Science.gov

Sample records for human neural crest-derived

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

    PubMed

    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.

  2. Existence of Neural Crest-Derived Progenitor Cells in Normal and Fuchs Endothelial Dystrophy Corneal Endothelium.

    PubMed

    Katikireddy, Kishore Reddy; Schmedt, Thore; Price, Marianne O; Price, Francis W; Jurkunas, Ula V

    2016-10-01

    Human corneal endothelial cells are derived from neural crest and because of postmitotic arrest lack competence to repair cell loss from trauma, aging, and degenerative disorders such as Fuchs endothelial corneal dystrophy (FECD). Herein, we identified a rapidly proliferating subpopulation of cells from the corneal endothelium of adult normal and FECD donors that exhibited features of neural crest-derived progenitor (NCDP) cells by showing absence of senescence with passaging, propensity to form spheres, and increased colony forming efficacy compared with the primary cells. The collective expression of stem cell-related genes SOX2, OCT4, LGR5, TP63 (p63), as well as neural crest marker genes PSIP1 (p75(NTR)), PAX3, SOX9, AP2B1 (AP-2β), and NES, generated a phenotypic footprint of endothelial NCDPs. NCDPs displayed multipotency by differentiating into microtubule-associated protein 2, β-III tubulin, and glial fibrillary acidic protein positive neurons and into p75(NTR)-positive human corneal endothelial cells that exhibited transendothelial resistance of functional endothelium. In conclusion, we found that mitotically incompetent ocular tissue cells contain adult NCDPs that exhibit a profile of transcription factors regulating multipotency and neural crest progenitor characteristics. Identification of normal NCDPs in FECD-affected endothelium holds promise for potential autologous cell therapies. PMID:27639969

  3. Neural crest derivatives in ocular development: discerning the eye of the storm.

    PubMed

    Williams, Antionette L; Bohnsack, Brenda L

    2015-06-01

    Neural crest cells (NCCs) are vertebrate-specific transient, multipotent, migratory stem cells that play a crucial role in many aspects of embryonic development. These cells emerge from the dorsal neural tube and subsequently migrate to different regions of the body, contributing to the formation of diverse cell lineages and structures, including much of the peripheral nervous system, craniofacial skeleton, smooth muscle, skin pigmentation, and multiple ocular and periocular structures. Indeed, abnormalities in neural crest development cause craniofacial defects and ocular anomalies, such as Axenfeld-Rieger syndrome and primary congenital glaucoma. Thus, understanding the molecular regulation of neural crest development is important to enhance our knowledge of the basis for congenital eye diseases, reflecting the contributions of these progenitors to multiple cell lineages. Particularly, understanding the underpinnings of neural crest formation will help to discern the complexities of eye development, as these NCCs are involved in every aspect of this process. In this review, we summarize the role of ocular NCCs in eye development, particularly focusing on congenital eye diseases associated with anterior segment defects and the interplay between three prominent molecules, PITX2, CYP1B1, and retinoic acid, which act in concert to specify a population of neural crest-derived mesenchymal progenitors for migration and differentiation, to give rise to distinct anterior segment tissues. We also describe recent findings implicating this stem cell population in ocular coloboma formation, and introduce recent evidence suggesting the involvement of NCCs in optic fissure closure and vascular development.

  4. Isolation of neural crest derived chromaffin progenitors from adult adrenal medulla.

    PubMed

    Chung, Kuei-Fang; Sicard, Flavie; Vukicevic, Vladimir; Hermann, Andreas; Storch, Alexander; Huttner, Wieland B; Bornstein, Stefan R; Ehrhart-Bornstein, Monika

    2009-10-01

    Chromaffin cells of the adrenal medulla are neural crest-derived cells of the sympathoadrenal lineage. Unlike the closely-related sympathetic neurons, a subpopulation of proliferation-competent cells exists even in the adult. Here, we describe the isolation, expansion, and in vitro characterization of proliferation-competent progenitor cells from the bovine adrenal medulla. Similar to neurospheres, these cells, when prevented from adherence to the culture dish, grew in spheres, which we named chromospheres. These chromospheres were devoid of mRNA specific for smooth muscle cells (MYH11) or endothelial cells (PECAM1). During sphere formation, markers for differentiated chromaffin cells, such as phenylethanolamine-N-methyl transferase, were downregulated while neural progenitor markers nestin, vimentin, musashi 1, and nerve growth factor receptor, as well as markers of neural crest progenitor cells such as Sox1 and Sox9, were upregulated. Clonal analysis and bromo-2'-deoxyuridine-incorporation analysis demonstrated the self-renewing capacity of chromosphere cells. Differentiation protocols using NGF and BMP4 or dexamethasone induced neuronal or endocrine differentiation, respectively. Electrophysiological analyses of neural cells derived from chromospheres revealed functional properties of mature nerve cells, such as tetrodotoxin-sensitive sodium channels and action potentials. Our study provides evidence that proliferation and differentiation competent chromaffin progenitor cells can be isolated from adult adrenal medulla and that these cells might harbor the potential for the treatment of neurodegenerative diseases, such as Parkinson's disease. PMID:19609938

  5. Colonization of the murine hindgut by sacral crest-derived neural precursors: experimental support for an evolutionarily conserved model.

    PubMed

    Kapur, R P

    2000-11-01

    Enteric ganglia in the hindgut are derived from separate vagal and sacral neural crest populations. Two conflicting models, based primarily on avian data, have been proposed to describe the contribution of sacral neural crest cells. One hypothesizes early colonization of the hindgut shortly after neurulation, and the other states that sacral crest cells reside transiently in the extraenteric ganglion of Remak and colonize the hindgut much later, after vagal crest-derived neural precursors arrive. In this study, I show that Wnt1-lacZ-transgene expression, an "early" marker of murine neural crest cells, is inconsistent with the "early-colonization" model. Although Wnt1-lacZ-positive sacral crest cells populate pelvic ganglia in the mesenchyme surrounding the hindgut, they are not found in the gut prior to the arrival of vagal crest cells. Similarly, segments of murine hindgut harvested prior to the arrival of vagal crest cells and grafted under the renal capsule fail to develop enteric neurons, unless adjacent pelvic mesenchyme is included in the graft. When pelvic mesenchyme from DbetaH-nlacZ transgenic embryos is apposed with nontransgenic hindgut, neural precursors from the mesenchyme colonize the hindgut and form intramural ganglion cells that express the transgenic marker. Contribution of sacral crest-derived cells to the enteric nervous system is not affected by cocolonization of grafts by vagal crest-derived neuroglial precursors. The findings complement recent studies of avian chimeras and support an evolutionarily conserved model in which sacral crest cells first colonize the extramural ganglion and secondarily enter the hindgut mesenchyme.

  6. Alternative generation of CNS neural stem cells and PNS derivatives from neural crest-derived peripheral stem cells.

    PubMed

    Weber, Marlen; Apostolova, Galina; Widera, Darius; Mittelbronn, Michel; Dechant, Georg; Kaltschmidt, Barbara; Rohrer, Hermann

    2015-02-01

    Neural crest-derived stem cells (NCSCs) from the embryonic peripheral nervous system (PNS) can be reprogrammed in neurosphere (NS) culture to rNCSCs that produce central nervous system (CNS) progeny, including myelinating oligodendrocytes. Using global gene expression analysis we now demonstrate that rNCSCs completely lose their previous PNS characteristics and acquire the identity of neural stem cells derived from embryonic spinal cord. Reprogramming proceeds rapidly and results in a homogenous population of Olig2-, Sox3-, and Lex-positive CNS stem cells. Low-level expression of pluripotency inducing genes Oct4, Nanog, and Klf4 argues against a transient pluripotent state during reprogramming. The acquisition of CNS properties is prevented in the presence of BMP4 (BMP NCSCs) as shown by marker gene expression and the potential to produce PNS neurons and glia. In addition, genes characteristic for mesenchymal and perivascular progenitors are expressed, which suggests that BMP NCSCs are directed toward a pericyte progenitor/mesenchymal stem cell (MSC) fate. Adult NCSCs from mouse palate, an easily accessible source of adult NCSCs, display strikingly similar properties. They do not generate cells with CNS characteristics but lose the neural crest markers Sox10 and p75 and produce MSC-like cells. These findings show that embryonic NCSCs acquire a full CNS identity in NS culture. In contrast, MSC-like cells are generated from BMP NCSCs and pNCSCs, which reveals that postmigratory NCSCs are a source for MSC-like cells up to the adult stage.

  7. Localization and osteoblastic differentiation potential of neural crest-derived cells in oral tissues of adult mice.

    PubMed

    Ono, Miki; Suzawa, Tetsuo; Takami, Masamichi; Yamamoto, Gou; Hosono, Tomohiko; Yamada, Atsushi; Suzuki, Dai; Yoshimura, Kentaro; Watahiki, Junichi; Hayashi, Ryuhei; Arata, Satoru; Mishima, Kenji; Nishida, Kohji; Osumi, Noriko; Maki, Koutaro; Kamijo, Ryutaro

    2015-09-01

    In embryos, neural crest cells emerge from the dorsal region of the fusing neural tube and migrate throughout tissues to differentiate into various types of cells including osteoblasts. In adults, subsets of neural crest-derived cells (NCDCs) reside as stem cells and are considered to be useful cell sources for regenerative medicine strategies. Numerous studies have suggested that stem cells with a neural crest origin persist into adulthood, especially those within the mammalian craniofacial compartment. However, their distribution as well as capacity to differentiate into osteoblasts in adults is not fully understood. To analyze the precise distribution and characteristics of NCDCs in adult oral tissues, we utilized an established line of double transgenic (P0-Cre/CAG-CAT-EGFP) mice in which NCDCs express green fluorescent protein (GFP) throughout their life. GFP-positive cells were scattered like islands throughout tissues of the palate, gingiva, tongue, and buccal mucosa in adult mice, with those isolated from the latter shown to form spheres, typical cell clusters composed of stem cells, under low-adherent conditions. Furthermore, GFP-positive cells had markedly increased alkaline phosphatase (a marker enzyme of osteoblast differentiation) activity and mineralization as shown by alizarin red staining, in the presence of bone morphogenetic protein (BMP)-2. These results suggest that NCDCs reside in various adult oral tissues and possess potential to differentiate into osteoblastic cells. NCDCs in adults may be a useful cell source for bone regeneration strategies.

  8. Neurogenesis of Neural Crest Derived Periodontal Ligament Stem Cells by EGF and bFGF

    PubMed Central

    Fortino, Veronica R.; Chen, Ren-Shiang; Pelaez, Daniel; Cheung, Herman S.

    2013-01-01

    Neuroregenerative medicine is an ever-growing field in which regeneration of lost cells/tissues due to a neurodegenerative disease is the ultimate goal. With the scarcity of available replacement alternatives, stem cells provide an attractive source for regenerating neural tissue. While many stem cell sources exist, including: mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), the limited cellular potency, technical difficulties, and ethical considerations associated with these make finding alternate sources a desirable goal. Periodontal ligament stem cells (PDLSCs) derived from the neural crest were induced into neural-like cells using a combination of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Morphological changes were evident in our treated group, seen under both light microscopy and scanning electron microscopy (SEM). A statistically significant increase in the expression of neuron-specific β-tubulin III and the neural stem/progenitor cell marker nestin, along with positive immunohistochemical staining for glial fibrillary acidic protein (GFAP), demonstrated the success of our treatment in inducing both neuronal and glial phenotypes. Positive staining for synaptophysin demonstrated neural connections and electrophysiological recordings indicated that when subjected to whole cell patch clamping, our treated cells displayed inward currents conducted through voltage-gated sodium (Na+) channels. Taken together, our results indicate the success of our treatment in inducing PDLSCs to neural-like cells. The ease of sourcing and expansion, their embryologic neural crest origin, and the lack of ethical implications in their use make PDLSCs an attractive source for use in neuroregenerative medicine. PMID:24105823

  9. Analysis of neural crest-derived clones reveals novel aspects of facial development.

    PubMed

    Kaucka, Marketa; Ivashkin, Evgeny; Gyllborg, Daniel; Zikmund, Tomas; Tesarova, Marketa; Kaiser, Jozef; Xie, Meng; Petersen, Julian; Pachnis, Vassilis; Nicolis, Silvia K; Yu, Tian; Sharpe, Paul; Arenas, Ernest; Brismar, Hjalmar; Blom, Hans; Clevers, Hans; Suter, Ueli; Chagin, Andrei S; Fried, Kaj; Hellander, Andreas; Adameyko, Igor

    2016-08-01

    Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been determined. We investigated how neural crest cells give rise to clonally organized ectomesenchyme and how this early ectomesenchyme behaves during the developmental processes that shape the face. Using a combination of mouse and zebrafish models, we analyzed individual migration, cell crowd movement, oriented cell division, clonal spatial overlapping, and multilineage differentiation. The early face appears to be built from multiple spatially defined overlapping ectomesenchymal clones. During early face development, these clones remain oligopotent and generate various tissues in a given location. By combining clonal analysis, computer simulations, mouse mutants, and live imaging, we show that facial shaping results from an array of local cellular activities in the ectomesenchyme. These activities mostly involve oriented divisions and crowd movements of cells during morphogenetic events. Cellular behavior that can be recognized as individual cell migration is very limited and short-ranged and likely results from cellular mixing due to the proliferation activity of the tissue. These cellular mechanisms resemble the strategy behind limb bud morphogenesis, suggesting the possibility of common principles and deep homology between facial and limb outgrowth.

  10. Epigenetic Marks Define the Lineage and Differentiation Potential of Two Distinct Neural Crest-Derived Intermediate Odontogenic Progenitor Populations

    PubMed Central

    Gopinathan, Gokul; Kolokythas, Antonia

    2013-01-01

    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. PMID:23379639

  11. Fibulin-1 is required for morphogenesis of neural crest-derived structures

    PubMed Central

    Cooley, Marion A.; Kern, Christine B.; Fresco, Victor M.; Wessels, Andy; Thompson, Robert P.; McQuinn, Tim C.; Twal, Waleed O.; Mjaatvedt, Corey H.; Drake, Christopher J.; Argraves, W. Scott

    2008-01-01

    Here we report that mouse embryos homozygous for a gene trap insertion in the fibulin-1 (Fbln1) gene are deficient in Fbln1 and exhibit cardiac ventricular wall thinning and ventricular septal defects with double outlet right ventricle or overriding aorta. Fbln1 nulls also display anomalies of aortic arch arteries, hypoplasia of the thymus and thyroid, underdeveloped skull bones, malformations of cranial nerves and hemorrhagic blood vessels in the head and neck. The spectrum of malformations is consistent with Fbln1 influencing neural crest cell (NCC)-dependent development of these tissues. This is supported by evidence that Fbln1 expression is associated with streams of cranial NCCs migrating adjacent to rhombomeres 2–7 and that Fbln1-deficient embryos display patterning anomalies of NCCs forming cranial nerves IX and X, which derive from rhombomeres 6 and 7. Additionally, Fbln1-deficient embryos show increased apoptosis in areas populated by NCCs derived from rhombomeres 4, 6 and 7. Based on these findings, it is concluded that Fbln1 is required for the directed migration and survival of cranial NCCs contributing to the development of pharyngeal glands, craniofacial skeleton, cranial nerves, aortic arch arteries, cardiac outflow tract and cephalic blood vessels. PMID:18538758

  12. TGF-β-activated Kinase 1 (Tak1) Mediates Agonist-induced Smad Activation and Linker Region Phosphorylation in Embryonic Craniofacial Neural Crest-derived Cells*

    PubMed Central

    Yumoto, Kenji; Thomas, Penny S.; Lane, Jamie; Matsuzaki, Kouichi; Inagaki, Maiko; Ninomiya-Tsuji, Jun; Scott, Gregory J.; Ray, Manas K.; Ishii, Mamoru; Maxson, Robert; Mishina, Yuji; Kaartinen, Vesa

    2013-01-01

    Although the importance of TGF-β superfamily signaling in craniofacial growth and patterning is well established, the precise details of its signaling mechanisms are still poorly understood. This is in part because of the concentration of studies on the role of the Smad-dependent (so-called “canonical”) signaling pathways relative to the Smad-independent ones in many biological processes. Here, we have addressed the role of TGF-β-activated kinase 1 (Tak1, Map3k7), one of the key mediators of Smad-independent (noncanonical) TGF-β superfamily signaling in craniofacial development, by deleting Tak1 specifically in the neural crest lineage. Tak1-deficient mutants display a round skull, hypoplastic maxilla and mandible, and cleft palate resulting from a failure of palatal shelves to appropriately elevate and fuse. Our studies show that in neural crest-derived craniofacial ecto-mesenchymal cells, Tak1 is not only required for TGF-β- and bone morphogenetic protein-induced p38 Mapk activation but also plays a role in agonist-induced C-terminal and linker region phosphorylation of the receptor-mediated R-Smads. Specifically, we demonstrate that the agonist-induced linker region phosphorylation of Smad2 at Thr-220, which has been shown to be critical for full transcriptional activity of Smad2, is dependent on Tak1 activity and that in palatal mesenchymal cells TGFβRI and Tak1 kinases mediate both overlapping and distinct TGF-β2-induced transcriptional responses. To summarize, our results suggest that in neural crest-derived ecto-mesenchymal cells, Tak1 provides a critical point of intersection in a complex dialogue between the canonical and noncanonical arms of TGF-β superfamily signaling required for normal craniofacial development. PMID:23546880

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

    SciTech Connect

    Wen, Xiujie; Liu, Luchuan; Deng, Manjing; Liu, Rui; Zhang, Li; Nie, Xin

    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

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

    PubMed

    Jiao, Jiao; Xiong, Wei; Wang, Lunchang; Yang, Jiong; Qiu, Ping; Hirai, Hiroyuki; Shao, Lina; Milewicz, Dianna; Chen, Y Eugene; Yang, Bo

    2016-08-01

    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. PMID:27394642

  15. Strict perpendicular orientation of neural crest-derived neurons in vitro is dependent on an extracellular gradient of voltage.

    PubMed

    Pan, Linjie; Borgens, Richard Ben

    2012-07-01

    We report extraordinary perpendicular orientations of neurons dependent on the presence of an external direct current (DC) voltage gradient. We chose chick dorsal root and postganglionic sympathetic neurons to evaluate. These were cultured in observation chambers in which the cells were separated from electrode products or substrate effects and maintained at 35°C. Both types of neurons showed a rapid restructuring of their anatomy. Typically, neurites that were not perpendicular to the voltage gradient were quickly resorbed into the cell body within a few minutes. Over 3-6 hr, significant new neurite growth occurred and was patterned perpendicular to the DC electrical field (Ef). This preferred asymmetry was dependent on the Ef, as was the initial retrograde degeneration of fibers. At 400-500 mV/mm, over 90% of the cells in culture assumed this orientation. Removal of the DC Ef led to a loss of the preferred orientation, with further random growth within the chambers. This is the first report of such responses in dorsal root ganglion neurons. We also used sympathetic neurons as a meaningful comparison to analyze whether there were any qualitative or quantitative differences between these two cell types of neural crest origin. We discuss the means by which these orientations were achieved.

  16. Transforming growth factor-beta 1 differentially regulates proliferation, morphology, and extracellular matrix expression by three neural crest-derived neuroblastoma cell lines.

    PubMed

    Rogers, S L; Cutts, J L; Gegick, P J; McGuire, P G; Rosenberger, C; Krisinski, S

    1994-04-01

    We reported previously (S. L. Rogers, P. J. Gegick, S. M. Alexander, and P. G. McGuire, Dev. Biol. 151, 191-203, 1992) that transforming growth factor-beta 1 (TGF beta 1) inhibited proliferation, up-regulated fibronectin synthesis, and suppressed melanogenesis in a population of quail neural crest cells in vitro. Here, we report that cell lines derived from the parent SK-N-SH neuroblastoma line (R. A. Ross, B. A. Spengler, and J. L. Biedler, J. Natl. Cancer Inst. 71, 741-747, 1983) respond differentially to TGF beta 1, and their responses provide further insights into the actions of this growth factor on neural crest subpopulations. The SH-EP cell line exhibits primarily nonneuronal traits and responded to TGF beta 1 with increased thymidine uptake after 6 days of culture, increased expression of fibronectin mRNA and protein, and decreased laminin synthesis. Many SH-EP cells also acquired a dramatically elongated morphology, reminiscent of Schwann cells in culture. Thymidine uptake by the neuronal SY5Y cell line was not substantially altered. Neither fibronectin mRNA nor protein was detectable in either TGF beta 1-treated or untreated cultures, although laminin synthesis was upregulated by the growth factor. In TGF beta 1-treated cultures of the intermediate SH-IN cell line, which has been reported to display both neuronal and nonneuronal characteristics, there was marked flattening of many cells, a steady decrease in thymidine uptake, and increased expression of both fibronectin and laminin. The observed responses of SH-IN cells mimic those observed in primary neural crest cultures and appear to represent similar differentiation toward a mesenchymal phenotype. These results substantiate the idea that closely related but diverging neural crest-derived cell types respond selectively to TGF beta 1 and demonstrate that these SK-N-SH-derived cell lines will be useful in experimental approaches that will allow us to infer mechanisms underlying regulation of neural crest

  17. Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease.

    PubMed

    Walters, Lauren C; Cantrell, V Ashley; Weller, Kevin P; Mosher, Jack T; Southard-Smith, E Michelle

    2010-11-15

    Abnormalities in the development of enteric neural crest-derived progenitors (ENPs) that generate the enteric nervous system (ENS) can lead to aganglionosis in a variable portion of the distal gastrointestinal tract. Cumulative evidence suggests that variation of aganglionosis is due to gene interactions that modulate the ability of ENPs to populate the intestine; however, the developmental processes underlying this effect are unknown. We hypothesized that differences in enteric ganglion deficits could be attributable to the effects of genetic background on early developmental processes, including migration, proliferation, or lineage divergence. Developmental processes were investigated in congenic Sox10(Dom) mice, an established Hirschsprung disease (HSCR) model, on distinct inbred backgrounds, C57BL/6J (B6) and C3HeB/FeJ (C3Fe). Immuno-staining on whole-mount fetal gut tissue and dissociated cell suspensions was used to assess migration and proliferation. Flow cytometry utilizing the cell surface markers p75 and HNK-1 was used to isolate live ENPs for analysis of developmental potential. Frequency of ENPs was reduced in Sox10(Dom) embryos relative to wild-type embryos, but was unaffected by genetic background. Both migration and developmental potential of ENPs in Sox10(Dom) embryos were altered by inbred strain background with the most highly significant differences seen for developmental potential between strains and genotypes. In vivo imaging of fetal ENPs and postnatal ganglia demonstrates that altered lineage divergence impacts ganglia in the proximal intestine. Our analysis demonstrates that genetic background alters early ENS development and suggests that abnormalities in lineage diversification can shift the proportions of ENP populations and thus may contribute to ENS deficiencies in vivo.

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

    PubMed

    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.

  19. FGF8 signaling sustains progenitor status and multipotency of cranial neural crest-derived mesenchymal cells in vivo and in vitro.

    PubMed

    Shao, Meiying; Liu, Chao; Song, Yingnan; Ye, Wenduo; He, Wei; Yuan, Guohua; Gu, Shuping; Lin, Congxin; Ma, Liang; Zhang, Yanding; Tian, Weidong; Hu, Tao; Chen, YiPing

    2015-10-01

    The cranial neural crest (CNC) cells play a vital role in craniofacial development and regeneration. They are multi-potent progenitors, being able to differentiate into various types of tissues. Both pre-migratory and post-migratory CNC cells are plastic, taking on diverse fates by responding to different inductive signals. However, what sustains the multipotency of CNC cells and derivatives remains largely unknown. In this study, we present evidence that FGF8 signaling is able to sustain progenitor status and multipotency of CNC-derived mesenchymal cells both in vivo and in vitro. We show that augmented FGF8 signaling in pre-migratory CNC cells prevents cell differentiation and organogenesis in the craniofacial region by maintaining their progenitor status. CNC-derived mesenchymal cells with Fgf8 overexpression or control cells in the presence of exogenous FGF8 exhibit prolonged survival, proliferation, and multi-potent differentiation capability in cell cultures. Remarkably, exogenous FGF8 also sustains the capability of CNC-derived mesenchymal cells to participate in organogenesis such as odontogenesis. Furthermore, FGF8-mediated signaling strongly promotes adipogenesis but inhibits osteogenesis of CNC-derived mesenchymal cells in vitro. Our results reveal a specific role for FGF8 in the maintenance of progenitor status and in fate determination of CNC cells, implicating a potential application in expansion and fate manipulation of CNC-derived cells in stem cell-based craniofacial regeneration. PMID:26243590

  20. FGF8 signaling sustains progenitor status and multipotency of cranial neural crest-derived mesenchymal cells in vivo and in vitro

    PubMed Central

    Shao, Meiying; Liu, Chao; Song, Yingnan; Ye, Wenduo; He, Wei; Yuan, Guohua; Gu, Shuping; Lin, Congxin; Ma, Liang; Zhang, Yanding; Tian, Weidong; Hu, Tao; Chen, YiPing

    2015-01-01

    The cranial neural crest (CNC) cells play a vital role in craniofacial development and regeneration. They are multi-potent progenitors, being able to differentiate into various types of tissues. Both pre-migratory and post-migratory CNC cells are plastic, taking on diverse fates by responding to different inductive signals. However, what sustains the multipotency of CNC cells and derivatives remains largely unknown. In this study, we present evidence that FGF8 signaling is able to sustain progenitor status and multipotency of CNC-derived mesenchymal cells both in vivo and in vitro. We show that augmented FGF8 signaling in pre-migratory CNC cells prevents cell differentiation and organogenesis in the craniofacial region by maintaining their progenitor status. CNC-derived mesenchymal cells with Fgf8 overexpression or control cells in the presence of exogenous FGF8 exhibit prolonged survival, proliferation, and multi-potent differentiation capability in cell cultures. Remarkably, exogenous FGF8 also sustains the capability of CNC-derived mesenchymal cells to participate in organogenesis such as odontogenesis. Furthermore, FGF8-mediated signaling strongly promotes adipogenesis but inhibits osteogenesis of CNC-derived mesenchymal cells in vitro. Our results reveal a specific role for FGF8 in the maintenance of progenitor status and in fate determination of CNC cells, implicating a potential application in expansion and fate manipulation of CNC-derived cells in stem cell-based craniofacial regeneration. PMID:26243590

  1. Human dental mesenchymal stem cells and neural regeneration.

    PubMed

    Xiao, Li; Tsutsui, Takeki

    2013-09-01

    Nerve tissue presents inherent difficulties for its effective regeneration. Stem cell transplantation is considered an auspicious treatment for neuronal injuries. Recently, human dental mesenchymal stem cells (DMSCs) have received extensive attention in the field of regenerative medicine due to their accessibility and multipotency. Since their origin is within the neural crest, they can be differentiated into neural crest-derived cells including neuron and glia cells both in vitro and in vivo. DMSCs are also able to secrete a wide variety of neurotrophins and chemokines, which promote neuronal cells to survival and differentiation. Experimental evidence has shown that human DMSCs engraftment recovered neuronal tissue damage in animal models of central nervous system injuries. Human DMSCs can be a new hope for treatment of nervous system diseases and deficits such as spinal cord injury, stroke and Parkinson's disease.

