor cells (NPCs and mature neurons by dual SMAD signaling inhibitors. Reprogramming efficiency was improved by supplementing the histone deacethylase inhibitor, valproic acid (VPA, and inhibitor of p160-Rho associated coiled-coil kinase (ROCK, Y-27632, after retroviral transduction. We obtained a number of iPS colonies that shared similar characteristics with human embryonic stem cells in terms of their morphology, cell surface antigens, pluripotency-associated gene and protein expressions as well as their in vitro and in vivo differentiation potentials. After treatment with Noggin and SB431542, inhibitors of the SMAD signaling pathway, HDF-iPSCs demonstrated rapid and efficient differentiation into neural lineages. Six days after neural induction, neuroepithelial cells (NEPCs were observed in the adherent monolayer culture, which had the ability to differentiate further into NPCs and neurons, as characterized by their morphology and the expression of neuron-specific transcripts and proteins. We propose that our study may be applied to generate neurological disease patient-specific iPSCs allowing better understanding of disease pathogenesis and drug sensitivity assays.

  1. Chromosome 7 and 19 trisomy in cultured human neural progenitor cells.

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    Dhruv Sareen

    Full Text Available BACKGROUND: Stem cell expansion and differentiation is the foundation of emerging cell therapy technologies. The potential applications of human neural progenitor cells (hNPCs are wide ranging, but a normal cytogenetic profile is important to avoid the risk of tumor formation in clinical trials. FDA approved clinical trials are being planned and conducted for hNPC transplantation into the brain or spinal cord for various neurodegenerative disorders. Although human embryonic stem cells (hESCs are known to show recurrent chromosomal abnormalities involving 12 and 17, no studies have revealed chromosomal abnormalities in cultured hNPCs. Therefore, we investigated frequently occurring chromosomal abnormalities in 21 independent fetal-derived hNPC lines and the possible mechanisms triggering such aberrations. METHODS AND FINDINGS: While most hNPC lines were karyotypically normal, G-band karyotyping and fluorescent in situ hybridization (FISH analyses revealed the emergence of trisomy 7 (hNPC(+7 and trisomy 19 (hNPC(+19, in 24% and 5% of the lines, respectively. Once detected, subsequent passaging revealed emerging dominance of trisomy hNPCs. DNA microarray and immunoblotting analyses demonstrate epidermal growth factor receptor (EGFR overexpression in hNPC(+7 and hNPC(+19 cells. We observed greater levels of telomerase (hTERT, increased proliferation (Ki67, survival (TUNEL, and neurogenesis (beta(III-tubulin in hNPC(+7 and hNPC(+19, using respective immunocytochemical markers. However, the trisomy lines underwent replicative senescence after 50-60 population doublings and never showed neoplastic changes. Although hNPC(+7 and hNPC(+19 survived better after xenotransplantation into the rat striatum, they did not form malignant tumors. Finally, EGF deprivation triggered a selection of trisomy 7 cells in a diploid hNPC line. CONCLUSIONS: We report that hNPCs are susceptible to accumulation of chromosome 7 and 19 trisomy in long-term cell culture. These

  2. Differential development of neuronal physiological responsiveness in two human neural stem cell lines.

    Science.gov (United States)

    Donato, Roberta; Miljan, Erik A; Hines, Susan J; Aouabdi, Sihem; Pollock, Kenneth; Patel, Sara; Edwards, Frances A; Sinden, John D

    2007-05-25

    Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to neurodegenerative disease. Overexpression of the myc family transcription factors in human primary cells from developing cortex and mesencephalon has produced two stable multipotential NSC lines (ReNcell VM and CX) that can be continuously expanded in monolayer culture. In the undifferentiated state, both ReNcell VM and CX are nestin positive and have resting membrane potentials of around -60 mV but do not display any voltage-activated conductances. As initially hypothesized, using standard methods (stdD) for differentiation, both cell lines can form neurons, astrocytes and oligodendrocytes according to immunohistological characteristics. However it became clear that this was not true for electrophysiological features which designate neurons, such as the firing of action potentials. We have thus developed a new differentiation protocol, designated 'pre-aggregation differentiation' (preD) which appears to favor development of electrophysiologically functional neurons and to lead to an increase in dopaminergic neurons in the ReNcell VM line. In contrast, the protocol used had little effect on the differentiation of ReNcell CX in which dopaminergic differentiation was not observed. Moreover, after a week of differentiation with the preD protocol, 100% of ReNcell VM featured TTX-sensitive Na+-channels and fired action potentials, compared to 25% after stdD. Currents via other voltage-gated channels did not appear to depend on the differentiation protocol. ReNcell CX did not display the same electrophysiological properties as the VM line, generating voltage-dependant K+ currents but no Na+ currents or action potentials under either stdD or preD differentiation. These data demonstrate that overexpression of myc in NSCs can be used to generate electrophysiologically active neurons in culture. Development of a functional neuronal phenotype may be dependent on parameters

  3. Differential development of neuronal physiological responsiveness in two human neural stem cell lines

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    Patel Sara

    2007-05-01

    Full Text Available Abstract Background Neural stem cells (NSCs are powerful research tools for the design and discovery of new approaches to neurodegenerative disease. Overexpression of the myc family transcription factors in human primary cells from developing cortex and mesencephalon has produced two stable multipotential NSC lines (ReNcell VM and CX that can be continuously expanded in monolayer culture. Results In the undifferentiated state, both ReNcell VM and CX are nestin positive and have resting membrane potentials of around -60 mV but do not display any voltage-activated conductances. As initially hypothesized, using standard methods (stdD for differentiation, both cell lines can form neurons, astrocytes and oligodendrocytes according to immunohistological characteristics. However it became clear that this was not true for electrophysiological features which designate neurons, such as the firing of action potentials. We have thus developed a new differentiation protocol, designated 'pre-aggregation differentiation' (preD which appears to favor development of electrophysiologically functional neurons and to lead to an increase in dopaminergic neurons in the ReNcell VM line. In contrast, the protocol used had little effect on the differentiation of ReNcell CX in which dopaminergic differentiation was not observed. Moreover, after a week of differentiation with the preD protocol, 100% of ReNcell VM featured TTX-sensitive Na+-channels and fired action potentials, compared to 25% after stdD. Currents via other voltage-gated channels did not appear to depend on the differentiation protocol. ReNcell CX did not display the same electrophysiological properties as the VM line, generating voltage-dependant K+ currents but no Na+ currents or action potentials under either stdD or preD differentiation. Conclusion These data demonstrate that overexpression of myc in NSCs can be used to generate electrophysiologically active neurons in culture. Development of a

  4. Comprehensive quantitative comparison of the membrane proteome, phosphoproteome, and sialiome of human embryonic and neural stem cells

    DEFF Research Database (Denmark)

    Melo-Braga, Marcella Nunes; Schulz, Melanie; Liu, Qiuyue

    2014-01-01

    Human embryonic stem cells (hESCs) can differentiate into neural stem cells (NSCs), which can further be differentiated into neurons and glia cells. Therefore, these cells have huge potential as source for treatment of neurological diseases. Membrane-associated proteins are very important...... in cellular signaling and recognition, and their function and activity are frequently regulated by post-translational modifications such as phosphorylation and glycosylation. To obtain information about membrane-associated proteins and their modified amino acids potentially involved in changes of h...... in which 78% of phosphopeptides were identified with ≥99% confidence in site assignment and 1810 unique formerly sialylated N-linked glycopeptides. Several proteins were identified as significantly regulated in hESCs and NSC, including proteins involved in the early embryonic and neural development...

  5. Cultivation of human neural progenitor cells in a 3-dimensional self-assembling peptide hydrogel.

    Science.gov (United States)

    Liedmann, Andrea; Rolfs, Arndt; Frech, Moritz J

    2012-01-11

    technique like fluorescence microscopes able to take z-stacks of the specimen. Furthermore this kind of analysis is extremely time consuming. Here we demonstrate a method to release cells from the 3D-scaffolds for the later analysis e.g. by flow cytometry. In this protocol human neural progenitor cells (hNPCs) of the ReNcell VM cell line (Millipore USA) were cultured and differentiated in 3D-scaffolds consisting of PuraMatrix (PM) or PuraMatrix supplemented with laminin (PML). In our hands a PM-concentration of 0.25% was optimal for the cultivation of the cells, however the concentration might be adapted to other cell types. The released cells can be used for e.g. immunocytochemical studies and subsequently analysed by flow cytometry. This speeds up the analysis and more over, the obtained data rest upon a wider base, improving the reliability of the data. Copyright © 2012 Journal of Visualized Experiments

  6. The in vivo developmental potential of porcine skin-derived progenitors and neural stem cells.

    Science.gov (United States)

    Zhao, Ming-Tao; Yang, Xiaoyu; Lee, Kiho; Mao, Jiude; Teson, Jennifer M; Whitworth, Kristin M; Samuel, Melissa S; Spate, Lee D; Murphy, Clifton N; Prather, Randall S

    2012-09-20

    Multipotent skin-derived progenitors (SKPs) can be traced back to embryonic neural crest cells and are able to differentiate into both neural and mesodermal progeny in vitro. Neural stem cells (NSCs) are capable of self-renewing and can contribute to neuron and glia in the nervous system. Recently, we derived porcine SKPs and NSCs from the same enhanced green fluorescent protein (EGFP) transgenic fetuses and demonstrated that SKPs could contribute to neural and mesodermal lineages in vivo. However, it remains unclear whether porcine SKPs and NSCs can generate ectoderm and mesoderm lineages or other germ layers in vivo. Embryonic chimeras are a well-established tool for investigating cell lineage determination and cell potency through normal embryonic development. Thus, the purpose of this study was to investigate the in vivo developmental potential of porcine SKPs and fetal brain-derived NSCs by chimera production. Porcine SKPs, NSCs, and fibroblasts were injected into precompact in vitro fertilized embryos (IVF) and then transferred into corresponding surrogates 24 h postinjection. We found that porcine SKPs could incorporate into the early embryos and contribute to various somatic tissues of the 3 germ layers in postnatal chimera, and especially have an endodermal potency. However, this developmental potential is compromised when they differentiate into fibroblasts. In addition, porcine NSCs fail to incorporate into host embryos and contribute to chimeric piglets. Therefore, neural crest-derived SKPs may represent a more primitive state than their counterpart neural stem cells in terms of their contributions to multiple cell lineages.

  7. Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes.

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    Waseem K Raja

    Full Text Available The dismal success rate of clinical trials for Alzheimer's disease (AD motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe. We report brain organoids that use pluripotent stem cells derived from AD patients and recapitulate AD-like pathologies such as amyloid aggregation, hyperphosphorylated tau protein, and endosome abnormalities. These pathologies are observed in an age-dependent manner in organoids derived from multiple familial AD (fAD patients harboring amyloid precursor protein (APP duplication or presenilin1 (PSEN1 mutation, compared to controls. The incidence of AD pathology was consistent amongst several fAD lines, which carried different mutations. Although these are complex assemblies of neural tissue, they are also highly amenable to experimental manipulation. We find that treatment of patient-derived organoids with β- and γ-secretase inhibitors significantly reduces amyloid and tau pathology. Moreover, these results show the potential of this model system to greatly increase the translatability of pre-clinical drug discovery in AD.

  8. Human Detection System by Fusing Depth Map-Based Method and Convolutional Neural Network-Based Method

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    Anh Vu Le

    2017-01-01

    Full Text Available In this paper, the depth images and the colour images provided by Kinect sensors are used to enhance the accuracy of human detection. The depth-based human detection method is fast but less accurate. On the other hand, the faster region convolutional neural network-based human detection method is accurate but requires a rather complex hardware configuration. To simultaneously leverage the advantages and relieve the drawbacks of each method, one master and one client system is proposed. The final goal is to make a novel Robot Operation System (ROS-based Perception Sensor Network (PSN system, which is more accurate and ready for the real time application. The experimental results demonstrate the outperforming of the proposed method compared with other conventional methods in the challenging scenarios.

  9. An Efficient Feature Extraction Method with Pseudo-Zernike Moment in RBF Neural Network-Based Human Face Recognition System

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    Ahmadi Majid

    2003-01-01

    Full Text Available This paper introduces a novel method for the recognition of human faces in digital images using a new feature extraction method that combines the global and local information in frontal view of facial images. Radial basis function (RBF neural network with a hybrid learning algorithm (HLA has been used as a classifier. The proposed feature extraction method includes human face localization derived from the shape information. An efficient distance measure as facial candidate threshold (FCT is defined to distinguish between face and nonface images. Pseudo-Zernike moment invariant (PZMI with an efficient method for selecting moment order has been used. A newly defined parameter named axis correction ratio (ACR of images for disregarding irrelevant information of face images is introduced. In this paper, the effect of these parameters in disregarding irrelevant information in recognition rate improvement is studied. Also we evaluate the effect of orders of PZMI in recognition rate of the proposed technique as well as RBF neural network learning speed. Simulation results on the face database of Olivetti Research Laboratory (ORL indicate that the proposed method for human face recognition yielded a recognition rate of 99.3%.

  10. Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury

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    Katja M. Piltti

    2015-09-01

    Full Text Available The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell (hNSC engraftment has not been quantitatively evaluated in the central nervous system. We investigated changes over time in engraftment/survival, proliferation, and migration of multipotent human central nervous system-derived neural stem cells (hCNS-SCns transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with measures of donor cell proliferation at 2 weeks post-transplant (WPT and dose-normalized engraftment at 16 WPT. Critically, mice receiving the highest cell dose exhibited an engraftment plateau, in which the total number of engrafted human cells never exceeded the initial dose. These data suggest that donor cell expansion was inversely regulated by target niche parameters and/or transplantation density. Investigation of the response of donor cells to the host microenvironment should be a key variable in defining target cell dose in pre-clinical models of CNS disease and injury.

  11. Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury.

    Science.gov (United States)

    Piltti, Katja M; Avakian, Sabrina N; Funes, Gabriella M; Hu, Antoinette; Uchida, Nobuko; Anderson, Aileen J; Cummings, Brian J

    2015-09-01

    The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell (hNSC) engraftment has not been quantitatively evaluated in the central nervous system. We investigated changes over time in engraftment/survival, proliferation, and migration of multipotent human central nervous system-derived neural stem cells (hCNS-SCns) transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with measures of donor cell proliferation at 2 weeks post-transplant (WPT) and dose-normalized engraftment at 16 WPT. Critically, mice receiving the highest cell dose exhibited an engraftment plateau, in which the total number of engrafted human cells never exceeded the initial dose. These data suggest that donor cell expansion was inversely regulated by target niche parameters and/or transplantation density. Investigation of the response of donor cells to the host microenvironment should be a key variable in defining target cell dose in pre-clinical models of CNS disease and injury. Published by Elsevier B.V.

  12. A Neural Network Model of the Structure and Dynamics of Human Personality

    Science.gov (United States)

    Read, Stephen J.; Monroe, Brian M.; Brownstein, Aaron L.; Yang, Yu; Chopra, Gurveen; Miller, Lynn C.

    2010-01-01

    We present a neural network model that aims to bridge the historical gap between dynamic and structural approaches to personality. The model integrates work on the structure of the trait lexicon, the neurobiology of personality, temperament, goal-based models of personality, and an evolutionary analysis of motives. It is organized in terms of two…

  13. Differential neural activity patterns for spatial relations in humans: a MEG study.

    Science.gov (United States)

    Scott, Nicole M; Leuthold, Arthur; Sera, Maria D; Georgopoulos, Apostolos P

    2016-02-01

    Children learn the words for above-below relations earlier than for left-right relations, despite treating these equally well in a simple visual categorization task. Even as adults--conflicts in congruency, such as when a stimulus is depicted in a spatially incongruent manner with respect to salient global cues--can be challenging. Here we investigated the neural correlates of encoding and maintaining in working memory above-below and left-right relational planes in 12 adults using magnetoencephalography in order to discover whether above-below relations are represented by the brain differently than left-right relations. Adults performed perfectly on the task behaviorally, so any differences in neural activity were attributed to the stimuli's cognitive attributes. In comparing above-below to left-right relations during stimulus encoding, we found the greatest differences in neural activity in areas associated with space and movement. In comparing congruent to incongruent trials, we found the greatest differential activity in premotor areas. For both contrasts, brain areas involved in the encoding phase were also involved in the maintenance phase, which provides evidence that those brain areas are particularly important in representing the relational planes or congruency types throughout the trial. When comparing neural activity associated with the relational planes during working memory, additional right posterior areas were implicated, whereas the congruent-incongruent contrast implicated additional bilateral frontal and temporal areas. These findings are consistent with the hypothesis left-right relations are represented differently than above-below relations.

  14. A walking robot called human: lessons to be learned from neural control of locomotion

    NARCIS (Netherlands)

    Duysens, J.; van de Crommert, H.W.A.A.; Smits-Engelsman, B.C.M.; van der Helm, F.C.T.

    2002-01-01

    From what we know at present with respect to the neural control of walking, it can be concluded that an optimal biologically inspired robot could have the following features. The limbs should include several joints in which position changes can be obtained by actuators across the joints. The control

  15. Sustained neural activity patterns during working memory in the human medial temporal lobe.

    NARCIS (Netherlands)

    Axmacher, N.; Mormann, F.; Fernandez, G.; Cohen, M.X.; Elger, C.E.; Fell, J.

    2007-01-01

    In contrast to classical findings that the medial temporal lobe (MTL) specifically underlies long-term memory, previous data suggest that MTL structures may also contribute to working memory (WM). However, the neural mechanisms by which the MTL supports WM have remained unknown. Here, we exploit

  16. Leukemia inhibitory factor (LIF) enhances MAP2 + and HUC/D + neurons and influences neurite extension during differentiation of neural progenitors derived from human embryonic stem cells.

    Science.gov (United States)

    Leukemia Inhibitory Factor (L1F), a member of the Interleukin 6 cytokine family, has a role in differentiation of Human Neural Progenitor (hNP) cells in vitro. hNP cells, derived from Human Embryonic Stem (hES) cells, have an unlimited capacity for self-renewal in monolayer cultu...

  17. Involvement of Neptune in induction of the hatching gland and neural crest in the Xenopus embryo.

    Science.gov (United States)

    Kurauchi, Takayuki; Izutsu, Yumi; Maéno, Mitsugu

    2010-01-01

    Neptune, a Krüppel-like transcription factor, is expressed in various regions of the developing Xenopus embryo and it has multiple functions in the process of development in various organs. In situ hybridization analysis showed that Neptune is expressed in the boundary region between neural and non-neural tissues at the neurula stage, but little is known about the function of Neptune in this region. Here, we examined the expression and function of Neptune in the neural plate border (NPB) in the Xenopus embryo. Depletion of Neptune protein in developing embryos by using antisense MO caused loss of the hatching gland and otic vesicle as well as malformation of neural crest-derived cranial cartilages and melanocytes. Neptune MO also suppressed the expression of hatching gland and neural crest markers such as he, snail2, sox9 and msx1 at the neurula stage. Subsequent experiments showed that Neptune is necessary and sufficient for the differentiation of hatching gland cells and that it is located downstream of pax3 in the signal regulating the differentiation of these cells. Thus, Neptune is a new member of hatching gland specifier and plays a physiological role in determination and specification of multiple lineages derived from the NPB region.

  18. Nanotubes impregnated human olfactory bulb neural stem cells promote neuronal differentiation in Trimethyltin-induced neurodegeneration rat model.

    Science.gov (United States)

    Marei, Hany E; Elnegiry, Ahmed A; Zaghloul, Adel; Althani, Asma; Afifi, Nahla; Abd-Elmaksoud, Ahmed; Farag, Amany; Lashen, Samah; Rezk, Shymaa; Shouman, Zeinab; Cenciarelli, Carlo; Hasan, Anwarul

    2017-12-01

    Neural stem cells (NSCs) are multipotent self-renewing cells that could be used in cellular-based therapy for a wide variety of neurodegenerative diseases including Alzheimer's diseases (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Being multipotent in nature, they are practically capable of giving rise to major cell types of the nervous tissue including neurons, astrocytes, and oligodendrocytes. This is in marked contrast to neural progenitor cells which are committed to a specific lineage fate. In previous studies, we have demonstrated the ability of NSCs isolated from human olfactory bulb (OB) to survive, proliferate, differentiate, and restore cognitive and motor deficits associated with AD, and PD rat models, respectively. The use of carbon nanotubes (CNTs) to enhance the survivability and differentiation potential of NSCs following their in vivo engraftment have been recently suggested. Here, in order to assess the ability of CNTs to enhance the therapeutic potential of human OBNSCs for restoring cognitive deficits and neurodegenerative lesions, we co-engrafted CNTs and human OBNSCs in TMT-neurodegeneration rat model. The present study revealed that engrafted human OBNSCS-CNTs restored cognitive deficits, and neurodegenerative changes associated with TMT-induced rat neurodegeneration model. Moreover, the CNTs seemed to provide a support for engrafted OBNSCs, with increasing their tendency to differentiate into neurons rather than into glia cells. The present study indicate the marked ability of CNTs to enhance the therapeutic potential of human OBNSCs which qualify this novel therapeutic paradigm as a promising candidate for cell-based therapy of different neurodegenerative diseases. © 2017 Wiley Periodicals, Inc.

  19. Comparison of neural responses to cat meows and human vowels in the anterior and posterior auditory field of awake cats.

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    Hanlu Ma

    Full Text Available For humans and animals, the ability to discriminate speech and conspecific vocalizations is an important physiological assignment of the auditory system. To reveal the underlying neural mechanism, many electrophysiological studies have investigated the neural responses of the auditory cortex to conspecific vocalizations in monkeys. The data suggest that vocalizations may be hierarchically processed along an anterior/ventral stream from the primary auditory cortex (A1 to the ventral prefrontal cortex. To date, the organization of vocalization processing has not been well investigated in the auditory cortex of other mammals. In this study, we examined the spike activities of single neurons in two early auditory cortical regions with different anteroposterior locations: anterior auditory field (AAF and posterior auditory field (PAF in awake cats, as the animals were passively listening to forward and backward conspecific calls (meows and human vowels. We found that the neural response patterns in PAF were more complex and had longer latency than those in AAF. The selectivity for different vocalizations based on the mean firing rate was low in both AAF and PAF, and not significantly different between them; however, more vocalization information was transmitted when the temporal response profiles were considered, and the maximum transmitted information by PAF neurons was higher than that by AAF neurons. Discrimination accuracy based on the activities of an ensemble of PAF neurons was also better than that of AAF neurons. Our results suggest that AAF and PAF are similar with regard to which vocalizations they represent but differ in the way they represent these vocalizations, and there may be a complex processing stream between them.

  20. Characterizing low dose and dose rate effects in rodent and human neural stem cells exposed to proton and gamma irradiation

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    Bertrand P. Tseng

    2013-01-01

    Full Text Available Past work has shown that exposure to gamma rays and protons elicit a persistent oxidative stress in rodent and human neural stem cells (hNSCs. We have now adapted these studies to more realistic exposure scenarios in space, using lower doses and dose rates of these radiation modalities, to further elucidate the role of radiation-induced oxidative stress in these cells. Rodent neural stem and precursor cells grown as neurospheres and human neural stem cells grown as monolayers were subjected to acute and multi-dosing paradigms at differing dose rates and analyzed for changes in reactive oxygen species (ROS, reactive nitrogen species (RNS, nitric oxide and superoxide for 2 days after irradiation. While acute exposures led to significant changes in both cell types, hNSCs in particular, exhibited marked and significant elevations in radiation-induced oxidative stress. Elevated oxidative stress was more significant in hNSCs as opposed to their rodent counterparts, and hNSCs were significantly more sensitive to low dose exposures in terms of survival. Combinations of protons and γ-rays delivered as lower priming or higher challenge doses elicited radioadaptive changes that were associated with improved survival, but in general, only under conditions where the levels of reactive species were suppressed compared to cells irradiated acutely. Protective radioadaptive effects on survival were eliminated in the presence of the antioxidant N-acetylcysteine, suggesting further that radiation-induced oxidative stress could activate pro-survival signaling pathways that were sensitive to redox state. Data corroborates much of our past work and shows that low dose and dose rate exposures elicit significant changes in oxidative stress that have functional consequences on survival.

  1. Evaluation of Raman spectra of human brain tumor tissue using the learning vector quantization neural network

    Science.gov (United States)

    Liu, Tuo; Chen, Changshui; Shi, Xingzhe; Liu, Chengyong

    2016-05-01

    The Raman spectra of tissue of 20 brain tumor patients was recorded using a confocal microlaser Raman spectroscope with 785 nm excitation in vitro. A total of 133 spectra were investigated. Spectra peaks from normal white matter tissue and tumor tissue were analyzed. Algorithms, such as principal component analysis, linear discriminant analysis, and the support vector machine, are commonly used to analyze spectral data. However, in this study, we employed the learning vector quantization (LVQ) neural network, which is typically used for pattern recognition. By applying the proposed method, a normal diagnosis accuracy of 85.7% and a glioma diagnosis accuracy of 89.5% were achieved. The LVQ neural network is a recent approach to excavating Raman spectra information. Moreover, it is fast and convenient, does not require the spectra peak counterpart, and achieves a relatively high accuracy. It can be used in brain tumor prognostics and in helping to optimize the cutting margins of gliomas.

  2. Neural responses during the anticipation and receipt of olfactory reward and punishment in human

    DEFF Research Database (Denmark)

    Zou, Lai-Quan; Zhou, Han-Yu; Zhuang, Yuan

    2018-01-01

    Pleasure experience is an important part of normal healthy life and is essential for general and mental well-being. Many neuroimaging studies have investigated the underlying neural processing of verbal and visual modalities of reward. However, how the brain processes rewards in the olfactory...... modality is not fully understood. This study aimed to examine the neural basis of olfactory rewards in 25 healthy participants using functional magnetic resonance imaging (fMRI). We developed an Olfactory Incentive Delay (OLID) imaging task distinguishing between the anticipation and receipt of olfactory...... rewards and punishments. We found that the pallidum was activated during the anticipation of both olfactory rewards and punishments. The bilateral insula was activated independently from the odours' hedonic valence during the receipt phase. In addition, right caudate activation during the anticipation...

  3. Fluorescent probes as a tool for cell population tracking in spontaneously active neural networks derived from human pluripotent stem cells.

    Science.gov (United States)

    Mäkinen, M; Joki, T; Ylä-Outinen, L; Skottman, H; Narkilahti, S; Aänismaa, R

    2013-04-30

    Applications such as 3D cultures and tissue modelling require cell tracking with non-invasive methods. In this work, the suitability of two fluorescent probes, CellTracker, CT, and long chain carbocyanine dye, DiD, was investigated for long-term culturing of labeled human pluripotent stem cell-derived neural cells. We found that these dyes did not affect the cell viability. However, proliferation was decreased in DiD labeled cell population. With both dyes the labeling was stable up to 4 weeks. CT and DiD labeled cells could be co-cultured and, importantly, these mixed populations had their normal ability to form spontaneous electrical network activity. In conclusion, human neural cells can be successfully labeled with these two fluorescent probes without significantly affecting the cell characteristics. These labeled cells could be utilized further in e.g. building controlled neuronal networks for neurotoxicity screening platforms, combining cells with biomaterials for 3D studies, and graft development. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. 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.

  5. Western Zika Virus in Human Fetal Neural Progenitors Persists Long Term with Partial Cytopathic and Limited Immunogenic Effects.

    Science.gov (United States)

    Hanners, Natasha W; Eitson, Jennifer L; Usui, Noriyoshi; Richardson, R Blake; Wexler, Eric M; Konopka, Genevieve; Schoggins, John W

    2016-06-14

    The recent Zika virus (ZIKV) outbreak in the Western hemisphere is associated with severe pathology in newborns, including microcephaly and brain damage. The mechanisms underlying these outcomes are under intense investigation. Here, we show that a 2015 ZIKV isolate replicates in multiple cell types, including primary human fetal neural progenitors (hNPs). In immortalized cells, ZIKV is cytopathic and grossly rearranges endoplasmic reticulum membranes similar to other flaviviruses. In hNPs, ZIKV infection has a partial cytopathic phase characterized by cell rounding, pyknosis, and activation of caspase 3. Despite notable cell death, ZIKV did not activate a cytokine response in hNPs. This lack of cell intrinsic immunity to ZIKV is consistent with our observation that virus replication persists in hNPs for at least 28 days. These findings, supported by published fetal neuropathology, establish a proof-of-concept that neural progenitors in the developing human fetus can be direct targets of detrimental ZIKV-induced pathology. Copyright © 2016. Published by Elsevier Inc.

  6. Human neural stem cell-derived cultures in three-dimensional substrates form spontaneously functional neuronal networks.

    Science.gov (United States)

    Smith, Imogen; Silveirinha, Vasco; Stein, Jason L; de la Torre-Ubieta, Luis; Farrimond, Jonathan A; Williamson, Elizabeth M; Whalley, Benjamin J

    2017-04-01

    Differentiated human neural stem cells were cultured in an inert three-dimensional (3D) scaffold and, unlike two-dimensional (2D) but otherwise comparable monolayer cultures, formed spontaneously active, functional neuronal networks that responded reproducibly and predictably to conventional pharmacological treatments to reveal functional, glutamatergic synapses. Immunocytochemical and electron microscopy analysis revealed a neuronal and glial population, where markers of neuronal maturity were observed in the former. Oligonucleotide microarray analysis revealed substantial differences in gene expression conferred by culturing in a 3D vs a 2D environment. Notable and numerous differences were seen in genes coding for neuronal function, the extracellular matrix and cytoskeleton. In addition to producing functional networks, differentiated human neural stem cells grown in inert scaffolds offer several significant advantages over conventional 2D monolayers. These advantages include cost savings and improved physiological relevance, which make them better suited for use in the pharmacological and toxicological assays required for development of stem cell-based treatments and the reduction of animal use in medical research. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  7. γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation.

    Science.gov (United States)

    D'Avanzo, Carla; Sliwinski, Christopher; Wagner, Steven L; Tanzi, Rudolph E; Kim, Doo Yeon; Kovacs, Dora M

    2015-08-01

    Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ42). However, their effect on the physiologic functions of γ-secretase has not been tested in human model systems. γ-Secretase regulates fate determination of neural progenitor cells. Thus, we studied the impact of SGSMs on the neuronal differentiation of ReNcell VM (ReN) human neural progenitor cells (hNPCs). Quantitative PCR analysis showed that treatment of neurosphere-like ReN cell aggregate cultures with γ-secretase inhibitors (GSIs), but not SGSMs, induced a 2- to 4-fold increase in the expression of the neuronal markers Tuj1 and doublecortin. GSI treatment also induced neuronal marker protein expression, as shown by Western blot analysis. In the same conditions, SGSM treatment selectively reduced endogenous Aβ42 levels by ∼80%. Mechanistically, we found that Notch target gene expressions were selectively inhibited by a GSI, not by SGSM treatment. We can assert, for the first time, that SGSMs do not affect the neuronal differentiation of hNPCs while selectively decreasing endogenous Aβ42 levels in the same conditions. Our results suggest that our hNPC differentiation system can serve as a useful model to test the impact of GSIs and SGSMs on both endogenous Aβ levels and γ-secretase physiologic functions including endogenous Notch signaling. © FASEB.

  8. Optimization of the magnetic labeling of human neural stem cells and MRI visualization in the hemiparkinsonian rat brain.

    Science.gov (United States)

    Ramos-Gómez, Milagros; Seiz, Emma G; Martínez-Serrano, Alberto

    2015-03-05

    Magnetic resonance imaging is the ideal modality for non-invasive in vivo cell tracking allowing for longitudinal studies over time. Cells labeled with superparamagnetic iron oxide nanoparticles have been shown to induce sufficient contrast for in vivo magnetic resonance imaging enabling the in vivo analysis of the final location of the transplanted cells. For magnetic nanoparticles to be useful, a high internalization efficiency of the particles is required without compromising cell function, as well as validation of the magnetic nanoparticles behaviour inside the cells. In this work, we report the development, optimization and validation of an efficient procedure to label human neural stem cells with commercial nanoparticles in the absence of transfection agents. Magnetic nanoparticles used here do not affect cell viability, cell morphology, cell differentiation or cell cycle dynamics. Moreover, human neural stem cells progeny labeled with magnetic nanoparticles are easily and non-invasively detected long time after transplantation in a rat model of Parkinson's disease (up to 5 months post-grafting) by magnetic resonance imaging. These findings support the use of commercial MNPs to track cells for short- and mid-term periods after transplantation for studies of brain cell replacement therapy. Nevertheless, long-term MR images should be interpreted with caution due to the possibility that some MNPs may be expelled from the transplanted cells and internalized by host microglial cells.

  9. Safety of epicenter versus intact parenchyma as a transplantation site for human neural stem cells for spinal cord injury therapy.

    Science.gov (United States)

    Piltti, Katja M; Salazar, Desirée L; Uchida, Nobuko; Cummings, Brian J; Anderson, Aileen J

    2013-03-01

    Neural stem cell transplantation may have the potential to yield repair and recovery of function in central nervous system injury and disease, including spinal cord injury (SCI). Multiple pathological processes are initiated at the epicenter of a traumatic spinal cord injury; these are generally thought to make the epicenter a particularly hostile microenvironment. Conversely, the injury epicenter is an appealing potential site of therapeutic human central nervous system-derived neural stem cell (hCNS-SCns) transplantation because of both its surgical accessibility and the avoidance of spared spinal cord tissue. In this study, we compared hCNS-SCns transplantation into the SCI epicenter (EPI) versus intact rostral/caudal (R/C) parenchyma in contusion-injured athymic nude rats, and assessed the cell survival, differentiation, and migration. Regardless of transplantation site, hCNS-SCns survived and proliferated; however, the total number of hCNS-SCns quantified in the R/C transplant animals was twice that in the EPI animals, demonstrating increased overall engraftment. Migration and fate profile were unaffected by transplantation site. However, although transplantation site did not alter the proportion of human astrocytes, EPI transplantation shifted the localization of these cells and exhibited a correlation with calcitonin gene-related peptide fiber sprouting. Critically, no changes in mechanical allodynia or thermal hyperalgesia were observed. Taken together, these data suggest that the intact parenchyma may be a more favorable transplantation site than the injury epicenter in the subacute period post-SCI.

  10. Expression of Nestin by Neural Cells in the Adult Rat and Human Brain

    OpenAIRE

    Hendrickson, Michael L.; Rao, Abigail J.; Demerdash, Omar N. A.; Kalil, Ronald E.

    2011-01-01

    Neurons and glial cells in the developing brain arise from neural progenitor cells (NPCs). Nestin, an intermediate filament protein, is thought to be expressed exclusively by NPCs in the normal brain, and is replaced by the expression of proteins specific for neurons or glia in differentiated cells. Nestin expressing NPCs are found in the adult brain in the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus. While significant attention has b...

  11. Large-scale nanoelectrode arrays to monitor the dopaminergic differentiation of human neural stem cells

    OpenAIRE

    Kim, Tae-Hyung; Yea, Cheol-Heon; Chueng, Sy-Tsong Dean; Yin, Perry To-Tien; Conley, Brian; Dardir, Kholud; Pak, Yusin; Jung, Gun Young; Choi, Jeong-Woo; Lee, Ki-Bum

    2015-01-01

    A novel cell-based biosensing platform (Large-scale Homogeneous Nanoelectrode Arryas, LHONA) is developed using a combination of sequential laser interference lithography and electrochemical deposition methods. This enables the sensitive discrimination of dopaminergic cells from other types of neural cells in a completely non-destructive manner owing to its enhanced biocompatibility and excellent electrochemical properties. As such, this platform/detection strategy holds great potential as an...

  12. Large-Scale Nanoelectrode Arrays to Monitor the Dopaminergic Differentiation of Human Neural Stem Cells.

    Science.gov (United States)

    Kim, Tae-Hyung; Yea, Cheol-Heon; Chueng, Sy-Tsong Dean; Yin, Perry To-Tien; Conley, Brian; Dardir, Kholud; Pak, Yusin; Jung, Gun Young; Choi, Jeong-Woo; Lee, Ki-Bum

    2015-11-04

    A novel cell-based biosensing platform is developed using a combination of sequential laser interference lithography and electrochemical deposition methods. This enables the sensitive discrimination of dopaminergic cells from other types of neural cells in a completely nondestructive manner. This platform and detection strategy may become an effective noninvasive in situ monitoring tool that can be used to determine stem cell fate for various regenerative applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Whole-brain 3D mapping of human neural transplant innervation.

    Science.gov (United States)

    Doerr, Jonas; Schwarz, Martin Karl; Wiedermann, Dirk; Leinhaas, Anke; Jakobs, Alina; Schloen, Florian; Schwarz, Inna; Diedenhofen, Michael; Braun, Nils Christian; Koch, Philipp; Peterson, Daniel A; Kubitscheck, Ulrich; Hoehn, Mathias; Brüstle, Oliver

    2017-01-19

    While transplantation represents a key tool for assessing in vivo functionality of neural stem cells and their suitability for neural repair, little is known about the integration of grafted neurons into the host brain circuitry. Rabies virus-based retrograde tracing has developed into a powerful approach for visualizing synaptically connected neurons. Here, we combine this technique with light sheet fluorescence microscopy (LSFM) to visualize transplanted cells and connected host neurons in whole-mouse brain preparations. Combined with co-registration of high-precision three-dimensional magnetic resonance imaging (3D MRI) reference data sets, this approach enables precise anatomical allocation of the host input neurons. Our data show that the same neural donor cell population grafted into different brain regions receives highly orthotopic input. These findings indicate that transplant connectivity is largely dictated by the circuitry of the target region and depict rabies-based transsynaptic tracing and LSFM as efficient tools for comprehensive assessment of host-donor cell innervation.

  14. Revocation of European patent for neural progenitors highlights patent challenges for inventions relating to human embryonic stem cells.

    Science.gov (United States)

    Rigby, Barbara

    2013-11-01

    Cells derived from human embryonic stem cells have great therapeutic potential. Patents are key to allowing companies that develop methods of generating such cells to recuperate their investment. However, in Europe, inventions relating to the use of human embryos for commercial purposes are excluded from patentability on moral grounds. The scope of this morality exclusion was recently tested before Germany's highest court and before the European Patent Office (EPO), with diverging results. The decision by the EPO's Opposition Division to revoke EP1040185 relating to neural precursors and methods for their generation has received a mixed reception. The decision has very recently been appealed, and the outcome of this Appeal should provide more definitive guidance on the scope of the morality exclusion.

  15. Persistent neural activity in auditory cortex is related to auditory working memory in humans and nonhuman primates.

    Science.gov (United States)

    Huang, Ying; Matysiak, Artur; Heil, Peter; König, Reinhard; Brosch, Michael

    2016-07-20

    Working memory is the cognitive capacity of short-term storage of information for goal-directed behaviors. Where and how this capacity is implemented in the brain are unresolved questions. We show that auditory cortex stores information by persistent changes of neural activity. We separated activity related to working memory from activity related to other mental processes by having humans and monkeys perform different tasks with varying working memory demands on the same sound sequences. Working memory was reflected in the spiking activity of individual neurons in auditory cortex and in the activity of neuronal populations, that is, in local field potentials and magnetic fields. Our results provide direct support for the idea that temporary storage of information recruits the same brain areas that also process the information. Because similar activity was observed in the two species, the cellular bases of some auditory working memory processes in humans can be studied in monkeys.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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.

  18. microRNA miR-34a regulates cytodifferentiation and targets multi-signaling pathways in human dental papilla cells.

    Directory of Open Access Journals (Sweden)

    Mian Wan

    Full Text Available Odontogenesis relies on the reciprocal signaling interactions between dental epithelium and neural crest-derived mesenchyme, which is regulated by several signaling pathways. Subtle changes in the activity of these major signaling pathways can have dramatic effects on tooth development. An important regulator of such subtle changes is the fine tuning function of microRNAs (miRNAs. However, the underlying mechanism by which miRNAs regulate tooth development remains elusive. This study determined the expression of miRNAs during cytodifferentiation in the human tooth germ and studied miR-34a as a regulator of dental papilla cell differentiation. Using microarrays, miRNA expression profiles were established at selected times during development (early bell stage or late bell stage of the human fetal tooth germ. We identified 29 differentially expressed miRNAs from early bell stage/late bell stage comparisons. Out of 6 miRNAs selected for validation by qPCR, all transcripts were confirmed to be differentially expressed. miR-34a was selected for further investigation because it has been previously reported to regulate organogenesis. miR-34a mimics and inhibitors were transfected into human fetal dental papilla cells, mRNA levels of predicted target genes were detected by quantitative real-time PCR, and levels of putative target proteins were examined by western blotting. ALP and DSPP expression were also tested by qPCR, western blotting, and immunofluorescence. Findings from these studies suggested that miR-34a may play important roles in dental papilla cell differentiation during human tooth development by targeting NOTCH and TGF-beta signaling.