  2. Multipotent caudal neural progenitors derived from human pluripotent stem cells that give rise to lineages of the central and peripheral nervous system.

    PubMed

    Denham, Mark; Hasegawa, Kouichi; Menheniott, Trevelyan; Rollo, Ben; Zhang, Dongcheng; Hough, Shelley; Alshawaf, Abdullah; Febbraro, Fabia; Ighaniyan, Samiramis; Leung, Jessie; Elliott, David A; Newgreen, Donald F; Pera, Martin F; Dottori, Mirella

    2015-06-01

    The caudal neural plate is a distinct region of the embryo that gives rise to major progenitor lineages of the developing central and peripheral nervous system, including neural crest and floor plate cells. We show that dual inhibition of the glycogen synthase kinase 3β and activin/nodal pathways by small molecules differentiate human pluripotent stem cells (hPSCs) directly into a preneuroepithelial progenitor population we named "caudal neural progenitors" (CNPs). CNPs coexpress caudal neural plate and mesoderm markers, and, share high similarities to embryonic caudal neural plate cells in their lineage differentiation potential. Exposure of CNPs to BMP2/4, sonic hedgehog, or FGF2 signaling efficiently directs their fate to neural crest/roof plate cells, floor plate cells, and caudally specified neuroepithelial cells, respectively. Neural crest derived from CNPs differentiated to neural crest derivatives and demonstrated extensive migratory properties in vivo. Importantly, we also determined the key extrinsic factors specifying CNPs from human embryonic stem cell include FGF8, canonical WNT, and IGF1. Our studies are the first to identify a multipotent neural progenitor derived from hPSCs, that is the precursor for major neural lineages of the embryonic caudal neural tube.

  3. Differentiation of human epidermal neural crest stem cells (hEPI-NCSC) into virtually homogenous populations of dopaminergic neurons.

    PubMed

    Narytnyk, Alla; Verdon, Bernard; Loughney, Andrew; Sweeney, Michele; Clewes, Oliver; Taggart, Michael J; Sieber-Blum, Maya

    2014-04-01

    Here we provide a protocol for the directed differentiation of hEPI-NCSC into midbrain dopaminergic neurons, which degenerate in Parkinson's disease. hEPI-NCSC are neural crest-derived multipotent stem cells that persist into adulthood in the bulge of hair follicles. The experimental design is distinctly different from conventional protocols for embryonic stem cells and induced pluripotent stem (iPS) cells. It includes pre-differentiation of the multipotent hEPI-NCSC into neural stem cell-like cells, followed by ventralizing, patterning, continued exposure to the TGFβ receptor inhibitor, SB431542, and at later stages of differentiation the presence of the WNT inhibitor, IWP-4. All cells expressed A9 midbrain dopaminergic neuron progenitor markers with gene expression levels comparable to those in normal human substantia nigra. The current study shows for the first time that virtually homogeneous populations of dopaminergic neurons can be derived ex vivo from somatic stem cells without the need for purification, with useful timeliness and high efficacy. This novel development is an important first step towards the establishment of fully functional dopaminergic neurons from an ontologically relevant stem cell type, hEPI-NCSC. PMID:24399192

  4. Galaxies, human eyes, and artificial neural networks.

    PubMed

    Lahav, O; Naim, A; Buta, R J; Corwin, H G; de Vaucouleurs, G; Dressler, A; Huchra, J P; van den Bergh, S; Raychaudhury, S; Sodré, L; Storrie-Lombardi, M C

    1995-02-10

    The quantitative morphological classification of galaxies is important for understanding the origin of type frequency and correlations with environment. However, galaxy morphological classification is still mainly done visually by dedicated individuals, in the spirit of Hubble's original scheme and its modifications. The rapid increase in data on galaxy images at low and high redshift calls for a re-examination of the classification schemes and for automatic methods. Here are shown results from a systematic comparison of the dispersion among human experts classifying a uniformly selected sample of more than 800 digitized galaxy images. These galaxy images were then classified by six of the authors independently. The human classifications are compared with each other and with an automatic classification by an artificial neural network, which replicates the classification by a human expert to the same degree of agreement as that between two human experts. PMID:17813914

  5. Human altruism: economic, neural, and evolutionary perspectives.

    PubMed

    Fehr, Ernst; Rockenbach, Bettina

    2004-12-01

    Human cooperation represents a spectacular outlier in the animal world. Unlike other creatures, humans frequently cooperate with genetically unrelated strangers, often in large groups, with people they will never meet again, and when reputation gains are small or absent. Experimental evidence and evolutionary models suggest that strong reciprocity, the behavioral propensity for altruistic punishment and altruistic rewarding, is of key importance for human cooperation. Here, we review both evidence documenting altruistic punishment and altruistic cooperation and recent brain imaging studies that combine the powerful tools of behavioral game theory with neuroimaging techniques. These studies show that mutual cooperation and the punishment of defectors activate reward related neural circuits, suggesting that evolution has endowed humans with proximate mechanisms that render altruistic behavior psychologically rewarding.

  6. A neural mediator of human anxiety sensitivity.

    PubMed

    Harrison, Ben J; Fullana, Miquel A; Soriano-Mas, Carles; Via, Esther; Pujol, Jesus; Martínez-Zalacaín, Ignacio; Tinoco-Gonzalez, Daniella; Davey, Christopher G; López-Solà, Marina; Pérez Sola, Victor; Menchón, José M; Cardoner, Narcís

    2015-10-01

    Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural mediators' of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex-a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder. PMID:26147233

  7. A neural mediator of human anxiety sensitivity.

    PubMed

    Harrison, Ben J; Fullana, Miquel A; Soriano-Mas, Carles; Via, Esther; Pujol, Jesus; Martínez-Zalacaín, Ignacio; Tinoco-Gonzalez, Daniella; Davey, Christopher G; López-Solà, Marina; Pérez Sola, Victor; Menchón, José M; Cardoner, Narcís

    2015-10-01

    Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural mediators' of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex-a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder.

  8. Neural correlates of human body perception.

    PubMed

    Aleong, Rosanne; Paus, Tomás

    2010-03-01

    The objective of this study was to investigate potential sex differences in the neural response to human bodies using fMRI carried out in healthy young adults. We presented human bodies in a block-design experiment to identify body-responsive regions of the brain, namely, extrastriate body area (EBA) and fusiform body area (FBA). In a separate event-related "adaptation" experiment, carried out in the same group of subjects, we presented sets of four human bodies of varying body size and shape. Varying levels of body morphing were introduced to assess the degree of morphing required for adaptation release. Analysis of BOLD signal in the block-design experiment revealed significant Sex x Hemisphere interactions in the EBA and the FBA responses to human bodies. Only women showed greater BOLD response to bodies in the right hemisphere compared with the left hemisphere for both EBA and FBA. The BOLD response in right EBA was higher in women compared with men. In the adaptation experiment, greater right versus left hemisphere response for EBA and FBA was also identified among women but not men. These findings are particularly novel in that they address potential sex differences in the lateralization of EBA and FBA responses to human body images. Although previous studies have found some degree of right hemisphere dominance in body perception, our results suggest that such a functional lateralization may differ between men and women.

  9. The neural basis of human tool use.

    PubMed

    Orban, Guy A; Caruana, Fausto

    2014-01-01

    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 anterior intraparietal (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. PMID

  10. The neural basis of human tool use

    PubMed Central

    Orban, Guy A.; Caruana, Fausto

    2014-01-01

    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 anterior intraparietal (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. PMID

  11. The neural basis of human tool use.

    PubMed

    Orban, Guy A; Caruana, Fausto

    2014-01-01

    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 anterior intraparietal (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.

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

    PubMed Central

    Ibarretxe, Gaskon; Crende, Olatz; Aurrekoetxea, Maitane; García-Murga, Victoria; Etxaniz, Javier; Unda, Fernando

    2012-01-01

    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. PMID:23093977

  13. Know Your Place: Neural Processing of Social Hierarchy in Humans

    PubMed Central

    Zink, Caroline F.; Tong, Yunxia; Chen, Qiang; Bassett, Danielle S.; Stein, Jason L.; Meyer-Lindenberg, Andreas

    2008-01-01

    Summary Social hierarchies guide behavior in many species, including humans, where status also has an enormous impact on motivation and health. However, little is known about the underlying neural representation of social hierarchies in humans. In the present study, we identify dissociable neural responses to perceived social rank using functional magnetic resonance imaging (fMRI) in an interactive simulated social context. In both stable and unstable social hierarchies, viewing a superior individual differentially engaged perceptual-attentional, saliency, and cognitive systems, notably dorsolateral prefrontal cortex. In the unstable hierarchy setting, additional regions were recruited related to emotional processing (amygdala), social cognition (medial prefrontal cortex), and behavioral readiness. Furthermore, social hierarchical consequences of performance were neurally dissociable and of comparable salience to monetary reward, providing a neural basis for the high motivational value of status. Our results identify neural mechanisms that may mediate the enormous influence of social status on human behavior and health. PMID:18439411

  14. Reprogramming of avian neural crest axial identity and cell fate.

    PubMed

    Simoes-Costa, Marcos; Bronner, Marianne E

    2016-06-24

    Neural crest populations along the embryonic body axis of vertebrates differ in developmental potential and fate, so that only the cranial neural crest can contribute to the craniofacial skeleton in vivo. We explored the regulatory program that imbues the cranial crest with its specialized features. Using axial-level specific enhancers to isolate and perform genome-wide profiling of the cranial versus trunk neural crest in chick embryos, we identified and characterized regulatory relationships between a set of cranial-specific transcription factors. Introducing components of this circuit into neural crest cells of the trunk alters their identity and endows these cells with the ability to give rise to chondroblasts in vivo. Our results demonstrate that gene regulatory circuits that support the formation of particular neural crest derivatives may be used to reprogram specific neural crest-derived cell types. PMID:27339986

  15. Differential neural network configuration during human path integration.

    PubMed

    Arnold, Aiden E G F; Burles, Ford; Bray, Signe; Levy, Richard M; Iaria, Giuseppe

    2014-01-01

    Path integration is a fundamental skill for navigation in both humans and animals. Despite recent advances in unraveling the neural basis of path integration in animal models, relatively little is known about how path integration operates at a neural level in humans. Previous attempts to characterize the neural mechanisms used by humans to visually path integrate have suggested a central role of the hippocampus in allowing accurate performance, broadly resembling results from animal data. However, in recent years both the central role of the hippocampus and the perspective that animals and humans share similar neural mechanisms for path integration has come into question. The present study uses a data driven analysis to investigate the neural systems engaged during visual path integration in humans, allowing for an unbiased estimate of neural activity across the entire brain. Our results suggest that humans employ common task control, attention and spatial working memory systems across a frontoparietal network during path integration. However, individuals differed in how these systems are configured into functional networks. High performing individuals were found to more broadly express spatial working memory systems in prefrontal cortex, while low performing individuals engaged an allocentric memory system based primarily in the medial occipito-temporal region. These findings suggest that visual path integration in humans over short distances can operate through a spatial working memory system engaging primarily the prefrontal cortex and that the differential configuration of memory systems recruited by task control networks may help explain individual biases in spatial learning strategies.

  16. Differential neural network configuration during human path integration

    PubMed Central

    Arnold, Aiden E. G. F; Burles, Ford; Bray, Signe; Levy, Richard M.; Iaria, Giuseppe

    2014-01-01

    Path integration is a fundamental skill for navigation in both humans and animals. Despite recent advances in unraveling the neural basis of path integration in animal models, relatively little is known about how path integration operates at a neural level in humans. Previous attempts to characterize the neural mechanisms used by humans to visually path integrate have suggested a central role of the hippocampus in allowing accurate performance, broadly resembling results from animal data. However, in recent years both the central role of the hippocampus and the perspective that animals and humans share similar neural mechanisms for path integration has come into question. The present study uses a data driven analysis to investigate the neural systems engaged during visual path integration in humans, allowing for an unbiased estimate of neural activity across the entire brain. Our results suggest that humans employ common task control, attention and spatial working memory systems across a frontoparietal network during path integration. However, individuals differed in how these systems are configured into functional networks. High performing individuals were found to more broadly express spatial working memory systems in prefrontal cortex, while low performing individuals engaged an allocentric memory system based primarily in the medial occipito-temporal region. These findings suggest that visual path integration in humans over short distances can operate through a spatial working memory system engaging primarily the prefrontal cortex and that the differential configuration of memory systems recruited by task control networks may help explain individual biases in spatial learning strategies. PMID:24808849

  17. Directed Differentiation of Human Embryonic Stem Cells into Neural Progenitors.

    PubMed

    Banda, Erin; Grabel, Laura

    2016-01-01

    A variety of protocols have been used to produce neural progenitors from human embryonic stem cells. We have focused on a monolayer culture approach that generates neural rosettes. To initiate differentiation, cells are plated in a serum-free nutrient-poor medium in the presence of a BMP inhibitor. Depending on the cell line used, additional growth factor inhibitors may be required to promote neural differentiation. Long-term culture and addition of the Notch inhibitor DAPT can promote terminal neuronal differentiation. Extent of differentiation is monitored using immunocytochemistry for cell type-specific markers.

  18. The Hectd1 Ubiquitin Ligase is Required for Development of the Head Mesenchyme and Neural Tube Closure

    PubMed Central

    Zohn, Irene E.; Anderson, Kathryn V.; Niswander, Lee

    2009-01-01

    Closure of the cranial neural tube depends on normal development of the head mesenchyme. Homozygous-mutant embryos for the ENU-induced open mind (opm) mutation exhibit exencephaly associated with defects in head mesenchyme development and dorsal-lateral hinge point formation. The head mesenchyme in opm mutant embryos is denser than in wildtype embryos and displays an abnormal cellular organization. Since cells that originate from both the cephalic paraxial mesoderm and the neural crest populate the head mesenchyme, we explored the origin of the abnormal head mesenchyme. opm mutant embryos show apparently normal development of neural crest-derived structures. Furthermore, the abnormal head mesenchyme in opm mutant embryos is not derived from the neural crest, but instead expresses molecular markers of cephalic mesoderm. We also report the identification of the opm mutation in the ubiquitously expressed Hectd1 E3 ubiquitin ligase. Two different Hectd1 alleles cause incompletely penetrant neural tube defects in heterozygous animals, indicating that Hectd1 function is required at a critical threshold for neural tube closure. This low penetrance of neural tube defects in embryos heterozygous for Hectd1 mutations suggests that Hectd1 should be considered as candidate susceptibility gene in human neural tube defects. PMID:17442300

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

    PubMed

    Fukusumi, Hayato; Shofuda, Tomoko; Bamba, Yohei; Yamamoto, Atsuyo; Kanematsu, Daisuke; Handa, Yukako; Okita, Keisuke; Nakamura, Masaya; Yamanaka, Shinya; Okano, Hideyuki; Kanemura, Yonehiro

    2016-01-01

    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.

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

    PubMed

    Fukusumi, Hayato; Shofuda, Tomoko; Bamba, Yohei; Yamamoto, Atsuyo; Kanematsu, Daisuke; Handa, Yukako; Okita, Keisuke; Nakamura, Masaya; Yamanaka, Shinya; Okano, Hideyuki; Kanemura, Yonehiro

    2016-01-01

    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. PMID:27212953

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

    PubMed Central

    Fukusumi, Hayato; Shofuda, Tomoko; Bamba, Yohei; Yamamoto, Atsuyo; Kanematsu, Daisuke; Handa, Yukako; Okita, Keisuke; Nakamura, Masaya; Yamanaka, Shinya; Okano, Hideyuki; Kanemura, Yonehiro

    2016-01-01

    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. PMID:27212953

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

    PubMed

    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.

  3. Human Identification with Electrocardiogram Signals: a Neural Network Approach

    NASA Astrophysics Data System (ADS)

    Wan, Yongbo; Yao, Jianchu

    2009-05-01

    This paper presents a neural network developed to identify human subjects using electrocardiogram (ECG) signals collected from an "in-house" wearable electrocardiogram (ECG) sensor. In this project, noises were first removed from the raw signals with wavelet filters. ECG cycles were then extracted from the filtered signals and decomposed into wavelet coefficient structures. These coefficient structures were used as input vectors to a 3-layer feedforward neural network that generates the identification results. In the current study, 61 datasets collected from 23 subjects were utilized to train the neural network, which thereafter was tested with 15 new datasets from 15 different subjects. All the 15 subjects in the experiment were successfully identified. The testing results demonstrate that the neural network is effective.

  4. Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain

    PubMed Central

    Ryu, Sun; Lee, Seung-Hoon; Kim, Seung U.; Yoon, Byung-Woo

    2016-01-01

    Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2′-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen NeuN, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2′-deoxyuridine-positive ⁄ anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke. PMID:27073384

  5. Induction of nerve growth factor receptors on cultured human melanocytes

    SciTech Connect

    Peacocke, M.; Yaar, M.; Mansur, C.P.; Chao, M.V.; Gilchrest, B.A. )

    1988-07-01

    Normal differentiation and malignant transformation of human melanocytes involve a complex series of interactions during which both genetic and environmental factors play roles. At present, the regulation of these processes is poorly understood. The authors have induced the expression of nerve growth factor (NGF) receptors on cultured human melanocytes with phorbol 12-tetradecanoate 13-acetate and have correlated this event with the appearance of a more differentiated, dendritic morphology. Criteria for NGF receptor expression included protein accumulation and cell-surface immunofluorescent staining with a monoclonal antibody directed against the human receptor and induction of the messenger RNA species as determined by blot-hybridization studies. The presence of the receptor could also be induced by UV irradiation or growth factor deprivation. The NGF receptor is inducible in cultured human melanocytes, and they suggest that NGF may modulate the behavior of this neural crest-derived cell in the skin.

  6. A neural circuit encoding sexual preference in humans.

    PubMed

    Poeppl, Timm B; Langguth, Berthold; Rupprecht, Rainer; Laird, Angela R; Eickhoff, Simon B

    2016-09-01

    Sexual preference determines mate choice for reproduction and hence guarantees conservation of species in mammals. Despite this fundamental role in human behavior, current knowledge on its target-specific neurofunctional substrate is based on lesion studies and therefore limited. We used meta-analytic remodeling of neuroimaging data from 364 human subjects with diverse sexual interests during sexual stimulation to quantify neural regions associated with sexual preference manipulations. We found that sexual preference is encoded by four phylogenetically old, subcortical brain structures. More specifically, sexual preference is controlled by the anterior and preoptic area of the hypothalamus, the anterior and mediodorsal thalamus, the septal area, and the perirhinal parahippocampus including the dentate gyrus. In contrast, sexual non-preference is regulated by the substantia innominata. We anticipate the identification of a core neural circuit for sexual preferences to be a starting point for further sophisticated investigations into the neural principles of sexual behavior and particularly of its aberrations.

  7. Human Immunodeficiency Virus Type 1 Infection of Neural Xenografts

    NASA Astrophysics Data System (ADS)

    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.

  8. Human immunodeficiency virus type 1 infection of neural xenografts.

    PubMed Central

    Cvetkovich, T A; Lazar, E; Blumberg, B M; Saito, Y; Eskin, T A; Reichman, R; Baram, D A; del Cerro, C; Gendelman, H E; del Cerro, M

    1992-01-01

    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. Images PMID:1594627

  9. Direct reprogramming of human neural stem cells by OCT4.

    PubMed

    Kim, Jeong Beom; Greber, Boris; Araúzo-Bravo, Marcos J; Meyer, Johann; Park, Kook In; Zaehres, Holm; Schöler, Hans R

    2009-10-01

    Induced pluripotent stem (iPS) cells have been generated from mouse and human somatic cells by ectopic expression of four transcription factors (OCT4 (also called POU5F1), SOX2, c-Myc and KLF4). We previously reported that Oct4 alone is sufficient to reprogram directly adult mouse neural stem cells to iPS cells. Here we report the generation of one-factor human iPS cells from human fetal neural stem cells (one-factor (1F) human NiPS cells) by ectopic expression of OCT4 alone. One-factor human NiPS cells resemble human embryonic stem cells in global gene expression profiles, epigenetic status, as well as pluripotency in vitro and in vivo. These findings demonstrate that the transcription factor OCT4 is sufficient to reprogram human neural stem cells to pluripotency. One-factor iPS cell generation will advance the field further towards understanding reprogramming and generating patient-specific pluripotent stem cells. PMID:19718018

  10. A signature of neural coding at human perceptual limits

    PubMed Central

    Bays, Paul M.

    2016-01-01

    Simple visual features, such as orientation, are thought to be represented in the spiking of visual neurons using population codes. I show that optimal decoding of such activity predicts characteristic deviations from the normal distribution of errors at low gains. Examining human perception of orientation stimuli, I show that these predicted deviations are present at near-threshold levels of contrast. The findings may provide a neural-level explanation for the appearance of a threshold in perceptual awareness whereby stimuli are categorized as seen or unseen. As well as varying in error magnitude, perceptual judgments differ in certainty about what was observed. I demonstrate that variations in the total spiking activity of a neural population can account for the empirical relationship between subjective confidence and precision. These results establish population coding and decoding as the neural basis of perception and perceptual confidence. PMID:27604067

  11. A signature of neural coding at human perceptual limits.

    PubMed

    Bays, Paul M

    2016-09-01

    Simple visual features, such as orientation, are thought to be represented in the spiking of visual neurons using population codes. I show that optimal decoding of such activity predicts characteristic deviations from the normal distribution of errors at low gains. Examining human perception of orientation stimuli, I show that these predicted deviations are present at near-threshold levels of contrast. The findings may provide a neural-level explanation for the appearance of a threshold in perceptual awareness whereby stimuli are categorized as seen or unseen. As well as varying in error magnitude, perceptual judgments differ in certainty about what was observed. I demonstrate that variations in the total spiking activity of a neural population can account for the empirical relationship between subjective confidence and precision. These results establish population coding and decoding as the neural basis of perception and perceptual confidence. PMID:27604067

  12. Repairing neural injuries using human umbilical cord blood.

    PubMed

    Sun, Tao; Ma, Quan-Hong

    2013-06-01

    Stem cells are promising sources for repairing damaged neurons and glial cells in neural injuries and for replacing dead cells in neurodegenerative diseases. An essential step for stem cell-based therapy is to generate large quantities of stem cells and develop reliable culture conditions to direct efficient differentiation of specific neuronal and glial subtypes. The human umbilical cord and umbilical cord blood (UCB) are rich sources of multiple stem cells, including hematopoietic stem cells, mesenchymal stem cells, unrestricted somatic stem cells, and embryonic-like stem cells. Human UC/UCB-derived cells are able to give rise to multiple cell types of neural lineages. Studies have shown that UCB and UCB-derived cells can survive in injured sites in animal models of ischemic brain damage and spinal cord injuries, and promote survival and prevent cell death of local neurons and glia. Human UCB is easy to harvest and purify. Moreover, unlike embryonic stem cells, the use of human UCB is not limited by ethical quandaries. Therefore, human UCB is an attractive source of stem cells for repairing neural injuries.

  13. Generating trunk neural crest from human pluripotent stem cells

    PubMed Central

    Huang, Miller; Miller, Matthew L.; McHenry, Lauren K.; Zheng, Tina; Zhen, Qiqi; Ilkhanizadeh, Shirin; Conklin, Bruce R.; Bronner, Marianne E.; Weiss, William A.

    2016-01-01

    Neural crest cells (NCC) are stem cells that generate different lineages, including neuroendocrine, melanocytic, cartilage, and bone. The differentiation potential of NCC varies according to the level from which cells emerge along the neural tube. For example, only anterior “cranial” NCC form craniofacial bone, whereas solely posterior “trunk” NCC contribute to sympathoadrenal cells. Importantly, the isolation of human fetal NCC carries ethical and scientific challenges, as NCC induction typically occur before pregnancy is detectable. As a result, current knowledge of NCC biology derives primarily from non-human organisms. Important differences between human and non-human NCC, such as expression of HNK1 in human but not mouse NCC, suggest a need to study human NCC directly. Here, we demonstrate that current protocols to differentiate human pluripotent stem cells (PSC) to NCC are biased toward cranial NCC. Addition of retinoic acid drove trunk-related markers and HOX genes characteristic of a posterior identity. Subsequent treatment with bone morphogenetic proteins (BMPs) enhanced differentiation to sympathoadrenal cells. Our approach provides methodology for detailed studies of human NCC, and clarifies roles for retinoids and BMPs in the differentiation of human PSC to trunk NCC and to sympathoadrenal lineages. PMID:26812940

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

    PubMed Central

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

    2015-01-01

    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. PMID:26392547

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

    PubMed

    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

    2015-10-01

    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.

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

    PubMed

    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

    2015-10-01

    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. PMID:26392547

  17. The Neural Basis of Vocal Pitch Imitation in Humans.

    PubMed

    Belyk, Michel; Pfordresher, Peter Q; Liotti, Mario; Brown, Steven

    2016-04-01

    Vocal imitation is a phenotype that is unique to humans among all primate species, and so an understanding of its neural basis is critical in explaining the emergence of both speech and song in human evolution. Two principal neural models of vocal imitation have emerged from a consideration of nonhuman animals. One hypothesis suggests that putative mirror neurons in the inferior frontal gyrus pars opercularis of Broca's area may be important for imitation. An alternative hypothesis derived from the study of songbirds suggests that the corticostriate motor pathway performs sensorimotor processes that are specific to vocal imitation. Using fMRI with a sparse event-related sampling design, we investigated the neural basis of vocal imitation in humans by comparing imitative vocal production of pitch sequences with both nonimitative vocal production and pitch discrimination. The strongest difference between these tasks was found in the putamen bilaterally, providing a striking parallel to the role of the analogous region in songbirds. Other areas preferentially activated during imitation included the orofacial motor cortex, Rolandic operculum, and SMA, which together outline the corticostriate motor loop. No differences were seen in the inferior frontal gyrus. The corticostriate system thus appears to be the central pathway for vocal imitation in humans, as predicted from an analogy with songbirds. PMID:26696298

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

    PubMed

    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.