  19. microRNA miR-34a Regulates Cytodifferentiation and Targets Multi-signaling Pathways in Human Dental Papilla Cells

    Science.gov (United States)

    Sun, Feifei; Tang, Yin; Ye, Ling; Fan, Yi; Klein, Ophir D.; Zhou, Xuedong; Zheng, Liwei

    2012-01-01

    Odontogenesis relies on the reciprocal signaling interactions between dental epithelium and neural crest-derived mesenchyme, which is regulated by several signaling pathways. Subtle changes in the activity of these major signaling pathways can have dramatic effects on tooth development. An important regulator of such subtle changes is the fine tuning function of microRNAs (miRNAs). However, the underlying mechanism by which miRNAs regulate tooth development remains elusive. This study determined the expression of miRNAs during cytodifferentiation in the human tooth germ and studied miR-34a as a regulator of dental papilla cell differentiation. Using microarrays, miRNA expression profiles were established at selected times during development (early bell stage or late bell stage) of the human fetal tooth germ. We identified 29 differentially expressed miRNAs from early bell stage/late bell stage comparisons. Out of 6 miRNAs selected for validation by qPCR, all transcripts were confirmed to be differentially expressed. miR-34a was selected for further investigation because it has been previously reported to regulate organogenesis. miR-34a mimics and inhibitors were transfected into human fetal dental papilla cells, mRNA levels of predicted target genes were detected by quantitative real-time PCR, and levels of putative target proteins were examined by western blotting. ALP and DSPP expression were also tested by qPCR, western blotting, and immunofluorescence. Findings from these studies suggested that miR-34a may play important roles in dental papilla cell differentiation during human tooth development by targeting NOTCH and TGF-beta signaling. PMID:23226240

  20. Quantitative Live Imaging of Human Embryonic Stem Cell Derived Neural Rosettes Reveals Structure-Function Dynamics Coupled to Cortical Development.

    Science.gov (United States)

    Ziv, Omer; Zaritsky, Assaf; Yaffe, Yakey; Mutukula, Naresh; Edri, Reuven; Elkabetz, Yechiel

    2015-10-01

    Neural stem cells (NSCs) are progenitor cells for brain development, where cellular spatial composition (cytoarchitecture) and dynamics are hypothesized to be linked to critical NSC capabilities. However, understanding cytoarchitectural dynamics of this process has been limited by the difficulty to quantitatively image brain development in vivo. Here, we study NSC dynamics within Neural Rosettes--highly organized multicellular structures derived from human pluripotent stem cells. Neural rosettes contain NSCs with strong epithelial polarity and are expected to perform apical-basal interkinetic nuclear migration (INM)--a hallmark of cortical radial glial cell development. We developed a quantitative live imaging framework to characterize INM dynamics within rosettes. We first show that the tendency of cells to follow the INM orientation--a phenomenon we referred to as radial organization, is associated with rosette size, presumably via mechanical constraints of the confining structure. Second, early forming rosettes, which are abundant with founder NSCs and correspond to the early proliferative developing cortex, show fast motions and enhanced radial organization. In contrast, later derived rosettes, which are characterized by reduced NSC capacity and elevated numbers of differentiated neurons, and thus correspond to neurogenesis mode in the developing cortex, exhibit slower motions and decreased radial organization. Third, later derived rosettes are characterized by temporal instability in INM measures, in agreement with progressive loss in rosette integrity at later developmental stages. Finally, molecular perturbations of INM by inhibition of actin or non-muscle myosin-II (NMII) reduced INM measures. Our framework enables quantification of cytoarchitecture NSC dynamics and may have implications in functional molecular studies, drug screening, and iPS cell-based platforms for disease modeling.

  1. Quantitative Live Imaging of Human Embryonic Stem Cell Derived Neural Rosettes Reveals Structure-Function Dynamics Coupled to Cortical Development.

    Directory of Open Access Journals (Sweden)

    Omer Ziv

    2015-10-01

    Full Text Available Neural stem cells (NSCs are progenitor cells for brain development, where cellular spatial composition (cytoarchitecture and dynamics are hypothesized to be linked to critical NSC capabilities. However, understanding cytoarchitectural dynamics of this process has been limited by the difficulty to quantitatively image brain development in vivo. Here, we study NSC dynamics within Neural Rosettes--highly organized multicellular structures derived from human pluripotent stem cells. Neural rosettes contain NSCs with strong epithelial polarity and are expected to perform apical-basal interkinetic nuclear migration (INM--a hallmark of cortical radial glial cell development. We developed a quantitative live imaging framework to characterize INM dynamics within rosettes. We first show that the tendency of cells to follow the INM orientation--a phenomenon we referred to as radial organization, is associated with rosette size, presumably via mechanical constraints of the confining structure. Second, early forming rosettes, which are abundant with founder NSCs and correspond to the early proliferative developing cortex, show fast motions and enhanced radial organization. In contrast, later derived rosettes, which are characterized by reduced NSC capacity and elevated numbers of differentiated neurons, and thus correspond to neurogenesis mode in the developing cortex, exhibit slower motions and decreased radial organization. Third, later derived rosettes are characterized by temporal instability in INM measures, in agreement with progressive loss in rosette integrity at later developmental stages. Finally, molecular perturbations of INM by inhibition of actin or non-muscle myosin-II (NMII reduced INM measures. Our framework enables quantification of cytoarchitecture NSC dynamics and may have implications in functional molecular studies, drug screening, and iPS cell-based platforms for disease modeling.

  2. Neural systems underlying aversive conditioning in humans with primary and secondary reinforcers

    Directory of Open Access Journals (Sweden)

    Mauricio R Delgado

    2011-05-01

    Full Text Available Money is a secondary reinforcer commonly used across a range of disciplines in experimental paradigms investigating reward learning and decision-making. The effectiveness of monetary reinforcers during aversive learning and its neural basis, however, remains a topic of debate. Specifically, it is unclear if the initial acquisition of aversive representations of monetary losses depends on similar neural systems as more traditional aversive conditioning that involves primary reinforcers. This study contrasts the efficacy of a biologically defined primary reinforcer (shock and a socially defined secondary reinforcer (money during aversive learning and its associated neural circuitry. During a two-part experiment, participants first played a gambling game where wins and losses were based on performance to gain an experimental bank. Participants were then exposed to two separate aversive conditioning sessions. In one session, a primary reinforcer (mild shock served as an unconditioned stimulus (US and was paired with one of two colored squares, the conditioned stimuli (CS+ and CS-, respectively. In another session, a secondary reinforcer (loss of money served as the US and was paired with one of two different CS. Skin conductance responses were greater for CS+ compared to CS- trials irrespective of type of reinforcer. Neuroimaging results revealed that the striatum, a region typically linked with reward-related processing, was found to be involved in the acquisition of aversive conditioned response irrespective of reinforcer type. In contrast, the amygdala was involved during aversive conditioning with primary reinforcers, as suggested by both an exploratory fMRI analysis and a follow-up case study with a patient with bilateral amygdala damage. Taken together, these results suggest that learning about potential monetary losses may depend on reinforcement learning related systems, rather than on typical structures involved in more biologically based

  3. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction.

    Science.gov (United States)

    Rilling, James K; Demarco, Ashley C; Hackett, Patrick D; Chen, Xu; Gautam, Pritam; Stair, Sabrina; Haroon, Ebrahim; Thompson, Richmond; Ditzen, Beate; Patel, Rajan; Pagnoni, Giuseppe

    2014-01-01

    Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses

  4. Complexity, chaos and human physiology: the justification for non-linear neural computational analysis.

    Science.gov (United States)

    Baxt, W G

    1994-03-15

    Background is presented to suggest that a great many biologic processes are chaotic. It is well known that chaotic processes can be accurately characterized by non-linear technologies. Evidence is presented that an artificial neural network, which is a known method for the application of non-linear statistics, is able to perform more accurately in identifying patients with and without myocardial infarction than either physicians or other computer paradigms. It is suggested that the improved performance may be due to the network's better ability to characterize what is a chaotic process imbedded in the problem of the clinical diagnosis of this entity.

  5. Neural differentiation of human embryonic stem cells as an in vitro tool for the study of the expression patterns of the neuronal cytoskeleton during neurogenesis.

    Science.gov (United States)

    Liu, Chao; Zhong, Yongwang; Apostolou, Andria; Fang, Shengyun

    2013-09-13

    The neural differentiation of human embryonic stem cells (ESCs) is a potential tool for elucidating the key mechanisms involved in human neurogenesis. Nestin and β-III-tubulin, which are cytoskeleton proteins, are marker proteins of neural stem cells (NSCs) and neurons, respectively. However, the expression patterns of nestin and β-III-tubulin in neural derivatives from human ESCs remain unclear. In this study, we found that neural progenitor cells (NPCs) derived from H9 cells express high levels of nestin and musashi-1. In contrast, β-III-tubulin was weakly expressed in a few NPCs. Moreover, in these cells, nestin formed filament networks, whereas β-III-tubulin was distributed randomly as small particles. As the differentiation proceeded, the nestin filament networks and the β-III-tubulin particles were found in both the cell soma and the cellular processes. Moreover, the colocalization of nestin and β-III-tubulin was found mainly in the cell processes and neurite-like structures and not in the cell soma. These results may aid our understanding of the expression patterns of nestin and β-III-tubulin during the neural differentiation of H9 cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Transplantation of Human Neural Stem Cells in a Parkinsonian Model Exerts Neuroprotection via Regulation of the Host Microenvironment

    Directory of Open Access Journals (Sweden)

    Fu-Xing Zuo

    2015-11-01

    Full Text Available Parkinson’s disease (PD is characterized by a progressive loss of dopaminergic neurons and consequent dopamine (DA deficit, and current treatment still remains a challenge. Although neural stem cells (NSCs have been evaluated as appealing graft sources, mechanisms underlying the beneficial phenomena are not well understood. Here, we investigate whether human NSCs (hNSCs transplantation could provide neuroprotection against DA depletion by recruiting endogenous cells to establish a favorable niche. Adult mice subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP were transplanted with hNSCs or vehicle into the striatum. Behavioral and histological analyses demonstrated significant neurorescue response observed in hNSCs-treated animals compared with the control mice. In transplanted animals, grafted cells survived, proliferated, and migrated within the astrocytic scaffold. Notably, more local astrocytes underwent de-differentiation, acquiring the properties of NSCs or neural precursor cells (NPCs in mice given hNSCs. Additionally, we also detected significantly higher expression of host-derived growth factors in hNSCs-transplanted mice compared with the control animals, together with inhibition of local microglia and proinflammatory cytokines. Overall, our results indicate that hNSCs transplantation exerts neuroprotection in MPTP-insulted mice via regulating the host niche. Harnessing synergistic interaction between the grafts and host cells may help optimize cell-based therapies for PD.

  7. Cross-linguistic differences in the neural representation of human language: evidence from users of signed languages.

    Science.gov (United States)

    Corina, David P; Lawyer, Laurel A; Cates, Deborah

    2012-01-01

    Studies of deaf individuals who are users of signed languages have provided profound insight into the neural representation of human language. Case studies of deaf signers who have incurred left- and right-hemisphere damage have shown that left-hemisphere resources are a necessary component of sign language processing. These data suggest that, despite frank differences in the input and output modality of language, core left perisylvian regions universally serve linguistic function. Neuroimaging studies of deaf signers have generally provided support for this claim. However, more fine-tuned studies of linguistic processing in deaf signers are beginning to show evidence of important differences in the representation of signed and spoken languages. In this paper, we provide a critical review of this literature and present compelling evidence for language-specific cortical representations in deaf signers. These data lend support to the claim that the neural representation of language may show substantive cross-linguistic differences. We discuss the theoretical implications of these findings with respect to an emerging understanding of the neurobiology of language.

  8. Cross-linguistic differences in the neural representation of human language: evidence from users of signed languages.

    Directory of Open Access Journals (Sweden)

    David eCorina

    2013-01-01

    Full Text Available Studies of deaf individuals who are users of signed languages have provided profound insight into the neural representation of human language. Case studies of deaf signers who have incurred left- and right-hemisphere damage have shown that left-hemisphere resources are a necessary component of sign language processing. These data suggest that, despite frank differences in the input and output modality of language,; core left perisylvian regions universally serve linguistic function. Neuroimaging studies of deaf signers have generally provided support for this claim. However, more fine-tuned studies of linguistic processing in deaf signers are beginning to show evidence of important differences in the representation of signed and spoken languages. In this paper, we provide a critical review of this literature and present compelling evidence for language-specific cortical representations in deaf signers. These data lend support to the claim that the neural representation of language may show substantive cross-linguistic differences. We discuss the theoretical implications of these findings with respect to an emerging understanding of the neurobiology of language.

  9. Modulation of calcium-induced cell death in human neural stem cells by the novel peptidylarginine deiminase-AIF pathway.

    Science.gov (United States)

    U, Kin Pong; Subramanian, Venkataraman; Nicholas, Antony P; Thompson, Paul R; Ferretti, Patrizia

    2014-06-01

    PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required for AIF (apoptosis inducing factor)-mediated apoptosis. PAD inhibition prevents association of PAD3 with AIF and AIF cleavage required for its translocation to the nucleus. Finally, PAD inhibition also hinders calcium-induced cytoskeleton disassembly and association of PAD3 with vimentin, that we show to be associated also with AIF; together this suggests that PAD-dependent cytoskeleton disassembly may play a role in AIF translocation to the nucleus. This is the first study highlighting a role of PAD activity in balancing hNSC survival/death, identifying PAD3 as an important upstream regulator of calcium-induced apoptosis, which could be targeted to reduce neural loss, and shedding light on the mechanisms involved. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Cross-Linguistic Differences in the Neural Representation of Human Language: Evidence from Users of Signed Languages

    Science.gov (United States)

    Corina, David P.; Lawyer, Laurel A.; Cates, Deborah

    2013-01-01

    Studies of deaf individuals who are users of signed languages have provided profound insight into the neural representation of human language. Case studies of deaf signers who have incurred left- and right-hemisphere damage have shown that left-hemisphere resources are a necessary component of sign language processing. These data suggest that, despite frank differences in the input and output modality of language, core left perisylvian regions universally serve linguistic function. Neuroimaging studies of deaf signers have generally provided support for this claim. However, more fine-tuned studies of linguistic processing in deaf signers are beginning to show evidence of important differences in the representation of signed and spoken languages. In this paper, we provide a critical review of this literature and present compelling evidence for language-specific cortical representations in deaf signers. These data lend support to the claim that the neural representation of language may show substantive cross-linguistic differences. We discuss the theoretical implications of these findings with respect to an emerging understanding of the neurobiology of language. PMID:23293624

  11. Transplantation of Human Neural Stem Cells in a Parkinsonian Model Exerts Neuroprotection via Regulation of the Host Microenvironment.

    Science.gov (United States)

    Zuo, Fu-Xing; Bao, Xin-Jie; Sun, Xi-Cai; Wu, Jun; Bai, Qing-Ran; Chen, Guo; Li, Xue-Yuan; Zhou, Qiang-Yi; Yang, Yuan-Fan; Shen, Qin; Wang, Ren-Zhi

    2015-11-05

    Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons and consequent dopamine (DA) deficit, and current treatment still remains a challenge. Although neural stem cells (NSCs) have been evaluated as appealing graft sources, mechanisms underlying the beneficial phenomena are not well understood. Here, we investigate whether human NSCs (hNSCs) transplantation could provide neuroprotection against DA depletion by recruiting endogenous cells to establish a favorable niche. Adult mice subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were transplanted with hNSCs or vehicle into the striatum. Behavioral and histological analyses demonstrated significant neurorescue response observed in hNSCs-treated animals compared with the control mice. In transplanted animals, grafted cells survived, proliferated, and migrated within the astrocytic scaffold. Notably, more local astrocytes underwent de-differentiation, acquiring the properties of NSCs or neural precursor cells (NPCs) in mice given hNSCs. Additionally, we also detected significantly higher expression of host-derived growth factors in hNSCs-transplanted mice compared with the control animals, together with inhibition of local microglia and proinflammatory cytokines. Overall, our results indicate that hNSCs transplantation exerts neuroprotection in MPTP-insulted mice via regulating the host niche. Harnessing synergistic interaction between the grafts and host cells may help optimize cell-based therapies for PD.

  12. Human avoidance and approach learning: evidence for overlapping neural systems and experiential avoidance modulation of avoidance neurocircuitry.

    Science.gov (United States)

    Schlund, Michael W; Magee, Sandy; Hudgins, Caleb D

    2011-12-01

    Adaptive functioning is thought to reflect a balance between approach and avoidance neural systems with imbalances often producing pathological forms of avoidance. Yet little evidence is available in healthy adults demonstrating a balance between approach and avoidance neural systems and modulation in avoidance neurocircuitry by vulnerability factors for avoidance. Consequently, we used functional magnetic resonance imaging (fMRI) to compare changes in brain activation associated with human avoidance and approach learning and modulation of avoidance neurocircuitry by experiential avoidance. fMRI tracked trial-by-trial increases in activation while adults learned through trial and error an avoidance response that prevented money loss and an approach response that produced money gain. Avoidance and approach cues elicited similar experience-dependent increases in activation in a fronto-limbic-striatal network. Positive and negative reinforcing outcomes (i.e., money gain and avoidance of loss) also elicited similar increases in activation in frontal and striatal regions. Finally, increased experiential avoidance and self-punishment coping was associated with decreased activation in medial/superior frontal regions, anterior cingulate, amygdala and hippocampus. These findings suggest avoidance and approach learning recruit a similar fronto-limbic-striatal network in healthy adults. Increased experiential avoidance also appears to be associated with reduced frontal and limbic reactivity in avoidance, establishing an important link between maladaptive avoidance coping and altered responses in avoidance neurocircuitry. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans.

    Science.gov (United States)

    Feng, C; Lori, A; Waldman, I D; Binder, E B; Haroon, E; Rilling, J K

    2015-09-01

    Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with functional magnetic resonance imaging while playing an iterated Prisoner's Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  14. Human cortical neural correlates of visual fatigue during binocular depth perception: An fNIRS study.

    Directory of Open Access Journals (Sweden)

    Tingting Cai

    Full Text Available Functional near-infrared spectroscopy (fNIRS was adopted to investigate the cortical neural correlates of visual fatigue during binocular depth perception for different disparities (from 0.1° to 1.5°. By using a slow event-related paradigm, the oxyhaemoglobin (HbO responses to fused binocular stimuli presented by the random-dot stereogram (RDS were recorded over the whole visual dorsal area. To extract from an HbO curve the characteristics that are correlated with subjective experiences of stereopsis and visual fatigue, we proposed a novel method to fit the time-course HbO curve with various response functions which could reflect various processes of binocular depth perception. Our results indicate that the parietal-occipital cortices are spatially correlated with binocular depth perception and that the process of depth perception includes two steps, associated with generating and sustaining stereovision. Visual fatigue is caused mainly by generating stereovision, while the amplitude of the haemodynamic response corresponding to sustaining stereovision is correlated with stereopsis. Combining statistical parameter analysis and the fitted time-course analysis, fNIRS could be a promising method to study visual fatigue and possibly other multi-process neural bases.

  15. Tracking cortical entrainment in neural activity: Auditory processes in human temporal cortex

    Directory of Open Access Journals (Sweden)

    Andrew eThwaites

    2015-02-01

    Full Text Available A primary objective for cognitive neuroscience is to identify how features of the sensory environment are encoded in neural activity. Current auditory models of loudness perception can be used to make detailed predictions about the neural activity of the cortex as an individual listens to speech. We used two such models (loudness-sones and loudness-phons, varying in their psychophysiological realism, to predict the instantaneous loudness contours produced by 480 isolated words. These two sets of 480 contours were used to search for electrophysiological evidence of loudness processing in whole-brain recordings of electro- and magneto-encephalographic (EMEG activity, recorded while subjects listened to the words. The technique identified a bilateral sequence of loudness processes, predicted by the more realistic loudness-sones model, that begin in auditory cortex at ~80 ms and subsequently reappear, tracking progressively down the superior temporal sulcus (STS at lags from 230 to 330 ms. The technique was then extended to search for regions sensitive to the fundamental frequency (F0 of the voiced parts of the speech. It identified a bilateral F0 process in auditory cortex at a lag of ~90 ms, which was not followed by activity in STS. The results suggest that loudness information is being used to guide the analysis of the speech stream as it proceeds beyond auditory cortex down STS towards the temporal pole.

  16. Multiparametric Phenotypic Screening System for Profiling Bioactive Compounds Using Human Fetal Hippocampal Neural Stem/Progenitor Cells.

    Science.gov (United States)

    Tabata, Yoshikuni; Murai, Norio; Sasaki, Takeo; Taniguchi, Sachie; Suzuki, Shuichi; Yamazaki, Kazuto; Ito, Masashi

    2015-10-01

    Stem cell research has been progressing rapidly, contributing to regenerative biology and regenerative medicine. In this field, small-molecule compounds affecting stem cell proliferation/differentiation have been explored to understand stem cell biology and support regenerative medicine. In this study, we established a multiparametric screening system to detect bioactive compounds affecting the cell fate of human neural stem/progenitor cells (NSCs/NPCs), using human fetal hippocampal NSCs/NPCs, HIP-009 cells. We examined effects of 410 compounds, which were collected based on mechanisms of action (MOAs) and chemotypes, on HIP-009's cell fate (self-renewal, neuronal and astrocytic differentiation) and morphology by automated multiparametric assays and profiled induced cellular phenotypes. We found that this screening classified compounds with the same MOAs into subgroups according to additional pharmacological effects (e.g., mammalian target of rapamycin complex 1 [mTORC1] inhibitors and mTORC1/mTORC2 dual inhibitors among mTOR inhibitors). Moreover, it identified compounds that have off-target effects under matrix analyses of MOAs and structure similarities (e.g., neurotropic effects of amitriptyline among tri- and tetracyclic compounds). Therefore, this automated, medium-throughput and multiparametric screening system is useful for finding compounds that affect the cell fate of human NSCs/NPCs for supporting regenerative medicine and to fingerprint compounds based on human stem cells' multipotency, leading to understanding of stem cell biology. © 2015 Society for Laboratory Automation and Screening.