  19. Neural correlate of human reciprocity in social interactions.

    PubMed

    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.

  20. Neural correlate of human reciprocity in social interactions

    PubMed Central

    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

  1. Effects of hypoxia on sympathetic neural control in humans

    NASA Technical Reports Server (NTRS)

    Smith, M. L.; Muenter, N. K.

    2000-01-01

    This special issue is principally focused on the time domain of the adaptive mechanisms of ventilatory responses to short-term, long-term and intermittent hypoxia. The purpose of this review is to summarize the limited literature on the sympathetic neural responses to sustained or intermittent hypoxia in humans and attempt to discern the time domain of these responses and potential adaptive processes that are evoked during short and long-term exposures to hypoxia.

  2. [Human pluripotent stem cell and neural differentiation].

    PubMed

    Wataya, Takafumi; Muguruma, Keiko; Sasai, Yoshiki

    2008-10-01

    Recovery of lost brain function is an important issue in medical studies because neurons of the central nervous system (CNS) have poor potential for regeneration. Since few CNS diseases can be treated completely by medicines, regenerative therapy by using stem cells should be studied as a new type of therapeutic intervention. The efficacy of cell replacement therapy in Parkinson's disease has been well investigated. Several studies on fetal tissue transplantation have revealed that quantity and purity of transplanted cells are necessary for recovery of symptoms. SFEB (Serum-free floating culture of embryoid body-like aggregates) method is capable of inducing multi-potential CNS progenitors that can be steered to differentiate into region-specific tissues. On the basis of the existing knowledge of embryology, we have succeeded in the generating of various types of neurons such as telencephalic, cerebeller (Purkinje and granule cells), retinal (photoreceptor cells) and hypothalamic neurons. Application of this culture method to human ES (hES) cells is necessary for clinical purpose: however, poor survival of hES cells in SFEB culture might limit the possibility of using these cells for future medical applications. We found that a selective Rho-associated kinase (ROCK) inhibitor, Y-27632, markedly diminished the dissociation-induced apoptosis of hES cells and enabled the cells to form aggregates in SFEB culture. For both mouse and human ES cells, SFEB culture is a favorable method that can generate large amounts of region-specific neurons. However, stem cell-based therapy continues to face several obstacles. It is important that researchers in the basic sciences and clinical medicine should discuss these problems together to overcome both scientific and ethical issues related to stem cells.

  3. Generation and Applications of Human Pluripotent Stem Cells Induced into Neural Lineages and Neural Tissues

    PubMed Central

    Martinez, Y.; Dubois-Dauphin, M.; Krause, K.-H.

    2012-01-01

    Human pluripotent stem cells (hPSCs) represent a new and exciting field in modern medicine, now the focus of many researchers and media outlets. The hype is well-earned because of the potential of stem cells to contribute to disease modeling, drug screening, and even therapeutic approaches. In this review, we focus first on neural differentiation of these cells. In a second part we compare the various cell types available and their advantages for in vitro modeling. Then we provide a “state-of-the-art” report about two major biomedical applications: (1) the drug and toxicity screening and (2) the neural tissue replacement. Finally, we made an overview about current biomedical research using differentiated hPSCs. PMID:22457650

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

    PubMed Central

    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

    Abstract. 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 (n=7) 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 1.23  J/cm2. 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 1.09  J/cm2 and a 2∶1 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. PMID:26157986

  5. Neural stem cells in the adult human brain

    PubMed Central

    Gonzalez-Perez, Oscar

    2012-01-01

    For decades, it was believed that the adult brain was a quiescent organ unable to produce new neurons. At the beginning of the1960's, this dogma was challenged by a small group of neuroscientists. To date, it is well-known that new neurons are generated in the adult brain throughout life. Adult neurogenesis is primary confined to the subventricular zone (SVZ) of the forebrain and the subgranular zone of the dentate gyrus within the hippocampus. In both the human and the rodent brain, the primary progenitor of adult SVZ is a subpopulation of astrocytes that have stem-cell-like features. The human SVZ possesses a peculiar cell composition and displays important organizational differences when compared to the SVZ of other mammals. Some evidence suggests that the human SVZ may be not only an endogenous source of neural precursor cells for brain repair, but also a source of brain tumors. In this review, we described the cytoarchitecture and cellular composition of the SVZ in the adult human brain. We also discussed some clinical implications of SVZ, such as: stem-cell-based therapies against neurodegenerative diseases and its potential as a source of malignant cells. Understanding the biology of human SVZ and its neural progenitors is one of the crucial steps to develop novel therapies against neurological diseases in humans. PMID:23181200

  6. The neural basis of human dance.

    PubMed

    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.

  7. Isolation of Human Neural Stem Cells from the Amniotic Fluid with Diagnosed Neural Tube Defects.

    PubMed

    Chang, Yu-Jen; Su, Hong-Lin; Hsu, Lee-Feng; Huang, Po-Jui; Wang, Tzu-Hao; Cheng, Fu-Chou; Hsu, Li-Wen; Tsai, Ming-Song; Chen, Chih-Ping; Chang, Yao-Lung; Chao, An-Shine; Hwang, Shiaw-Min

    2015-08-01

    Human neural stem cells (NSCs) are particularly valuable for the study of neurogenesis process and have a therapeutic potential in treating neurodegenerative disorders. However, current progress in the use of human NSCs is limited due to the available NSC sources and the complicated isolation and culture techniques. In this study, we describe an efficient method to isolate and propagate human NSCs from the amniotic fluid with diagnosed neural tube defects (NTDs), specifically, anencephaly. These amniotic fluid-derived NSCs (AF-NSCs) formed neurospheres and underwent long-term expansion in vitro. In addition, these cells showed normal karyotypes and telomerase activity and expressed NSC-specific markers, including Nestin, Sox2, Musashi-1, and the ATP-binding cassette G2 (ABCG2). AF-NSCs displayed typical morphological patterns and expressed specific markers that were consistent with neurons, astrocytes, oligodendrocytes, and dopaminergic neurons after proper induction conditions. Furthermore, grafted AF-NSCs improved the physiological functions in a rat stroke model. The ability to isolate and bank human NSCs from this novel source provides a unique opportunity for translational studies of neurological disorders. PMID:25923707

  8. Substrate-mediated reprogramming of human fibroblasts into neural crest stem-like cells and their applications in neural repair.

    PubMed

    Tseng, Ting-Chen; Hsieh, Fu-Yu; Dai, Niann-Tzyy; Hsu, Shan-Hui

    2016-09-01

    Cell- and gene-based therapies have emerged as promising strategies for treating neurological diseases. The sources of neural stem cells are limited while the induced pluripotent stem (iPS) cells have risk of tumor formation. Here, we proposed the generation of self-renewable, multipotent, and neural lineage-related neural crest stem-like cells by chitosan substrate-mediated gene transfer of a single factor forkhead box D3 (FOXD3) for the use in neural repair. A simple, non-toxic, substrate-mediated method was applied to deliver the naked FOXD3 plasmid into human fibroblasts. The transfection of FOXD3 increased cell proliferation and up-regulated the neural crest marker genes (FOXD3, SOX2, and CD271), stemness marker genes (OCT4, NANOG, and SOX2), and neural lineage-related genes (Nestin, β-tubulin and GFAP). The expression levels of stemness marker genes and neural crest maker genes in the FOXD3-transfected fibroblasts were maintained until the fifth passage. The FOXD3 reprogrammed fibroblasts based on the new method significantly rescued the neural function of the impaired zebrafish. The chitosan substrate-mediated delivery of naked plasmid showed feasibility in reprogramming somatic cells. Particularly, the FOXD3 reprogrammed fibroblasts hold promise as an easily accessible cellular source with neural crest stem-like behavior for treating neural diseases in the future. PMID:27341268

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

    PubMed Central

    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. PMID:24293267

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

    PubMed

    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.

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

    PubMed Central

    Ouchi, Takehito; Shibata, Shinsuke; Fujimura, Takumi; Kawana, Hiromasa; Okano, Hideyuki; Nakagawa, Taneaki

    2016-01-01

    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. PMID:27006661

  12. WNT/β-catenin signaling mediates human neural crest induction via a pre-neural border intermediate.

    PubMed

    Leung, Alan W; Murdoch, Barbara; Salem, Ahmed F; Prasad, Maneeshi S; Gomez, Gustavo A; García-Castro, Martín I

    2016-02-01

    Neural crest (NC) cells arise early in vertebrate development, migrate extensively and contribute to a diverse array of ectodermal and mesenchymal derivatives. Previous models of NC formation suggested derivation from neuralized ectoderm, via meso-ectodermal, or neural-non-neural ectoderm interactions. Recent studies using bird and amphibian embryos suggest an earlier origin of NC, independent of neural and mesodermal tissues. Here, we set out to generate a model in which to decipher signaling and tissue interactions involved in human NC induction. Our novel human embryonic stem cell (ESC)-based model yields high proportions of multipotent NC cells (expressing SOX10, PAX7 and TFAP2A) in 5 days. We demonstrate a crucial role for WNT/β-catenin signaling in launching NC development, while blocking placodal and surface ectoderm fates. We provide evidence of the delicate temporal effects of BMP and FGF signaling, and find that NC development is separable from neural and/or mesodermal contributions. We further substantiate the notion of a neural-independent origin of NC through PAX6 expression and knockdown studies. Finally, we identify a novel pre-neural border state characterized by early WNT/β-catenin signaling targets that displays distinct responses to BMP and FGF signaling from the traditional neural border genes. In summary, our work provides a fast and efficient protocol for human NC differentiation under signaling constraints similar to those identified in vivo in model organisms, and strengthens a framework for neural crest ontogeny that is separable from neural and mesodermal fates. PMID:26839343

  13. Intraspinal transplantation of mouse and human neural precursor cells

    PubMed Central

    Weinger, Jason G.; Chen, Lu; Coleman, Ronald; Leang, Ronika; Plaisted, Warren C.; Loring, Jeanne F.; Lane, Thomas E.

    2013-01-01

    This unit describes the preparation and transplantation of human neural precursor cells (hNPCs) and mouse neural precursor cells (mNPCs) into the thoracic region of the mouse spinal cord. The techniques in this unit also describe how to prepare the mouse for surgery by performing a laminectomy to expose the spinal cord for transplantation. Here we show NPCs genetically labeled with eGFP transplanted into the spinal cord of a mouse following viralmediated demyelination can efficiently be detected via eGFP expression. Transplantation of these cells into the spinal cord is an efficacious way to determine their effects in neurological disorders such as multiple sclerosis, Alzheimer's disease, and spinal cord injury. PMID:24510791

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

    PubMed

    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. PMID:26685796

  15. Neural mirroring mechanisms and imitation in human infants

    PubMed Central

    Marshall, Peter J.; Meltzoff, Andrew N.

    2014-01-01

    Studying human infants will increase our understanding of the nature, origins and function of neural mirroring mechanisms. Human infants are prolific imitators. Infant imitation indicates observation–execution linkages in the brain prior to language and protracted learning. Investigations of neural aspects of these linkages in human infants have focused on the sensorimotor mu rhythm in the electroencephalogram, which occurs in the alpha frequency range over central electrode sites. Recent results show that the infant mu rhythm is desynchronized during action execution as well as action observation. Current work is elucidating properties of the infant mu rhythm and how it may relate to prelinguistic action processing and social understanding. Here, we consider this neuroscience research in relation to developmental psychological theory, particularly the ‘Like-Me’ framework, which holds that one of the chief cognitive tasks of the human infant is to map the similarity between self and other. We elucidate the value of integrating neuroscience findings with behavioural studies of infant imitation, and the reciprocal benefit of examining mirroring mechanisms from an ontogenetic perspective. PMID:24778387

  16. Neural pattern in the human pollical distal phalanx.

    PubMed

    Johnson, Richard K; Shrewsbury, Marvin M

    2005-09-01

    A morphological study of the neural pattern in the human ungual region of the pollical distal phalanx was carried out on eight male cadavers. The dissections showed a palmar neural arrangement consisting of four designated ungual nerves, two proximal and two distal, for each of the ulnar and radial palmar digital nerves at the lateral sides of the thumb. This neural configuration was associated with the compartmentalization of its ungual pulp, the difference between the type of sensory receptors within the ungual pulp, the overlapping of the tactile composition at the thumb tip, seen clinically after laceration of one of the palmar digital nerves, and the sensory supply to the nail bed in the dorsal portion of the thumb. The proximal ungual pulp compartment had a single proximal medial ungual nerve, which did not appear, as far as visually possible, to overlap at the midline of the proximal ungual pulp. In contrast, the distal ungual pulp compartment was supplied by a medial and a lateral ungual nerve, both of which did appear to overlap to their contralateral sides in the thumb tip. A single proximal dorsal sensory nerve branched dorsally from each of ulnar and radial palmar digital nerves at the level of the proximal ungual pulp to supply the nail bed on the dorsum of the thumb.

  17. Human capacity for explosive force production: neural and contractile determinants.

    PubMed

    Folland, J P; Buckthorpe, M W; Hannah, R

    2014-12-01

    This study assessed the integrative neural and contractile determinants of human knee extension explosive force production. Forty untrained participants performed voluntary and involuntary (supramaximally evoked twitches and octets - eight pulses at 300 Hz that elicit the maximum possible rate of force development) explosive isometric contractions of the knee extensors. Explosive force (F0-150 ms) and sequential rate of force development (RFD, 50-ms epochs) were measured. Surface electromyography (EMG) amplitude was recorded (superficial quadriceps and hamstrings, 50-ms epochs) and normalized (quadriceps to Mmax, hamstrings to EMGmax). Maximum voluntary force (MVF) was also assessed. Multiple linear regressions assessed the significant neural and contractile determinants of absolute and relative (%MVF) explosive force and sequential RFD. Explosive force production exhibited substantial interindividual variability, particularly during the early phase of contraction [F50, 13-fold (absolute); 7.5-fold (relative)]. Multiple regression explained 59-93% (absolute) and 35-60% (relative) of the variance in explosive force production. The primary determinants of explosive force changed during the contraction (F0-50, quadriceps EMG and Twitch F; RFD50-100, Octet RFD0-50; F100-150, MVF). In conclusion, explosive force production was largely explained by predictor neural and contractile variables, but the specific determinants changed during the phase of contraction.

  18. Neural Correlates of the Cortisol Awakening Response in Humans.

    PubMed

    Boehringer, Andreas; Tost, Heike; Haddad, Leila; Lederbogen, Florian; Wüst, Stefan; Schwarz, Emanuel; Meyer-Lindenberg, Andreas

    2015-08-01

    The cortisol rise after awakening (cortisol awakening response, CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation related to psychosocial stress and stress-related psychiatric disorders. However, the neural regulation of the CAR has not been examined in humans. Here, we studied neural regulation related to the CAR in a sample of 25 healthy human participants using an established psychosocial stress paradigm together with multimodal functional and structural (voxel-based morphometry) magnetic resonance imaging. Across subjects, a smaller CAR was associated with reduced grey matter volume and increased stress-related brain activity in the perigenual ACC, a region which inhibits HPA axis activity during stress that is implicated in risk mechanisms and pathophysiology of stress-related mental diseases. Moreover, functional connectivity between the perigenual ACC and the hypothalamus, the primary controller of HPA axis activity, was associated with the CAR. Our findings provide support for a role of the perigenual ACC in regulating the CAR in humans and may aid future research on the pathophysiology of stress-related illnesses, such as depression, and environmental risk for illnesses such as schizophrenia. PMID:25781268

  19. Attention selects informative neural populations in human V1.

    PubMed

    Verghese, Preeti; Kim, Yee-Joon; Wade, Alex R

    2012-11-14

    In a neural population driven by a simple grating stimulus, different subpopulations are maximally informative about changes to the grating's orientation and contrast. In theory, observers should attend to the optimal subpopulation when switching between orientation and contrast discrimination tasks. Here we used source-imaged, steady-state visual evoked potentials and visual psychophysics to determine whether this is the case. Observers fixated centrally while static targets were presented bilaterally along with a cue indicating task type (contrast or orientation modulation detection) and task location (left or right). Changes in neuronal activity were measured by quantifying frequency-tagged responses from flickering "reporter" gratings surrounding the targets. To determine the orientation tuning of attentionally modulated neurons, we measured responses for three different probe-reporter angles: 0, 20, and 45°. We estimated frequency-tagged cortical activity using a minimum norm inverse procedure combined with realistic MR-derived head models and retinotopically mapped visual areas. Estimates of neural activity from regions of interest centered on V1 showed that attention to a spatial location clearly increased the amplitude of the neural response in that location. More importantly, the pattern of modulation depended on the task. For orientation discrimination, attentional modulation showed a sharp peak in the population tuned 20° from the target orientation, whereas for contrast discrimination the enhancement was more broadly tuned. Similar tuning functions for orientation and contrast discrimination were obtained from psychophysical adaptation studies. These findings indicate that humans attend selectively to the most informative neural population and that these populations change depending on the nature of the task. PMID:23152620

  20. Selective Expression of Galanin in Neuronal-Like Cells of the Human Carotid Body.

    PubMed

    Di Giulio, Camillo; Marconi, Guya Diletta; Zara, Susi; Di Tano, Andrea; Porzionato, Andrea; Pokorski, Mieczyslaw; Cataldi, Amelia; Mazzatenta, Andrea

    2015-01-01

    The carotid body is a neural-crest-derived organ devoted to respiratory homeostasis through sensing changes in blood oxygen levels. The sensory units are the glomeruli composed of clusters of neuronal-like (type I) cells surrounded by glial-like (type II) cells. During chronic hypoxia, the carotid body shows growth, with increasing neuronal-like cell numbers. We are interested in the signals involved in the mechanisms that underlie such response, because they are not well understood and described. Considering that, in literature, galanin is involved in neurotrophic or neuroprotective role in cell proliferation and is expressed in animal carotid body, we investigated its expression in human. Here, we have shown the expression and localisation of galanin in the human carotid body.

  1. Autonomic neural control of dynamic cerebral autoregulation in humans

    NASA Technical Reports Server (NTRS)

    Zhang, Rong; Zuckerman, Julie H.; Iwasaki, Kenichi; Wilson, Thad E.; Crandall, Craig G.; Levine, Benjamin D.

    2002-01-01

    BACKGROUND: The purpose of the present study was to determine the role of autonomic neural control of dynamic cerebral autoregulation in humans. METHODS AND RESULTS: We measured arterial pressure and cerebral blood flow (CBF) velocity in 12 healthy subjects (aged 29+/-6 years) before and after ganglion blockade with trimethaphan. CBF velocity was measured in the middle cerebral artery using transcranial Doppler. The magnitude of spontaneous changes in mean blood pressure and CBF velocity were quantified by spectral analysis. The transfer function gain, phase, and coherence between these variables were estimated to quantify dynamic cerebral autoregulation. After ganglion blockade, systolic and pulse pressure decreased significantly by 13% and 26%, respectively. CBF velocity decreased by 6% (P<0.05). In the very low frequency range (0.02 to 0.07 Hz), mean blood pressure variability decreased significantly (by 82%), while CBF velocity variability persisted. Thus, transfer function gain increased by 81%. In addition, the phase lead of CBF velocity to arterial pressure diminished. These changes in transfer function gain and phase persisted despite restoration of arterial pressure by infusion of phenylephrine and normalization of mean blood pressure variability by oscillatory lower body negative pressure. CONCLUSIONS: These data suggest that dynamic cerebral autoregulation is altered by ganglion blockade. We speculate that autonomic neural control of the cerebral circulation is tonically active and likely plays a significant role in the regulation of beat-to-beat CBF in humans.

  2. Neural systems for landmark-based wayfinding in humans

    PubMed Central

    Epstein, Russell A.; Vass, Lindsay K.

    2014-01-01

    Humans and animals use landmarks during wayfinding to determine where they are in the world and to guide their way to their destination. To implement this strategy, known as landmark-based piloting, a navigator must be able to: (i) identify individual landmarks, (ii) use these landmarks to determine their current position and heading, (iii) access long-term knowledge about the spatial relationships between locations and (iv) use this knowledge to plan a route to their navigational goal. Here, we review neuroimaging, neuropsychological and neurophysiological data that link the first three of these abilities to specific neural systems in the human brain. This evidence suggests that the parahippocampal place area is critical for landmark recognition, the retrosplenial/medial parietal region is centrally involved in localization and orientation, and both medial temporal lobe and retrosplenial/medial parietal lobe regions support long-term spatial knowledge. PMID:24366141

  3. Neural crest contributions to the lamprey head

    NASA Technical Reports Server (NTRS)

    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. Neural basis of rhythmic timing networks in the human brain.

    PubMed

    Thaut, Michael H

    2003-11-01

    The study of rhythmicity provides insights into the understanding of temporal coding of music and temporal information processing in the human brain. Auditory rhythms rapidly entrain motor responses into stable steady synchronization states below and above conscious perception thresholds. Studying the neural dynamics of entrainment by measuring brain wave responses (MEG) we found nonlinear scaling of M100 amplitudes generated in primary auditory cortex relative to changes in the period of the rhythmic interval during subliminal and supraliminal tempo modulations. In recent brain imaging studies we have described the neural networks involved in motor synchronization to auditory rhythm. Activated regions include primary sensorimotor and cingulate areas, bilateral opercular premotor areas, bilateral SII, ventral prefrontal cortex, and, subcortically, anterior insula, putamen, and thalamus. Within the cerebellum, vermal regions and anterior hemispheres ipsilateral to the movement became significantly activated. Tracking temporal modulations additionally activated predominantly right prefrontal, anterior cingulate, and intraparietal regions as well as posterior cerebellar hemispheres. Furthermore, strong evidence exists for the substantial benefits of rhythmic stimuli in rehabilitation training with motor disorders. PMID:14681157

  5. Human neural tube defects: genetic causes and prevention.

    PubMed

    De Marco, Patrizia; Merello, Elisa; Cama, Armando; Kibar, Zoha; Capra, Valeria

    2011-01-01

    Neural tube defects (NTDs) are severe congenital malformations affecting 1-2 in 1,000 live births, whose etiology is multifactorial, involving environmental and genetic factors. NTDs arise as consequence of the failure of fusion of the neural tube early during embryogenesis. NTDs' pathogenesis has been linked to genes involved in folate metabolism, consistent with an epidemiologic evidence that 70% of NTDs can be prevented by maternal periconceptional supplementation. However, polymorphisms in such genes are not linked in all populations, suggesting that other genetic factors and environmental factors could be involved. Animal models have provided crucial mechanistic information and possible candidate genes to explain susceptibility to NTDs. A crucial role has been assigned to the planar cell polarity (PCP) pathway, a highly conserved, non-canonical Wnt-frizzled-dishevelled signaling cascade that plays a key role in establishing and maintaining polarity in the plane of the epithelium and in the process of convergent extension during gastrulation and neurulation in vertebrates. The Loop-tail (Lp) mouse that develops craniorachischisis carry missense mutations in the PCP core gene Vangl2, that is the mammalian homolog of the Drosophila Strabismus/Van gogh (Stbm/Vang). The presence of mutations in human VANGL1 and VANGL2 genes encourages us to extend the investigation to other PCP genes that, with VANGL, play an essential role in neurulation during development.

  6. Applications of neural networks in human shape visual perception.

    PubMed

    Wu, Bo-Wen; Fang, Yi-Chin; Lin, David Pei-Cheng

    2015-12-01

    Advances in optical and electronic technology can immensely reduce noise in images and greatly enhance human visual recognition. However, it is still difficult for human eyes to identify low-resolution thermal images, due to the limits imposed by psychological and physiological factors. In addition, changes in monitor brightness and lens resolution may also interfere with visual recognition abilities. To overcome these limitations, we devised a suitable and effective recognition method which may help the military in revising the shape parameters of long-range targets. The modulation transfer function was used as a basis to extend the visual characteristics of the human visual model and a new model was produced through the incorporation of new shape parameters. The new human visual model was next used in combination with a backpropagation neural network for better recognition of low-resolution thermal images. The new model was then tested in experiments and the results showed that the accuracy rate of recognition steadily rose by over 95%.

  7. Minimal humanity cues induce neural empathic reactions towards non-human entities.

    PubMed

    Vaes, Jeroen; Meconi, Federica; Sessa, Paola; Olechowski, Mateusz

    2016-08-01

    The present study tested whether the attribution of humanness by means of a minimal humanity cue is sufficient for the occurrence of empathic neural reactions towards non-human entities that are painfully stimulated. Vegetables have been used as a control condition to explore empathy towards humans' pain before. In the context of the present study, they were given a minimal humanity cue (i.e., a human name) or not (i.e., an adjective). Human associations with these different types of vegetables were measured and where either represented: pricked by a needle (painful condition) or touched by a Q-tip (touch condition) while recording electroencephalographic activity from a sample of 18 healthy students. Event-related potentials (ERP) indicated that those participants classified as high humanizers, showed an increased neural reaction when vegetables with a name were painfully rather than neutrally stimulated compared to vegetables without a name. These reactions occurred both in an early (P2: 130-180 ms) and a later (P3: 360-540 ms) ERP time-window. Moreover, this differential reaction on the P3 significantly correlated with participants' explicit empathic tendencies. Overall, these findings suggest that empathy can be triggered for non-human entities as long as they are seen as minimally human. PMID:27288560

  8. Neural mechanisms underlying human consensus decision-making

    PubMed Central

    Suzuki, Shinsuke; Adachi, Ryo; Dunne, Simon; Bossaerts, Peter; O'Doherty, John P.

    2015-01-01

    SUMMARY Consensus building in a group is a hallmark of animal societies, yet little is known about its underlying computational and neural mechanisms. Here, we applied a novel computational framework to behavioral and fMRI data from human participants performing a consensus decision-making task with up to five other participants. We found that participants reached consensus decisions through integrating their own preferences with information about the majority of group-members’ prior choices, as well as inferences about how much each option was stuck to by the other people. These distinct decision variables were separately encoded in distinct brain areas: the ventromedial prefrontal cortex, posterior superior temporal sulcus/temporoparietal junction and intraparietal sulcus, and were integrated in the dorsal anterior cingulate cortex. Our findings provide support for a theoretical account in which collective decisions are made through integrating multiple types of inference about oneself, others and environments, processed in distinct brain modules. PMID:25864634

  9. Hypothetical neural control of human bipedal walking with voluntary modulation.

    PubMed

    Jo, Sungho

    2008-02-01

    A hypothetical neuromusculoskeletal model is developed to simulate human normal walking and its modulated behaviors. A small set of neural periodic patterns drive spinal muscle synergies which in turn lead to specific pattern of muscle activation and supraspinal feedback systems maintain postural balance during walking. Then, the model demonstrates modulated behaviors by superimposing voluntary perturbations on the underlying walking pattern. Motions of kicking a ball and obstacle avoidance during walking are simulated as examples. The superposition of the new pulse command to a set of invariant pulses representing spino-locomotor is sufficient to achieve the coordinated behaviors. Also, forward bent walking motion is demonstrated by applying similar superposition. The composition of activations avoids a complicated computation of motor program for a specific task and presents a simple control scheme for different walking patterns.

  10. Finding the beat: a neural perspective across humans and non-human primates.

    PubMed

    Merchant, Hugo; Grahn, Jessica; Trainor, Laurel; Rohrmeier, Martin; Fitch, W Tecumseh

    2015-03-19

    Humans possess an ability to perceive and synchronize movements to the beat in music ('beat perception and synchronization'), and recent neuroscientific data have offered new insights into this beat-finding capacity at multiple neural levels. Here, we review and compare behavioural and neural data on temporal and sequential processing during beat perception and entrainment tasks in macaques (including direct neural recording and local field potential (LFP)) and humans (including fMRI, EEG and MEG). These abilities rest upon a distributed set of circuits that include the motor cortico-basal-ganglia-thalamo-cortical (mCBGT) circuit, where the supplementary motor cortex (SMA) and the putamen are critical cortical and subcortical nodes, respectively. In addition, a cortical loop between motor and auditory areas, connected through delta and beta oscillatory activity, is deeply involved in these behaviours, with motor regions providing the predictive timing needed for the perception of, and entrainment to, musical rhythms. The neural discharge rate and the LFP oscillatory activity in the gamma- and beta-bands in the putamen and SMA of monkeys are tuned to the duration of intervals produced during a beat synchronization-continuation task (SCT). Hence, the tempo during beat synchronization is represented by different interval-tuned cells that are activated depending on the produced interval. In addition, cells in these areas are tuned to the serial-order elements of the SCT. Thus, the underpinnings of beat synchronization are intrinsically linked to the dynamics of cell populations tuned for duration and serial order throughout the mCBGT. We suggest that a cross-species comparison of behaviours and the neural circuits supporting them sets the stage for a new generation of neurally grounded computational models for beat perception and synchronization. PMID:25646516

  11. Finding the beat: a neural perspective across humans and non-human primates

    PubMed Central

    Merchant, Hugo; Grahn, Jessica; Trainor, Laurel; Rohrmeier, Martin; Fitch, W. Tecumseh

    2015-01-01

    Humans possess an ability to perceive and synchronize movements to the beat in music (‘beat perception and synchronization’), and recent neuroscientific data have offered new insights into this beat-finding capacity at multiple neural levels. Here, we review and compare behavioural and neural data on temporal and sequential processing during beat perception and entrainment tasks in macaques (including direct neural recording and local field potential (LFP)) and humans (including fMRI, EEG and MEG). These abilities rest upon a distributed set of circuits that include the motor cortico-basal-ganglia–thalamo-cortical (mCBGT) circuit, where the supplementary motor cortex (SMA) and the putamen are critical cortical and subcortical nodes, respectively. In addition, a cortical loop between motor and auditory areas, connected through delta and beta oscillatory activity, is deeply involved in these behaviours, with motor regions providing the predictive timing needed for the perception of, and entrainment to, musical rhythms. The neural discharge rate and the LFP oscillatory activity in the gamma- and beta-bands in the putamen and SMA of monkeys are tuned to the duration of intervals produced during a beat synchronization–continuation task (SCT). Hence, the tempo during beat synchronization is represented by different interval-tuned cells that are activated depending on the produced interval. In addition, cells in these areas are tuned to the serial-order elements of the SCT. Thus, the underpinnings of beat synchronization are intrinsically linked to the dynamics of cell populations tuned for duration and serial order throughout the mCBGT. We suggest that a cross-species comparison of behaviours and the neural circuits supporting them sets the stage for a new generation of neurally grounded computational models for beat perception and synchronization. PMID:25646516

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

    PubMed

    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

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

    PubMed Central

    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

  14. Functional 3D Neural Mini-Tissues from Printed Gel-Based Bioink and Human Neural Stem Cells.

    PubMed

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

    2016-06-01

    Direct-write printing of stem cells within biomaterials presents an opportunity to engineer tissue for in vitro modeling and regenerative medicine. Here, a first example of constructing neural tissue by printing human neural stem cells that are differentiated in situ to functional neurons and supporting neuroglia is reported. The supporting biomaterial incorporates a novel clinically relevant polysaccharide-based bioink comprising alginate, carboxymethyl-chitosan, and agarose. The printed bioink rapidly gels by stable cross-linking to form a porous 3D scaffold encapsulating stem cells for in situ expansion and differentiation. Differentiated neurons form synaptic contacts, establish networks, are spontaneously active, show a bicuculline-induced increased calcium response, and are predominantly gamma-aminobutyric acid expressing. The 3D tissues will facilitate investigation of human neural development, function, and disease, and may be adaptable for engineering other 3D tissues from different stem cell types. PMID:27028356

  15. Functional 3D Neural Mini-Tissues from Printed Gel-Based Bioink and Human Neural Stem Cells.

    PubMed

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

    2016-06-01

    Direct-write printing of stem cells within biomaterials presents an opportunity to engineer tissue for in vitro modeling and regenerative medicine. Here, a first example of constructing neural tissue by printing human neural stem cells that are differentiated in situ to functional neurons and supporting neuroglia is reported. The supporting biomaterial incorporates a novel clinically relevant polysaccharide-based bioink comprising alginate, carboxymethyl-chitosan, and agarose. The printed bioink rapidly gels by stable cross-linking to form a porous 3D scaffold encapsulating stem cells for in situ expansion and differentiation. Differentiated neurons form synaptic contacts, establish networks, are spontaneously active, show a bicuculline-induced increased calcium response, and are predominantly gamma-aminobutyric acid expressing. The 3D tissues will facilitate investigation of human neural development, function, and disease, and may be adaptable for engineering other 3D tissues from different stem cell types.

  16. Neural crest requires Impdh2 for development of the enteric nervous system, great vessels, and craniofacial skeleton.

    PubMed

    Lake, Jonathan I; Avetisyan, Marina; Zimmermann, Albert G; Heuckeroth, Robert O

    2016-01-01

    Mutations that impair the proliferation of enteric neural crest-derived cells (ENCDC) cause Hirschsprung disease, a potentially lethal birth defect where the enteric nervous system (ENS) is absent from distal bowel. Inosine 5' monophosphate dehydrogenase (IMPDH) activity is essential for de novo GMP synthesis, and chemical inhibition of IMPDH induces Hirschsprung disease-like pathology in mouse models by reducing ENCDC proliferation. Two IMPDH isoforms are ubiquitously expressed in the embryo, but only IMPDH2 is required for life. To further understand the role of IMPDH2 in ENS and neural crest development, we characterized a conditional Impdh2 mutant mouse. Deletion of Impdh2 in the early neural crest using the Wnt1-Cre transgene produced defects in multiple neural crest derivatives including highly penetrant intestinal aganglionosis, agenesis of the craniofacial skeleton, and cardiac outflow tract and great vessel malformations. Analysis using a Rosa26 reporter mouse suggested that some or all of the remaining ENS in Impdh2 conditional-knockout animals was derived from cells that escaped Wnt1-Cre mediated DNA recombination. These data suggest that IMPDH2 mediated guanine nucleotide synthesis is essential for normal development of the ENS and other neural crest derivatives.

  17. Neural crest development: the interplay between morphogenesis and cell differentiation.

    PubMed

    Erickson, C A; Reedy, M V

    1998-01-01

    The final pattern of tissues established during embryogenesis reflects the outcome of two developmental processes: differentiation and morphogenesis. Avian neural crest cells are an excellent system in which to study this interaction. In the first phase of neural crest cell migration, neural crest cells separate from the neural epithelium via an epithelial-mesenchymal transformation. We present three models to account for this process: (1) separation by asymmetric mitosis, (2) separation by generating tractional force in order to rupture cell adhesions and (3) loss of expression or function of cell-cell adhesion molecules that keep the presumptive neural crest cells tethered to the neural epithelium. Evidence is presented that the segregation of the neural crest lineage apart from the neural epithelium is caused by the epithelial-mesenchymal transformation. Once they have detached from the neural tube, neural crest cells take two pathways in the trunk of the chick embryo: (1) the ventral path between the neural tube and somite, where neural crest cells give rise to neurons and glial cells of the peripheral nervous systems, and (2) the dorsolateral path between the ectoderm and dermamyotome of the somite, where they differentiate into pigment cells of the skin. We present data to suggest that the migration and differentiation along the ventral path is controlled primarily by environmental cues, which we refer to as the environment-directed model of neural crest morphogenesis. Conversely, only melanoblasts can migrate into the dorsolateral space, and the ability to invade that path is dependent upon their early specification as melanoblasts. We call this the phenotype-directed model for neural crest cell migration and suggest that this latter model for the positioning of neural crest derivatives in the embryo may be more common than previously suspected. These observations invite a re-examination of patterning of other crest derivates, which previously were believed

  18. Brief Azacytidine Step Allows The Conversion of Suspension Human Fibroblasts into Neural Progenitor-Like Cells

    PubMed Central

    Mirakhori, Fahimeh; Zeynali, Bahman; Kiani, Sahar; Baharvand, Hossein

    2015-01-01

    In recent years transdifferentiation technology has enabled direct conversion of human fibroblasts to become a valuable, abundant and accessible cell source for patient-specific induced cell generation in biomedical research. The majority of transdifferentiation approaches rely upon viral gene delivery which due to random integration with the host genome can cause genome instability and tumorigenesis upon transplantation. Here, we provide a simple way to induce neural progenitor-like cells from human fibroblasts without genetic manipulation by changing physicochemical culture properties from monolayer culture into a suspension in the presence of a chemical DNA methyltransferase inhibitor agent, Azacytidine. We have demonstrated the expression of neural progenitor-like markers, morphology and the ability to spontaneously differentiate into neural-like cells. This approach is simple, inexpensive, lacks genetic manipulation and could be a foundation for future chemical neural transdifferentiation and a safe induction of neural progenitor cells from human fibroblasts for clinical applications. PMID:25870845

  19. The neural representation of postural control in humans

    PubMed Central

    Karnath, Hans-Otto; Ferber, Susanne; Dichgans, Johannes

    2000-01-01

    Lesion of the “vestibular cortex” in the human posterior insula leads to a tilted perception of visual vertical but not to tilted body posture and loss of lateral balance. However, some stroke patients show the reverse pattern. Although their processing of visual and vestibular inputs for orientation perception of the visual world is undisturbed, they push away actively from the ipsilesional side (the side of lesion location), leading to a contraversive tilt of the body (tilt toward the side opposite to the lesion) and falling to that side. Recently, the origin of contraversive pushing was identified as an altered perception of the body's orientation in relation to gravity. These patients experience their body as oriented “upright” when actually tilted enormously to the ipsilesional side (18° on average). The findings argued for a separate pathway in humans for sensing body orientation in relation to gravity apart from the one projecting to the vestibular cortex. The present study aimed at identifying this brain area. The infarcted brain regions of 23 consecutively admitted patients with severe contraversive pushing were projected onto a template MRI scan, which had been normalized to Talairach space. The overlapping area of these infarctions centered on the posterolateral thalamus. Our finding necessitates reinterpretation of this area as being only a “relay structure” of the vestibular pathway on its way from the brainstem to the vestibular cortex. The ventral posterior and lateral posterior nuclei of the posterolateral thalamus (and probably its cortical projections) rather seem to be fundamentally involved in the neural representation of a second graviceptive system in humans decisive for our control of upright body posture. PMID:11087818

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

    PubMed Central

    Prajumwongs, Piya; Weeranantanapan, Oratai; Jaroonwitchawan, Thiranut; Noisa, Parinya

    2016-01-01

    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. PMID:27239201

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

    PubMed Central

    Maucksch, C; Firmin, E; Butler-Munro, C; Montgomery, JM; Dottori, M; Connor, B

    2012-01-01

    Recent studies have reported direct reprogramming of human fibroblasts to mature neurons by the introduction of defined neural genes. This technology has potential use in the areas of neurological disease modeling and drug development. However, use of induced neurons for large-scale drug screening and cell-based replacement strategies is limited due to their inability to expand once reprogrammed. We propose it would be more desirable to induce expandable neural precursor cells directly from human fibroblasts. To date several pluripotent and neural transcription factors have been shown to be capable of converting mouse fibroblasts to neural stem/precursor-like cells when delivered by viral vectors. Here we extend these findings and demonstrate that transient ectopic insertion of the transcription factors SOX2 and PAX6 to adult human fibroblasts through use of non-viral plasmid transfection or protein transduction allows the generation of induced neural precursor (iNP) colonies expressing a range of neural stem and pro-neural genes. Upon differentiation, iNP cells give rise to neurons exhibiting typical neuronal morphologies and expressing multiple neuronal markers including tyrosine hydroxylase and GAD65/67. Importantly, iNP-derived neurons demonstrate electrophysiological properties of functionally mature neurons with the capacity to generate action potentials. In addition, iNP cells are capable of differentiating into glial fibrillary acidic protein (GFAP)-expressing astrocytes. This study represents a novel virusfree approach for direct reprogramming of human fibroblasts to a neural precursor fate. PMID:24693194

  2. Isolation and propagation of primary human and rodent embryonic neural progenitor cells and cortical neurons

    PubMed Central

    Darbinyan, Armine; Kaminski, Rafal; White, Martyn K; Darbinian, Nune; Khalili, Kamel

    2014-01-01

    Summary The research on human neural progenitor cells holds great potential for the understanding the molecular programs that control differentiation of cells of glial and neuronal lineages and pathogenetic mechanisms of neurological diseases. Stem cell technologies provide also opportunities for pharmaceutical industry to develop new approaches for regenerative medicine. Here we describe the protocol for isolation and maintenance of neural progenitor cells and cortical neurons using human fetal brain tissue. This protocol can be successfully adapted for preparation of rodent neural and oligodendrocyte progenitor cells. While several methods for isolation of neural and ologodendrocyte progenitors from rodent brain tissue have been described, including techniques which use gene transfer and magnetisc resonsnce beads, few methods are focused on derivation of human oligodendrocyte progenitor cells. Development of human culture provides the most physiologically relevent system for investigation of mechanisms which regulate function of oligodendrocyte, specifically of human origin. PMID:23975820

  3. Neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands.

    PubMed

    Bozhok, G A; Sidorenko, O S; Plaksina, E M; Gurina, T M; Sukach, A N; Kholodnyy, V S; Ustichenko, V D; Bilyavskaya, S B; Bondarenko, T P; Legach, E I

    2016-10-01

    Stem/progenitor cells are thought to have the potential in the treatment of severe neurodegenerative diseases. Recently, sympathoadrenal progenitors expressing specific markers of neural crest derivatives and capable to differentiate into neurons were discovered in adult bovine and human adrenal glands, but there was no reported data on cryopreservation of sympathoadrenal progenitors. The aim of the present study was to examine the neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands. Considering impact of various initial state of frozen biomaterial on cell recovery, we carried out a comparative estimation of cryopreservation outcome both for adrenal tissue fragments and isolated primary cells. The estimation consisted of determining cell yield, viability, ability to adhere, proliferate and differentiate in vitro. Cells isolated from the fresh adrenal glands were cultured until confluence. A formation of sympathoadrenal progenitors-embedded spherical cell colonies, whose cells are differentiated then into βIII-tubulin-positive cells with neuron-like morphology, was observed on the monolayer. The colonies were well preserved after cryopreservation of cell culture with a cooling rate of 1 °C/min in the cryoprotectant media containing 5-15% of dimethylsulfoxide. Adrenal tissue fragments were cryopreserved in the presence of 10% dimethylsulfoxide at the cooling rates of 0.3; 1: 5; 40 and > 100 °C/min. Sympathoadrenal progenitors were recovered after cryopreservation with 0.3 °C/min cooling rate but not higher. PMID:27539465

  4. Neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands.

    PubMed

    Bozhok, G A; Sidorenko, O S; Plaksina, E M; Gurina, T M; Sukach, A N; Kholodnyy, V S; Ustichenko, V D; Bilyavskaya, S B; Bondarenko, T P; Legach, E I

    2016-10-01

    Stem/progenitor cells are thought to have the potential in the treatment of severe neurodegenerative diseases. Recently, sympathoadrenal progenitors expressing specific markers of neural crest derivatives and capable to differentiate into neurons were discovered in adult bovine and human adrenal glands, but there was no reported data on cryopreservation of sympathoadrenal progenitors. The aim of the present study was to examine the neural differentiation potential of sympathoadrenal progenitors derived from fresh and cryopreserved neonatal porcine adrenal glands. Considering impact of various initial state of frozen biomaterial on cell recovery, we carried out a comparative estimation of cryopreservation outcome both for adrenal tissue fragments and isolated primary cells. The estimation consisted of determining cell yield, viability, ability to adhere, proliferate and differentiate in vitro. Cells isolated from the fresh adrenal glands were cultured until confluence. A formation of sympathoadrenal progenitors-embedded spherical cell colonies, whose cells are differentiated then into βIII-tubulin-positive cells with neuron-like morphology, was observed on the monolayer. The colonies were well preserved after cryopreservation of cell culture with a cooling rate of 1 °C/min in the cryoprotectant media containing 5-15% of dimethylsulfoxide. Adrenal tissue fragments were cryopreserved in the presence of 10% dimethylsulfoxide at the cooling rates of 0.3; 1: 5; 40 and > 100 °C/min. Sympathoadrenal progenitors were recovered after cryopreservation with 0.3 °C/min cooling rate but not higher.

  5. Neural Origins of Human Sickness in Interoceptive Responses to Inflammation

    PubMed Central

    Harrison, Neil A.; Brydon, Lena; Walker, Cicely; Gray, Marcus A.; Steptoe, Andrew; Dolan, Raymond J.; Critchley, Hugo D.

    2009-01-01

    Background Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. Methods In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. Results Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. Conclusions These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states. PMID:19409533

  6. The Hippo pathway member YAP enhances human neural crest cell fate and migration

    PubMed Central

    Hindley, Christopher J.; Condurat, Alexandra Larisa; Menon, Vishal; Thomas, Ria; Azmitia, Luis M.; Davis, Jason A.; Pruszak, Jan

    2016-01-01

    The Hippo/YAP pathway serves as a major integrator of cell surface-mediated signals and regulates key processes during development and tumorigenesis. The neural crest is an embryonic tissue known to respond to multiple environmental cues in order to acquire appropriate cell fate and migration properties. Using multiple in vitro models of human neural development (pluripotent stem cell-derived neural stem cells; LUHMES, NTERA2 and SH-SY5Y cell lines), we investigated the role of Hippo/YAP signaling in neural differentiation and neural crest development. We report that the activity of YAP promotes an early neural crest phenotype and migration, and provide the first evidence for an interaction between Hippo/YAP and retinoic acid signaling in this system. PMID:26980066

  7. An Fgf8 Mouse Mutant Phenocopies Human 22q11 Deletion Syndrome

    PubMed Central

    Frank, Deborah U.; Fotheringham, Lori K.; Brewer, Judson A.; Muglia, Louis J.; Tristani-Firouzi, Martin; Capecchi, Mario R.; Moon, Anne M.

    2006-01-01

    SUMMARY Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormalities. Because ablation of neural crest in chicks produces many features of the deletion 22q11 syndrome, it has been proposed that haploinsufficiency in this region impacts neural crest function during cardiac and pharyngeal arch development. Few factors required for migration, survival, proliferation and subsequent differentiation of pharyngeal arch neural crest and mesoderm-derived mesenchyme into their respective cardiovascular, musculoskeletal, and glandular derivatives have been identified. However, the importance of epithelial-mesenchymal interactions and pharyngeal endoderm function is becoming increasingly clear. Fibroblast growth factor 8 is a signaling molecule expressed in the ectoderm and endoderm of the developing pharyngeal arches and known to play an important role in survival and patterning of first arch tissues. We demonstrate a dosage-sensitive requirement for FGF8 during development of pharyngeal arch, pharyngeal pouch and neural crest-derived tissues. We show that FGF8 deficient embryos have lethal malformations of the cardiac outflow tract, great vessels and heart due, at least in part, to failure to form the fourth pharyngeal arch arteries, altered expression of Fgf10 in the pharyngeal mesenchyme, and abnormal apoptosis in pharyngeal and cardiac neural crest. The Fgf8 mutants described herein display the complete array of cardiovascular, glandular and craniofacial phenotypes seen in human deletion 22q11 syndromes. This represents the first single gene

  8. Transcriptional profiling of adult neural stem-like cells from the human brain.

    PubMed

    Sandberg, Cecilie Jonsgar; Vik-Mo, Einar O; Behnan, Jinan; Helseth, Eirik; Langmoen, Iver A

    2014-01-01

    There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33-60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate.

  9. Transcriptional Profiling of Adult Neural Stem-Like Cells from the Human Brain

    PubMed Central

    Sandberg, Cecilie Jonsgar; Vik-Mo, Einar O.; Behnan, Jinan; Helseth, Eirik; Langmoen, Iver A.

    2014-01-01

    There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33–60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate. PMID

  10. Methods for derivation of multipotent neural crest cells derived from human pluripotent stem cells

    PubMed Central

    Avery, John; Dalton, Stephen

    2016-01-01

    Summary 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. PMID:25986498

  11. Declined Neural Efficiency in Cognitively Stable Human Immunodeficiency Virus Patients

    PubMed Central

    Ernst, Thomas; Yakupov, Renat; Nakama, Helenna; Crocket, Grace; Cole, Michael; Watters, Michael; Ricardo-Dukelow, Mary Lynn; Chang, Linda

    2009-01-01

    Objective To determine whether brain activation changes in clinically and neurocognitively normal human immunodeficiency virus (HIV)–infected and in HIV-seronegative control (SN) participants over a 1-year period. Methods Functional magnetic resonance imaging (fMRI) was performed in 32 SN and 31 HIV patients (all with stable combination antiretroviral treatment) at baseline and after 1 year. Each participant performed a set of visual attention tasks with increasing attentional load (from tracking two, three, or four balls). All HIV and SN participants had normal neuropsychological function at both examinations. Results Over 1 year, HIV patients showed no change in their neurocognitive status or in task performance during fMRI. However, HIV patients showed significant 1-year increases in fMRI signals in the prefrontal and posterior parietal cortices for the more difficult tasks, whereas SN control participants showed only decreases in brain activation in these regions. This resulted in significant interactions between HIV status and time of study in left insula, left parietal, left temporal, and several frontal regions (left and right middle frontal gyrus, and anterior cingulate). Interpretation Because fMRI task performance remained unchanged in both groups, the HIV patients appeared to maintain performance by increasing usage of the attention network, whereas the control participants reduced usage of the attention network after 1 year. These findings suggest improved efficiency or a practice effect in the SN participants but declined efficiency of the neural substrate in HIV patients, possibly because of ongoing brain injury associated with the HIV infection, despite their apparent stable clinical course. PMID:19334060

  12. The Human Factor: Behavioral and Neural Correlates of Humanized Perception in Moral Decision Making

    PubMed Central

    Majdandžić, Jasminka; Bauer, Herbert; Windischberger, Christian; Moser, Ewald; Engl, Elisabeth; Lamm, Claus

    2012-01-01

    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. PMID:23082194

  13. In our own image? Emotional and neural processing differences when observing human-human vs human-robot interactions.

    PubMed

    Wang, Yin; Quadflieg, Susanne

    2015-11-01

    Notwithstanding the significant role that human-robot interactions (HRI) will play in the near future, limited research has explored the neural correlates of feeling eerie in response to social robots. To address this empirical lacuna, the current investigation examined brain activity using functional magnetic resonance imaging while a group of participants (n = 26) viewed a series of human-human interactions (HHI) and HRI. Although brain sites constituting the mentalizing network were found to respond to both types of interactions, systematic neural variation across sites signaled diverging social-cognitive strategies during HHI and HRI processing. Specifically, HHI elicited increased activity in the left temporal-parietal junction indicative of situation-specific mental state attributions, whereas HRI recruited the precuneus and the ventromedial prefrontal cortex (VMPFC) suggestive of script-based social reasoning. Activity in the VMPFC also tracked feelings of eeriness towards HRI in a parametric manner, revealing a potential neural correlate for a phenomenon known as the uncanny valley. By demonstrating how understanding social interactions depends on the kind of agents involved, this study highlights pivotal sub-routes of impression formation and identifies prominent challenges in the use of humanoid robots.

  14. In our own image? Emotional and neural processing differences when observing human-human vs human-robot interactions.

    PubMed

    Wang, Yin; Quadflieg, Susanne

    2015-11-01

    Notwithstanding the significant role that human-robot interactions (HRI) will play in the near future, limited research has explored the neural correlates of feeling eerie in response to social robots. To address this empirical lacuna, the current investigation examined brain activity using functional magnetic resonance imaging while a group of participants (n = 26) viewed a series of human-human interactions (HHI) and HRI. Although brain sites constituting the mentalizing network were found to respond to both types of interactions, systematic neural variation across sites signaled diverging social-cognitive strategies during HHI and HRI processing. Specifically, HHI elicited increased activity in the left temporal-parietal junction indicative of situation-specific mental state attributions, whereas HRI recruited the precuneus and the ventromedial prefrontal cortex (VMPFC) suggestive of script-based social reasoning. Activity in the VMPFC also tracked feelings of eeriness towards HRI in a parametric manner, revealing a potential neural correlate for a phenomenon known as the uncanny valley. By demonstrating how understanding social interactions depends on the kind of agents involved, this study highlights pivotal sub-routes of impression formation and identifies prominent challenges in the use of humanoid robots. PMID:25911418

  15. SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects

    PubMed Central

    Deak, Kristen L.; Boyles, Abee L.; Etchevers, Heather C.; Melvin, Elizabeth C.; Siegel, Deborah G.; Graham, Felicia L.; Slifer, Susan H.; Enterline, David S.; George, Timothy M.; Vekemans, Michel; McClay, David; Bassuk, Alexander G.; Kessler, John A.; Linney, Elwood; Gilbert, John R.