  17. Therapeutic effect of BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) in a rodent model of middle cerebral artery occlusion.

    Science.gov (United States)

    Chang, Da-Jeong; Lee, Nayeon; Choi, Chunggab; Jeon, Iksoo; Oh, Seung-Hun; Shin, Dong Ah; Hwang, Tae-Sun; Lee, Hong J; Kim, Seung U; Moon, Hyeyoung; Hong, Kwan Soo; Kang, Kyung-Sun; Song, Jihwan

    2013-01-01

    Ischemic stroke mainly caused by middle cerebral artery occlusion (MCAo) represents the major type of stroke; however, there are still very limited therapeutic options for the stroke-damaged patients. In this study, we evaluated the neurogenic and therapeutic potentials of human neural stem cells (NSCs) overexpressing brain-derived neurotrophic factor (HB1.F3.BDNF) following transplantation into a rodent model of MCAo. F3.BDNF human NSCs (F3.BDNF) were transplanted into the contralateral side of striatum at 7 days after MCAo, and the transplanted animals were monitored up to 8 weeks using animal MRI and various behavioral tests before they were sacrificed for immunohistochemical analysis. Interestingly, animal MRI results indicate that the majority of contralaterally transplanted neural stem cells were migrated to the peri-infarct area, showing a pathotropism. Transplanted animals exhibited significant behavioral improvements in stepping, rotarod, and modified neurological severity score (mNSS) tests. We also found that the transplanted human cells were colocalized with nestin, DCX, MAP2, DARPP-32, TH, GAD65/67-positive cells, of which results can be correlated with neural regeneration and behavioral recovery in the transplanted animals. More importantly, we were able to detect high levels of human BDNF protein expression, presumably derived from the transplanted F3.BDNF. Taken together, these results provide strong evidence that human neural stem cells (F3.BDNF) are effective in treating stroke animal models.

  18. Multiple cranial organ defects after conditionally knocking out Fgf10 in the neural crest

    Directory of Open Access Journals (Sweden)

    Tathyane H.N. Teshima

    2016-10-01

    Full Text Available Fgf10 is necessary for the development of a number of organs that fail to develop or are reduced in size in the null mutant. Here we have knocked out Fgf10 specifically in the neural crest driven by Wnt1cre. The Wnt1creFgf10fl/fl mouse phenocopies many of the null mutant defects, including cleft palate, loss of salivary glands and ocular glands, highlighting the neural crest origin of the Fgf10 expressing mesenchyme surrounding these organs. In contrast tissues such as the limbs and lungs, where Fgf10 is expressed by the surrounding mesoderm, were unaffected, as was the pituitary gland where Fgf10 is expressed by the neuroepithelium. The circumvallate papilla of the tongue formed but was hypoplastic in the conditional and Fgf10 null embryos, suggesting that other sources of FGF can compensate in development of this structure. The tracheal cartilage rings showed normal patterning in the conditional knockout, indicating that the source of Fgf10 for this tissue is mesodermal, which was confirmed using Wnt1cre-dtTom to lineage trace the boundary of the neural crest in this region. The thyroid, thymus and parathyroid glands surrounding the trachea were present but hypoplastic in the conditional mutant, indicating that a neighbouring source of mesodermal Fgf10 might be able to partially compensate for loss of neural crest derived Fgf10.

  19. Combined effect of pulsed electromagnetic field and sound wave on In vitro and In vivo neural differentiation of human mesenchymal stem cells.

    Science.gov (United States)

    Choi, Yun-Kyong; Urnukhsaikhan, Enerelt; Yoon, Hee-Hoon; Seo, Young-Kwon; Cho, Hyunjin; Jeong, Jong-Seob; Kim, Soo-Chan; Park, Jung-Keug

    2017-01-01

    Biophysical wave stimulus has been used as an effective tool to promote cellular maturation and differentiation in the construction of engineered tissue. Pulsed electromagnetic fields (PEMFs) and sound waves have been selected as effective stimuli that can promote neural differentiation. The aim of this study was to investigate the synergistic effect of PEMFs and sound waves on the neural differentiation potential in vitro and in vivo using human bone marrow mesenchymal stem cells (hBM-MSCs). In vitro, neural-related genes in hBM-MSCs were accelerated by the combined exposure to both waves more than by individual exposure to PEMFs or sound waves. The combined wave also up-regulated the expression of neural and synaptic-related proteins in a three-dimensional (3-D) culture system through the phosphorylation of extracellular signal-related kinase. In a mouse model of photochemically induced ischemia, exposure to the combined wave reduced the infarction volume and improved post-injury behavioral activity. These results indicate that a combined stimulus of biophysical waves, PEMFs and sound can enhance and possibly affect the differentiation of MSCs into neural cells. Our study is meaningful for highlighting the potential of combined wave for neurogenic effects and providing new therapeutic approaches for neural cell therapy. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:201-211, 2017. © 2016 American Institute of Chemical Engineers.

  20. Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina.

    Science.gov (United States)

    Mollick, Tanzina; Mohlin, Camilla; Johansson, Kjell

    2016-09-01

    Retinal neurodegenerative disorders like retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy and retinal detachment decrease retinal functionality leading to visual impairment. The pathological events are characterized by photoreceptor degeneration, synaptic disassembly, remodeling of postsynaptic neurons and activation of glial cells. Despite intense research, no effective treatment has been found for these disorders. The current study explores the potential of human neural progenitor cell (hNPC) derived factors to slow the degenerative processes in adult porcine retinal explants. Retinas were cultured for 3 days with or without hNPCs as a feeder layer and investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, western blot and quantitative real time-polymerase chain reaction (qRT-PCR) techniques. TUNEL showed that hNPCs had the capacity to limit photoreceptor cell death. Among cone photoreceptors, hNPC coculture resulted in better maintenance of cone outer segments and reduced opsin mislocalization. Additionally, maintained synaptic structural integrity and preservation of second order calbindin positive horizontal cells was also observed. However, Müller cell gliosis only seemed to be alleviated in terms of reduced Müller cell density. Our observations indicate that at 3 days of coculture, hNPC derived factors had the capacity to protect photoreceptors, maintain synaptic integrity and support horizontal cell survival. Human neural progenitor cell applied treatment modalities may be an effective strategy to help maintain retinal functionality in neurodegenerative pathologies. Whether hNPCs can independently hinder Müller cell gliosis by utilizing higher concentrations or by combination with other pharmacological agents still needs to be determined. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Studies on the differentiation of dopaminergic traits in human neural progenitor cells in vitro and in vivo.

    Science.gov (United States)

    Yang, Ming; Donaldson, Angela E; Marshall, Cheryl E; Shen, James; Iacovitti, Lorraine

    2004-01-01

    The development of cell replacement therapies for the treatment of neurodegenerative disorders such as Parkinson's disease (PD) may depend upon the successful differentiation of human neural stem/progenitor cells into dopamine (DA) neurons. We show here that primary human neural progenitors (HNPs) can be expanded and maintained in culture both as neurospheres (NSPs) and attached monolayers where they develop into neurons and glia. When transplanted into the 6-hydroxydopamine-lesioned rat striatum, undifferentiated NSPs survive longer (60% graft survival at 8-16 weeks vs. 30% graft survival at 8-13 weeks) and migrate farther than their attached counterparts. While both NSP and attached cells continue to express neuronal traits after transplantation, the spontaneous expression of differentiated transmitter-related traits is not observed in either cell type. However, following predifferentiation in culture using a previously described cocktail of reagents, approximately 25% of HNPs can permanently express the DA enzyme tyrosine hydroxylase (TH), even following replating and removal of the DA differentiation cocktail. When these predifferentiated HNPs are transplanted into the brain, however, TH staining is not observed, either because expression is lost or TH-expressing cells preferentially die. Consistent with the latter view is a decrease in total cell survival and migration, and an enhanced glial response in these grafts. In contrast, we found that the overall survival of HNPs is improved when cells engraft near blood vessels or CSF compartments or when they are placed into an intact unlesioned brain, suggesting that there are factors, as yet unidentified, that can better support the development of engrafted HNPs.

  2. Phantom lower limb as a perceptual marker of neural plasticity in the mature human brain.

    Science.gov (United States)

    Aglioti, S; Bonazzi, A; Cortese, F

    1994-03-22

    Three lower limb amputees, who reported phantom sensations, referred somatic stimuli delivered to skin regions proximal to the stump to select points on the phantom limb. Stimuli on the rectum and anus (e.g. during defecation) and on genital areas (e.g. during sexual intercourse) induced analogous, although less precise, mislocation to the phantom limb. Although the representation of the stump in the somatosensory pathway is lateral to that of the amputated lower limb, both anus and genitals are mapped medially to the areas formerly subserving the amputated lower limb. Therefore the mislocalization phenomenon can be considered as a perceptual landmark of new functional connections between the deprived areas and the adjacent ones, thus suggesting a dynamic neural remodelling in the mature nervous system, which was previously considered as a static entity.

  3. Visual gravity cues in the interpretation of biological movements: neural correlates in humans.

    Science.gov (United States)

    Maffei, Vincenzo; Indovina, Iole; Macaluso, Emiliano; Ivanenko, Yuri P; A Orban, Guy; Lacquaniti, Francesco

    2015-01-01

    Our visual system takes into account the effects of Earth gravity to interpret biological motion (BM), but the neural substrates of this process remain unclear. Here we measured functional magnetic resonance (fMRI) signals while participants viewed intact or scrambled stick-figure animations of walking, running, hopping, and skipping recorded at normal or reduced gravity. We found that regions sensitive to BM configuration in the occipito-temporal cortex (OTC) were more active for reduced than normal gravity but with intact stimuli only. Effective connectivity analysis suggests that predictive coding of gravity effects underlies BM interpretation. This process might be implemented by a family of snapshot neurons involved in action monitoring. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. The neural plasticity of early-passage human bone marrow-derived mesenchymal stem cells and their modulation with chromatin-modifying agents.

    Science.gov (United States)

    Zhang, Zhiying; Alexanian, Arshak R

    2014-05-01

    Mesenchymal stem cells (MSCs) in their immature state express a variety of genes of the three germ layers at relatively low or moderate levels that might explain their phenomenal plasticity. Numerous recent studies have demonstrated that under the appropriate conditions in vitro and in vivo the expression of different sets of these genes can be upregulated, turning MSCs into variety of cell lineages of mesodermal, ectodermal and endodermal origin. While transdifferentiation of MSCs is still controversial, these unique properties make MSCs an ideal autologous source of easily reprogrammable cells. Recently, using the approach of cell reprogramming by biological active compounds that interfere with chromatin structure and function, as well as with specific signalling pathways that promote neural fate commitment, we have been able to generate neural-like cells from human bone marrow (BM)-derived MSCs (hMSCs). However, the efficiency of neural transformation of hMSCs induced by this approach gradually declined with passaging. To elucidate the mechanisms that underlie the higher plasticity of early-passage hMSCs, comparative analysis of the expression levels of several pluripotent and neural genes was conducted for early- and late-passage hMSCs. The results demonstrated that early-passage hMSCs expressed the majority of these genes at low and moderate levels that gradually declined at late passages. Neural induction further increased the expression of some of these genes in hMSCs, accompanied by morphological changes into neural-like cells. We concluded that low and moderate expression of several pluripotent and neural genes in early-passage hMSCs could explain their higher plasticity and pliability for neural induction. Copyright © 2012 John Wiley & Sons, Ltd.

  5. LNGFR(+)THY-1(+) human pluripotent stem cell-derived neural crest-like cells have the potential to develop into mesenchymal stem cells.

    Science.gov (United States)

    Ouchi, Takehito; Morikawa, Satoru; Shibata, Shinsuke; Fukuda, Kimiko; Okuno, Hironobu; Fujimura, Takumi; Kuroda, Tatsuo; Ohyama, Manabu; Akamatsu, Wado; Nakagawa, Taneaki; Okano, Hideyuki

    2016-12-01

    Mesenchymal stem cells (MSCs) are defined as non-hematopoietic, plastic-adherent, self-renewing cells that are capable of tri-lineage differentiation into bone, cartilage or fat in vitro. Thus, MSCs are promising candidates for cell-based medicine. However, classifications of MSCs have been defined retrospectively; moreover, this conventional criterion may be inaccurate due to contamination with other hematopoietic lineage cells. Human MSCs can be enriched by selection for LNGFR and THY-1, and this population may be analogous to murine PDGFRα(+)Sca-1(+) cells, which are developmentally derived from neural crest cells (NCCs). Murine NCCs were labeled by fluorescence, which provided definitive proof of neural crest lineage, however, technical considerations prevent the use of a similar approach to determine the origin of human LNGFR(+)THY-1(+) MSCs. To further clarify the origin of human MSCs, human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) were used in this study. Under culture conditions required for the induction of neural crest cells, human ESCs and iPSCs-derived cells highly expressed LNGFR and THY-1. These LNGFR(+)THY-1(+) neural crest-like cells, designated as LT-NCLCs, showed a strong potential to differentiate into both mesenchymal and neural crest lineages. LT-NCLCs proliferated to form colonies and actively migrated in response to serum concentration. Furthermore, we transplanted LT-NCLCs into chick embryos, and traced their potential for survival, migration and differentiation in the host environment. These results suggest that LNGFR(+)THY-1(+) cells identified following NCLC induction from ESCs/iPSCs shared similar potentials with multipotent MSCs. Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

  6. Pyrolysed 3D-Carbon Scaffolds Induce Spontaneous Differentiation of Human Neural Stem Cells and Facilitate Real-Time Dopamine Detection

    DEFF Research Database (Denmark)

    Amato, Letizia; Heiskanen, Arto; Caviglia, Claudia

    2014-01-01

    Structurally patterned pyrolysed three-dimensional carbon scaffolds (p3Dcarbon) are fabricated and applied for differentiation of human neural stem cells (hNSCs) developed for cell replacement therapy and sensing of released dopamine. In the absence of differentiation factors (DF) the pyrolysed...

  7. Neural differentiation of the human neuroblastoma cell line IMR32 induces production of a thyrotropin-releasing hormone-like peptide

    NARCIS (Netherlands)

    J.M.M. Rondeel (Jan); W. Klootwijk (Willem); E. Linkels; W.J. de Greef (W.); T.J. Visser (Theo)

    1994-01-01

    textabstractThe human neuroblastoma cell line IMR32 produces and secretes substantial amounts of TRH-immunoreactivity (TRH-IR) as measured with radioimmunoassay (RIA) using the nonspecific antiserum 4319. It was found that synthesis of TRH-IR is dependent on neural differentiation: under serum-free

  8. Human fetal striatum-derived neural stem (NS) cells differentiate to mature neurons in vitro and in vivo.

    Science.gov (United States)

    Monni, Emanuela; Cusulin, Carlo; Cavallaro, Maurizio; Lindvall, Olle; Kokaia, Zaal

    2014-01-01

    Clonogenic neural stem (NS) cell lines grown in adherent cultures have previously been established from embryonic stem cells and fetal and adult CNS in rodents and from human fetal brain and spinal cord. Here we describe the isolation of a new cell line from human fetal striatum (hNS cells). These cells showed properties of NS cells in vitro such as monolayer growth, high proliferation rate and expression of radial glia markers. The hNS cells expressed an early neuronal marker while being in the proliferative state. Under appropriate conditions, the hNS cells were efficiently differentiated to neurons, and after 4 weeks about 50% of the cells were βIII tubulin positive. They also expressed the mature neuronal marker NeuN and markers of neuronal subtypes, GABA, calbindin, and DARPP32. After intrastriatal implantation into newborn rats, the hNS cells survived and many of them migrated outside the transplant core into the surrounding tissue. A high percentage of cells in the grafts expressed the neuroblast marker DCX, indicating their neurogenic potential, and some of the cells differentiated to NeuN+ mature neurons. The human fetal striatum-derived NS cell line described here should be a useful tool for studies on cell replacement strategies in models of the striatal neuronal loss occurring in Huntington's disease and stroke.

  9. Differentiated human midbrain-derived neural progenitor cells express excitatory strychnine-sensitive glycine receptors containing α2β subunits.

    Directory of Open Access Journals (Sweden)

    Florian Wegner

    Full Text Available BACKGROUND: Human fetal midbrain-derived neural progenitor cells (NPCs may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+-K(+-Cl(- co-transporter 1 (NKCC1-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. CONCLUSIONS/SIGNIFICANCE: These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.

  10. The ability to recognize objects from bottlenose dolphin (Tursiops truncatus) echoes generalizes across multiple orientations in humans and neural networks.

    Science.gov (United States)

    DeLong, Caroline M; Heberle, Amanda L; Wisniewski, Matthew G; Mercado, Eduardo

    2014-05-01

    Object constancy, the ability to recognize objects despite changes in orientation, has not been well studied in the auditory modality. Dolphins use echolocation for object recognition, and objects ensonified by dolphins produce echoes that can vary significantly as a function of orientation. In this experiment, human listeners had to classify echoes from objects varying in material, shape, and size that were ensonified with dolphin signals. Participants were trained to discriminate among the objects using an 18-echo stimulus from a 10° range of aspect angles, then tested with novel aspect angles across a 60° range. Participants were typically successful recognizing the objects at all angles (M = 78 %). Artificial neural networks were trained and tested with the same stimuli with the purpose of identifying acoustic cues that enable object recognition. A multilayer perceptron performed similarly to the humans and revealed that recognition was enabled by both the amplitude and frequency of echoes, as well as the temporal dynamics of these features over the course of echo trains. These results provide insight into representational processes underlying echoic recognition in dolphins and suggest that object constancy perceived through the auditory modality is likely to parallel what has been found in the visual domain in studies with both humans and animals.

  11. Artificial neural networks from MATLAB in medicinal chemistry. Bayesian-regularized genetic neural networks (BRGNN): application to the prediction of the antagonistic activity against human platelet thrombin receptor (PAR-1).

    Science.gov (United States)

    Caballero, Julio; Fernández, Michael

    2008-01-01

    Artificial neural networks (ANNs) have been widely used for medicinal chemistry modeling. In the last two decades, too many reports used MATLAB environment as an adequate platform for programming ANNs. Some of these reports comprise a variety of applications intended to quantitatively or qualitatively describe structure-activity relationships. A powerful tool is obtained when there are combined Bayesian-regularized neural networks (BRANNs) and genetic algorithm (GA): Bayesian-regularized genetic neural networks (BRGNNs). BRGNNs can model complicated relationships between explanatory variables and dependent variables. Thus, this methodology is regarded as useful tool for QSAR analysis. In order to demonstrate the use of BRGNNs, we developed a reliable method for predicting the antagonistic activity of 5-amino-3-arylisoxazole derivatives against Human Platelet Thrombin Receptor (PAR-1), using classical 3D-QSAR methodologies: Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). In addition, 3D vectors generated from the molecular structures were correlated with antagonistic activities by multivariate linear regression (MLR) and Bayesian-regularized neural networks (BRGNNs). All models were trained with 34 compounds, after which they were evaluated for predictive ability with additional 6 compounds. CoMFA and CoMSIA were unable to describe this structure-activity relationship, while BRGNN methodology brings the best results according to validation statistics.

  12. Survival of transplanted human neural stem cell line (ReNcell VM) into the rat brain with and without immunosuppression.

    Science.gov (United States)

    Hovakimyan, M; Müller, J; Wree, A; Ortinau, S; Rolfs, A; Schmitt, O

    2012-09-01

    Functional replacement of specific neuronal populations through transplantation of neural tissue represents an attractive therapeutic strategy for treating neurodegenerative disorders like Parkinson's disease (PD). Even though the brain is a partially immune privileged site, immunosuppression is still needed for the prevention of host immune response, and thus, xenograft rejection. Here, we investigated the fate of human ventral mesencephalon derived immortalized cell line ReNcell VM upon unilateral transplantation into the intact rat striatum with or without immunosuppression with cyclosporine A (CsA). The status of xenografted human ReNcell VM cells was analysed by immunohistochemistry/immunofluorescence 4 and 6weeks after transplantation. Four weeks after transplantation, ReNcell VM cells could be detected in both groups, although the number of survived cells was significantly higher in brains of immunosuppressed rats. In contrast, only 2 out of 6 brains grafted without immunosuppression revealed human ReNcell VM cells 6weeks post grafting, whereas a considerable number of human cells could still be found in all the brains of immunosuppressed rats. Immunohistochemical analysis of grafted cells showed almost no evidence of neuronal differentiation, but rather astroglial development. In summary, we have shown that the immunosuppression is needed for the survival of human VM derived progenitor cells in the rat striatum. CsA affected cell survival, but not differentiation capacity: in both groups, grafted either with or without immunosuppression, the ReNcell VM cells lacked neuronal phenotype and developed preferentially into astroglia. Copyright © 2012 Elsevier GmbH. All rights reserved.