    2011-01-01

    Neural tube defects (NTDs) are common birth defects, occurring in approximately 1/1,000 births; both genetic and environmental factors are implicated. To date, no major genetic risk factors have been identified. Throughout development, cell adhesion molecules are strongly implicated in cell–cell interactions, and may play a role in the formation and closure of the neural tube. To evaluate the role of neural cell adhesion molecule 1 (NCAM1) in risk of human NTDs, we screened for novel single-nucleotide polymorphisms (SNPs) within the gene. Eleven SNPs across NCAM1 were genotyped using TaqMan. We utilized a family-based approach to evaluate evidence for association and/or linkage disequilibrium. We evaluated American Caucasian simplex lumbosacral myelomeningocele families (n=132 families) using the family based association test (FBAT) and the pedigree disequilibrium test (PDT). Association analysis revealed a significant association between risk for NTDs and intronic SNP rs2298526 using both the FBAT test (P=0.0018) and the PDT (P=0.0025). Using the HBAT version of the FBAT to look for haplotype association, all pairwise comparisons with SNP rs2298526 were also significant. A replication study set, consisting of 72 additional families showed no significant association; however, the overall trend for overtransmission of the less common allele of SNP rs2298526 remained significant in the combined sample set. In addition, we analyzed the expression pattern of the NCAM1 protein in human embryos, and while NCAM1 is not expressed within the neural tube at the time of closure, it is expressed in the surrounding and later in differentiated neurons of the CNS. These results suggest variations in NCAM1 may influence risk for human NTDs. PMID:15883837

  16. Neural evidence that human emotions share core affective properties.

    PubMed

    Wilson-Mendenhall, Christine D; Barrett, Lisa Feldman; Barsalou, Lawrence W

    2013-06-01

    Research on the "emotional brain" remains centered around the idea that emotions like fear, happiness, and sadness result from specialized and distinct neural circuitry. Accumulating behavioral and physiological evidence suggests, instead, that emotions are grounded in core affect--a person's fluctuating level of pleasant or unpleasant arousal. A neuroimaging study revealed that participants' subjective ratings of valence (i.e., pleasure/displeasure) and of arousal evoked by various fear, happiness, and sadness experiences correlated with neural activity in specific brain regions (orbitofrontal cortex and amygdala, respectively). We observed these correlations across diverse instances within each emotion category, as well as across instances from all three categories. Consistent with a psychological construction approach to emotion, the results suggest that neural circuitry realizes more basic processes across discrete emotions. The implicated brain regions regulate the body to deal with the world, producing the affective changes at the core of emotions and many other psychological phenomena.

  17. Auditory training improves neural timing in the human brainstem.

    PubMed

    Russo, Nicole M; Nicol, Trent G; Zecker, Steven G; Hayes, Erin A; Kraus, Nina

    2005-01-01

    The auditory brainstem response reflects neural encoding of the acoustic characteristic of a speech syllable with remarkable precision. Some children with learning impairments demonstrate abnormalities in this preconscious measure of neural encoding especially in background noise. This study investigated whether auditory training targeted to remediate perceptually-based learning problems would alter the neural brainstem encoding of the acoustic sound structure of speech in such children. Nine subjects, clinically diagnosed with a language-based learning problem (e.g., dyslexia), worked with auditory perceptual training software. Prior to beginning and within three months after completing the training program, brainstem responses to the syllable /da/ were recorded in quiet and background noise. Subjects underwent additional auditory neurophysiological, perceptual, and cognitive testing. Ten control subjects, who did not participate in any remediation program, underwent the same battery of tests at time intervals equivalent to the trained subjects. Transient and sustained (frequency-following response) components of the brainstem response were evaluated. The primary pathway afferent volley -- neural events occurring earlier than 11 ms after stimulus onset -- did not demonstrate plasticity. However, quiet-to-noise inter-response correlations of the sustained response ( approximately 11-50 ms) increased significantly in the trained children, reflecting improved stimulus encoding precision, whereas control subjects did not exhibit this change. Thus, auditory training can alter the preconscious neural encoding of complex sounds by improving neural synchrony in the auditory brainstem. Additionally, several measures of brainstem response timing were related to changes in cortical physiology, as well as perceptual, academic, and cognitive measures from pre- to post-training.

  18. Class III β-tubulin, a novel biomarker in the human melanocyte lineage.

    PubMed

    Locher, Heiko; de Rooij, Karien E; de Groot, John C M J; van Doorn, Remco; Gruis, Nelleke A; Löwik, Clemens W G M; Chuva de Sousa Lopes, Susana M; Frijns, Johan H M; Huisman, Margriet A

    2013-01-01

    It is generally thought that class III β-tubulin expression is limited to cells of the neural lineage and is therefore often used to identify neurons amongst other cell types, both in vivo and in vitro. Melanocytes are derived from the neural crest and share both morphological features and functional characteristics with peripheral neurons. Here, we show that these similarities extend to class III β-tubulin (TUBB3) expression, and that human melanocytes express this protein both in vivo and in vitro. In addition, we studied the expression of class III β-tubulin in two murine melanogenic cell lines and show that expression of this protein starts as melanoblasts mature into melanocytes. Melanin bleaching experiments revealed close proximity between melanin and TUBB3 proteins. In vitro stimulation of primary human melanocytes by α-MSH indicated separate regulatory mechanisms for melanogenesis and to TUBB3 expression. Together, these observations imply that human melanocytes express TUBB3 and that this protein should be recognized as a wider marker for multiple neural crest-derived cells.

  19. A Neural Basis of Facial Action Recognition in Humans

    PubMed Central

    Srinivasan, Ramprakash; Golomb, Julie D.

    2016-01-01

    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. SIGNIFICANCE STATEMENT 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

  20. Wnt-YAP interactions in the neural fate of human pluripotent stem cells and the implications for neural organoid formation.

    PubMed

    Bejoy, Julie; Song, Liqing; Li, Yan

    2016-01-01

    Human pluripotent stem cells (hPSCs) have shown the ability to self-organize into different types of neural organoids (e.g., whole brain organoids, cortical spheroids, midbrain organoids etc.) recently. The extrinsic and intrinsic signaling elicited by Wnt pathway, Hippo/Yes-associated protein (YAP) pathway, and extracellular microenvironment plays a critical role in brain tissue morphogenesis. This article highlights recent advances in neural tissue patterning from hPSCs, in particular the role of Wnt pathway and YAP activity in this process. Understanding the Wnt-YAP interactions should provide us the guidance to predict and modulate brain-like tissue structure through the regulation of extracellular microenvironment of hPSCs. PMID:26901039

  1. Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment

    PubMed Central

    Kulesa, Paul M.; Kasemeier-Kulesa, Jennifer C.; Teddy, Jessica M.; Margaryan, Naira V.; Seftor, Elisabeth A.; Seftor, Richard E. B.; Hendrix, Mary J. C.

    2006-01-01

    Human metastatic melanoma cells express a dedifferentiated, plastic phenotype, which may serve as a selective advantage, because melanoma cells invade various microenvironments. Over the last three decades, there has been an increased focus on the role of the tumor microenvironment in cancer progression, with the goal of reversing the metastatic phenotype. Here, using an embryonic chick model, we explore the possibility of reverting the metastatic melanoma phenotype to its cell type of origin, the neural-crest-derived melanocyte. GFP-labeled adult human metastatic melanoma cells were transplanted in ovo adjacent to host chick premigratory neural crest cells and analyzed 48 and 96 h after egg reincubation. Interestingly, the transplanted melanoma cells do not form tumors. Instead, we find that transplanted melanoma cells invade surrounding chick tissues in a programmed manner, distributing along host neural-crest-cell migratory pathways. The invading melanoma cells display neural-crest-cell-like morphologies and populate host peripheral structures, including the branchial arches, dorsal root and sympathetic ganglia. Analysis of a melanocyte-specific phenotype marker (MART-1) and a neuronal marker (Tuj1) revealed a subpopulation of melanoma cells that invade the chick periphery and express MART-1 and Tuj1. Our results demonstrate the ability of adult human metastatic melanoma cells to respond to chick embryonic environmental cues, a subset of which may undergo a reprogramming of their metastatic phenotype. This model has the potential to provide insights into the regulation of tumor cell plasticity by an embryonic milieu, which may hold significant therapeutic promise. PMID:16505384

  2. Human placenta-derived mesenchymal stem cells acquire neural phenotype under the appropriate niche conditions.

    PubMed

    Martini, Maristela Maria; Jeremias, Talita da Silva; Kohler, Maria Cecília; Marostica, Lucas Lourenço; Trentin, Andréa Gonçalves; Alvarez-Silva, Marcio

    2013-02-01

    Mesenchymal stem cells (MSCs) are multipotent stem cells with clinical interest. It has been reported that MSCs can be isolated from the human term placenta. We investigated the ability of human placenta-derived MSCs to differentiate into a neural phenotype in coculture assays with astrocytes obtained from neonatal rats. Placenta-derived MSCs were cocultured on a confluent monolayer of astrocytes obtained from the rat cerebellum to evaluate the differences in morphology. The extracellular matrix (ECM) produced by astrocytes as well as the growth factors produced by the astrocyte-conditioned medium were evaluated. The expression of the neural markers glial fibrillate acid protein (GFAP) and Nestin was studied in MSCs by immunocytochemistry. MSCs were able to respond to the astrocyte niche in coculture assays. They expressed the neural markers GFAP, Nestin, or β-Tubulin III, followed by an outgrowth of cell processes. The ECM from astrocytes was not effective in inducing the neural phenotype in MSCs, although the expression of β-Tubulin III was observed. When MSCs were cocultured with cerebellar astrocytes from newborn rats, a neural phenotype was achieved. This was determined by immunocytochemistry to GFAP, Nestin, or β-Tubulin III and by morphological changes. It was achieved without the addition of exogenous differentiation factors. This demonstrates that placenta-derived MSCs may be able to differentiate into neural cell types when in direct contact with a neural environment.

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

    PubMed Central

    Hurst, Jillian H; Mumaw, Jennifer; Machacek, David W; Sturkie, Carla; Callihan, Phillip; Stice, Steve L; Hooks, Shelley B

    2008-01-01

    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. PMID:19077254

  4. Macroscopic Neural Oscillation during Skilled Reaching Movements in Humans

    PubMed Central

    Chung, Chun Kee

    2016-01-01

    The neural mechanism of skilled movements, such as reaching, has been considered to differ from that of rhythmic movement such as locomotion. It is generally thought that skilled movements are consciously controlled by the brain, while rhythmic movements are usually controlled autonomously by the spinal cord and brain stem. However, several studies in recent decades have suggested that neural networks in the spinal cord may also be involved in the generation of skilled movements. Moreover, a recent study revealed that neural activities in the motor cortex exhibit rhythmic oscillations corresponding to movement frequency during reaching movements as rhythmic movements. However, whether the oscillations are generated in the spinal cord or the cortical circuit in the motor cortex causes the oscillations is unclear. If the spinal cord is involved in the skilled movements, then similar rhythmic oscillations with time delays should be found in macroscopic neural activity. We measured whole-brain MEG signals during reaching. The MEG signals were analyzed using a dynamical analysis method. We found that rhythmic oscillations with time delays occur in all subjects during reaching movements. The results suggest that the corticospinal system is involved in the generation and control of the skilled movements as rhythmic movements. PMID:27524996

  5. Pigment pattern evolution by differential deployment of neural crest and post-embryonic melanophore lineages in Danio fishes.

    PubMed

    Quigley, Ian K; Turner, Jessica M; Nuckels, Richard J; Manuel, Joan L; Budi, Erine H; MacDonald, Erin L; Parichy, David M

    2004-12-01

    demonstrate an important role for latent precursors in the diversification of pigment patterns across danios. More generally, differences in the deployment of post-embryonic neural crest-derived stem cells or their specified progeny may contribute substantially to the evolutionary diversification of adult form in vertebrates, particularly in species that undergo a metamorphosis.

  6. Migratory neuronal progenitors arise from the neural plate borders in tunicates

    PubMed Central

    Stolfi, Alberto; Ryan, Kerrianne; Meinertzhagen, Ian A.; Christiaen, Lionel

    2015-01-01

    The neural crest is an evolutionary novelty that fostered the emergence of vertebrate anatomical innovations such as the cranium and jaws1. During embryonic development, multipotent neural crest cells are specified at the lateral borders of the neural plate before delaminating, migrating, and differentiating into various cell types. In invertebrate chordates (cephalochordates and tunicates), neural plate border cells express conserved factors such as Msx, Snail, and Pax3/7 and generate melanin-containing pigment cells2-4, a derivative of the neural crest in vertebrates. However, invertebrate neural plate border cells have not been shown to generate homologues of other neural crest derivatives. Thus, proposed models of neural crest evolution postulate vertebrate-specific elaborations on an ancestral neural plate border program, through acquisition of migratory capabilities and the potential to generate multiple cell types5-7. Here we show that a particular neuronal cell type in the tadpole larva of the tunicate Ciona intestinalis, the bipolar tail neuron, shares a set of features with neural crest-derived spinal ganglia neurons in vertebrates. Bipolar tail neuron precursors derive from caudal neural plate border cells, delaminate, and migrate along the paraxial mesoderm on either side of the neural tube, eventually differentiating into afferent neurons that form synaptic contacts with both epidermal sensory cells and motor neurons. We propose that the neural plate borders of the chordate ancestor already produced migratory peripheral neurons and pigment cells, and that the neural crest evolved through the acquisition of a multipotent progenitor regulatory state upstream of multiple, pre-existing neural plate border cell differentiation programs. PMID:26524532

  7. Migratory neuronal progenitors arise from the neural plate borders in tunicates.

    PubMed

    Stolfi, Alberto; Ryan, Kerrianne; Meinertzhagen, Ian A; Christiaen, Lionel

    2015-11-19

    The neural crest is an evolutionary novelty that fostered the emergence of vertebrate anatomical innovations such as the cranium and jaws. During embryonic development, multipotent neural crest cells are specified at the lateral borders of the neural plate before delaminating, migrating and differentiating into various cell types. In invertebrate chordates (cephalochordates and tunicates), neural plate border cells express conserved factors such as Msx, Snail and Pax3/7 and generate melanin-containing pigment cells, a derivative of the neural crest in vertebrates. However, invertebrate neural plate border cells have not been shown to generate homologues of other neural crest derivatives. Thus, proposed models of neural crest evolution postulate vertebrate-specific elaborations on an ancestral neural plate border program, through acquisition of migratory capabilities and the potential to generate several cell types. Here we show that a particular neuronal cell type in the tadpole larva of the tunicate Ciona intestinalis, the bipolar tail neuron, shares a set of features with neural-crest-derived spinal ganglia neurons in vertebrates. Bipolar tail neuron precursors derive from caudal neural plate border cells, delaminate and migrate along the paraxial mesoderm on either side of the neural tube, eventually differentiating into afferent neurons that form synaptic contacts with both epidermal sensory cells and motor neurons. We propose that the neural plate borders of the chordate ancestor already produced migratory peripheral neurons and pigment cells, and that the neural crest evolved through the acquisition of a multipotent progenitor regulatory state upstream of multiple, pre-existing neural plate border cell differentiation programs. PMID:26524532

  8. Spatial and temporal control of cell aggregation efficiently directs human pluripotent stem cells towards neural commitment.

    PubMed

    Miranda, Cláudia C; Fernandes, Tiago G; Pascoal, Jorge F; Haupt, Simone; Brüstle, Oliver; Cabral, Joaquim M S; Diogo, Maria Margarida

    2015-10-01

    3D suspension culture is generally considered a promising method to achieve efficient expansion and controlled differentiation of human pluripotent stem cells (hPSCs). In this work, we focused on developing an integrated culture platform for expansion and neural commitment of hPSCs into neural precursors using 3D suspension conditions and chemically-defined culture media. We evaluated different inoculation methodologies for hPSC expansion as 3D aggregates and characterized the resulting cultures in terms of aggregate size distribution. It was demonstrated that upon single-cell inoculation, after four days of culture, 3D aggregates were composed of homogenous populations of hPSC and were characterized by an average diameter of 139 ± 26 μm, which was determined to be the optimal size to initiate neural commitment. Temporal analysis revealed that upon neural specification it is possible to maximize the percentage of neural precursor cells expressing the neural markers Sox1 and Pax6 after nine days of culture. These results highlight our ability to define a robust method for production of hPSC-derived neural precursors that minimizes processing steps and that constitutes a promising alternative to the traditional planar adherent culture system due to a high potential for scaling-up. PMID:25866360

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

    PubMed

    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).

  10. Comparison of different protocols for neural differentiation of human induced pluripotent stem cells.

    PubMed

    Salimi, Ali; Nadri, Samad; Ghollasi, Marzieh; Khajeh, Khosro; Soleimani, Masoud

    2014-03-01

    Although embryonic stem cells (ESCs) have enormous potentials due to their pluripotency, their therapeutic use is limited by ethical, biological and safety issues. Compared to ESCs, induced pluripotent stem cells (iPSCs) can be obtained from mouse or human fibroblasts by reprogramming. Numerous studies have established many protocols for differentiation of human iPSCs (hiPSCs) into neural lineages. However, the low differentiation efficiency of such protocols motivates researchers to design new protocols for high yield differentiation. Herein, we compared neural differentiation potential of three induction media for conversion of hiPSCs into neural lineages. In this study, hiPSCs-derived embryoid bodies were plated on laminin coated dishes and were treated with three induction media including (1) bFGF, EGF (2) RA and (3) forskolin, IBMX. Immunofluorescence staining and quantitative real-time PCR (qPCR) analysis were used to detect the expression of neural genes and proteins. qPCR analysis showed that the expression of neural genes in differentiated hiPSCs in forskolin, IBMX supplemented media was significantly higher than undifferentiated cells and those in induction media containing bFGF, EGF or RA. In conclusion, our results indicated a successful establishment protocol with high efficiency for differentiation of hiPSCs into neural lineages.

  11. Neural processing of gravitoinertial cues in humans. III. Modeling tilt and translation responses.

    PubMed

    Merfeld, D M; Zupan, L H

    2002-02-01

    All linear accelerometers measure gravitoinertial force, which is the sum of gravitational force (tilt) and inertial force due to linear acceleration (translation). Neural strategies must exist to elicit tilt and translation responses from this ambiguous cue. To investigate these neural processes, we developed a model of human responses and simulated a number of motion paradigms used to investigate this tilt/translation ambiguity. In this model, the separation of GIF into neural estimates of gravity and linear acceleration is accomplished via an internal model made up of three principal components: 1) the influence of rotational cues (e.g., semicircular canals) on the neural representation of gravity, 2) the resolution of gravitoinertial force into neural representations of gravity and linear acceleration, and 3) the neural representation of the dynamics of the semicircular canals. By combining these simple hypotheses within the internal model framework, the model mimics human responses to a number of different paradigms, ranging from simple paradigms, like roll tilt, to complex paradigms, like postrotational tilt and centrifugation. It is important to note that the exact same mechanisms can explain responses induced by simple movements as well as by more complex paradigms; no additional elements or hypotheses are needed to match the data obtained during more complex paradigms. Therefore these modeled response characteristics are consistent with available data and with the hypothesis that the nervous system uses internal models to estimate tilt and translation in the presence of ambiguous sensory cues. PMID:11826049

  12. Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (Phospho)Proteomic Profiling.

    PubMed

    Singec, Ilyas; Crain, Andrew M; Hou, Junjie; Tobe, Brian T D; Talantova, Maria; Winquist, Alicia A; Doctor, Kutbuddin S; Choy, Jennifer; Huang, Xiayu; La Monaca, Esther; Horn, David M; Wolf, Dieter A; Lipton, Stuart A; Gutierrez, Gustavo J; Brill, Laurence M; Snyder, Evan Y

    2016-09-13

    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. PMID:27569059

  13. Isolation and Culture of Neural Crest Stem Cells from Human Hair Follicles.

    PubMed

    Yang, Ruifeng; Xu, Xiaowei

    2016-01-01

    The hair follicle undergoes lifelong cycling and growth. Previous studies have been focused on epithelial stem cells in the hair follicles. Neural crest stem cells (NCSCs) are pluripotent cells that can persist in adult tissues. We have previously demonstrated that human NCSCs can be isolated from hair follicles. Here, we present a protocol to isolate NCSCs from human hair follicles based on their specific surface-marker expression of CD271/HNK1 or CD271/CD49D (alpha4 integrin). NCSCs can be expanded in the culture as neural spheres or attached cells.

  14. Splanchnic neural regulation of somatostatin secretion in the isolated perfused human pancreas.

    PubMed Central

    Brunicardi, F C; Elahi, D; Andersen, D K

    1994-01-01

    OBJECTIVE: The somatostatin-secreting delta cells in the islets of Langerhans appear to be regulated by neural mechanisms that have not been defined clearly. In this study, the celiac neural bundle of the human pancreas was electrically stimulated in the presence and absence of selective neural antagonists. SUMMARY BACKGROUND DATA: The authors previously reported on studies of the splanchnic neural regulation of insulin, glucagon, and pancreatic polypeptide secretion. In these studies, alpha-adrenergic fibers appeared to have a predominant effect, strongly inhibiting the secretion of insulin, glucagon, and pancreatic polypeptide secretion. Cholinergic fibers appeared to stimulate strongly, although beta-adrenergic fibers weakly stimulated, the secretion of these hormones. Investigations of neural regulatory mechanisms governing human somatostatin release in vitro have not been previously reported. METHODS: Pancreata were obtained from eight cadaveric organ donors. The isolated perfused human pancreas technique was used to assess the regulation of somatostatin secretion by the various neural fibers contained within the celiac plexus. The secretory response of somatostatin was examined in the presence of 16.7 mmol/L glucose, with and without neural stimulation, and specific neural antagonists. RESULTS: The basal somatostatin secretion was 88 +/- 26 fmol/g/min and increased 131 +/- 23% (n = 8, p < 0.01) in response to 16.7 mmol/L glucose. The augmentation seen with glucose was inhibited 66 +/- 22% (n = 8, p < 0.05) during celiac neural bundle stimulation. Alpha-adrenergic blockade resulted in a 90 +/- 30% (n = 6, p < 0.01) augmentation of somatostatin release. Beta-adrenergic blockade caused a 13 +/- 2% (n = 6, p < 0.05) suppression of somatostatin release. Complete adrenergic blockade resulted in a 25 +/- 23% (n = 5, p = not significant) inhibition of somatostatin release. Cholinergic blockade resulted in a 40 +/- 10% (n = 6, p < 0.02) suppression of somatostatin

  15. Molecular stages of rapid and uniform neuralization of human embryonic stem cells.

    PubMed

    Bajpai, R; Coppola, G; Kaul, M; Talantova, M; Cimadamore, F; Nilbratt, M; Geschwind, D H; Lipton, S A; Terskikh, A V

    2009-06-01

    Insights into early human development are fundamental for our understanding of human biology. Efficient differentiation of human embryonic stem cells (hESCs) into neural precursor cells is critical for future cell-based therapies. Here, using defined conditions, we characterized a new method for rapid and uniform differentiation of hESCs into committed neural precursor cells (designated C-NPCs). Dynamic gene expression analysis identified several distinct stages of ESC neuralization and revealed functional modules of coregulated genes and pathways. The first wave of gene expression changes, likely corresponding to the transition through primitive ectoderm, started at day 3, preceding the formation of columnar neuroepithelial rosettes. The second wave started at day 5, coinciding with the formation of rosettes. The majority of C-NPCs were positive for both anterior and posterior markers of developing neuroepithelium. In culture, C-NPCs became electrophysiologically functional neurons; on transplantation into neonatal mouse brains, C-NPCs integrated into the cortex and olfactory bulb, acquiring appropriate neuronal morphologies and markers. Compared to rosette-NPCs,(1) C-NPCs exhibited limited in vitro expansion capacity and did not express potent oncogenes such as PLAG1 or RSPO3. Concordantly, we never detected tumors or excessive neural proliferation after transplantation of C-NPCs into mouse brains. In conclusion, our study provides a framework for future analysis of molecular signaling during ESC neuralization.

  16. Molecular stages of rapid and uniform neuralization of human embryonic stem cells

    PubMed Central

    Bajpai, R; Coppola, G; Kaul, M; Talantova, M; Cimadamore, F; Nilbratt, M; Geschwind, DH; Lipton, SA; Terskikh, AV

    2009-01-01

    Insights into early human development are fundamental for our understanding of human biology. Efficient differentiation of human embryonic stem cells (hESCs) into neural precursor cells is critical for future cell-based therapies. Here, using defined conditions, we characterized a new method for rapid and uniform differentiation of hESCs into committed neural precursor cells (designated C-NPCs). Dynamic gene expression analysis identified several distinct stages of ESC neuralization and revealed functional modules of coregulated genes and pathways. The first wave of gene expression changes, likely corresponding to the transition through primitive ectoderm, started at day 3, preceding the formation of columnar neuroepithelial rosettes. The second wave started at day 5, coinciding with the formation of rosettes. The majority of C-NPCs were positive for both anterior and posterior markers of developing neuroepithelium. In culture, C-NPCs became electrophysiologically functional neurons; on transplantation into neonatal mouse brains, C-NPCs integrated into the cortex and olfactory bulb, acquiring appropriate neuronal morphologies and markers. Compared to rosette-NPCs,1 C-NPCs exhibited limited in vitro expansion capacity and did not express potent oncogenes such as PLAG1 or RSPO3. Concordantly, we never detected tumors or excessive neural proliferation after transplantation of C-NPCs into mouse brains. In conclusion, our study provides a framework for future analysis of molecular signaling during ESC neuralization. PMID:19282867

  17. Monitoring the differentiation and migration patterns of neural cells derived from human embryonic stem cells using a microfluidic culture system.

    PubMed

    Lee, Nayeon; Park, Jae Woo; Kim, Hyung Joon; Yeon, Ju Hun; Kwon, Jihye; Ko, Jung Jae; Oh, Seung-Hun; Kim, Hyun Sook; Kim, Aeri; Han, Baek Soo; Lee, Sang Chul; Jeon, Noo Li; Song, Jihwan

    2014-06-01

    Microfluidics can provide unique experimental tools to visualize the development of neural structures within a microscale device, which is followed by guidance of neurite growth in the axonal isolation compartment. We utilized microfluidics technology to monitor the differentiation and migration of neural cells derived from human embryonic stem cells (hESCs). We co-cultured hESCs with PA6 stromal cells, and isolated neural rosette-like structures, which subsequently formed neurospheres in suspension culture. Tuj1-positive neural cells, but not nestin-positive neural precursor cells (NPCs), were able to enter the microfluidics grooves (microchannels), suggesting that neural cell-migratory capacity was dependent upon neuronal differentiation stage. We also showed that bundles of axons formed and extended into the microchannels. Taken together, these results demonstrated that microfluidics technology can provide useful tools to study neurite outgrowth and axon guidance of neural cells, which are derived from human embryonic stem cells.