  13. 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…

  14. Exploring the Role of Spatial Frequency Information during Neural Emotion Processing in Human Infants

    Directory of Open Access Journals (Sweden)

    Sarah Jessen

    2017-10-01

    Full Text Available Enhanced attention to fear expressions in adults is primarily driven by information from low as opposed to high spatial frequencies contained in faces. However, little is known about the role of spatial frequency information in emotion processing during infancy. In the present study, we examined the role of low compared to high spatial frequencies in the processing of happy and fearful facial expressions by using filtered face stimuli and measuring event-related brain potentials (ERPs in 7-month-old infants (N = 26. Our results revealed that infants’ brains discriminated between emotional facial expressions containing high but not between expressions containing low spatial frequencies. Specifically, happy faces containing high spatial frequencies elicited a smaller Nc amplitude than fearful faces containing high spatial frequencies and happy and fearful faces containing low spatial frequencies. Our results demonstrate that already in infancy spatial frequency content influences the processing of facial emotions. Furthermore, we observed that fearful facial expressions elicited a comparable Nc response for high and low spatial frequencies, suggesting a robust detection of fearful faces irrespective of spatial frequency content, whereas the detection of happy facial expressions was contingent upon frequency content. In summary, these data provide new insights into the neural processing of facial emotions in early development by highlighting the differential role played by spatial frequencies in the detection of fear and happiness.

  15. Human Adult Dental Pulp Stem Cells Enhance Poststroke Functional Recovery Through Non‐Neural Replacement Mechanisms

    National Research Council Canada - National Science Library

    Leong, Wai Khay; Henshall, Tanya L; Arthur, Agnes; Kremer, Karlea L; Lewis, Martin D; Helps, Stephen C; Field, John; Hamilton-Bruce, Monica A; Warming, Scott; Manavis, Jim; Vink, Robert; Gronthos, Stan; Koblar, Simon A

    2012-01-01

    Human adult dental pulp stem cells (DPSCs), derived from third molar teeth, are multipotent and have the capacity to differentiate into neurons under inductive conditions both in vitro and following transplantation into the avian embryo...

  16. Tracking Human-like Natural Motion Using Deep Recurrent Neural Networks

    OpenAIRE

    Park, Youngbin; Moon, Sungphill; Suh, Il Hong

    2016-01-01

    Kinect skeleton tracker is able to achieve considerable human body tracking performance in convenient and a low-cost manner. However, The tracker often captures unnatural human poses such as discontinuous and vibrated motions when self-occlusions occur. A majority of approaches tackle this problem by using multiple Kinect sensors in a workspace. Combination of the measurements from different sensors is then conducted in Kalman filter framework or optimization problem is formulated for sensor ...

  17. Exploiting elasticity: Modeling the influence of neural control on mechanics and energetics of ankle muscle-tendons during human hopping.

    Science.gov (United States)

    Robertson, Benjamin D; Sawicki, Gregory S

    2014-07-21

    We present a simplified Hill-type model of the human triceps surae-Achilles tendon complex working on a gravitational-inertial load during cyclic contractions (i.e. vertical hopping). Our goal was to determine the role that neural control plays in governing muscle, or contractile element (CE), and tendon, or series elastic element (SEE), mechanics and energetics within a compliant muscle-tendon unit (MTU). We constructed a 2D parameter space consisting of many combinations of stimulation frequency and magnitude (i.e. neural control strategies). We compared the performance of each control strategy by evaluating peak force and average positive mechanical power output for the system (MTU) and its respective components (CE, SEE), force-length (F-L) and -velocity (F-V) operating point of the CE during active force production, average metabolic rate for the CE, and both MTU and CE apparent efficiency. Our results suggest that frequency of stimulation plays a primary role in governing whole-MTU mechanics. These include the phasing of both activation and peak force relative to minimum MTU length, average positive power, and apparent efficiency. Stimulation amplitude was primarily responsible for governing average metabolic rate and within MTU mechanics, including peak force generation and elastic energy storage and return in the SEE. Frequency and amplitude of stimulation both played integral roles in determining CE F-L operating point, with both higher frequency and amplitude generally corresponding to lower CE strains, reduced injury risk, and elimination of the need for passive force generation in the CE parallel elastic element (PEE). Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. The effect of exogenous cortisol during sleep on the behavioral and neural correlates of emotional memory consolidation in humans.

    Science.gov (United States)

    van Marle, Hein J F; Hermans, Erno J; Qin, Shaozheng; Overeem, Sebastiaan; Fernández, Guillén

    2013-09-01

    A host of animal work demonstrates that the retention benefit for emotionally aversive over neutral memories is regulated by glucocorticoid action during memory consolidation. Particularly, glucocorticoids may affect systems-level processes that promote the gradual reorganization of emotional memory traces. These effects remain largely uninvestigated in humans. Therefore, in this functional magnetic resonance imaging study we administered hydrocortisone during a polysomnographically monitored night of sleep directly after healthy volunteers studied negative and neutral pictures in a double-blind, placebo-controlled, between-subjects design. The following evening memory consolidation was probed during a recognition memory test in the MR scanner by assessing the difference in brain activity associated with memory for the consolidated items studied before sleep and new, unconsolidated items studied shortly before test (remote vs. recent memory paradigm). Hydrocortisone administration resulted in elevated cortisol levels throughout the experimental night with no group difference at recent encoding or test. Behaviorally, we showed that cortisol enhanced the difference between emotional and neutral consolidated memory, effectively prioritizing emotional memory consolidation. On a neural level, we found that cortisol reduced amygdala reactivity related to the retrieval of these same consolidated, negative items. These findings show that cortisol administration during first post-encoding sleep had a twofold effect on the first 24h of emotional memory consolidation. While cortisol prioritized recognition memory for emotional items, it reduced reactivation of the neural circuitry underlying emotional responsiveness during retrieval. These findings fit recent theories on emotional depotentiation following consolidation during sleep, although future research should establish the sleep-dependence of this effect. Moreover, our data may shed light on mechanisms underlying

  19. A Hybrid Neural Network Approach for Kinematic Modeling of a Novel 6-UPS Parallel Human-Like Mastication Robot

    Directory of Open Access Journals (Sweden)

    Hadi Kalani

    2016-04-01

    Full Text Available Introduction we aimed to introduce a 6-universal-prismatic-spherical (UPS parallel mechanism for the human jaw motion and theoretically evaluate its kinematic problem. We proposed a strategy to provide a fast and accurate solution to the kinematic problem. The proposed strategy could accelerate the process of solution-finding for the direct kinematic problem by reducing the number of required iterations in order to reach the desired accuracy level. Materials and Methods To overcome the direct kinematic problem, an artificial neural network and third-order Newton-Raphson algorithm were combined to provide an improved hybrid method. In this method, approximate solution was presented for the direct kinematic problem by the neural network. This solution could be considered as the initial guess for the third-order Newton-Raphson algorithm to provide an answer with the desired level of accuracy. Results The results showed that the proposed combination could help find a approximate solution and reduce the execution time for the direct kinematic problem, The results showed that muscular actuations showed periodic behaviors, and the maximum length variation of temporalis muscle was larger than that of masseter and pterygoid muscles. By reducing the processing time for solving the direct kinematic problem, more time could be devoted to control calculations.. In this method, for relatively high levels of accuracy, the number of iterations and computational time decreased by 90% and 34%, respectively, compared to the conventional Newton method. Conclusion The present analysis could allow researchers to characterize and study the mastication process by specifying different chewing patterns (e.g., muscle displacements.

  20. Functional assessment of the acute local and distal transplantation of human neural stem cells after spinal cord injury.

    Science.gov (United States)

    Cheng, Ivan; Mayle, Robert E; Cox, Christopher A; Park, Don Y; Smith, Robert L; Corcoran-Schwartz, Ian; Ponnusamy, Karthikeyan E; Oshtory, Rayshad; Smuck, Matthew W; Mitra, Raj; Kharazi, Alexander I; Carragee, Eugene J

    2012-11-01

    Spinal cord injury can lead to severe functional impairments secondary to axonal damage, neuronal loss, and demyelination. The injured spinal cord has limited regrowth of damaged axons. Treatment remains controversial, given inconsistent functional improvement. Previous studies demonstrated functional recovery of rats with spinal cord contusion after transplantation of rat fetal neural stem cells. We hypothesized that acute transplantation of human fetal neural stem cells (hNSCs) both locally at the injury site as well as distally via intrathecal injection would lead to improved functional recovery compared with controls. Twenty-four adult female Long-Evans hooded rats were randomized into four groups with six animals in each group: two experimental and two control. Functional assessment was measured after injury and then weekly for 6 weeks using the Basso, Beattie, and Bresnahan Locomotor Rating Score. Data were analyzed using two-sample t test and linear mixed-effects model analysis. Posterior exposure and laminectomy at T10 level was used. Moderate spinal cord contusion was induced by the Multicenter Animal Spinal Cord Injury Study Impactor with 10-g weight dropped from a height of 25 mm. Experimental subjects received either a subdural injection of hNSCs locally at the injury site or intrathecal injection of hNSCs through a separate distal laminotomy. Controls received control media injection either locally or distally. Statistically significant functional improvement was observed in local or distal hNSCs subjects versus controls (p=.034 and 0.016, respectively). No significant difference was seen between local or distal hNSC subjects (p=.66). Acute local and distal transplantation of hNSCs into the contused spinal cord led to significant functional recovery in the rat model. No statistical difference was found between the two techniques. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. An additional human chromosome 21 causes suppression of neural fate of pluripotent mouse embryonic stem cells in a teratoma model

    Directory of Open Access Journals (Sweden)

    Fisher Elizabeth

    2007-11-01

    Full Text Available Abstract Background Down syndrome (DS, caused by trisomy of human chromosome 21 (HSA21, is the most common genetic cause of mental retardation in humans. Among complex phenotypes, it displays a number of neural pathologies including smaller brain size, reduced numbers of neurons, reduced dendritic spine density and plasticity, and early Alzheimer-like neurodegeneration. Mouse models for DS show behavioural and cognitive defects, synaptic plasticity defects, and reduced hippocampal and cerebellar neuron numbers. Early postnatal development of both human and mouse-model DS shows the reduced capability of neuronal precursor cells to generate neurons. The exact molecular cause of this reduction, and the role played by increased dosage of individual HSA21 genes, remain unknown. Results We have subcutaneously injected mouse pluripotent ES cells containing a single freely segregating supernumerary human chromosome 21 (HSA21 into syngeneic mice, to generate transchromosomic teratomas. Transchromosomic cells and parental control cells were injected into opposite flanks of thirty mice in three independent experiments. Tumours were grown for 30 days, a time-span equivalent to combined intra-uterine, and early post-natal mouse development. When paired teratomas from the same animals were compared, transchromosomic tumours showed a three-fold lower percentage of neuroectodermal tissue, as well as significantly reduced mRNA levels for neuron specific (Tubb3 and glia specific (Gfap genes, relative to euploid controls. Two thirds of transchromosomic tumours also showed a lack of PCR amplification with multiple primers specific for HSA21, which were present in the ES cells at the point of injection, thus restricting a commonly retained trisomy to less than a third of HSA21 genes. Conclusion We demonstrate that a supernumerary chromosome 21 causes Inhibition of Neuroectodermal DIfferentiation (INDI of pluripotent ES cells. The data suggest that trisomy of less

  2. An Integrated Miniature Bioprocessing for Personalized Human Induced Pluripotent Stem Cell Expansion and Differentiation into Neural Stem Cells

    Science.gov (United States)

    Lin, Haishuang; Li, Qiang; Lei, Yuguo

    2017-01-01

    Human induced pluripotent stem cells (iPSCs) are ideal cell sources for personalized cell therapies since they can be expanded to generate large numbers of cells and differentiated into presumably all the cell types of the human body in vitro. In addition, patient specific iPSC-derived cells induce minimal or no immune response in vivo. However, with current cell culture technologies and bioprocessing, the cost for biomanufacturing clinical-grade patient specific iPSCs and their derivatives are very high and not affordable for majority of patients. In this paper, we explored the use of closed and miniature cell culture device for biomanufacturing patient specific neural stem cells (NSCs) from iPSCs. We demonstrated that, with the assist of a thermoreversible hydrogel scaffold, the bioprocessing including iPSC expansion, iPSC differentiation into NSCs, the subsequent depletion of undifferentiated iPSCs from the NSCs, and concentrating and transporting the purified NSCs to the surgery room, could be integrated and completed within two closed 15 ml conical tubes. PMID:28057917

  3. Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase.

    Directory of Open Access Journals (Sweden)

    Xi-Juan Liu

    2017-07-01

    Full Text Available Congenital human cytomegalovirus (HCMV infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs. As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1 is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1 is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase.

  4. Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase.

    Science.gov (United States)

    Liu, Xi-Juan; Yang, Bo; Huang, Sheng-Nan; Wu, Cong-Cong; Li, Xiao-Jun; Cheng, Shuang; Jiang, Xuan; Hu, Fei; Ming, Ying-Zi; Nevels, Michael; Britt, William J; Rayner, Simon; Tang, Qiyi; Zeng, Wen-Bo; Zhao, Fei; Luo, Min-Hua

    2017-07-01

    Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1) is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1) is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase.

  5. Improvement of cognitive function and physical activity of aging mice by human neural stem cells over-expressing choline acetyltransferase.

    Science.gov (United States)

    Park, Dongsun; Yang, Yun-Hui; Bae, Dae Kwon; Lee, Sun Hee; Yang, Goeun; Kyung, Jangbeen; Kim, Dajeong; Choi, Ehn-Kyoung; Lee, Seong Won; Kim, Gon Hyung; Hong, Jin Tae; Choi, Kyung-Chul; Lee, Hong Jun; Kim, Seung U; Kim, Yun-Bae

    2013-11-01

    Aging is characterized by progressive loss of cognitive and memory functions as well as decrease in physical activities. In the present study, a human neural stem cell line (F3 NSC) over-expressing choline acetyltransferase (F3.ChAT), an enzyme responsible for acetylcholine synthesis, was generated and transplanted in the brain of 18-month-old male ICR mice. Four weeks post-transplantation, neurobehavioral functions, expression of ChAT enzyme, production of acetylcholine and neurotrophic factors, and expression of cholinergic nervous system markers in transplanted animals were investigated. F3.ChAT NSCs markedly improved both the cognitive function and physical activity of aging animals, in parallel with the elevation of brain acetylcholine level. Transplanted F3 and F3.ChAT cells were found to differentiate into neurons and astrocytes, and to produce ChAT proteins. Transplantation of the stem cells increased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), enhanced expression of Trk B, and restored host microtubule-associated protein 2 and cholinergic nervous system. The results demonstrate that human NSCs over-expressing ChAT improve cognitive function and physical activity of aging mice, not only by producing ACh directly but also by restoring cholinergic neuronal integrity, which might be mediated by neurotrophins BDNF and NGF. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Design of a high-throughput human neural crest cell migration assay to indicate potential developmental toxicants.

    Science.gov (United States)

    Nyffeler, Johanna; Karreman, Christiaan; Leisner, Heidrun; Kim, Yong Jun; Lee, Gabsang; Waldmann, Tanja; Leist, Marcel

    2017-01-01

    Migration of neural crest cells (NCCs) is one of the pivotal processes of human fetal development. Malformations arise if NCC migration and differentiation are impaired genetically or by toxicants. In the currently available test systems for migration inhibition of NCC (MINC), the manual generation of a cell-free space results in extreme operator dependencies, and limits throughput. Here a new test format was established. The assay avoids scratching by plating cells around a commercially available circular stopper. Removal of the stopper barrier after cell attachment initiates migration. This microwell-based circular migration zone NCC function assay (cMINC) was further optimized for toxicological testing of human pluripotent stem cell (hPSC)-derived NCCs. The challenge of obtaining data on viability and migration by automated image processing was addressed by developing a freeware. Data on cell proliferation were obtained by labelling replicating cells, and by careful assessment of cell viability for each experimental sample. The role of cell proliferation as an experimental confounder was tested experimentally by performing the cMINC in the presence of the proliferation-inhibiting drug cytosine arabinoside (AraC), and by a careful evaluation of mitotic events over time. Data from these studies led to an adaptation of the test protocol, so that toxicant exposure was limited to 24 h. Under these conditions, a prediction model was developed that allows classification of toxicants as either inactive, leading to unspecific cytotoxicity, or specifically inhibiting NC migration at non-cytotoxic concentrations.

  7. Healthy human CSF promotes glial differentiation of hESC-derived neural cells while retaining spontaneous activity in existing neuronal networks

    Directory of Open Access Journals (Sweden)

    Heikki Kiiski

    2013-05-01

    The possibilities of human pluripotent stem cell-derived neural cells from the basic research tool to a treatment option in regenerative medicine have been well recognized. These cells also offer an interesting tool for in vitro models of neuronal networks to be used for drug screening and neurotoxicological studies and for patient/disease specific in vitro models. Here, as aiming to develop a reductionistic in vitro human neuronal network model, we tested whether human embryonic stem cell (hESC-derived neural cells could be cultured in human cerebrospinal fluid (CSF in order to better mimic the in vivo conditions. Our results showed that CSF altered the differentiation of hESC-derived neural cells towards glial cells at the expense of neuronal differentiation. The proliferation rate was reduced in CSF cultures. However, even though the use of CSF as the culture medium altered the glial vs. neuronal differentiation rate, the pre-existing spontaneous activity of the neuronal networks persisted throughout the study. These results suggest that it is possible to develop fully human cell and culture-based environments that can further be modified for various in vitro modeling purposes.

  8. Using artificial neural networks for the transformation of human body postures based on landmarks

    NARCIS (Netherlands)

    Zhang, B.

    2005-01-01

    Designers, engineers and ergonomists are seeking to exploit the opportunities offered by the 3D anthropometric technologies. These technologies make 3D measurements possible and provide us with a more detailed description of human body in comparison with the traditional 1D or 2D data processing. In

  9. Neural Coding of Relational Invariance in Speech: Human Language Analogs to the Barn Owl.

    Science.gov (United States)

    Sussman, Harvey M.

    1989-01-01

    The neuronal model shown to code sound-source azimuth in the barn owl by H. Wagner et al. in 1987 is used as the basis for a speculative brain-based human model, which can establish contrastive phonetic categories to solve the problem of perception "non-invariance." (SLD)

  10. The use of artificial neural network to evaluate the effects of human ...

    African Journals Online (AJOL)

    Increase in human factors coupled with physiographic factors will impact stock volume in forest ecosystems. The scale of this process and critical information in forestry management provide an incentive for the development of model to predict the forest stock volume. In this paper, we use data derived from Siahrood, Guilan ...

  11. Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury.

    Science.gov (United States)

    Haus, Daniel L; López-Velázquez, Luci; Gold, Eric M; Cunningham, Kelly M; Perez, Harvey; Anderson, Aileen J; Cummings, Brian J

    2016-07-01

    Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal tissue volume. Instead, we

  12. Sensitive Tumorigenic Potential Evaluation of Adult Human Multipotent Neural Cells Immortalized by hTERT Gene Transduction.

    Science.gov (United States)

    Lee, Kee Hang; Nam, Hyun; Jeong, Da Eun; Kim, Sung Soo; Song, Hye Jin; Pyeon, Hee Jang; Kang, Kyeongjin; Hong, Seung-Cheol; Nam, Do-Hyun; Joo, Kyeung Min

    2016-01-01

    Stem cells and therapeutic genes are emerging as a new therapeutic approach to treat various neurodegenerative diseases with few effective treatment options. However, potential formation of tumors by stem cells has hampered their clinical application. Moreover, adequate preclinical platforms to precisely test tumorigenic potential of stem cells are controversial. In this study, we compared the sensitivity of various animal models for in vivo stem cell tumorigenicity testing to identify the most sensitive platform. Then, tumorigenic potential of adult human multipotent neural cells (ahMNCs) immortalized by the human telomerase reverse transcriptase (hTERT) gene was examined as a stem cell model with therapeutic genes. When human glioblastoma (GBM) cells were injected into adult (4-6-week-old) Balb/c-nu, adult NOD/SCID, adult NOG, or neonate (1-2-week-old) NOG mice, the neonate NOG mice showed significantly faster tumorigenesis than that of the other groups regardless of intracranial or subcutaneous injection route. Two kinds of ahMNCs (682TL and 779TL) were primary cultured from surgical samples of patients with temporal lobe epilepsy. Although the ahMNCs were immortalized by lentiviral hTERT gene delivery (hTERT-682TL and hTERT-779TL), they did not form any detectable masses, even in the most sensitive neonate NOG mouse platform. Moreover, the hTERT-ahMNCs had no gross chromosomal abnormalities on a karyotype analysis. Taken together, our data suggest that neonate NOG mice could be a sensitive animal platform to test tumorigenic potential of stem cell therapeutics and that ahMNCs could be a genetically stable stem cell source with little tumorigenic activity to develop regenerative treatments for neurodegenerative diseases.

  13. Nop2 is expressed during proliferation of neural stem cells and in adult mouse and human brain.

    Science.gov (United States)

    Kosi, Nina; Alić, Ivan; Kolačević, Matea; Vrsaljko, Nina; Jovanov Milošević, Nataša; Sobol, Margarita; Philimonenko, Anatoly; Hozák, Pavel; Gajović, Srećko; Pochet, Roland; Mitrečić, Dinko

    2015-02-09

    The nucleolar protein 2 gene encodes a protein specific for the nucleolus. It is assumed that it plays a role in the synthesis of ribosomes and regulation of the cell cycle. Due to its link to cell proliferation, higher expression of Nop2 indicates a worse tumor prognosis. In this work we used Nop2(gt1gaj) gene trap mouse strain. While lethality of homozygous animals suggested a vital role of this gene, heterozygous animals allowed the detection of expression of Nop2 in various tissues, including mouse brain. Histochemistry, immunohistochemistry and immunoelectron microscopy techniques, applied to a mature mouse brain, human brain and on mouse neural stem cells revealed expression of Nop2 in differentiating cells, including astrocytes, as well as in mature neurons. Nop2 was detected in various regions of mouse and human brain, mostly in large pyramidal neurons. In the human, Nop2 was strongly expressed in supragranular and infragranular layers of the somatosensory cortex and in layer III of the cingulate cortex. Also, Nop2 was detected in CA1 and the subiculum of the hippocampus. Subcellular analyses revealed predominant location of Nop2 within the dense fibrillar component of the nucleolus. To test if Nop2 expression correlates to cell proliferation occurring during tissue regeneration, we induced strokes in mice by middle cerebral artery occlusion. Two weeks after stroke, the number of Nop2/nestin double positive cells in the region affected by ischemia and the periventricular zone substantially increased. Our findings suggest a newly discovered role of Nop2 in both mature neurons and in cells possibly involved in the regeneration of nervous tissue. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

  14. Neural constraints on eye motion in human eye-head saccades.

    Science.gov (United States)

    Misslisch, H; Tweed, D; Vilis, T

    1998-02-01

    We examined two ways in which the neural control system for eye-head saccades constrains the motion of the eye in the head. The first constraint involves Listing's law, which holds ocular torsion at zero during head-fixed saccades. During eye-head saccades, does this law govern the eye's motion in space or in the head? Our subjects, instructed to saccade between space-fixed targets with the head held still in different positions, systematically violated Listing's law of the eye in space in a way that approximately, but not perfectly, preserved Listing's law of the eye in head. This finding implies that the brain does not compute desired eye position based on the desired gaze direction alone but also considers head position. The second constraint we studied was saturation, the process where desired-eye-position commands in the brain are "clipped" to keep them within an effective oculomotor range (EOMR), which is smaller than the mechanical range of eye motion. We studied the adaptability of the EOMR by asking subjects to make head-only saccades. As predicted by current eye-head models, subjects failed to hold their eyes still in their orbits. Unexpectedly, though, the range of eye-in-head motion in the horizontal-vertical plane was on average 31% smaller in area than during normal eye-head saccades, suggesting that the EOMR had been reduced by effort of will. Larger reductions were possible with altered visual input: when subjects donned pinhole glasses, the EOMR immediately shrank by 80%. But even with its reduced EOMR, the eye still moved into the "blind" region beyond the pinhole aperture during eye-head saccades. Then, as the head movement brought the saccade target toward the pinhole, the eyes reversed their motion, anticipating or roughly matching the target's motion even though it was still outside the pinhole and therefore invisible. This finding shows that the backward rotation of the eye is timed by internal computations, not by vision. When subjects wore

  15. How social is error observation? The neural mechanisms underlying the observation of human and machine errors.

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    Desmet, Charlotte; Deschrijver, Eliane; Brass, Marcel

    2014-04-01

    Recently, it has been shown that the medial prefrontal cortex (MPFC) is involved in error execution as well as error observation. Based on this finding, it has been argued that recognizing each other's mistakes might rely on motor simulation. In the current functional magnetic resonance imaging (fMRI) study, we directly tested this hypothesis by investigating whether medial prefrontal activity in error observation is restricted to situations that enable simulation. To this aim, we compared brain activity related to the observation of errors that can be simulated (human errors) with brain activity related to errors that cannot be simulated (machine errors). We show that medial prefrontal activity is not only restricted to the observation of human errors but also occurs when observing errors of a machine. In addition, our data indicate that the MPFC reflects a domain general mechanism of monitoring violations of expectancies.

  16. Task-dependent spatial distribution of neural activation pattern in human rectus femoris muscle.

    Science.gov (United States)

    Watanabe, Kohei; Kouzaki, Motoki; Moritani, Toshio

    2012-04-01

    Compartmentalization of skeletal muscle by multiple motor nerve branches, named as neuromuscular compartment (NMC), has been demonstrated in animals as well as humans. While different functional roles among individual NMCs were reported in the animal studies, no studies have clarified the region-specific functional role within a muscle related with NMCs arrangement in human skeletal muscle. It was reported that the rectus femoris (RF) muscle is innervated by two nerve branches attached at proximal and distal parts of the muscle. The purpose of the present study is to clarify the possible region-specific functional role in the human RF muscle. Multi-channel surface electromyography (SEMG) were recorded from the RF muscle by using 128 electrodes during two different submaximal isometric contractions that the muscle contributes, i.e. isometric knee extension and hip flexion, at 20%, 40%, 60% and 80% of maximal voluntary contraction (MVC). Results indicated that the central locus activation for the amplitude map of SEMG during hip flexion located at more proximal region compared with that during knee extension. Significant higher normalized root mean square (RMS) values were observed at the proximal region during the hip flexion in comparison to those at middle and distal regions at 60% and 80% of MVC (p<0.05). In while, significant higher normalized RMS values were demonstrated at the distal region comparing with that at the proximal region at 80% of MVC (p<0.05). The results of the present study suggest possible region-specific functional role in the human RF muscle. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Neural correlates of Early Stone Age toolmaking: technology, language and cognition in human evolution.

    Science.gov (United States)

    Stout, Dietrich; Toth, Nicholas; Schick, Kathy; Chaminade, Thierry

    2008-06-12

    Archaeological and palaeontological evidence from the Early Stone Age (ESA) documents parallel trends of brain expansion and technological elaboration in human evolution over a period of more than 2Myr. However, the relationship between these defining trends remains controversial and poorly understood. Here, we present results from a positron emission tomography study of functional brain activation during experimental ESA (Oldowan and Acheulean) toolmaking by expert subjects. Together with a previous study of Oldowan toolmaking by novices, these results document increased demands for effective visuomotor coordination and hierarchical action organization in more advanced toolmaking. This includes an increased activation of ventral premotor and inferior parietal elements of the parietofrontal praxis circuits in both the hemispheres and of the right hemisphere homologue of Broca's area. The observed patterns of activation and of overlap with language circuits suggest that toolmaking and language share a basis in more general human capacities for complex, goal-directed action. The results are consistent with coevolutionary hypotheses linking the emergence of language, toolmaking, population-level functional lateralization and association cortex expansion in human evolution.

  18. Neural control of cursor trajectory and click by a human with tetraplegia 1000 days after implant of an intracortical microelectrode array

    Science.gov (United States)

    Simeral, J. D.; Kim, S.-P.; Black, M. J.; Donoghue, J. P.; Hochberg, L. R.

    2011-04-01

    The ongoing pilot clinical trial of the BrainGate neural interface system aims in part to assess the feasibility of using neural activity obtained from a small-scale, chronically implanted, intracortical microelectrode array to provide control signals for a neural prosthesis system. Critical questions include how long implanted microelectrodes will record useful neural signals, how reliably those signals can be acquired and decoded, and how effectively they can be used to control various assistive technologies such as computers and robotic assistive devices, or to enable functional electrical stimulation of paralyzed muscles. Here we examined these questions by assessing neural cursor control and BrainGate system characteristics on five consecutive days 1000 days after implant of a 4 × 4 mm array of 100 microelectrodes in the motor cortex of a human with longstanding tetraplegia subsequent to a brainstem stroke. On each of five prospectively-selected days we performed time-amplitude sorting of neuronal spiking activity, trained a population-based Kalman velocity decoding filter combined with a linear discriminant click state classifier, and then assessed closed-loop point-and-click cursor control. The participant performed both an eight-target center-out task and a random target Fitts metric task which was adapted from a human-computer interaction ISO standard used to quantify performance of computer input devices. The neural interface system was further characterized by daily measurement of electrode impedances, unit waveforms and local field potentials. Across the five days, spiking signals were obtained from 41 of 96 electrodes and were successfully decoded to provide neural cursor point-and-click control with a mean task performance of 91.3% ± 0.1% (mean ± s.d.) correct target acquisition. Results across five consecutive days demonstrate that a neural interface system based on an intracortical microelectrode array can provide repeatable, accurate point

  19. Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2

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    Aram S. Modrek

    2017-10-01

    Full Text Available Summary: Low-grade astrocytomas (LGAs carry neomorphic mutations in isocitrate dehydrogenase (IDH concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs. These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis. : In a human neural stem cell model of low-grade astrocytoma, Modrek et al. show that mutant IDH1 and loss of P53 and ATRX together block differentiation via disassociation of SOX2 from putative enhancers. This occurs because of disruption of chromatin looping secondary to hypermethylation at CTCF motifs. Keywords: low-grade glioma, astrocytoma, IDH, P53, ATRX, neural stem cells, SOX2, chromatin looping, CTCF, DNA methylation

  20. The Metal Neurotoxins: An Important Role in Current Human Neural Epidemics?

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    Keith Schofield

    2017-12-01

    Full Text Available Many published studies have illustrated that several of the present day neurological epidemics (autism, attention deficit disorder, Alzheimer’s cannot be correlated to any single neurotoxicant. However, the present scientific examination of the numerous global blood monitoring databases for adults that include the concentrations of the neurotoxic elements, aluminum (Al, arsenic (As, lead (Pb, manganese (Mn, mercury (Hg, and selenium (Se clearly indicate that, when considered in combination, for some, the human body may become easily over-burdened. This can be explained by changes in modern lifestyles. Similar data, solely for pregnant women, have been examined confirming this. All these elements are seen to be present in the human body and at not insignificant magnitudes. Currently suggested minimum risk levels (MRL for humans are discussed and listed together with averages of the reported distributions, together with their spread and maximum values. One observation is that many distributions for pregnant women are not too dissimilar from those of general populations. Women obviously have their individual baseline of neurotoxin values before pregnancy and any efforts to modify this to any significant degree is not yet clearly apparent. For any element, distribution shapes are reasonably similar showing broad distributions with extended tails with numerous outlier values. There are a certain fraction of people that lie well above the MRL values and may be at risk, especially if genetically susceptible. Additionally, synergistic effects between neurotoxins and with other trace metals are now also being reported. It appears prudent for women of child-bearing age to establish their baseline values well before pregnancy. Those at risk then can be better identified. Adequate instrumental testing now is commercially available for this. In addition, directives are necessary for vaccination programs to use only non-neurotoxic adjuvants, especially for

  1. Physical and neural entrainment to rhythm: human sensorimotor coordination across tasks and effector systems

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    Jessica Marie Ross

    2014-08-01

    Full Text Available The human sensorimotor system can be readily entrained to environmental rhythms, through multiple sensory modalities. In this review, we provide an overview of theories of timekeeping that make this neuroentrainment possible. First, we present recent evidence that contests the assumptions made in classic timekeeper models. The role of state estimation, sensory feedback and movement parameters on the organization of sensorimotor timing are discussed in the context of recent experiments that examined simultaneous timing and force control. This discussion is extended to the study of coordinated multi-effector movements and how they may be entrained.

  2. Comparative Effects of Human Neural Stem Cells and Oligodendrocyte Progenitor Cells on the Neurobehavioral Disorders of Experimental Autoimmune Encephalomyelitis Mice

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    Dae-Kwon Bae

    2016-01-01

    Full Text Available Since multiple sclerosis (MS is featured with widespread demyelination caused by autoimmune response, we investigated the recovery effects of F3.olig2 progenitors, established by transducing human neural stem cells (F3 NSCs with Olig2 transcription factor, in myelin oligodendrocyte glycoprotein- (MOG- induced experimental autoimmune encephalomyelitis (EAE model mice. Six days after EAE induction, F3 or F3.olig2 cells (1 × 106/mouse were intravenously transplanted. MOG-injected mice displayed severe neurobehavioral deficits which were remarkably attenuated and restored by cell transplantation, in which F3.olig2 cells were superior to its parental F3 cells. Transplanted cells migrated to the injured spinal cord, matured to oligodendrocytes, and produced myelin basic proteins (MBP. The F3.olig2 cells expressed growth and neurotrophic factors including brain-derived neurotrophic factor (BDNF, nerve growth factor (NGF, ciliary neurotrophic factor (CNTF, and leukemia inhibitory factor (LIF. In addition, the transplanted cells markedly attenuated inflammatory cell infiltration, reduced cytokine levels in the spinal cord and lymph nodes, and protected host myelins. The results indicate that F3.olig2 cells restore neurobehavioral symptoms of EAE mice by regulating autoimmune inflammatory responses as well as by stimulating remyelination and that F3.olig2 progenitors could be a candidate for the cell therapy of demyelinating diseases including MS.

  3. An Empirical Study of Neural Network-Based Audience Response Technology in a Human Anatomy Course for Pharmacy Students.

    Science.gov (United States)

    Fernández-Alemán, José Luis; López-González, Laura; González-Sequeros, Ofelia; Jayne, Chrisina; López-Jiménez, Juan José; Carrillo-de-Gea, Juan Manuel; Toval, Ambrosio

    2016-04-01

    This paper presents an empirical study of a formative neural network-based assessment approach by using mobile technology to provide pharmacy students with intelligent diagnostic feedback. An unsupervised learning algorithm was integrated with an audience response system called SIDRA in order to generate states that collect some commonality in responses to questions and add diagnostic feedback for guided learning. A total of 89 pharmacy students enrolled on a Human Anatomy course were taught using two different teaching methods. Forty-four students employed intelligent SIDRA (i-SIDRA), whereas 45 students received the same training but without using i-SIDRA. A statistically significant difference was found between the experimental group (i-SIDRA) and the control group (traditional learning methodology), with T (87) = 6.598, p SIDRA and the methodology used during the process of learning anatomy (M = 4.59). The new empirical contribution presented in this paper allows instructors to perform post hoc analyses of each particular student's progress to ensure appropriate training.

  4. Neural differentiation of human embryonic stem cells induced by the transgene-mediated overexpression of single transcription factors.

    Science.gov (United States)

    Matsushita, Misako; Nakatake, Yuhki; Arai, Itaru; Ibata, Keiji; Kohda, Kazuhisa; Goparaju, Sravan K; Murakami, Miyako; Sakota, Miki; Chikazawa-Nohtomi, Nana; Ko, Shigeru B H; Kanai, Takanori; Yuzaki, Michisuke; Ko, Minoru S H

    2017-08-19

    Pluripotent human embryonic stem cells (hESCs) can differentiate into multiple cell lineages, thus, providing one of the best platforms to study molecular mechanisms during cell differentiation. Recently, we have reported rapid and efficient differentiation of hESCs into functional neurons by introducing a cocktail of synthetic mRNAs encoding five transcription factors (TFs): NEUROG1, NEUROG2, NEUROG3, NEUROD1, and NEUROD2. Here we further tested a possibility that even single transcription factors, when expressed ectopically, can differentiate hESCs into neurons. To this end, we established hESC lines in which each of these TFs can be overexpressed by the doxycycline-inducible piggyBac vector. The overexpression of any of these five TFs indeed caused a rapid and rather uniform differentiation of hESCs, which were identified as neurons based on their morphologies, qRT-PCR, and immunohistochemistry. Furthermore, calcium-imaging analyses and patch clamp recordings demonstrated that these differentiated cells are electrophysiologically functional. Interestingly, neural differentiations occurred despite the cell culture conditions that rather promote the maintenance of the undifferentiated state. These results indicate that over-expression of each of these five TFs can override the pluripotency-specific gene network and force hESCs to differentiate into neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Classification of Fourier transform infrared microscopic imaging data of human breast cells by cluster analysis and artificial neural networks.

    Science.gov (United States)

    Zhang, Lin; Small, Gary W; Haka, Abigail S; Kidder, Linda H; Lewis, E Neil

    2003-01-01

    Cluster analysis and artificial neural networks (ANNs) are applied to the automated assessment of disease state in Fourier transform infrared microscopic imaging measurements of normal and carcinomatous immortalized human breast cell lines. K-means clustering is used to implement an automated algorithm for the assignment of pixels in the image to cell and non-cell categories. Cell pixels are subsequently classified into carcinoma and normal categories through the use of a feed-forward ANN computed with the Broyden-Fletcher-Goldfarb-Shanno training algorithm. Inputs to the ANN consist of principal component scores computed from Fourier filtered absorbance data. A grid search optimization procedure is used to identify the optimal network architecture and filter frequency response. Data from three images corresponding to normal cells, carcinoma cells, and a mixture of normal and carcinoma cells are used to build and test the classification methodology. A successful classifier is developed through this work, although differences in the spectral backgrounds between the three images are observed to complicate the classification problem. The robustness of the final classifier is improved through the use of a rejection threshold procedure to prevent classification of outlying pixels.

  6. Engineered neural tissue with Schwann cell differentiated human dental pulp stem cells: potential for peripheral nerve repair?

    Science.gov (United States)

    Sanen, Kathleen; Martens, Wendy; Georgiou, Melanie; Ameloot, Marcel; Lambrichts, Ivo; Phillips, James

    2017-01-04

    Despite the spontaneous regenerative capacity of the peripheral nervous system, large gap peripheral nerve injuries (PNIs) require bridging strategies. The limitations and suboptimal results obtained with autografts or hollow nerve conduits in the clinic urge the need for alternative treatments. Recently, we have described promising neuroregenerative capacities of Schwann cells derived from differentiated human dental pulp stem cells (d-hDPSCs) in vitro. Here, we extended the in vitro assays to show the pro-angiogenic effects of d-hDPSCs, such as enhanced endothelial cell proliferation, migration and differentiation. In addition, for the first time we evaluated the performance of d-hDPSCs in an in vivo rat model of PNI. Eight weeks after transplantation of NeuraWrap™ conduits filled with engineered neural tissue (EngNT) containing aligned d-hDPSCs in 15-mm rat sciatic nerve defects, immunohistochemistry and ultrastructural analysis revealed ingrowing neurites, myelinated nerve fibres and blood vessels along the construct. Although further research is required to optimize the delivery of this EngNT, our findings suggest that d-hDPSCs are able to exert a positive effect in the regeneration of nerve tissue in vivo. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  7. Expression of neural cell adhesion molecule in human liver development and in congenital and acquired liver diseases.

    Science.gov (United States)

    Libbrecht, L; Cassiman, D; Desmet, V; Roskams, T

    2001-09-01

    In the liver, neural cell adhesion molecule (NCAM) is a marker of immature cells committed to the biliary lineage and is expressed by reactive bile ductules in human liver diseases. We investigated the possible role of NCAM in the development of intrahepatic bile ducts and aimed at determining whether immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases. Therefore, we performed immunohistochemistry for NCAM and bile duct cell markers cytokeratin 7 and cytokeratin 19 on frozen sections of 85 liver specimens taken from 14 fetuses, 10 donor livers, 18 patients with congenital liver diseases characterized by ductal plate malformations (DPMs), and 43 cirrhotic explant livers. Duplicated ductal plates and incorporating bile ducts during development showed a patchy immunoreactivity for NCAM, while DPMs were continuously positive for NCAM. Bile ducts showing complete or patchy immunoreactivity for NCAM were found in cirrhotic livers, with higher frequency in biliary than in posthepatitic cirrhosis. Our results suggest that NCAM may have a function in the development of the intrahepatic bile ducts and that NCAM-positive immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases.

  8. Neutrophils Induce Astroglial Differentiation and Migration of Human Neural Stem Cells via C1q and C3a Synthesis

    Science.gov (United States)

    Benavente, Francisca; Flanagan, Lisa; Uchida, Nobuko; Anderson, Aileen J.