  18. Use of Microfluidic Technology to Monitor the Differentiation and Migration of Human ESC-Derived Neural Cells.

    PubMed

    Bae, Jiwoo; Lee, Nayeon; Choi, Wankyu; Lee, Suji; Ko, Jung Jae; Han, Baek Soo; Lee, Sang Chul; Jeon, Noo Li; Song, Jihwan

    2016-01-01

    Microfluidics forms the basis of unique experimental approaches that visualize the development of neural structure using micro-scale devices and aids the guidance of neurite growth in an axonal isolation compartment. We utilized microfluidics technology to monitor the differentiation and migration of neural cells derived from human embryonic stems cells (hESC). We cocultured hESC with PA6 stromal cells and isolated neural rosette-like structures, which subsequently formed neurospheres in a suspension culture. We found that Tuj1-positive neural cells but not nestin-positive neural precursor cells (NPC) were able to enter the microfluidics grooves (microchannels), suggesting a neural cell-migratory capacity that was dependent on neuronal differentiation. We also showed that bundles of axons formed and extended into the microchannels.Taken together, these results demonstrated that microfluidics technology can provide useful tools to study neurite outgrowth and axon guidance of neural cells, which are derived from human embryonic stem cells. PMID:27062598

  19. Folic acid, methylation and neural tube closure in humans.

    PubMed

    Blom, Henk J

    2009-04-01

    This review provides a brief description of folate use and folic acid metabolism in relation to neural tube defect (NTD) risk. First, a meta-analysis of reduction in NTD recurrence and occurrence risk with periconceptional folic acid supplementation is presented. Second, an overview of the complex folate metabolism is given. Third, SNPs for genes involved in folate and homocysteine metabolism that have been studied in relation to NTD riskare discussed. Fourth, the questions whether folate receptor autoantibodies or hampered methylation are mechanisms underlying NTDs are briefly discussed.

  20. The role of empathy in the neural responses to observed human social touch.

    PubMed

    Peled-Avron, Leehe; Levy-Gigi, Einat; Richter-Levin, Gal; Korem, Nachshon; Shamay-Tsoory, Simone G

    2016-10-01

    One of the ways in which individuals convey feelings and thoughts to one another is through touch. Although the neural responses to felt and observed tactile stimuli between an inanimate object and a part of the human body have been vastly explored, the neural responses to observed human interaction involving touch are not well understood. Considering that the observation of social touch involves vicarious sharing of emotions, we hypothesized that levels of empathic traits modulate the neural responses to observed touch and focused on the attenuation in the mu\\alpha rhythm (8-13Hz), a neural marker that has been related to sensorimotor resonance. Fifty-four participants observed photos depicting social touch, nonsocial touch, or no touch while their electroencephalography (EEG) activity was recorded. Results showed that interindividual differences in levels of empathic traits modulated both behavioral and electrophysiological responses to human social touch, such that highly empathic participants evaluated human social touch as inducing more pleasant emotions and exhibited greater mu suppression upon observation of human social touch compared to less empathic participants. Specifically, both the behavioral and the electrophysiological responses to observed social touch were predicted by levels of personal distress, a measure of emotional contagion. These findings indicate that the behavioral and electrophysiological responses to observed social touch are modulated by levels of empathy. PMID:27165338

  1. Reward motivation accelerates the onset of neural novelty signals in humans to 85 milliseconds.

    PubMed

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

    2009-08-11

    The neural responses that distinguish novel from familiar items in recognition memory tasks are remarkably fast in both humans and nonhuman primates. In humans, the earliest onsets of neural novelty effects emerge at about approximately 150-200 ms after stimulus onset. However, in recognition memory studies with nonhuman primates, novelty effects can arise at as early as 70-80 ms. Here, we address the possibility that this large species difference in onset latencies is caused experimentally by the necessity of using reward reinforcement to motivate the detection of novel or familiar items in nonhuman primates but not in humans. Via magnetoencephalography in humans, we show in two experiments that the onset of neural novelty signals is accelerated from approximately 200 ms to approximately 85 ms if correct recognition memory for either novel or familiar items is rewarded. Importantly, this acceleration is independent of whether the detection of the novel or the familiar scenes is rewarded. Furthermore, this early novelty effect contributed to memory retrieval because neural reward responses, which were contingent upon novelty detection, followed approximately 100 ms later. Thus, under the contextual influence of reward motivation, behaviorally relevant novelty signals emerge much faster than previously held possible in humans.

  2. The role of empathy in the neural responses to observed human social touch.

    PubMed

    Peled-Avron, Leehe; Levy-Gigi, Einat; Richter-Levin, Gal; Korem, Nachshon; Shamay-Tsoory, Simone G

    2016-10-01

    One of the ways in which individuals convey feelings and thoughts to one another is through touch. Although the neural responses to felt and observed tactile stimuli between an inanimate object and a part of the human body have been vastly explored, the neural responses to observed human interaction involving touch are not well understood. Considering that the observation of social touch involves vicarious sharing of emotions, we hypothesized that levels of empathic traits modulate the neural responses to observed touch and focused on the attenuation in the mu\\alpha rhythm (8-13Hz), a neural marker that has been related to sensorimotor resonance. Fifty-four participants observed photos depicting social touch, nonsocial touch, or no touch while their electroencephalography (EEG) activity was recorded. Results showed that interindividual differences in levels of empathic traits modulated both behavioral and electrophysiological responses to human social touch, such that highly empathic participants evaluated human social touch as inducing more pleasant emotions and exhibited greater mu suppression upon observation of human social touch compared to less empathic participants. Specifically, both the behavioral and the electrophysiological responses to observed social touch were predicted by levels of personal distress, a measure of emotional contagion. These findings indicate that the behavioral and electrophysiological responses to observed social touch are modulated by levels of empathy.

  3. Flexible neural mechanisms of cognitive control within human prefrontal cortex.

    PubMed

    Braver, Todd S; Paxton, Jessica L; Locke, Hannah S; Barch, Deanna M

    2009-05-01

    A major challenge in research on executive control is to reveal its functional decomposition into underlying neural mechanisms. A typical assumption is that this decomposition occurs solely through anatomically based dissociations. Here we tested an alternative hypothesis that different cognitive control processes may be implemented within the same brain regions, with fractionation and dissociation occurring on the basis of temporal dynamics. Regions within lateral prefrontal cortex (PFC) were examined that, in a prior study, exhibited contrasting temporal dynamics between older and younger adults during performance of the AX-CPT cognitive control task. The temporal dynamics in younger adults fit a proactive control pattern (primarily cue-based activation), whereas in older adults a reactive control pattern was found (primarily probe-based activation). In the current study, we found that following a period of task-strategy training, these older adults exhibited a proactive shift within a subset of the PFC regions, normalizing their activity dynamics toward young adult patterns. Conversely, under conditions of penalty-based monetary incentives, the younger adults exhibited a reactive shift some of the same regions, altering their temporal dynamics toward the older adult baseline pattern. These experimentally induced crossover patterns of temporal dynamics provide strong support for dual modes of cognitive control that can be flexibly shifted within PFC regions, via modulation of neural responses to changing task conditions or behavioral goals. PMID:19380750

  4. Non-coding RNAs in pluripotency and neural differentiation of human pluripotent stem cells.

    PubMed

    Lukovic, Dunja; Moreno-Manzano, Victoria; Klabusay, Martin; Stojkovic, Miodrag; Bhattacharya, Shomi S; Erceg, Slaven

    2014-01-01

    Several studies have demonstrated the important role of non-coding RNAs as regulators of posttranscriptional processes, including stem cells self-renewal and neural differentiation. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (ihPSCs) show enormous potential in regenerative medicine due to their capacity to differentiate to virtually any type of cells of human body. Deciphering the role of non-coding RNAs in pluripotency, self-renewal and neural differentiation will reveal new molecular mechanisms involved in induction and maintenances of pluripotent state as well as triggering these cells toward clinically relevant cells for transplantation. In this brief review we will summarize recently published studies which reveal the role of non-coding RNAs in pluripotency and neural differentiation of hESCs and ihPSC.

  5. Regulation of neural stem cell in the human SVZ by trophic and morphogenic factors

    PubMed Central

    Alvarez-Palazuelos, Lucia E.; Robles-Cervantes, Martha S.; Castillo-Velazquez, Gabriel; Rivas-Souza, Mario; Guzman-Muniz, Jorge; Moy-Lopez, Norma; Gonzalez-Castaneda, Rocio E.; Luquin, Sonia; Gonzalez-Perez, Oscar

    2011-01-01

    The subventricular zone (SVZ), lining the lateral ventricular system, is the largest germinal region in mammals. In there, neural stem cells express markers related to astoglial lineage that give rise to new neurons and oligodendrocytes in vivo. In the adult human brain, in vitro evidence has also shown that astrocytic cells isolated from the SVZ can generate new neurons and oligodendrocytes. These proliferative cells are strongly controlled by a number of signals and molecules that modulate, activate or repress the cell division, renewal, proliferation and fate of neural stem cells. In this review, we summarize the cellular composition of the adult human SVZ (hSVZ) and discuss the increasing evidence showing that some trophic modulators strongly control the function of neural stem cells in the SVZ. PMID:22053150

  6. Alcohol-Induced Molecular Dysregulation in Human Embryonic Stem Cell-Derived Neural Precursor Cells

    PubMed Central

    Kim, Yi Young; Roubal, Ivan; Lee, Youn Soo; Kim, Jin Seok; Hoang, Michael; Mathiyakom, Nathan; Kim, Yong

    2016-01-01

    Adverse effect of alcohol on neural function has been well documented. Especially, the teratogenic effect of alcohol on neurodevelopment during embryogenesis has been demonstrated in various models, which could be a pathologic basis for fetal alcohol spectrum disorders (FASDs). While the developmental defects from alcohol abuse during gestation have been described, the specific mechanisms by which alcohol mediates these injuries have yet to be determined. Recent studies have shown that alcohol has significant effect on molecular and cellular regulatory mechanisms in embryonic stem cell (ESC) differentiation including genes involved in neural development. To test our hypothesis that alcohol induces molecular alterations during neural differentiation we have derived neural precursor cells from pluripotent human ESCs in the presence or absence of ethanol treatment. Genome-wide transcriptomic profiling identified molecular alterations induced by ethanol exposure during neural differentiation of hESCs into neural rosettes and neural precursor cell populations. The Database for Annotation, Visualization and Integrated Discovery (DAVID) functional analysis on significantly altered genes showed potential ethanol’s effect on JAK-STAT signaling pathway, neuroactive ligand-receptor interaction, Toll-like receptor (TLR) signaling pathway, cytokine-cytokine receptor interaction and regulation of autophagy. We have further quantitatively verified ethanol-induced alterations of selected candidate genes. Among verified genes we further examined the expression of P2RX3, which is associated with nociception, a peripheral pain response. We found ethanol significantly reduced the level of P2RX3 in undifferentiated hESCs, but induced the level of P2RX3 mRNA and protein in hESC-derived NPCs. Our result suggests ethanol-induced dysregulation of P2RX3 along with alterations in molecules involved in neural activity such as neuroactive ligand-receptor interaction may be a molecular event

  7. Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition of neurite outgrowth

    SciTech Connect

    Harrill, Joshua A.; Freudenrich, Theresa M.; Robinette, Brian L.; Mundy, William R.

    2011-11-15

    There is a need for rapid, efficient and cost-effective alternatives to traditional in vivo developmental neurotoxicity testing. In vitro cell culture models can recapitulate many of the key cellular processes of nervous system development, including neurite outgrowth, and may be used as screening tools to identify potential developmental neurotoxicants. The present study compared primary rat cortical cultures and human embryonic stem cell-derived neural cultures in terms of: 1) reproducibility of high content image analysis based neurite outgrowth measurements, 2) dynamic range of neurite outgrowth measurements and 3) sensitivity to chemicals which have been shown to inhibit neurite outgrowth. There was a large increase in neurite outgrowth between 2 and 24 h in both rat and human cultures. Image analysis data collected across multiple cultures demonstrated that neurite outgrowth measurements in rat cortical cultures were more reproducible and had higher dynamic range as compared to human neural cultures. Human neural cultures were more sensitive than rat cortical cultures to chemicals previously shown to inhibit neurite outgrowth. Parallel analysis of morphological (neurite count, neurite length) and cytotoxicity (neurons per field) measurements were used to detect selective effects on neurite outgrowth. All chemicals which inhibited neurite outgrowth in rat cortical cultures did so at concentrations which did not concurrently affect the number of neurons per field, indicating selective effects on neurite outgrowth. In contrast, more than half the chemicals which inhibited neurite outgrowth in human neural cultures did so at concentrations which concurrently decreased the number of neurons per field, indicating that effects on neurite outgrowth were secondary to cytotoxicity. Overall, these data demonstrate that the culture models performed differently in terms of reproducibility, dynamic range and sensitivity to neurite outgrowth inhibitors. While human neural

  8. This Neural Implant is designed to be implanted in the Human Central and Nervous System

    SciTech Connect

    2013-10-29

    A new class of neural implants being developed at the Livermore Lab are the first clinical quality devices capable of two-way conversations with the human nervous systems. Unlike existing interfaces that only sense or only stimulate, these devices are capable of stimulating and sensing using both electric and chemical signals.

  9. Characterization of Human Neural Progenitor Cell Models for Developmental Neurotoxicity Screening

    EPA Science Inventory

    Current testing methods for developmental neurotoxicity (DNT) make evaluation of the effects of large numbers of chemicals impractical and prohibitively expensive. As such, we are evaluating two different human neural progenitor cell (hNPC) models for their utility in screens for...

  10. Evolution of neural computations: Mantis shrimp and human color decoding.

    PubMed

    Zaidi, Qasim; Marshall, Justin; Thoen, Hanne; Conway, Bevil R

    2014-01-01

    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.

  11. NEURAL PLASTICITY, HUMAN GENETICS, AND RISK FOR ALCOHOL DEPENDENCE

    PubMed Central

    Hill, Shirley Y.

    2013-01-01

    Opportunities for advances in the neurobiology of alcohol dependence have been facilitated by the development of sophisticated neurophysiological and neuroimaging techniques that allow us to have a window on developmental changes in brain structure and function. The search for genes that may increase susceptibility to alcohol dependence has been greatly facilitated by the recognition that intermediate phenotypes, sometimes referred to as endophenotypes. may be closer to the genetic variation than is the more complex alcohol dependence phenotype. This chapter will review the evidence that the brain is highly plastic, exhibiting major postnatal changes, especially during adolescence, in neural circuits that appear to influence addiction susceptibility. This chapter will suggest that heritable aspects of brain structure and function that are seen developmentally may be an important endophenotypic characteristic associated with familial risk for developing alcohol dependence. Finally, a review of studies showing associations between brain structural and functional characteristics and specific genes will be offered. PMID:20813240

  12. Evolution of neural computations: Mantis shrimp and human color decoding.

    PubMed

    Zaidi, Qasim; Marshall, Justin; Thoen, Hanne; Conway, Bevil R

    2014-01-01

    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. PMID:26034560

  13. Evolution of neural computations: Mantis shrimp and human color decoding

    PubMed Central

    Zaidi, Qasim; Marshall, Justin; Thoen, Hanne; Conway, Bevil R.

    2014-01-01

    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. PMID:26034560

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

    PubMed Central

    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

    2015-01-01

    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. Clinical trial registration: NCT00912041. DOI: http://dx.doi.org/10.7554/eLife.07436.001 PMID:26099302

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

    PubMed

    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. PMID:27333401

  16. Generation of the Human Biped Stance by a Neural Controller Able to Compensate Neurological Time Delay

    PubMed Central

    Jiang, Ping; Chiba, Ryosuke; Takakusaki, Kaoru; Ota, Jun

    2016-01-01

    The development of a physiologically plausible computational model of a neural controller that can realize a human-like biped stance is important for a large number of potential applications, such as assisting device development and designing robotic control systems. In this paper, we develop a computational model of a neural controller that can maintain a musculoskeletal model in a standing position, while incorporating a 120-ms neurological time delay. Unlike previous studies that have used an inverted pendulum model, a musculoskeletal model with seven joints and 70 muscular-tendon actuators is adopted to represent the human anatomy. Our proposed neural controller is composed of both feed-forward and feedback controls. The feed-forward control corresponds to the constant activation input necessary for the musculoskeletal model to maintain a standing posture. This compensates for gravity and regulates stiffness. The developed neural controller model can replicate two salient features of the human biped stance: (1) physiologically plausible muscle activations for quiet standing; and (2) selection of a low active stiffness for low energy consumption. PMID:27655271

  17. Contour junctions underlie neural representations of scene categories in high-level human visual cortex.

    PubMed

    Choo, Heeyoung; Walther, Dirk B

    2016-07-15

    Humans efficiently grasp complex visual environments, making highly consistent judgments of entry-level category despite their high variability in visual appearance. How does the human brain arrive at the invariant neural representations underlying categorization of real-world environments? We here show that the neural representation of visual environments in scene-selective human visual cortex relies on statistics of contour junctions, which provide cues for the three-dimensional arrangement of surfaces in a scene. We manipulated line drawings of real-world environments such that statistics of contour orientations or junctions were disrupted. Manipulated and intact line drawings were presented to participants in an fMRI experiment. Scene categories were decoded from neural activity patterns in the parahippocampal place area (PPA), the occipital place area (OPA) and other visual brain regions. Disruption of junctions but not orientations led to a drastic decrease in decoding accuracy in the PPA and OPA, indicating the reliance of these areas on intact junction statistics. Accuracy of decoding from early visual cortex, on the other hand, was unaffected by either image manipulation. We further show that the correlation of error patterns between decoding from the scene-selective brain areas and behavioral experiments is contingent on intact contour junctions. Finally, a searchlight analysis exposes the reliance of visually active brain regions on different sets of contour properties. Statistics of contour length and curvature dominate neural representations of scene categories in early visual areas and contour junctions in high-level scene-selective brain regions.

  18. Neural correlates of gesture processing across human development.

    PubMed

    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. PMID:23662858

  19. Fast fMRI can detect oscillatory neural activity in humans

    PubMed Central

    Lewis, Laura D.; Setsompop, Kawin; Rosen, Bruce R.; Polimeni, Jonathan R.

    2016-01-01

    Oscillatory neural dynamics play an important role in the coordination of large-scale brain networks. High-level cognitive processes depend on dynamics evolving over hundreds of milliseconds, so measuring neural activity in this frequency range is important for cognitive neuroscience. However, current noninvasive neuroimaging methods are not able to precisely localize oscillatory neural activity above 0.2 Hz. Electroencephalography and magnetoencephalography have limited spatial resolution, whereas fMRI has limited temporal resolution because it measures vascular responses rather than directly recording neural activity. We hypothesized that the recent development of fast fMRI techniques, combined with the extra sensitivity afforded by ultra-high-field systems, could enable precise localization of neural oscillations. We tested whether fMRI can detect neural oscillations using human visual cortex as a model system. We detected small oscillatory fMRI signals in response to stimuli oscillating at up to 0.75 Hz within single scan sessions, and these responses were an order of magnitude larger than predicted by canonical linear models. Simultaneous EEG–fMRI and simulations based on a biophysical model of the hemodynamic response to neuronal activity suggested that the blood oxygen level-dependent response becomes faster for rapidly varying stimuli, enabling the detection of higher frequencies than expected. Accounting for phase delays across voxels further improved detection, demonstrating that identifying vascular delays will be of increasing importance with higher-frequency activity. These results challenge the assumption that the hemodynamic response is slow, and demonstrate that fMRI has the potential to map neural oscillations directly throughout the brain. PMID:27729529

  20. Neural representations of ethologically relevant hand/mouth synergies in the human precentral gyrus.

    PubMed

    Desmurget, Michel; Richard, Nathalie; Harquel, Sylvain; Baraduc, Pierre; Szathmari, Alexandru; Mottolese, Carmine; Sirigu, Angela

    2014-04-15

    Complex motor responses are often thought to result from the combination of elemental movements represented at different neural sites. However, in monkeys, evidence indicates that some behaviors with critical ethological value, such as self-feeding, are represented as motor primitives in the precentral gyrus (PrG). In humans, such primitives have not yet been described. This could reflect well-known interspecies differences in the organization of sensorimotor regions (including PrG) or the difficulty of identifying complex neural representations in peroperative settings. To settle this alternative, we focused on the neural bases of hand/mouth synergies, a prominent example of human behavior with high ethological value. By recording motor- and somatosensory-evoked potentials in the PrG of patients undergoing brain surgery (2-60 y), we show that two complex nested neural representations can mediate hand/mouth actions within this structure: (i) a motor representation, resembling self-feeding, where electrical stimulation causes the closing hand to approach the opening mouth, and (ii) a motor-sensory representation, likely associated with perioral exploration, where cross-signal integration is accomplished at a cortical site that generates hand/arm actions while receiving mouth sensory inputs. The first finding extends to humans' previous observations in monkeys. The second provides evidence that complex neural representations also exist for perioral exploration, a finely tuned skill requiring the combination of motor and sensory signals within a common control loop. These representations likely underlie the ability of human children and newborns to accurately produce coordinated hand/mouth movements, in an otherwise general context of motor immaturity.

  1. Recapitulating amyloid β and tau pathology in human neural cell culture models: clinical implications

    PubMed Central

    Choi, Se Hoon; Kim, Young Hye; D’Avanzo, Carla; Aronson, Jenna; Tanzi, Rudolph E.; Kim, Doo Yeon

    2015-01-01

    Summary The “amyloid β hypothesis” of Alzheimer’s disease (AD) has been the reigning hypothesis explaining pathogenic mechanisms of AD over the last two decades. However, this hypothesis has not been fully validated in animal models, and several major unresolved issues remain. We recently developed a human neural cell culture model of AD based on a three-dimensional (3D) cell culture system. This unique, cellular model recapitulates key events of the AD pathogenic cascade, including β-amyloid plaques and neurofibrillary tangles. Our 3D human neural cell culture model system provides a premise for a new generation of cellular AD models that can serve as a novel platform for studying pathogenic mechanisms and for high-throughput drug screening in a human brain-like environment. PMID:27019672

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

    NASA Astrophysics Data System (ADS)

    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].

  3. Neural-Induced Human Mesenchymal Stem Cells Promote Cochlear Cell Regeneration in Deaf Guinea Pigs

    PubMed Central

    Jang, Sujeong; Cho, Hyong-Ho; Kim, Song-Hee; Lee, Kyung-Hwa; Jun, Jae Yeoul; Park, Jong-Seong; Jeong, Han-Seong

    2015-01-01

    Objectives In mammals, cochlear hair cell loss is irreversible and may result in a permanent sensorineural hearing loss. Secondary to this hair cell loss, a progressive loss of spiral ganglion neurons (SGNs) is presented. In this study, we have investigated the effects of neural-induced human mesenchymal stem cells (NI-hMSCs) from human bone marrow on sensory neuronal regeneration from neomycin treated deafened guinea pig cochleae. Methods HMSCs were isolated from the bone marrow which was obtained from the mastoid process during mastoidectomy for ear surgery. Following neural induction with basic fibroblast growth factor and forskolin, we studied the several neural marker and performed electrophysiological analysis. NI-hMSCs were transplanted into the neomycin treated deafened guinea pig cochlea. Engraftment of NI-hMSCs was evaluated immunohistologically at 8 weeks after transplantation. Results Following neural differentiation, hMSCs expressed high levels of neural markers, ionic channel markers, which are important in neural function, and tetrodotoxin-sensitive voltage-dependent sodium currents. After transplantation into the scala tympani of damaged cochlea, NI-hMSCs-injected animals exhibited a significant increase in the number of SGNs compared to Hanks balanced salt solution-injected animals. Transplanted NI-hMSCs were found within the perilymphatic space, the organ of Corti, along the cochlear nerve fibers, and in the spiral ganglion. Furthermore, the grafted NI-hMSCs migrated into the spiral ganglion where they expressed the neuron-specific marker, NeuN. Conclusion The results show the potential of NI-hMSCs to give rise to replace the lost cochlear cells in hearing loss mammals. PMID:26045904

  4. Changes of neural markers expression during late neurogenic differentiation of human adipose-derived stem cells

    PubMed Central

    Razavi, Shahnaz; Khosravizadeh, Zahra; Bahramian, Hamid; Kazemi, Mohammad

    2015-01-01

    Background: Different studies have been done to obtain sufficient number of neural cells for treatment of neurodegenerative diseases, spinal cord, and traumatic brain injury because neural stem cells are limited in central nerves system. Recently, several studies have shown that adipose-derived stem cells (ADSCs) are the appropriate source of multipotent stem cells. Furthermore, these cells are found in large quantities. The aim of this study was an assessment of proliferation and potential of neurogenic differentiation of ADSCs with passing time. Materials and Methods: Neurosphere formation was used for neural induction in isolated human ADSCs (hADSCs). The rate of proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and potential of neural differentiation of induced hADSCs was evaluated by immunocytochemical and real-time reverse transcription polymerase chain reaction analysis after 10 and 14 days post-induction. Results: The rate of proliferation of induced hADSCs increased after 14 days while the expression of nestin, glial fibrillary acidic protein, and microtubule-associated protein 2 was decreased with passing time during neurogenic differentiation. Conclusion: These findings showed that the proliferation of induced cells increased with passing time, but in early neurogenic differentiation of hADSCs, neural expression was higher than late of differentiation. Thus, using of induced cells in early differentiation may be suggested for in vivo application. PMID:26605238

  5. Derivation of Neural Precursor Cells from Human Embryonic Stem Cells for DNA Methylomic Analysis.

    PubMed

    Roubal, Ivan; Park, Sun Joo; Kim, Yong

    2016-01-01

    Embryonic stem cells are self-renewing pluripotent cells with competency to differentiate into all three-germ lineages. Many studies have demonstrated the importance of genetic and epigenetic molecular mechanisms in the maintenance of self-renewal and pluripotency. Stem cells are under unique molecular and cellular regulations different from somatic cells. Proper regulation should be ensured to maintain their unique self-renewal and undifferentiated characteristics. Understanding key mechanisms in stem cell biology will be important for the successful application of stem cells for regenerative therapeutic medicine. More importantly practical use of stem cells will require our knowledge on how to properly direct and differentiate stem cells into the necessary type of cells. Embryonic stem cells and adult stem cells have been used as study models to unveil molecular and cellular mechanisms in various signaling pathways. They are especially beneficial to developmental studies where in vivo molecular/cellular study models are not available. We have derived neural stem cells from human embryonic stem cells as a model to study the effect of teratogen in neural development. We have tested commercial neural differentiation system and successfully derived neural precursor cells exhibiting key molecular features of neural stem cells, which will be useful for experimental application.

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

    NASA Astrophysics Data System (ADS)

    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.