    2017-01-01

    Inflammatory processes play a key role in pathophysiology of many neurologic diseases/trauma, but the effect of immune cells and factors on neurotransplantation strategies remains unclear. We hypothesized that cellular and humoral components of innate immunity alter fate and migration of human neural stem cells (hNSC). In these experiments, conditioned media collected from polymorphonuclear leukocytes (PMN) selectively increased hNSC astrogliogenesis and promoted cell migration in vitro. PMN were shown to generate C1q and C3a; exposure of hNSC to PMN-synthesized concentrations of these complement proteins promoted astrogliogenesis and cell migration. Furthermore, in vitro, Abs directed against C1q and C3a reversed the fate and migration effects observed. In a proof-of-concept in vivo experiment, blockade of C1q and C3a transiently altered hNSC migration and reversed astroglial fate after spinal cord injury. Collectively, these data suggest that modulation of the innate/humoral inflammatory microenvironment may impact the potential of cell-based therapies for recovery and repair following CNS pathology. PMID:28687659

  9. O34-pathogen sensing by human odontoblasts.

    Science.gov (United States)

    Fargues, J-C; Keller, J-F; Carrouel, F; Kufer, T A; Baudouin, C; Msika, P; Bleicher, F; Staquet, M-J

    2011-04-11

    Human odontoblasts are neural crest-derived, dentin-producing mesenchymal cells aligned at the periphery of the dental pulp. They become exposed to cariogenic oral bacteria as these progressively demineralise enamel then dentin to gain access to the pulp. Due to their situation at the dentin-pulp interface, odontoblasts are the first cells encountered by invading pathogens and/or their released components, and represent, in the tooth, the first line of defence for the host. Previous studies have shown that odontoblasts are able to sense pathogens and elicit innate immunity. In particular, they express several pathogen recognition receptors of the Toll-like receptor (TLR) and nucleotide-binding oligomerisation domain (NOD) families, which allow them to recognize specific bacterial and viral components. So far, most studies aiming at elucidating the role of odontoblasts in the dental pulp innate response have focused on Gram-positive bacteria, as these largely dominate the carious microflora in initial and moderate dentin caries lesions. In vitro, odontoblasts were found to be sensitive to Gram-positive bacteria-derived components, mainly lipoteichoic acid which is recognized through cell membrane TLR2. Our studies have shown that engagement of odontoblast TLR2 by LTA triggers TLR2 and NOD2 up-regulation, NF-B nuclear translocation, production of various chemokines including CCL2, CXCL1, CXCL2, CXCL8 and CXCL10, while promoting immature dendritic cell recruitment. Conversely, LTA down-regulates major dentin matrix components, including collagen type I and dentin sialophosphoprotein, as well as TGF-b1, a known inducer of dentin formation. We provide here additional data showing the fine localization of NOD2 in healthy dental pulps, as well as differential regulation of TLR2, TLR4, NOD2, CCL2 and CXCL8 genes by LTA and the synthetic TLR2 agonists Pam2CSK4 and Pam3CSK4. It appears from the aforementioned data that odontoblast-triggered immune events constitute

  10. [Neural representation of human body schema and corporeal self-consciousness].

    Science.gov (United States)

    Naito, Eiichi; Morita, Tomoyo

    2014-04-01

    The human brain processes every sensation evoked by altered posture and builds up a constantly changing postural model of the body. This is called a body schema, and somatic signals originating from skeletal muscles and joints, i.e. proprioceptive signals, largely contribute its formation. Recent neuroimaging techniques have revealed neuronal substrates for human body schema. A dynamic limb position model seems to be computed in the central motor network (represented by the primary motor cortex). Here, proprioceptive (kinesthetic) signals from muscle spindles are transformed into motor commands, which may underlie somatic perception of limb movement and facilitate its efficient motor control. Somatic signals originating from different body parts are integrated in the course of hierarchical somatosensory processing, and activity in higher-order somatosensory parietal cortices is capable of representing a postural model of the entire body. The left fronto-parietal network associates internal motor representation with external object representation, allowing the embodiment of external objects. In contrast, the right fronto-parietal regions connected by the most inferior branch of superior longitudinal fasciculus fibers seem to have the functions of monitoring bodily states and updating body schema. We hypothesize that activity in these right-sided fronto-parietal regions is deeply involved in corporeal self-consciousness.

  11. Attention to Color Sharpens Neural Population Tuning via Feedback Processing in the Human Visual Cortex Hierarchy.

    Science.gov (United States)

    Bartsch, Mandy V; Loewe, Kristian; Merkel, Christian; Heinze, Hans-Jochen; Schoenfeld, Mircea A; Tsotsos, John K; Hopf, Jens-Max

    2017-10-25

    Attention can facilitate the selection of elementary object features such as color, orientation, or motion. This is referred to as feature-based attention and it is commonly attributed to a modulation of the gain and tuning of feature-selective units in visual cortex. Although gain mechanisms are well characterized, little is known about the cortical processes underlying the sharpening of feature selectivity. Here, we show with high-resolution magnetoencephalography in human observers (men and women) that sharpened selectivity for a particular color arises from feedback processing in the human visual cortex hierarchy. To assess color selectivity, we analyze the response to a color probe that varies in color distance from an attended color target. We find that attention causes an initial gain enhancement in anterior ventral extrastriate cortex that is coarsely selective for the target color and transitions within ∼100 ms into a sharper tuned profile in more posterior ventral occipital cortex. We conclude that attention sharpens selectivity over time by attenuating the response at lower levels of the cortical hierarchy to color values neighboring the target in color space. These observations support computational models proposing that attention tunes feature selectivity in visual cortex through backward-propagating attenuation of units less tuned to the target.SIGNIFICANCE STATEMENT Whether searching for your car, a particular item of clothing, or just obeying traffic lights, in everyday life, we must select items based on color. But how does attention allow us to select a specific color? Here, we use high spatiotemporal resolution neuromagnetic recordings to examine how color selectivity emerges in the human brain. We find that color selectivity evolves as a coarse to fine process from higher to lower levels within the visual cortex hierarchy. Our observations support computational models proposing that feature selectivity increases over time by attenuating the

  12. Long-term survival of human neural stem cells in the ischemic rat brain upon transient immunosuppression.

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    Laura Rota Nodari

    Full Text Available Understanding the physiology of human neural stem cells (hNSCs in the context of cell therapy for neurodegenerative disorders is of paramount importance, yet large-scale studies are hampered by the slow-expansion rate of these cells. To overcome this issue, we previously established immortal, non-transformed, telencephalic-diencephalic hNSCs (IhNSCs from the fetal brain. Here, we investigated the fate of these IhNSC's immediate progeny (i.e. neural progenitors; IhNSC-Ps upon unilateral implantation into the corpus callosum or the hippocampal fissure of adult rat brain, 3 days after global ischemic injury. One month after grafting, approximately one fifth of the IhNSC-Ps had survived and migrated through the corpus callosum, into the cortex or throughout the dentate gyrus of the hippocampus. By the fourth month, they had reached the ipsilateral subventricular zone, CA1-3 hippocampal layers and the controlateral hemisphere. Notably, these results could be accomplished using transient immunosuppression, i.e administering cyclosporine for 15 days following the ischemic event. Furthermore, a concomitant reduction of reactive microglia (Iba1+ cells and of glial, GFAP+ cells was also observed in the ipsilateral hemisphere as compared to the controlateral one. IhNSC-Ps were not tumorigenic and, upon in vivo engraftment, underwent differentiation into GFAP+ astrocytes, and β-tubulinIII+ or MAP2+ neurons, which displayed GABAergic and GLUTAmatergic markers. Electron microscopy analysis pointed to the formation of mature synaptic contacts between host and donor-derived neurons, showing the full maturation of the IhNSC-P-derived neurons and their likely functional integration into the host tissue. Thus, IhNSC-Ps possess long-term survival and engraftment capacity upon transplantation into the globally injured ischemic brain, into which they can integrate and mature into neurons, even under mild, transient immunosuppressive conditions. Most notably

  13. Dynamic dependence on ATR and ATM for double-strand break repair in human embryonic stem cells and neural descendants.

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    Bret R Adams

    2010-04-01

    Full Text Available The DNA double-strand break (DSB is the most toxic form of DNA damage. Studies aimed at characterizing DNA repair during development suggest that homologous recombination repair (HRR is more critical in pluripotent cells compared to differentiated somatic cells in which nonhomologous end joining (NHEJ is dominant. We have characterized the DNA damage response (DDR and quality of DNA double-strand break (DSB repair in human embryonic stem cells (hESCs, and in vitro-derived neural cells. Resolution of ionizing radiation-induced foci (IRIF was used as a surrogate for DSB repair. The resolution of gamma-H2AX foci occurred at a slower rate in hESCs compared to neural progenitors (NPs and astrocytes perhaps reflective of more complex DSB repair in hESCs. In addition, the resolution of RAD51 foci, indicative of active homologous recombination repair (HRR, showed that hESCs as well as NPs have high capacity for HRR, whereas astrocytes do not. Importantly, the ATM kinase was shown to be critical for foci formation in astrocytes, but not in hESCs, suggesting that the DDR is different in these cells. Blocking the ATM kinase in astrocytes not only prevented the formation but also completely disassembled preformed repair foci. The ability of hESCs to form IRIF was abrogated with caffeine and siRNAs targeted against ATR, implicating that hESCs rely on ATR, rather than ATM for regulating DSB repair. This relationship dynamically changed as cells differentiated. Interestingly, while the inhibition of the DNA-PKcs kinase (and presumably non-homologous endjoining [NHEJ] in astrocytes slowed IRIF resolution it did not in hESCs, suggesting that repair in hESCs does not utilize DNA-PKcs. Altogether, our results show that hESCs have efficient DSB repair that is largely ATR-dependent HRR, whereas astrocytes critically depend on ATM for NHEJ, which, in part, is DNA-PKcs-independent.

  14. Cardiovascular and sympathetic neural responses to handgrip and cold pressor stimuli in humans before, during and after spaceflight

    Science.gov (United States)

    Fu, Qi; Levine, Benjamin D.; Pawelczyk, James A.; Ertl, Andrew C.; Diedrich, Andre; Cox, James F.; Zuckerman, Julie H.; Ray, Chester A.; Smith, Michael L.; Iwase, Satoshi; hide

    2002-01-01

    Astronauts returning to Earth have reduced orthostatic tolerance and exercise capacity. Alterations in autonomic nervous system and neuromuscular function after spaceflight might contribute to this problem. In this study, we tested the hypothesis that exposure to microgravity impairs autonomic neural control of sympathetic outflow in response to peripheral afferent stimulation produced by handgrip and a cold pressor test in humans. We studied five astronauts approximately 72 and 23 days before, and on landing day after the 16 day Neurolab (STS-90) space shuttle mission, and four of the astronauts during flight (day 12 or 13). Heart rate, arterial pressure and peroneal muscle sympathetic nerve activity (MSNA) were recorded before and during static handgrip sustained to fatigue at 40 % of maximum voluntary contraction, followed by 2 min of circulatory arrest pre-, in- and post-flight. The cold pressor test was applied only before (five astronauts) and during flight (day 12 or 13, four astronauts). Mean (+/- S.E.M.) baseline heart rates and arterial pressures were similar among pre-, in- and post-flight measurements. At the same relative fatiguing force, the peak systolic pressure and mean arterial pressure during static handgrip were not different before, during and after spaceflight. The peak diastolic pressure tended to be higher post- than pre-flight (112 +/- 6 vs. 99 +/- 5 mmHg, P = 0.088). Contraction-induced rises in heart rate were similar pre-, in- and post-flight. MSNA was higher post-flight in all subjects before static handgrip (26 +/- 4 post- vs. 15 +/- 4 bursts min(-1) pre-flight, P = 0.017). Contraction-evoked peak MSNA responses were not different before, during, and after spaceflight (41 +/- 4, 38 +/- 5 and 46 +/- 6 bursts min(-1), all P > 0.05). MSNA during post-handgrip circulatory arrest was higher post- than pre- or in-flight (41 +/- 1 vs. 33 +/- 3 and 30 +/- 5 bursts min(-1), P = 0.038 and 0.036). Similarly, responses of MSNA and blood pressure

  15. Sox10 expressing cells in the lateral wall of the aged mouse and human cochlea.

    Directory of Open Access Journals (Sweden)

    Xinping Hao

    Full Text Available Age-related hearing loss (presbycusis is a common human disorder, affecting one in three Americans aged 60 and over. Previous studies have shown that presbyacusis is associated with a loss of non-sensory cells in the cochlear lateral wall. Sox10 is a transcription factor crucial to the development and maintenance of neural crest-derived cells including some non-sensory cell types in the cochlea. Mutations of the Sox10 gene are known to cause various combinations of hearing loss and pigmentation defects in humans. This study investigated the potential relationship between Sox10 gene expression and pathological changes in the cochlear lateral wall of aged CBA/CaJ mice and human temporal bones from older donors. Cochlear tissues prepared from young adult (1-3 month-old and aged (2-2.5 year-old mice, and human temporal bone donors were examined using quantitative immunohistochemical analysis and transmission electron microscopy. Cells expressing Sox10 were present in the stria vascularis, outer sulcus and spiral prominence in mouse and human cochleas. The Sox10(+ cell types included marginal and intermediate cells and outer sulcus cells, including those that border the scala media and those extending into root processes (root cells in the spiral ligament. Quantitative analysis of immunostaining revealed a significant decrease in the number of Sox10(+ marginal cells and outer sulcus cells in aged mice. Electron microscopic evaluation revealed degenerative alterations in the surviving Sox10(+ cells in aged mice. Strial marginal cells in human cochleas from donors aged 87 and older showed only weak immunostaining for Sox10. Decreases in Sox10 expression levels and a loss of Sox10(+ cells in both mouse and human aged ears suggests an important role of Sox10 in the maintenance of structural and functional integrity of the lateral wall. A loss of Sox10(+ cells may also be associated with a decline in the repair capabilities of non-sensory cells in the

  16. Neural mechanisms of economic commitment in the human medial prefrontal cortex.

    Science.gov (United States)

    Tsetsos, Konstantinos; Wyart, Valentin; Shorkey, S Paul; Summerfield, Christopher

    2014-10-21

    Neurobiologists have studied decisions by offering successive, independent choices between goods or gambles. However, choices often have lasting consequences, as when investing in a house or choosing a partner. Here, humans decided whether to commit (by acceptance or rejection) to prospects that provided sustained financial return. BOLD signals in the rostral medial prefrontal cortex (rmPFC) encoded stimulus value only when acceptance or rejection was deferred into the future, suggesting a role in integrating value signals over time. By contrast, the dorsal anterior cingulate cortex (dACC) encoded stimulus value only when participants rejected (or deferred accepting) a prospect. dACC BOLD signals reflected two decision biases-to defer commitments to later, and to weight potential losses more heavily than gains-that (paradoxically) maximised reward in this task. These findings offer fresh insights into the pressures that shape economic decisions, and the computation of value in the medial prefrontal cortex.

  17. Neural coding and perception of pitch in the normal and impaired human auditory system

    DEFF Research Database (Denmark)

    Santurette, Sébastien

    2011-01-01

    for a variety of basic auditory tasks, indicating that it may be a crucial measure to consider for hearing-loss characterization. In contrast to hearing-impaired listeners, adults with dyslexia showed no deficits in binaural pitch perception, suggesting intact low-level auditory mechanisms. The second part...... into the fundamental auditory mechanisms underlying pitch perception, and may have implications for future pitch-perception models, as well as strategies for auditory-profile characterization and restoration of accurate pitch perception in impaired hearing.......Pitch is an important attribute of hearing that allows us to perceive the musical quality of sounds. Besides music perception, pitch contributes to speech communication, auditory grouping, and perceptual segregation of sound sources. In this work, several aspects of pitch perception in humans were...

  18. Functional Comparison of Neuronal Cells Differentiated from Human Induced Pluripotent Stem Cell-Derived Neural Stem Cells under Different Oxygen and Medium Conditions.

    Science.gov (United States)

    Yamazaki, Kazuto; Fukushima, Kazuyuki; Sugawara, Michiko; Tabata, Yoshikuni; Imaizumi, Yoichi; Ishihara, Yasuharu; Ito, Masashi; Tsukahara, Kappei; Kohyama, Jun; Okano, Hideyuki

    2016-12-01

    Because neurons are difficult to obtain from humans, generating functional neurons from human induced pluripotent stem cells (hiPSCs) is important for establishing physiological or disease-relevant screening systems for drug discovery. To examine the culture conditions leading to efficient differentiation of functional neural cells, we investigated the effects of oxygen stress (2% or 20% O2) and differentiation medium (DMEM/F12:Neurobasal-based [DN] or commercial [PhoenixSongs Biologicals; PS]) on the expression of genes related to neural differentiation, glutamate receptor function, and the formation of networks of neurons differentiated from hiPSCs (201B7) via long-term self-renewing neuroepithelial-like stem (lt-NES) cells. Expression of genes related to neural differentiation occurred more quickly in PS and/or 2% O2 than in DN and/or 20% O2, resulting in high responsiveness of neural cells to glutamate, N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and ( S)-3,5-dihydroxyphenylglycine (an agonist for mGluR1/5), as revealed by calcium imaging assays. NMDA receptors, AMPA receptors, mGluR1, and mGluR5 were functionally validated by using the specific antagonists MK-801, NBQX, JNJ16259685, and 2-methyl-6-(phenylethynyl)-pyridine, respectively. Multielectrode array analysis showed that spontaneous firing occurred earlier in cells cultured in 2% O2 than in 20% O2. Optimization of O2 tension and culture medium for neural differentiation of hiPSCs can efficiently generate physiologically relevant cells for screening systems.

  19. Sound Waves Induce Neural Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells via Ryanodine Receptor-Induced Calcium Release and Pyk2 Activation.

    Science.gov (United States)

    Choi, Yura; Park, Jeong-Eun; Jeong, Jong Seob; Park, Jung-Keug; Kim, Jongpil; Jeon, Songhee

    2016-10-01

    Mesenchymal stem cells (MSCs) have shown considerable promise as an adaptable cell source for use in tissue engineering and other therapeutic applications. The aims of this study were to develop methods to test the hypothesis that human MSCs could be differentiated using sound wave stimulation alone and to find the underlying mechanism. Human bone marrow (hBM)-MSCs were stimulated with sound waves (1 kHz, 81 dB) for 7 days and the expression of neural markers were analyzed. Sound waves induced neural differentiation of hBM-MSC at 1 kHz and 81 dB but not at 1 kHz and 100 dB. To determine the signaling pathways involved in the neural differentiation of hBM-MSCs by sound wave stimulation, we examined the Pyk2 and CREB phosphorylation. Sound wave induced an increase in the phosphorylation of Pyk2 and CREB at 45 min and 90 min, respectively, in hBM-MSCs. To find out the upstream activator of Pyk2, we examined the intracellular calcium source that was released by sound wave stimulation. When we used ryanodine as a ryanodine receptor antagonist, sound wave-induced calcium release was suppressed. Moreover, pre-treatment with a Pyk2 inhibitor, PF431396, prevented the phosphorylation of Pyk2 and suppressed sound wave-induced neural differentiation in hBM-MSCs. These results suggest that specific sound wave stimulation could be used as a neural differentiation inducer of hBM-MSCs.

  20. Differentiation of human olfactory bulb-derived neural stem cells toward oligodendrocyte.

    Science.gov (United States)

    Marei, Hany E; Shouman, Zeinab; Althani, Asma; Afifi, Nahla; A, Abd-Elmaksoud; Lashen, Samah; Hasan, Anwarul; Caceci, Thomas; Rizzi, Roberto; Cenciarelli, Carlo; Casalbore, Patrizia

    2018-02-01

    In the central nervous system (CNS), oligodendrocytes are the glial element in charge of myelin formation. Obtaining an overall presence of oligodendrocyte precursor cells/oligodendrocytes (OPCs/OLs) in culture from different sources of NSCs is an important research area, because OPCs/OLs may provide a promising therapeutic strategy for diseases affecting myelination of axons. The present study was designed to differentiate human olfactory bulb NSCs (OBNSCs) into OPCs/OLs and using expression profiling (RT-qPCR) gene, immunocytochemistry, and specific protein expression to highlight molecular mechanism(s) underlying differentiation of human OBNSCs into OPCs/OLs. The differentiation of OBNSCs was characterized by a simultaneous appearance of neurons and glial cells. The differentiation medium, containing cAMP, PDGFA, T3, and all-trans-retinoic acid (ATRA), promotes OBNSCs to generate mostly oligodendrocytes (OLs) displaying morphological changes, and appearance of long cytoplasmic processes. OBNSCs showed, after 5 days in OLs differentiation medium, a considerable decrease in the number of nestin positive cells, which was associated with a concomitant increase of NG2 immunoreactive cells and few O4(+)-OPCs. In addition, a significant up regulation in gene and protein expression profile of stage specific cell markers for OPCs/OLs (CNPase, Galc, NG2, MOG, OLIG1, OLIG2, MBP), neurons, and astrocytes (MAP2, β-TubulinIII, GFAP) and concomitant decrease of OBNSCs pluripotency markers (Oct4, Sox2, Nestin), was demonstrated following induction of OBNSCs differentiation. Taken together, the present study demonstrate the marked ability of a cocktail of factors containing PDGFA, T3, cAMP, and ATRA, to induce OBNSCs differentiation into OPCs/OLs and shed light on the key genes and pathological pathways involved in this process. © 2017 Wiley Periodicals, Inc.