  7. Oscillatory neural responses evoked by natural vestibular stimuli in humans.

    PubMed

    Gale, Steven; Prsa, Mario; Schurger, Aaron; Gay, Annietta; Paillard, Aurore; Herbelin, Bruno; Guyot, Jean-Philippe; Lopez, Christophe; Blanke, Olaf

    2016-03-01

    While there have been numerous studies of the vestibular system in mammals, less is known about the brain mechanisms of vestibular processing in humans. In particular, of the studies that have been carried out in humans over the last 30 years, none has investigated how vestibular stimulation (VS) affects cortical oscillations. Here we recorded high-density electroencephalography (EEG) in healthy human subjects and a group of bilateral vestibular loss patients (BVPs) undergoing transient and constant-velocity passive whole body yaw rotations, focusing our analyses on the modulation of cortical oscillations in response to natural VS. The present approach overcame significant technical challenges associated with combining natural VS with human electrophysiology and reveals that both transient and constant-velocity VS are associated with a prominent suppression of alpha power (8-13 Hz). Alpha band suppression was localized over bilateral temporo-parietal scalp regions, and these alpha modulations were significantly smaller in BVPs. We propose that suppression of oscillations in the alpha band over temporo-parietal scalp regions reflects cortical vestibular processing, potentially comparable with alpha and mu oscillations in the visual and sensorimotor systems, respectively, opening the door to the investigation of human cortical processing under various experimental conditions during natural VS. PMID:26683063

  8. Cardiovascular Development and the Colonizing Cardiac Neural Crest Lineage

    PubMed Central

    Snider, Paige; Olaopa, Michael; Firulli, Anthony B.

    2008-01-01

    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 secrete factor/s that

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

    NASA Technical Reports Server (NTRS)

    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

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

    PubMed

    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

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

    PubMed

    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

  12. Neural Differentiation in the Third Dimension: Generating a Human Midbrain.

    PubMed

    Marton, Rebecca M; Paşca, Sergiu P

    2016-08-01

    In recent years, technological improvements in three-dimensional (3D) culture systems have enabled the generation of organoids or spheroids representing a variety of tissues, including the brain. In this issue of Cell Stem Cell, Jo et al. (2016) describe a 3D culture model of the human midbrain containing dopaminergic neurons and neuromelanin. PMID:27494668

  13. Altered temporal dynamics of neural adaptation in the aging human auditory cortex.

    PubMed

    Herrmann, Björn; Henry, Molly J; Johnsrude, Ingrid S; Obleser, Jonas

    2016-09-01

    Neural response adaptation plays an important role in perception and cognition. Here, we used electroencephalography to investigate how aging affects the temporal dynamics of neural adaptation in human auditory cortex. Younger (18-31 years) and older (51-70 years) normal hearing adults listened to tone sequences with varying onset-to-onset intervals. Our results show long-lasting neural adaptation such that the response to a particular tone is a nonlinear function of the extended temporal history of sound events. Most important, aging is associated with multiple changes in auditory cortex; older adults exhibit larger and less variable response magnitudes, a larger dynamic response range, and a reduced sensitivity to temporal context. Computational modeling suggests that reduced adaptation recovery times underlie these changes in the aging auditory cortex and that the extended temporal stimulation has less influence on the neural response to the current sound in older compared with younger individuals. Our human electroencephalography results critically narrow the gap to animal electrophysiology work suggesting a compensatory release from cortical inhibition accompanying hearing loss and aging. PMID:27459921

  14. The neural oscillations of conflict adaptation in the human frontal region.

    PubMed

    Tang, Dandan; Hu, Li; Chen, Antao

    2013-07-01

    Incongruency between print color and the semantic meaning of a word in a classical Stroop task activates the human conflict monitoring system and triggers a behavioral conflict. Conflict adaptation has been suggested to mediate the cortical processing of neural oscillations in such a conflict situation. However, the basic mechanisms that underlie the influence of conflict adaptation on the changes of neural oscillations are not clear. In the present study, electroencephalography (EEG) data were recorded from sixteen healthy human participants while they were performing a color-word Stroop task within a novel look-to-do transition design that included two response modalities. In the 'look' condition, participants were informed to look at the color of presented words but no responses were required; in the 'do' condition, they were informed to make arranged responses to the color of presented words. Behaviorally, a reliable conflict adaptation was observed. Time-frequency analysis revealed that (1) in the 'look' condition, theta-band activity in the left- and right-frontal regions reflected a conflict-related process at a response inhibition level; and (2) in the 'do' condition, both theta-band activity in the left-frontal region and alpha-band activity in the left-, right-, and centro-frontal regions reflected a process of conflict control, which triggered neural and behavioral adaptation. Taken together, these results suggest that there are frontal mechanisms involving neural oscillations that can mediate response inhibition processes and control behavioral conflict.

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

    PubMed

    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 (<10) of presynaptic inputs, whereas a small set of hub-like neurons have large numbers of synaptic connections (>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.

  16. Prior Knowledge about Objects Determines Neural Color Representation in Human Visual Cortex.

    PubMed

    Vandenbroucke, A R E; Fahrenfort, J J; Meuwese, J D I; Scholte, H S; Lamme, V A F

    2016-04-01

    To create subjective experience, our brain must translate physical stimulus input by incorporating prior knowledge and expectations. For example, we perceive color and not wavelength information, and this in part depends on our past experience with colored objects ( Hansen et al. 2006; Mitterer and de Ruiter 2008). Here, we investigated the influence of object knowledge on the neural substrates underlying subjective color vision. In a functional magnetic resonance imaging experiment, human subjects viewed a color that lay midway between red and green (ambiguous with respect to its distance from red and green) presented on either typical red (e.g., tomato), typical green (e.g., clover), or semantically meaningless (nonsense) objects. Using decoding techniques, we could predict whether subjects viewed the ambiguous color on typical red or typical green objects based on the neural response of veridical red and green. This shift of neural response for the ambiguous color did not occur for nonsense objects. The modulation of neural responses was observed in visual areas (V3, V4, VO1, lateral occipital complex) involved in color and object processing, as well as frontal areas. This demonstrates that object memory influences wavelength information relatively early in the human visual system to produce subjective color vision. PMID:25323417

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

    PubMed Central

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

    2016-01-01

    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. PMID:27543293

  18. Morphological changes in human neural cells following tick-borne encephalitis virus infection.

    PubMed

    Růzek, Daniel; Vancová, Marie; Tesarová, Martina; Ahantarig, Arunee; Kopecký, Jan; Grubhoffer, Libor

    2009-07-01

    Tick-borne encephalitis (TBE) is one of the leading and most dangerous human viral neuroinfections in Europe and north-eastern Asia. The clinical manifestations include asymptomatic infections, fevers and debilitating encephalitis that might progress into chronic disease or fatal infection. To understand TBE pathology further in host nervous systems, three human neural cell lines, neuroblastoma, medulloblastoma and glioblastoma, were infected with TBE virus (TBEV). The susceptibility and virus-mediated cytopathic effect, including ultrastructural and apoptotic changes of the cells, were examined. All the neural cell lines tested were susceptible to TBEV infection. Interestingly, the neural cells produced about 100- to 10,000-fold higher virus titres than the conventional cell lines of extraneural origin, indicating the highly susceptible nature of neural cells to TBEV infection. The infection of medulloblastoma and glioblastoma cells was associated with a number of major morphological changes, including proliferation of membranes of the rough endoplasmic reticulum and extensive rearrangement of cytoskeletal structures. The TBEV-infected cells exhibited either necrotic or apoptotic morphological features. We observed ultrastructural apoptotic signs (condensation, margination and fragmentation of chromatin) and other alterations, such as vacuolation of the cytoplasm, dilatation of the endoplasmic reticulum cisternae and shrinkage of cells, accompanied by a high density of the cytoplasm. On the other hand, infected neuroblastoma cells did not exhibit proliferation of membranous structures. The virions were present in both the endoplasmic reticulum and the cytoplasm. Cells were dying preferentially by necrotic mechanisms rather than apoptosis. The neuropathological significance of these observations is discussed. PMID:19264624

  19. BAC transgenesis in human embryonic stem cells as a novel tool to define the human neural lineage.

    PubMed

    Placantonakis, Dimitris G; Tomishima, Mark J; Lafaille, Fabien; Desbordes, Sabrina C; Jia, Fan; Socci, Nicholas D; Viale, Agnes; Lee, Hyojin; Harrison, Neil; Tabar, Viviane; Studer, Lorenz

    2009-03-01

    Human embryonic stem cells (hESCs) have enormous potential for applications in basic biology and regenerative medicine. However, harnessing the potential of hESCs toward generating homogeneous populations of specialized cells remains challenging. Here we describe a novel technology for the genetic identification of defined hESC-derived neural cell types using bacterial artificial chromosome (BAC) transgenesis. We generated hESC lines stably expressing Hes5::GFP, Dll1::GFP, and HB9::GFP BACs that yield green fluorescent protein (GFP)(+) neural stem cells, neuroblasts, and motor neurons, respectively. Faithful reporter expression was confirmed by cell fate analysis and appropriate transgene regulation. Prospective isolation of HB9::GFP(+) cells yielded purified human motor neurons with proper marker expression and electrophysiological activity. Global mRNA and microRNA analyses of Hes5::GFP(+) and HB9::GFP(+) populations revealed highly specific expression signatures, suggesting that BAC transgenesis will be a powerful tool for establishing expression libraries that define the human neural lineage and for accessing defined cell types in applications of human disease. PMID:19074416

  20. A neural circuitry that emphasizes spinal feedback generates diverse behaviours of human locomotion

    PubMed Central

    Song, Seungmoon; Geyer, Hartmut

    2015-01-01

    Neural networks along the spinal cord contribute substantially to generating locomotion behaviours in humans and other legged animals. However, the neural circuitry involved in this spinal control remains unclear. We here propose a specific circuitry that emphasizes feedback integration over central pattern generation. The circuitry is based on neurophysiologically plausible muscle-reflex pathways that are organized in 10 spinal modules realizing limb functions essential to legged systems in stance and swing. These modules are combined with a supraspinal control layer that adjusts the desired foot placements and selects the leg that is to transition into swing control during double support. Using physics-based simulation, we test the proposed circuitry in a neuromuscular human model that includes neural transmission delays, musculotendon dynamics and compliant foot–ground contacts. We find that the control network is sufficient to compose steady and transitional 3-D locomotion behaviours including walking and running, acceleration and deceleration, slope and stair negotiation, turning, and deliberate obstacle avoidance. The results suggest feedback integration to be functionally more important than central pattern generation in human locomotion across behaviours. In addition, the proposed control architecture may serve as a guide in the search for the neurophysiological origin and circuitry of spinal control in humans. PMID:25920414

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

    NASA Astrophysics Data System (ADS)

    Oniga, Stefan; József, Sütő

    2015-12-01

    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.

  2. The vestibulosympathetic reflex in humans: neural interactions between cardiovascular reflexes

    NASA Technical Reports Server (NTRS)

    Ray, Chester A.; Monahan, Kevin D.

    2002-01-01

    1. Over the past 5 years, there has been emerging evidence that the vestibular system regulates sympathetic nerve activity in humans. We have studied this issue in humans by using head-down rotation (HDR) in the prone position. 2. These studies have clearly demonstrated increases in muscle sympathetic nerve activity (MSNA) and calf vascular resistance during HDR. These responses are mediated by engagement of the otolith organs and not the semicircular canals. 3. However, differential activation of sympathetic nerve activity has been observed during HDR. Unlike MSNA, skin sympathetic nerve activity does not increase with HDR. 4. Examination of the vestibulosympathetic reflex with other cardiovascular reflexes (i.e. barorereflexes and skeletal muscle reflexes) has shown an additive interaction for MSNA. 5. The additive interaction between the baroreflexes and vestibulosympathetic reflex suggests that the vestibular system may assist in defending against orthostatic challenges in humans by elevating MSNA beyond that of the baroreflexes. 6. In addition, the further increase in MSNA via otolith stimulation during isometric handgrip, when arterial pressure is elevated markedly, indicates that the vestibulosympathetic reflex is a powerful activator of MSNA and may contribute to blood pressure and flow regulation during dynamic exercise. 7. Future studies will help evaluate the importance of the vestibulosympathetic reflex in clinical conditions associated with orthostatic hypotension.

  3. Deep Neural Networks as a Computational Model for Human Shape Sensitivity

    PubMed Central

    Op de Beeck, Hans P.

    2016-01-01

    Theories of object recognition agree that shape is of primordial importance, but there is no consensus about how shape might be represented, and so far attempts to implement a model of shape perception that would work with realistic stimuli have largely failed. Recent studies suggest that state-of-the-art convolutional ‘deep’ neural networks (DNNs) capture important aspects of human object perception. We hypothesized that these successes might be partially related to a human-like representation of object shape. Here we demonstrate that sensitivity for shape features, characteristic to human and primate vision, emerges in DNNs when trained for generic object recognition from natural photographs. We show that these models explain human shape judgments for several benchmark behavioral and neural stimulus sets on which earlier models mostly failed. In particular, although never explicitly trained for such stimuli, DNNs develop acute sensitivity to minute variations in shape and to non-accidental properties that have long been implicated to form the basis for object recognition. Even more strikingly, when tested with a challenging stimulus set in which shape and category membership are dissociated, the most complex model architectures capture human shape sensitivity as well as some aspects of the category structure that emerges from human judgments. As a whole, these results indicate that convolutional neural networks not only learn physically correct representations of object categories but also develop perceptually accurate representational spaces of shapes. An even more complete model of human object representations might be in sight by training deep architectures for multiple tasks, which is so characteristic in human development. PMID:27124699

  4. Nonlinear spatio-temporal interactions and neural connections in human vision using transient and M-sequence stimuli

    SciTech Connect

    Chen, H.W.; Aine, C.J.; Flynn, E.R.; Wood, C.C.

    1996-02-01

    Reciprocal connections, in essence, are the dynamic wiring (connections) of the neural network circuitry. Given the high complexity of the neural circuitry in the human brain, it is quite a challenge to study the dynamic wiring of highly parallel and widely distributed neural networks. The measurements of stimulus evoked coherent oscillations provide indirect evidence of dynamic wiring. In this study, in addition to the coherent oscillation measurements, two more techniques are discussed for testing possible dynamic wiring: measurements of spatio-temporal interactions beyond the classical receptive fields, and neural structural testing using nonlinear systems analysis.

  5. Microneurography as a tool in clinical neurophysiology to investigate peripheral neural traffic in humans.

    PubMed

    Mano, Tadaaki; Iwase, Satoshi; Toma, Shinobu

    2006-11-01

    Microneurography is a method using metal microelectrodes to investigate directly identified neural traffic in myelinated as well as unmyelinated efferent and afferent nerves leading to and coming from muscle and skin in human peripheral nerves in situ. The present paper reviews how this technique has been used in clinical neurophysiology to elucidate the neural mechanisms of autonomic regulation, motor control and sensory functions in humans under physiological and pathological conditions. Microneurography is particularly important to investigate efferent and afferent neural traffic in unmyelinated C fibers. The recording of efferent discharges in postganglionic sympathetic C efferent fibers innervating muscle and skin (muscle sympathetic nerve activity; MSNA and skin sympathetic nerve activity; SSNA) provides direct information about neural control of autonomic effector organs including blood vessels and sweat glands. Sympathetic microneurography has become a potent tool to reveal neural functions and dysfunctions concerning blood pressure control and thermoregulation. This recording has been used not only in wake conditions but also in sleep to investigate changes in sympathetic neural traffic during sleep and sleep-related events such as sleep apnea. The same recording was also successfully carried out by astronauts during spaceflight. Recordings of afferent discharges from muscle mechanoreceptors have been used to understand the mechanisms of motor control. Muscle spindle afferent information is particularly important for the control of fine precise movements. It may also play important roles to predict behavior outcomes during learning of a motor task. Recordings of discharges in myelinated afferent fibers from skin mechanoreceptors have provided not only objective information about mechanoreceptive cutaneous sensation but also the roles of these signals in fine motor control. Unmyelinated mechanoreceptive afferent discharges from hairy skin seem to be

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

    PubMed Central

    Montzka, Katrin; Lassonczyk, Nina; Tschöke, Beate; Neuss, Sabine; Führmann, Tobias; Franzen, Rachelle; Smeets, Ralf; Brook, Gary A; Wöltje, Michael

    2009-01-01

    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 well as contributing to the

  7. Intra-Operatively Obtained Human Tissue: Protocols and Techniques for the Study of Neural Stem Cells

    PubMed Central

    Chaichana, Kaisorn; Guerrero-Cazares, Hugo; Capilla-Gonzalez, Vivian; Zamora-Berridi, Grettel; Achanta, Praganthi; Gonzalez-Perez, Oscar; Jallo, George I.; Garcia-Verdugo, Jose Manuel; Quiñones-Hinojosa, Alfredo

    2009-01-01

    The discoveries of neural (NSCs) and brain tumor stem cells (BTSCs) in the adult human brain and in brain tumors, respectively, have led to a new era in neuroscience research. These cells represent novel approaches to studying normal phenomena such as memory and learning, as well as pathological conditions such as Parkinson’s disease, stroke, and brain tumors. This new paradigm stresses the importance of understanding how these cells behave in vitro and in vivo. It also stresses the need to use human-derived tissue to study human disease because animal models may not necessarily accurately replicate the processes that occur in humans. An important, but often underused, source of human tissue and, consequently, both NSCs and BTSCs, is the operating room. This study describes in detail both current and newly developed laboratory techniques, which in our experience are used to process and study human NSCs and BTSCs from tissue obtained directly from the operating room. PMID:19427538

  8. Expression of GD2 and GD3 gangliosides in human embryonic neural stem cells

    PubMed Central

    Yanagisawa, Makoto; Yoshimura, Saori; Yu, Robert K

    2011-01-01

    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. PMID:21395555

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

    PubMed Central

    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 (<3% in 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. PMID:21278024

  10. A neural representation of categorization uncertainty in the human brain.

    PubMed

    Grinband, Jack; Hirsch, Joy; Ferrera, Vincent P

    2006-03-01

    The ability to classify visual objects into discrete categories ("friend" versus "foe"; "edible" versus "poisonous") is essential for survival and is a fundamental cognitive function. The cortical substrates that mediate this function, however, have not been identified in humans. To identify brain regions involved in stimulus categorization, we developed a task in which subjects classified stimuli according to a variable categorical boundary. Psychophysical functions were used to define a decision variable, categorization uncertainty, which was systematically manipulated. Using event-related functional MRI, we discovered that activity in a fronto-striatal-thalamic network, consisting of the medial frontal gyrus, anterior insula, ventral striatum, and dorsomedial thalamus, was modulated by categorization uncertainty. We found this network to be distinct from the frontoparietal attention network, consisting of the frontal and parietal eye fields, where activity was not correlated with categorization uncertainty. PMID:16504950

  11. Human Dermal Fibroblasts Demonstrate Positive Immunostaining for Neuron- and Glia- Specific Proteins

    PubMed Central

    Janmaat, C. J.; de Rooij, K. E; Locher, H; de Groot, S. C.; de Groot, J. C. M. J.; Frijns, J. H. M.; Huisman, M. A.

    2015-01-01

    In stem cell cultures from adult human tissue, undesirable contamination with fibroblasts is frequently present. The presence of fibroblasts obscures the actual number of stem cells and may result in extracellular matrix production after transplantation. Identification of fibroblasts is difficult because of the lack of specific fibroblast markers. In our laboratory, we isolate and expand neural-crest-derived stem cells from human hair follicle bulges and investigate their potential to differentiate into neural cells. To establish cellular identities, we perform immunohistochemistry with antibodies specific for glial and neuronal markers, and use fibroblasts as negative control. We frequently observe that human adult dermal fibroblasts also express some glial and neuronal markers. In this study, we have sought to determine whether our observations represent actual expression of these markers or result from cross-reactivity. Immunohistochemistry was performed on human adult dermal fibroblasts using acknowledged glial and neuronal antibodies followed by verification of the data using RT-qPCR. Human adult dermal fibroblasts showed expression of the glia-specific markers SOX9, glial fibrillary acidic protein and EGR2 (KROX20) as well as for the neuron-specific marker class III β-tubulin, both at the protein and mRNA level. Furthermore, human adult dermal fibroblasts showed false-positive immunostaining for S100β and GAP43 and to a lower extent for OCT6. Our results indicate that immunophenotyping as a tool to determine cellular identity is not as reliable as generally assumed, especially since human adult dermal fibroblasts may be mistaken for neural cells, indicating that the ultimate proof of glial or neuronal identity can only be provided by their functionality. PMID:26678612

  12. Human Dermal Fibroblasts Demonstrate Positive Immunostaining for Neuron- and Glia- Specific Proteins.

    PubMed

    Janmaat, C J; de Rooij, K E; Locher, H; de Groot, S C; de Groot, J C M J; Frijns, J H M; Huisman, M A

    2015-01-01

    In stem cell cultures from adult human tissue, undesirable contamination with fibroblasts is frequently present. The presence of fibroblasts obscures the actual number of stem cells and may result in extracellular matrix production after transplantation. Identification of fibroblasts is difficult because of the lack of specific fibroblast markers. In our laboratory, we isolate and expand neural-crest-derived stem cells from human hair follicle bulges and investigate their potential to differentiate into neural cells. To establish cellular identities, we perform immunohistochemistry with antibodies specific for glial and neuronal markers, and use fibroblasts as negative control. We frequently observe that human adult dermal fibroblasts also express some glial and neuronal markers. In this study, we have sought to determine whether our observations represent actual expression of these markers or result from cross-reactivity. Immunohistochemistry was performed on human adult dermal fibroblasts using acknowledged glial and neuronal antibodies followed by verification of the data using RT-qPCR. Human adult dermal fibroblasts showed expression of the glia-specific markers SOX9, glial fibrillary acidic protein and EGR2 (KROX20) as well as for the neuron-specific marker class III β-tubulin, both at the protein and mRNA level. Furthermore, human adult dermal fibroblasts showed false-positive immunostaining for S100β and GAP43 and to a lower extent for OCT6. Our results indicate that immunophenotyping as a tool to determine cellular identity is not as reliable as generally assumed, especially since human adult dermal fibroblasts may be mistaken for neural cells, indicating that the ultimate proof of glial or neuronal identity can only be provided by their functionality. PMID:26678612

  13. Triple-pulse TMS to study interactions between neural circuits in human cortex.

    PubMed

    Ni, Zhen; Müller-Dahlhaus, Florian; Chen, Robert; Ziemann, Ulf

    2011-10-01

    Transcranial magnetic stimulation (TMS) is a widely used brain stimulation technique that allows noninvasive examination of different excitatory and inhibitory circuits at the systems level in the intact human brain. In recent years, considerable knowledge has been accumulated about the physiology of several of these facilitatory and inhibitory processes individually. However, activity in the corresponding neural circuits is not independent of each other. This paper reviews the experiments using triple-pulse TMS that are specifically designed to study interactions between intracortical circuits. These studies have provided evidence for a complex network of interconnected neural circuits within and across cerebral hemispheres. The current knowledge about the functional organization of this network, its pharmacology and functional implications for human motor control are discussed in detail. These findings have clinical relevance because specific interactions between neural circuits may be impaired in neurologic and psychiatric disorders. We conclude that triple-pulse TMS studies will help to integrate and better understand the physiologic processes involved in human motor behavior.

  14. Insulin concentration is critical in culturing human neural stem cells and neurons.

    PubMed

    Rhee, Y-H; Choi, M; Lee, H-S; Park, C-H; Kim, S-M; Yi, S-H; Oh, S-M; Cha, H-J; Chang, M-Y; Lee, S-H

    2013-08-08

    Cell culture of human-derived neural stem cells (NSCs) is a useful tool that contributes to our understanding of human brain development and allows for the development of therapies for intractable human brain disorders. Human NSC (hNSC) cultures, however, are not commonly used, mainly because of difficulty with consistently maintaining the cells in a healthy state. In this study, we show that hNSC cultures, unlike NSCs of rodent origins, are extremely sensitive to insulin, an indispensable culture supplement, and that the previously reported difficulty in culturing hNSCs is likely because of a lack of understanding of this relationship. Like other neural cell cultures, insulin is required for hNSC growth, as withdrawal of insulin supplementation results in massive cell death and delayed cell growth. However, severe apoptotic cell death was also detected in insulin concentrations optimized to rodent NSC cultures. Thus, healthy hNSC cultures were only produced in a narrow range of relatively low insulin concentrations. Insulin-mediated cell death manifested not only in all human NSCs tested, regardless of origin, but also in differentiated human neurons. The underlying cell death mechanism at high insulin concentrations was similar to insulin resistance, where cells became less responsive to insulin, resulting in a reduction in the activation of the PI3K/Akt pathway critical to cell survival signaling.

  15. Counterfactual choice and learning in a neural network centered on human lateral frontopolar cortex.

    PubMed

    Boorman, Erie D; Behrens, Timothy E; Rushworth, Matthew F

    2011-06-01

    Decision making and learning in a real-world context require organisms to track not only the choices they make and the outcomes that follow but also other untaken, or counterfactual, choices and their outcomes. Although the neural system responsible for tracking the value of choices actually taken is increasingly well understood, whether a neural system tracks counterfactual information is currently unclear. Using a three-alternative decision-making task, a Bayesian reinforcement-learning algorithm, and fMRI, we investigated the coding of counterfactual choices and prediction errors in the human brain. Rather than representing evidence favoring multiple counterfactual choices, lateral frontal polar cortex (lFPC), dorsomedial frontal cortex (DMFC), and posteromedial cortex (PMC) encode the reward-based evidence favoring the best counterfactual option at future decisions. In addition to encoding counterfactual reward expectations, the network carries a signal for learning about counterfactual options when feedback is available-a counterfactual prediction error. Unlike other brain regions that have been associated with the processing of counterfactual outcomes, counterfactual prediction errors within the identified network cannot be related to regret theory. Furthermore, individual variation in counterfactual choice-related activity and prediction error-related activity, respectively, predicts variation in the propensity to switch to profitable choices in the future and the ability to learn from hypothetical feedback. Taken together, these data provide both neural and behavioral evidence to support the existence of a previously unidentified neural system responsible for tracking both counterfactual choice options and their outcomes.