  1. The visual development of hand-centered receptive fields in a neural network model of the primate visual system trained with experimentally recorded human gaze changes

    OpenAIRE

    Galeazzi, Juan M.; Navajas, Joaquin; Mender, Bedeho M. W.; Quian Quiroga, Rodrigo; Minini, Loredana; Stringer, Simon M.

    2016-01-01

    ABSTRACT Neurons have been found in the primate brain that respond to objects in specific locations in hand-centered coordinates. A key theoretical challenge is to explain how such hand-centered neuronal responses may develop through visual experience. In this paper we show how hand-centered visual receptive fields can develop using an artificial neural network model, VisNet, of the primate visual system when driven by gaze changes recorded from human test subjects as they completed a jigsaw....

  2. Central role of RET in thyroid cancer.

    Science.gov (United States)

    Santoro, Massimo; Carlomagno, Francesca

    2013-12-01

    RET (rearranged during transfection) is a receptor tyrosine kinase involved in the development of neural crest derived cell lineages, kidney, and male germ cells. Different human cancers, including papillary and medullary thyroid carcinomas, lung adenocarcinomas, and myeloproliferative disorders display gain-of-function mutations in RET. Accordingly, RET protein has become a promising molecular target for cancer treatment.

  3. Neural and psychophysiological correlates of human performance under stress and high mental workload.

    Science.gov (United States)

    Mandrick, Kevin; Peysakhovich, Vsevolod; Rémy, Florence; Lepron, Evelyne; Causse, Mickaël

    2016-12-01

    In our anxiogenic and stressful world, the maintenance of an optimal cognitive performance is a constant challenge. It is particularly true in complex working environments (e.g. flight deck, air traffic control tower), where individuals have sometimes to cope with a high mental workload and stressful situations. Several models (i.e. processing efficiency theory, cognitive-energetical framework) have attempted to provide a conceptual basis on how human performance is modulated by high workload and stress/anxiety. These models predict that stress can reduce human cognitive efficiency, even in the absence of a visible impact on the task performance. Performance may be protected under stress thanks to compensatory effort, but only at the expense of a cognitive cost. Yet, the psychophysiological cost of this regulation remains unclear. We designed two experiments involving pupil diameter, cardiovascular and prefrontal oxygenation measurements. Participants performed the Toulouse N-back Task that intensively engaged both working memory and mental calculation processes under the threat (or not) of unpredictable aversive sounds. The results revealed that higher task difficulty (higher n level) degraded the performance and induced an increased tonic pupil diameter, heart rate and activity in the lateral prefrontal cortex, and a decreased phasic pupil response and heart rate variability. Importantly, the condition of stress did not impact the performance, but at the expense of a psychophysiological cost as demonstrated by lower phasic pupil response, and greater heart rate and prefrontal activity. Prefrontal cortex seems to be a central region for mitigating the influence of stress because it subserves crucial functions (e.g. inhibition, working memory) that can promote the engagement of coping strategies. Overall, findings confirmed the psychophysiological cost of both mental effort and stress. Stress likely triggered increased motivation and the recruitment of additional

  4. Neural computations mediating one-shot learning in the human brain.

    Science.gov (United States)

    Lee, Sang Wan; O'Doherty, John P; Shimojo, Shinsuke

    2015-04-01

    Incremental learning, in which new knowledge is acquired gradually through trial and error, can be distinguished from one-shot learning, in which the brain learns rapidly from only a single pairing of a stimulus and a consequence. Very little is known about how the brain transitions between these two fundamentally different forms of learning. Here we test a computational hypothesis that uncertainty about the causal relationship between a stimulus and an outcome induces rapid changes in the rate of learning, which in turn mediates the transition between incremental and one-shot learning. By using a novel behavioral task in combination with functional magnetic resonance imaging (fMRI) data from human volunteers, we found evidence implicating the ventrolateral prefrontal cortex and hippocampus in this process. The hippocampus was selectively "switched" on when one-shot learning was predicted to occur, while the ventrolateral prefrontal cortex was found to encode uncertainty about the causal association, exhibiting increased coupling with the hippocampus for high-learning rates, suggesting this region may act as a "switch," turning on and off one-shot learning as required.

  5. Variability in neural excitability and plasticity induction in the human cortex: A brain stimulation study.

    Science.gov (United States)

    Hordacre, Brenton; Goldsworthy, Mitchell R; Vallence, Ann-Maree; Darvishi, Sam; Moezzi, Bahar; Hamada, Masashi; Rothwell, John C; Ridding, Michael C

    The potential of non-invasive brain stimulation (NIBS) for both probing human neuroplasticity and the induction of functionally relevant neuroplastic change has received significant interest. However, at present the utility of NIBS is limited due to high response variability. One reason for this response variability is that NIBS targets a diffuse cortical population and the net outcome to stimulation depends on the relative levels of excitability in each population. There is evidence that the relative excitability of complex oligosynaptic circuits (late I-wave circuits) as assessed by transcranial magnetic stimulation (TMS) is useful in predicting NIBS response. Here we examined whether an additional marker of cortical excitability, MEP amplitude variability, could provide additional insights into response variability following application of the continuous theta burst stimulation (cTBS) NIBS protocol. Additionally we investigated whether I-wave recruitment was associated with MEP variability. Thirty-four healthy subjects (15 male, aged 18-35 years) participated in two experiments. Experiment 1 investigated baseline MEP variability and cTBS response. Experiment 2 determined if I-wave recruitment was associated with MEP variability. Data show that both baseline MEP variability and late I-wave recruitment are associated with cTBS response, but were independent of each other; together, these variables predict 31% of the variability in cTBS response. This study provides insight into the physiological mechanisms underpinning NIBS plasticity responses and may facilitate development of more reliable NIBS protocols. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Neurite extension and neuronal differentiation of human induced pluripotent stem cell derived neural stem cells on polyethylene glycol hydrogels containing a continuous Young's Modulus gradient.

    Science.gov (United States)

    Mosley, Matthew C; Lim, Hyun Ju; Chen, Jing; Yang, Yueh-Hsun; Li, Shenglan; Liu, Ying; Smith Callahan, Laura A

    2017-03-01

    Mechanotransduction in neural cells involves multiple signaling pathways that are not fully understood. Differences in lineage and maturation state are suggested causes for conflicting reports on neural cell mechanosensitivity. To optimize matrices for use in stem cell therapy treatments transplanting human induced pluripotent stem cell derived neural stem cells (hNSC) into lesions after spinal cord injury, the effects of Young's Modulus changes on hNSC behavior must be understood. The present study utilizes polyethylene glycol hydrogels containing a continuous gradient in Young's modulus to examine changes in the Young's Modulus of the culture substrate on hNSC neurite extension and neural differentiation. Changes in the Young's Modulus of the polyethylene glycol hydrogels was found to affect neurite extension and cellular organization on the matrices. hNSC cultured on 907 Pa hydrogels were found to extend longer neurites than hNSC cultured on other tested Young's Moduli hydrogels. The gene expression of β tubulin III and microtubule-associated protein 2 in hNSC was affected by changes in the Young's Modulus of the hydrogel. The combinatory method approach used in the present study demonstrates that hNSC are mechanosensitive and the matrix Young's Modulus should be a design consideration for hNSC transplant applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 824-833, 2017. © 2016 Wiley Periodicals, Inc.

  7. Polypyrrole/Alginate Hybrid Hydrogels: Electrically Conductive and Soft Biomaterials for Human Mesenchymal Stem Cell Culture and Potential Neural Tissue Engineering Applications.

    Science.gov (United States)

    Yang, Sumi; Jang, LindyK; Kim, Semin; Yang, Jongcheol; Yang, Kisuk; Cho, Seung-Woo; Lee, Jae Young

    2016-11-01

    Electrically conductive biomaterials that can efficiently deliver electrical signals to cells or improve electrical communication among cells have received considerable attention for potential tissue engineering applications. Conductive hydrogels are desirable particularly for neural applications, as they can provide electrical signals and soft microenvironments that can mimic native nerve tissues. In this study, conductive and soft polypyrrole/alginate (PPy/Alg) hydrogels are developed by chemically polymerizing PPy within ionically cross-linked alginate hydrogel networks. The synthesized hydrogels exhibit a Young's modulus of 20-200 kPa. Electrical conductance of the PPy/Alg hydrogels could be enhanced by more than one order of magnitude compared to that of pristine alginate hydrogels. In vitro studies with human bone marrow-derived mesenchymal stem cells (hMSCs) reveal that cell adhesion and growth are promoted on the PPy/Alg hydrogels. Additionally, the PPy/Alg hydrogels support and greatly enhance the expression of neural differentiation markers (i.e., Tuj1 and MAP2) of hMSCs compared to tissue culture plate controls. Subcutaneous implantation of the hydrogels for eight weeks induces mild inflammatory reactions. These soft and conductive hydrogels will serve as a useful platform to study the effects of electrical and mechanical signals on stem cells and/or neural cells and to develop multifunctional neural tissue engineering scaffolds. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Cross-sensory facilitation reveals neural interactions between visual and tactile motion in humans

    Directory of Open Access Journals (Sweden)

    Monica eGori

    2011-04-01

    Full Text Available Many recent studies show that the human brain integrates information across the different senses and that stimuli of one sensory modality can enhance the perception of other modalities. Here we study the processes that mediate cross-modal facilitation and summation between visual and tactile motion. We find that while summation produced a generic, non-specific improvement of thresholds, probably reflecting higher-order interaction of decision signals, facilitation reveals a strong, direction-specific interaction, which we believe reflects sensory interactions. We measured visual and tactile velocity discrimination thresholds over a wide range of base velocities and conditions. Thresholds for both visual and tactile stimuli showed the characteristic dipper function, with the minimum thresholds occurring at a given pedestal speed. When visual and tactile coherent stimuli were combined (summation condition the thresholds for these multi-sensory stimuli also showed a dipper function with the minimum thresholds occurring in a similar range to that for unisensory signals. However, the improvement of multisensory thresholds was weak and not directionally specific, well predicted by the maximum likelihood estimation model (agreeing with previous research. A different technique (facilitation did, however, reveal direction-specific enhancement. Adding a non-informative pedestal motion stimulus in one sensory modality (vision or touch selectively lowered thresholds in the other, by the same amount as pedestals in the same modality. Facilitation did not occur for neutral stimuli like sounds (that would also have reduced temporal uncertainty, nor for motion in opposite direction, even in blocked trials where the subjects knew that the motion was in the opposite direction showing that the facilitation was not under subject control. Cross-sensory facilitation is strong evidence for functionally relevant cross-sensory integration at early levels of sensory

  9. The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.

    Science.gov (United States)

    Felsky, D; Szeszko, P; Yu, L; Honer, W G; De Jager, P L; Schneider, J A; Malhotra, A K; Lencz, T; Ikuta, T; Pipitone, J; Chakravarty, M M; Lobaugh, N J; Mulsant, B H; Pollock, B G; Kennedy, J L; Bennett, D A; Voineskos, A N

    2014-10-01

    Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.

  10. Neural mechanisms influencing interlimb coordination during locomotion in humans: presynaptic modulation of forearm H-reflexes during leg cycling.

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Nakajima

    conservation of neural control mechanisms between the arms and legs during locomotor behaviors in humans.

  11. Comparative performance analysis of human iPSC-derived and primary neural progenitor cells (NPC grown as neurospheres in vitro

    Directory of Open Access Journals (Sweden)

    Maxi Hofrichter

    2017-12-01

    hiPSC-NPCs-derived neurospheres seem to be useful for DNT evaluation representing early neural development in vitro. More system characterization by compound testing is needed to gain higher confidence in this method.

  12. Genome-Wide Definition of Promoter and Enhancer Usage during Neural Induction of Human Embryonic Stem Cells

    National Research Council Canada - National Science Library

    Poletti, Valentina; Delli Carri, Alessia; Malagoli Tagliazucchi, Guidantonio; Faedo, Andrea; Petiti, Luca; Mazza, Emilia Maria Cristina; Peano, Clelia; De Bellis, Gianluca; Bicciato, Silvio; Miccio, Annarita; Cattaneo, Elena; Mavilio, Fulvio

    2015-01-01

    ... are cell-specific and account for most of the epigenetic changes occurring during neural induction, and most likely for the modulation of the promoters to generate cell-specific gene expression programs...

  13. Genome-Wide Definition of Promoter and Enhancer Usage during Neural Induction of Human Embryonic Stem Cells: e0126590

    National Research Council Canada - National Science Library

    Valentina Poletti; Alessia Delli Carri; Guidantonio Malagoli Tagliazucchi; Andrea Faedo; Luca Petiti; Emilia Maria Cristina Mazza; Clelia Peano; Gianluca De Bellis; Silvio Bicciato; Annarita Miccio; Elena Cattaneo; Fulvio Mavilio

    2015-01-01

    ... are cell-specific and account for most of the epigenetic changes occurring during neural induction, and most likely for the modulation of the promoters to generate cell-specific gene expression programs...

  14. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans

    National Research Council Canada - National Science Library

    Feng, C; Lori, A; Waldman, I. D; Binder, E. B; Haroon, E; Rilling, J. K

    2015-01-01

    .... However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene ( OXTR...

  15. Neural activity in human primary motor cortex areas 4a and 4p is modulated differentially by attention to action

    OpenAIRE

    Binkofski, F.; Fink, Gereon R.; Geyer, Stefan; Buccino, G.; Gruber, Oliver; Shah, N. Jon; Taylor, John G.; Seitz, Rüdiger J.; Zilles, Karl; Freund, Hans-Joachim

    2002-01-01

    The mechanisms underlying attention to action are poorly understood. Although distracted by something else, we often maintain the accuracy of a movement, which suggests that differential neural mechanisms for the control of attended and nonattended action exist. Using functional magnetic resonance imaging (fMRI) in normal volunteers and probabilistic cytoarchitectonic maps, we observed that neural activity in subarea 4p (posterior) within the primary motor cortex was modulated by attention to...

  16. Isolation, characterization, and differentiation of multipotent neural progenitor cells from human cerebrospinal fluid in fetal cystic myelomeningocele.

    Science.gov (United States)

    Marotta, Mario; Fernández-Martín, Alejandra; Oria, Marc; Fontecha, Cesar G; Giné, Carles; Martínez-Ibáñez, Vicente; Carreras, Elena; Belfort, Michael A; Pelizzo, Gloria; Peiró, Jose L

    2017-07-01

    Despite benefits of prenatal in utero repair of myelomeningocele, a severe type of spina bifida aperta, many of these patients will still suffer mild to severe impairment. One potential source of stem cells for new regenerative medicine-based therapeutic approaches for spinal cord injury repair is neural progenitor cells (NPCs) in cerebrospinal fluid (CSF). To this aim, we extracted CSF from the cyst surrounding the exposed neural placode during the surgical repair of myelomeningocele in 6 fetuses (20 to 26weeks of gestation). In primary cultured CSF-derived cells, neurogenic properties were confirmed by in vitro differentiation into various neural lineage cell types, and NPC markers expression (TBR2, CD15, SOX2) were detected by immunofluorescence and RT-PCR analysis. Differentiation into three neural lineages was corroborated by arbitrary differentiation (depletion of growths factors) or explicit differentiation as neuronal, astrocyte, or oligodendrocyte cell types using specific induction mediums. Differentiated cells showed the specific expression of neural differentiation markers (βIII-tubulin, GFAP, CNPase, oligo-O1). In myelomeningocele patients, CSF-derived cells could become a potential source of NPCs with neurogenic capacity. Our findings support the development of innovative stem-cell-based therapeutics by autologous transplantation of CSF-derived NPCs in damaged spinal cords, such as myelomeningocele, thus promoting neural tissue regeneration in fetuses. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling

    Directory of Open Access Journals (Sweden)

    Sujeong Jang

    2015-01-01

    Full Text Available Stem cells are a powerful resource for cell-based transplantation therapies, but understanding of stem cell differentiation at the molecular level is not clear yet. We hypothesized that the Wnt pathway controls stem cell maintenance and neural differentiation. We have characterized the transcriptional expression of Wnt during the neural differentiation of hADSCs. After neural induction, the expressions of Wnt2, Wnt4, and Wnt11 were decreased, but the expression of Wnt5a was increased compared with primary hADSCs in RT-PCR analysis. In addition, the expression levels of most Fzds and LRP5/6 ligand were decreased, but not Fzd3 and Fzd5. Furthermore, Dvl1 and RYK expression levels were downregulated in NI-hADSCs. There were no changes in the expression of ß-catenin and GSK3ß. Interestingly, Wnt5a expression was highly increased in NI-hADSCs by real time RT-PCR analysis and western blot. Wnt5a level was upregulated after neural differentiation and Wnt3, Dvl2, and Naked1 levels were downregulated. Finally, we found that the JNK expression was increased after neural induction and ERK level was decreased. Thus, this study shows for the first time how a single Wnt5a ligand can activate the neural differentiation pathway through the activation of Wnt5a/JNK pathway by binding Fzd3 and Fzd5 and directing Axin/GSK-3ß in hADSCs.

  18. Isolation, characterization, and differentiation of multipotent neural progenitor cells from human cerebrospinal fluid in fetal cystic myelomeningocele

    Directory of Open Access Journals (Sweden)

    Mario Marotta

    2017-07-01

    Full Text Available Despite benefits of prenatal in utero repair of myelomeningocele, a severe type of spina bifida aperta, many of these patients will still suffer mild to severe impairment. One potential source of stem cells for new regenerative medicine-based therapeutic approaches for spinal cord injury repair is neural progenitor cells (NPCs in cerebrospinal fluid (CSF. To this aim, we extracted CSF from the cyst surrounding the exposed neural placode during the surgical repair of myelomeningocele in 6 fetuses (20 to 26 weeks of gestation. In primary cultured CSF-derived cells, neurogenic properties were confirmed by in vitro differentiation into various neural lineage cell types, and NPC markers expression (TBR2, CD15, SOX2 were detected by immunofluorescence and RT-PCR analysis. Differentiation into three neural lineages was corroborated by arbitrary differentiation (depletion of growths factors or explicit differentiation as neuronal, astrocyte, or oligodendrocyte cell types using specific induction mediums. Differentiated cells showed the specific expression of neural differentiation markers (βIII-tubulin, GFAP, CNPase, oligo-O1. In myelomeningocele patients, CSF-derived cells could become a potential source of NPCs with neurogenic capacity. Our findings support the development of innovative stem-cell-based therapeutics by autologous transplantation of CSF-derived NPCs in damaged spinal cords, such as myelomeningocele, thus promoting neural tissue regeneration in fetuses.

  19. Engrafted human induced pluripotent stem cell-derived anterior specified neural progenitors protect the rat crushed optic nerve.

    Directory of Open Access Journals (Sweden)

    Leila Satarian

    Full Text Available BACKGROUND: Degeneration of retinal ganglion cells (RGCs is a common occurrence in several eye diseases. This study examined the functional improvement and protection of host RGCs in addition to the survival, integration and neuronal differentiation capabilities of anterior specified neural progenitors (NPs following intravitreal transplantation. METHODOLOGY/PRINCIPAL FINDINGS: NPs were produced under defined conditions from human induced pluripotent stem cells (hiPSCs and transplanted into rats whose optic nerves have been crushed (ONC. hiPSCs were induced to differentiate into anterior specified NPs by the use of Noggin and retinoic acid. The hiPSC-NPs were labeled by green fluorescent protein or a fluorescent tracer 1,1' -dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI and injected two days after induction of ONC in hooded rats. Functional analysis according to visual evoked potential recordings showed significant amplitude recovery in animals transplanted with hiPSC-NPs. Retrograde labeling by an intra-collicular DiI injection showed significantly higher numbers of RGCs and spared axons in ONC rats treated with hiPSC-NPs or their conditioned medium (CM. The analysis of CM of hiPSC-NPs showed the secretion of ciliary neurotrophic factor, basic fibroblast growth factor, and insulin-like growth factor. Optic nerve of cell transplanted groups also had increased GAP43 immunoreactivity and myelin staining by FluoroMyelin™ which imply for protection of axons and myelin. At 60 days post-transplantation hiPSC-NPs were integrated into the ganglion cell layer of the retina and expressed neuronal markers. CONCLUSIONS/SIGNIFICANCE: The transplantation of anterior specified NPs may improve optic nerve injury through neuroprotection and differentiation into neuronal lineages. These NPs possibly provide a promising new therapeutic approach for traumatic optic nerve injuries and loss of RGCs caused by other diseases.

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