  16. Generation of Neural Progenitor Spheres from Human Pluripotent Stem Cells in a Suspension Bioreactor.

    PubMed

    Yan, Yuanwei; Song, Liqing; Tsai, Ang-Chen; Ma, Teng; Li, Yan

    2016-01-01

    Conventional two-dimensional (2-D) culture systems cannot provide large numbers of human pluripotent stem cells (hPSCs) and their derivatives that are demanded for commercial and clinical applications in in vitro drug screening, disease modeling, and potentially cell therapy. The technologies that support three-dimensional (3-D) suspension culture, such as a stirred bioreactor, are generally considered as promising approaches to produce the required cells. Recently, suspension bioreactors have also been used to generate mini-brain-like structure from hPSCs for disease modeling, showing the important role of bioreactor in stem cell culture. This chapter describes a detailed culture protocol for neural commitment of hPSCs into neural progenitor cell (NPC) spheres using a spinner bioreactor. The basic steps to prepare hPSCs for bioreactor inoculation are illustrated from cell thawing to cell propagation. The method for generating NPCs from hPSCs in the spinner bioreactor along with the static control is then described. The protocol in this study can be applied to the generation of NPCs from hPSCs for further neural subtype specification, 3-D neural tissue development, or potential preclinical studies or clinical applications in neurological diseases. PMID:26837215

  17. Human Neural Tissue Construct Fabrication Based on Scaffold-Free Tissue Engineering.

    PubMed

    Takahashi, Hironobu; Itoga, Kazuyoshi; Shimizu, Tatsuya; Yamato, Masayuki; Okano, Teruo

    2016-08-01

    Current neural tissue engineering strategies involve the development and application of neural tissue constructs produced by using an anisotropic polymeric scaffold. This study reports a scaffold-free method of tissue engineering to create a tubular neural tissue construct containing unidirectional neuron bundles. The surface patterning of a thermoresponsive culture substrate and a coculture system of neurons with patterned astrocytes can provide an anisotropic structure and easy handling of the neural tissue construct without the use of a scaffold. Furthermore, using a gelatin gel-coated plunger, the neuron bundles can be laid out in the same direction at regulated intervals within multilayered astrocyte sheets. Since the 3D tissue construct is composed only by neurons and astrocytes, they can communicate physiologically without obstruction of a scaffold. The medical benefits of scaffold-free tissue generation provide new opportunities for the development of human cell-based tissue models required to better understand the mechanisms of neurodegenerative diseases. Therefore, this new tissue engineering approach may be useful to establish a technology for regenerative medicine and drug discovery using the patient's own neurons. PMID:27331769

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

    PubMed

    Saby, Joni N; Meltzoff, Andrew N; Marshall, Peter J

    2013-01-01

    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.

  19. Neural bases of personal and extrapersonal neglect in humans.

    PubMed

    Committeri, Giorgia; Pitzalis, Sabrina; Galati, Gaspare; Patria, Fabiana; Pelle, Gina; Sabatini, Umberto; Castriota-Scanderbeg, Alessandro; Piccardi, Laura; Guariglia, Cecilia; Pizzamiglio, Luigi

    2007-02-01

    Human awareness of left space may be disrupted by cerebral lesions to the right hemisphere (hemispatial neglect). Current knowledge on the anatomical bases of this complex syndrome is based on the results of group studies that investigated primarily the best known aspect of the syndrome, which is visual neglect for near extrapersonal (or peripersonal) space. However, another component-neglect for personal space-is more often associated with, than double-dissociated from, extrapersonal neglect, especially, in chronic patients. The present investigation aimed at exploring the anatomical substrate of both extrapersonal and personal neglect by using different advanced methodological approaches to lesion-function correlation. Fifty-two right ischaemic patients were submitted to neuropsychological assessment and in-depth MRI evaluation. The borders of each patient's lesion were delimited onto its own high-resolution anatomical image and then submitted to an automated spatial normalization algorithm. Besides conventional lesion density plots and subtraction analysis, region-based statistical analyses were performed on percentage values of the lesioned tissue also using a new parcellation of the white matter (WM). Data were finally submitted to voxelwise statistical analysis using a recently proposed method (voxel-based lesion-symptom mapping). Results converged in showing that awareness of extrapersonal space is based on the integrity of a circuit of right frontal (ventral premotor cortex and middle frontal gyrus) and superior temporal regions, whereas awareness of personal space is rooted in right inferior parietal regions (supramarginal gyrus, post-central gyrus and especially the WM medial to them). Common but less crucial regions for both neglect sub-types were located in the temporo-peri-Sylvian cortex. We suggest that extrapersonal space awareness critically involves a ventral circuit recently described for the exogenous allocation and reorienting of attention in

  20. Consciousness: a neural capacity for objectivity, especially pronounced in humans.

    PubMed

    Dijker, Anton J M

    2014-01-01

    Consciousness tends to be viewed either as subjective experience of sensations and feelings, or as perception and internal representation of objects. This paper argues that neither view sufficiently acknowledges that consciousness may refer to the brain's most adaptive property: its capacity to produce states of objectivity. It is proposed that this capacity relies on multiple sensorimotor networks for internally representing objects and their properties in terms of expectancies, as well as on motivational and motor mechanisms involved in exploration, play, and care for vulnerable living and non-living objects. States of objectivity are associated with a very special phenomenal aspect; the experience that subjective aspects are absent and one is "just looking" at the world as it really is and can be. However, these states are normally closely preceded and followed by (and tend to be combined or fused with) sensations and feelings which are caused by activation of sensory and motivational mechanisms. A capacity for objectivity may have evolved in different species and can be conceived as a common basis for other elusive psychological properties such as intelligence, conscience, and esthetic experience; all three linked to crucial behaviors in human evolution such as tool making, cooperation, and art. The brain's pervasive tendency to objectify may be responsible for wrongly equating consciousness with feelings and wrongly opposing it to well-learned or habitual ("unconscious") patterns of perception and behavior.

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

    PubMed

    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.

  2. Consciousness: a neural capacity for objectivity, especially pronounced in humans

    PubMed Central

    Dijker, Anton J. M.

    2014-01-01

    Consciousness tends to be viewed either as subjective experience of sensations and feelings, or as perception and internal representation of objects. This paper argues that neither view sufficiently acknowledges that consciousness may refer to the brain’s most adaptive property: its capacity to produce states of objectivity. It is proposed that this capacity relies on multiple sensorimotor networks for internally representing objects and their properties in terms of expectancies, as well as on motivational and motor mechanisms involved in exploration, play, and care for vulnerable living and non-living objects. States of objectivity are associated with a very special phenomenal aspect; the experience that subjective aspects are absent and one is “just looking” at the world as it really is and can be. However, these states are normally closely preceded and followed by (and tend to be combined or fused with) sensations and feelings which are caused by activation of sensory and motivational mechanisms. A capacity for objectivity may have evolved in different species and can be conceived as a common basis for other elusive psychological properties such as intelligence, conscience, and esthetic experience; all three linked to crucial behaviors in human evolution such as tool making, cooperation, and art. The brain’s pervasive tendency to objectify may be responsible for wrongly equating consciousness with feelings and wrongly opposing it to well-learned or habitual (“unconscious”) patterns of perception and behavior. PMID:24672506

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

    PubMed

    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. PMID:26990572

  4. Scalable Expansion of Human Pluripotent Stem Cell-Derived Neural Progenitors in Stirred Suspension Bioreactor Under Xeno-free Condition.

    PubMed

    Nemati, Shiva; Abbasalizadeh, Saeed; Baharvand, Hossein

    2016-01-01

    Recent advances in neural differentiation technology have paved the way to generate clinical grade neural progenitor populations from human pluripotent stem cells. These cells are an excellent source for the production of neural cell-based therapeutic products to treat incurable central nervous system disorders such as Parkinson's disease and spinal cord injuries. This progress can be complemented by the development of robust bioprocessing technologies for large scale expansion of clinical grade neural progenitors under GMP conditions for promising clinical use and drug discovery applications. Here, we describe a protocol for a robust, scalable expansion of human neural progenitor cells from pluripotent stem cells as 3D aggregates in a stirred suspension bioreactor. The use of this platform has resulted in easily expansion of neural progenitor cells for several passages with a fold increase of up to 4.2 over a period of 5 days compared to a maximum 1.5-2-fold increase in the adherent static culture over a 1 week period. In the bioreactor culture, these cells maintained self-renewal, karyotype stability, and cloning efficiency capabilities. This approach can be also used for human neural progenitor cells derived from other sources such as the human fetal brain. PMID:26867543

  5. Sp8 expression in putative neural progenitor cells in guinea pig and human cerebrum.

    PubMed

    Zhang, Xue-Mei; Cai, Yan; Wang, Fang; Wu, Jun; Mo, Lin; Zhang, Feng; Patrylo, Peter R; Pan, Aihua; Ma, Chao; Fu, Jin; Yan, Xiao-Xin

    2016-09-01

    Neural stem/progenitor cells have been characterized at neurogenic sites in adult mammalian brain with various molecular markers. Here it has been demonstrated that Sp8, a transcription factor typically expressed among mature GABAergic interneurons, also labels putative neural precursors in adult guinea pig and human cerebrum. In guinea pigs, Sp8 immunoreactive (Sp8+) cells were localized largely in the superficial layers of the cortex including layer I, as well as the subventricular zone (SVZ) and subgranular zone (SGZ). Sp8+ cells at the SGZ showed little colocalization with mature and immature neuronal markers, but co-expressed neural stem cell markers including Sox2. Some layer I Sp8+ cells also co-expressed Sox2. The amount of Sp8+ cells in the dentate gyrus was maintained 2 weeks after X-ray irradiation, while that of doublecortin (DCX+) cells was greatly reduced. Mild ischemic insult caused a transient increase of Sp8+ cells in the SGZ and layer I, with the subgranular Sp8+ cells exhibited an increased colabeling for the mitotic marker Ki67 and pulse-chased bromodeoxyuridine (BrdU). Sp8+ cells in the dentate gyrus showed an age-related decline in guinea pigs, in parallel with the loss of DCX+ cells in the same region. In adult humans, Sp8+ cells exhibited comparable morphological features as seen in guinea pigs, with those at the SGZ and some in cortical layer I co-expressed Sox2. Together, these results suggested that Sp8 may label putative neural progenitors in guinea pig and human cerebrum, with the labeled cells in the SGZ appeared largely not mitotically active under normal conditions. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 939-955, 2016.

  6. Brain activation during human navigation: gender-different neural networks as substrate of performance.

    PubMed

    Grön, G; Wunderlich, A P; Spitzer, M; Tomczak, R; Riepe, M W

    2000-04-01

    Visuospatial navigation in animals and human subjects is generally studied using maze exploration. We used functional MRI to observe brain activation in male and female subjects as they searched for the way out of a complex, three-dimensional, virtual-reality maze. Navigation activated the medial occipital gyri, lateral and medial parietal regions, posterior cingulate and parahippocampal gyri as well as the right hippocampus proper. Gender-specific group analysis revealed distinct activation of the left hippocampus in males, whereas females consistently recruited right parietal and right prefrontal cortex. Thus we demonstrate a neural substrate of well established human gender differences in spatial-cognition performance.

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

    NASA Astrophysics Data System (ADS)

    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.

  8. Modeling human neural functionality in vitro: three-dimensional culture for dopaminergic differentiation.

    PubMed

    Simão, Daniel; Pinto, Catarina; Piersanti, Stefania; Weston, Anne; Peddie, Christopher J; Bastos, André E P; Licursi, Valerio; Schwarz, Sigrid C; Collinson, Lucy M; Salinas, Sara; Serra, Margarida; Teixeira, Ana P; Saggio, Isabella; Lima, Pedro A; Kremer, Eric J; Schiavo, Giampietro; Brito, Catarina; Alves, Paula M

    2015-02-01

    Advances in mechanistic knowledge of human neurological disorders have been hindered by the lack of adequate human in vitro models. Three-dimensional (3D) cellular models displaying higher biological relevance are gaining momentum; however, their lack of robustness and scarcity of analytical tools adapted to three dimensions hampers their widespread implementation. Herein we show that human midbrain-derived neural progenitor cells, cultured as 3D neurospheres in stirred culture systems, reproducibly differentiate into complex tissue-like structures containing functional dopaminergic neurons, as well as astrocytes and oligodendrocytes. Moreover, an extensive toolbox of analytical methodologies has been adapted to 3D neural cell models, allowing molecular and phenotypic profiling and interrogation. The generated neurons underwent synaptogenesis and elicit spontaneous Ca(2+) transients. Synaptic vesicle trafficking and release of dopamine in response to depolarizing stimuli was also observed. Under whole-cell current-and-voltage clamp, recordings showed polarized neurons (Vm=-70 mV) and voltage-dependent potassium currents, which included A-type-like currents. Glutamate-induced currents sensitive to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate antagonists revealed the existence of functional glutamate receptors. Molecular and phenotypic profiling showed recapitulation of midbrain patterning events, and remodeling toward increased similarity to human brain features, such as extracellular matrix composition and metabolic signature. We have developed a robust and reproducible human 3D neural cell model, which may be extended to patient-derived induced pluripotent stem cells, broadening the applicability of this model. PMID:25257211

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

    SciTech Connect

    Villa, Ana; Liste, Isabel; Courtois, Elise T.; Seiz, Emma G.; Ramos, Milagros; Meyer, Morten; Juliusson, Bengt; Kusk, Philip

    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.

  10. Susceptibility of human embryonic stem cell-derived neural cells to Japanese encephalitis virus infection.

    PubMed

    Shen, Shih-Cheng; Shen, Ching-I; Lin, Ho; Chen, Chun-Jung; Chang, Chia-Yu; Chen, Sheng-Mei; Lee, Hsiu-Chin; Lai, Ping-Shan; Su, Hong-Lin

    2014-01-01

    Pluripotent human embryonic stem cells (hESCs) can be efficiently directed to become immature neuroepithelial precursor cells (NPCs) and functional mature neural cells, including neurotransmitter-secreting neurons and glial cells. Investigating the susceptibility of these hESCs-derived neural cells to neurotrophic viruses, such as Japanese encephalitis virus (JEV), provides insight into the viral cell tropism in the infected human brain. We demonstrate that hESC-derived NPCs are highly vulnerable to JEV infection at a low multiplicity of infection (MOI). In addition, glial fibrillary acid protein (GFAP)-expressing glial cells are also susceptible to JEV infection. In contrast, only a few mature neurons were infected at MOI 10 or higher on the third day post-infection. In addition, functional neurotransmitter-secreting neurons are also resistant to JEV infection at high MOI. Moreover, we discover that vimentin intermediate filament, reported as a putative neurovirulent JEV receptor, is highly expressed in NPCs and glial cells, but not mature neurons. These results indicate that the expression of vimentin in neural cells correlates to the cell tropism of JEV. Finally, we further demonstrate that membranous vimentin is necessary for the susceptibility of hESC-derived NPCs to JEV infection.

  11. Neural and Synaptic Defects in slytherin a Zebrafish Model for Human Congenital Disorders of Glycosylation

    SciTech Connect

    Y Song; J Willer; P Scherer; J Panzer; A Kugath; E Skordalakes; R Gregg; G Willer; R Balice-Gordon

    2011-12-31

    Congenital disorder of glycosylation type IIc (CDG IIc) is characterized by mental retardation, slowed growth and severe immunodeficiency, attributed to the lack of fucosylated glycoproteins. While impaired Notch signaling has been implicated in some aspects of CDG IIc pathogenesis, the molecular and cellular mechanisms remain poorly understood. We have identified a zebrafish mutant slytherin (srn), which harbors a missense point mutation in GDP-mannose 4,6 dehydratase (GMDS), the rate-limiting enzyme in protein fucosylation, including that of Notch. Here we report that some of the mechanisms underlying the neural phenotypes in srn and in CGD IIc are Notch-dependent, while others are Notch-independent. We show, for the first time in a vertebrate in vivo, that defects in protein fucosylation leads to defects in neuronal differentiation, maintenance, axon branching, and synapse formation. Srn is thus a useful and important vertebrate model for human CDG IIc that has provided new insights into the neural phenotypes that are hallmarks of the human disorder and has also highlighted the role of protein fucosylation in neural development.

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

    PubMed

    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.

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

    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. PMID:26795421

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

    PubMed

    Zhu, Liang; Dong, Chuanming; Sun, Chenxi; Ma, Rongjie; Yang, Danjing; Zhu, Hongwen; Xu, Jun

    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. PMID:26159917

  16. Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence.

    PubMed

    Parada, Carolina; Han, Dong; Grimaldi, Alexandre; Sarrión, Patricia; Park, Shery S; Pelikan, Richard; Sanchez-Lara, Pedro A; Chai, Yang

    2015-11-01

    Disrupted ERK1/2 signaling is associated with several developmental syndromes in humans. To understand the function of ERK2 (MAPK1) in the postmigratory neural crest populating the craniofacial region, we studied two mouse models: Wnt1-Cre;Erk2(fl/fl) and Osr2-Cre;Erk2(fl/fl). Wnt1-Cre;Erk2(fl/fl) mice exhibited cleft palate, malformed tongue, micrognathia and mandibular asymmetry. Cleft palate in these mice was associated with delay/failure of palatal shelf elevation caused by tongue malposition and micrognathia. Osr2-Cre;Erk2(fl/fl) mice, in which the Erk2 deletion is restricted to the palatal mesenchyme, did not display cleft palate, suggesting that palatal clefting in Wnt1-Cre;Erk2(fl/fl) mice is a secondary defect. Tongues in Wnt1-Cre;Erk2(fl/fl) mice exhibited microglossia, malposition, disruption of the muscle patterning and compromised tendon development. The tongue phenotype was extensively rescued after culture in isolation, indicating that it might also be a secondary defect. The primary malformations in Wnt1-Cre;Erk2(fl/fl) mice, namely micrognathia and mandibular asymmetry, are linked to an early osteogenic differentiation defect. Collectively, our study demonstrates that mutation of Erk2 in neural crest derivatives phenocopies the human Pierre Robin sequence and highlights the interconnection of palate, tongue and mandible development. Because the ERK pathway serves as a crucial point of convergence for multiple signaling pathways, our study will facilitate a better understanding of the molecular regulatory mechanisms of craniofacial development.

  17. Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

    PubMed Central

    Parada, Carolina; Han, Dong; Grimaldi, Alexandre; Sarrión, Patricia; Park, Shery S.; Pelikan, Richard; Sanchez-Lara, Pedro A.; Chai, Yang

    2015-01-01

    Disrupted ERK1/2 signaling is associated with several developmental syndromes in humans. To understand the function of ERK2 (MAPK1) in the postmigratory neural crest populating the craniofacial region, we studied two mouse models: Wnt1-Cre;Erk2fl/fl and Osr2-Cre;Erk2fl/fl. Wnt1-Cre;Erk2fl/fl mice exhibited cleft palate, malformed tongue, micrognathia and mandibular asymmetry. Cleft palate in these mice was associated with delay/failure of palatal shelf elevation caused by tongue malposition and micrognathia. Osr2-Cre;Erk2fl/fl mice, in which the Erk2 deletion is restricted to the palatal mesenchyme, did not display cleft palate, suggesting that palatal clefting in Wnt1-Cre;Erk2fl/fl mice is a secondary defect. Tongues in Wnt1-Cre;Erk2fl/fl mice exhibited microglossia, malposition, disruption of the muscle patterning and compromised tendon development. The tongue phenotype was extensively rescued after culture in isolation, indicating that it might also be a secondary defect. The primary malformations in Wnt1-Cre;Erk2fl/fl mice, namely micrognathia and mandibular asymmetry, are linked to an early osteogenic differentiation defect. Collectively, our study demonstrates that mutation of Erk2 in neural crest derivatives phenocopies the human Pierre Robin sequence and highlights the interconnection of palate, tongue and mandible development. Because the ERK pathway serves as a crucial point of convergence for multiple signaling pathways, our study will facilitate a better understanding of the molecular regulatory mechanisms of craniofacial development. PMID:26395480

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

    PubMed Central

    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. PMID:26881089

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

    PubMed

    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.

  20. Detection of some anaemia types in human blood smears using neural networks

    NASA Astrophysics Data System (ADS)

    Elsalamony, Hany A.

    2016-08-01

    The identification process based on measuring the level of haemoglobin and the classification of red blood cells using microscopic examination of blood smears is the principal way to diagnose anaemia. This paper presents a proposed algorithm for detecting some anaemia types like sickle and elliptocytosis and trying to count them with healthy ones in human red blood smears based on the circular Hough transform and some morphological tools. Some cells with unknown shapes (not platelets or white cells) also have been detected. The extracted data from the detection process has been analyzed by neural network. The experimental results have demonstrated high accuracy, and the proposed algorithm has achieved the highest detection of around 98.9% out of all the cells in 27 microscopic images. Effectiveness rates up to 100%, 98%, and 99.3% have been achieved by using neural networks for sickle, elliptocytosis and cells with unknown shapes, respectively.

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

    PubMed Central

    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. PMID:25161607

  2. Interplay between human microglia and neural stem/progenitor cells in an allogeneic co-culture model.

    PubMed

    Liu, Jia; Hjorth, Erik; Zhu, Mingqin; Calzarossa, Cinzia; Samuelsson, Eva-Britt; Schultzberg, Marianne; Åkesson, Elisabet

    2013-11-01

    Experimental neural cell therapies, including donor neural stem/progenitor cells (NPCs) have been reported to offer beneficial effects on the recovery after an injury and to counteract inflammatory and degenerative processes in the central nervous system (CNS). The interplay between donor neural cells and the host CNS still to a large degree remains unclear, in particular in human allogeneic conditions. Here, we focused our studies on the interaction of human NPCs and microglia utilizing a co-culture model. In co-cultures, both NPCs and microglia showed increased survival and proliferation compared with mono-cultures. In the presence of microglia, a larger subpopulation of NPCs expressed the progenitor cell marker nestin, whereas a smaller group of NPCs expressed the neural markers polysialylated neural cell adhesion molecule, A2B5 and glial fibrillary acidic protein compared with NPC mono-cultures. Microglia thus hindered differentiation of NPCs. The presence of human NPCs increased microglial phagocytosis of latex beads. Furthermore, we observed that the expression of CD200 molecules on NPCs and the CD200 receptor protein on microglia was enhanced in co-cultures, whereas the release of transforming growth factor-β was increased suggesting anti-inflammatory features of the co-cultures. To conclude, the interplay between human allogeneic NPCs and microglia, significantly affected their respective proliferation and phenotype. Neural cell therapy including human donor NPCs may in addition to offering cell replacement, modulate host microglial phenotypes and functions to benefit neuroprotection and repair.

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

    PubMed

    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.

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

    SciTech Connect

    Zhu, Liang; Dong, Chuanming; Sun, Chenxi; Ma, Rongjie; Yang, Danjing; Zhu, Hongwen; Xu, Jun

    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.

  5. Neural Correlates of Human Action Observation in Hearing and Deaf Subjects

    PubMed Central

    Corina, David; Chiu, Yi-Shiuan; Knapp, Heather; Greenwald, Ralf; Jose-Robertson, Lucia San; Braun, Allen

    2007-01-01

    Accumulating evidence has suggested the existence of a human action recognition system involving inferior frontal, parietal, and superior temporal regions that may participate in both the perception and execution of actions. However, little is known about the specificity of this system in response to different forms of human action. Here we present data from PET neuroimaging studies from passive viewing of three distinct action types, intransitive self-oriented actions (e.g., stretching, rubbing one’s eyes, etc.), transitive object-oriented actions (e.g., opening a door, lifting a cup to the lips to drink), and the abstract, symbolic actions–signs used in American Sign Language. Our results show that these different classes of human actions engage a frontal/parietal/STS human action recognition system in a highly similar fashion. However, the results indicate that this neural consistency across motion classes is true primarily for hearing subjects. Data from deaf signers shows a non-uniform response to different classes of human actions. As expected, deaf signers engaged left-hemisphere perisylvian language areas during the perception of signed language signs. Surprisingly, these subjects did not engage the expected frontal/parietal/STS circuitry during passive viewing of non-linguistic actions, but rather reliably activated middle-occipital temporal-ventral regions which are known to participate in the detection of human bodies, faces, and movements. Comparisons with data from hearing subjects establish statistically significant contributions of middle-occipital temporal-ventral during the processing of non-linguistic actions in deaf signers. These results suggest that during human motion processing, deaf individuals may engage specialized neural systems that allow for rapid, online differentiation of meaningful linguistic actions from non-linguistic human movements. PMID:17459349

  6. Sox2-mediated regulation of adult neural crest precursors and skin repair.

    PubMed

    Johnston, Adam P W; Naska, Sibel; Jones, Karen; Jinno, Hiroyuki; Kaplan, David R; Miller, Freda D

    2013-01-01

    Nerve-derived neural crest cells are essential for regeneration in certain animals, such as newts. Here, we asked whether they play a similar role during mammalian tissue repair, focusing on Sox2-positive neural crest precursors in skin. In adult skin, Sox2 was expressed in nerve-terminal-associated neural crest precursor cells (NCPCs) around the hair follicle bulge, and following injury was induced in nerve-derived cells, likely dedifferentiated Schwann cell precursors. At later times postinjury, Sox2-positive cells were scattered throughout the regenerating dermis, and lineage tracing showed that these were all neural-crest-derived NCPCs. These Sox2-positive NCPCs were functionally important, since acute deletion of Sox2 prior to injury caused a decrease of NCPCs in the wound and aberrant skin repair. These data demonstrate that Sox2 regulates skin repair, likely by controlling NCPCs, and raise the possibility that nerve-derived NCPCs may play a general role in mammalian tissue repair.

  7. 3D cultures of human neural progenitor cells: dopaminergic differentiation and genetic modification. [corrected].

    PubMed

    Brito, Catarina; Simão, Daniel; Costa, Inês; Malpique, Rita; Pereira, Cristina I; Fernandes, Paulo; Serra, Margarida; Schwarz, Sigrid C; Schwarz, Johannes; Kremer, Eric J; Alves, Paula M

    2012-03-01

    Central nervous system (CNS) disorders remain a formidable challenge for the development of efficient therapies. Cell and gene therapy approaches are promising alternatives that can have a tremendous impact by treating the causes of the disease rather than the symptoms, providing specific targeting and prolonged duration of action. Hampering translation of gene-based therapeutic treatments of neurodegenerative diseases from experimental to clinical gene therapy is the lack of valid and reliable pre-clinical models that can contribute to evaluate feasibility and safety. Herein we describe a robust and reproducible methodology for the generation of 3D in vitro models of the human CNS following a systematic technological approach based on stirred culture systems. We took advantage of human midbrain-derived neural progenitor cells (hmNPCs) capability to differentiate into the various neural phenotypes and of their commitment to the dopaminergic lineage to generate differentiated neurospheres enriched in dopaminergic neurons. Furthermore, we describe a protocol for efficient gene transfer into differentiated neurospheres using CAV-2 viral vectors and stable expression of the transgene for at least 10 days. CAV-2 vectors, derived from canine adenovirus type 2, are promising tools to understand and treat neurodegenerative diseases, in particular Parkinson's disease. CAV-2 vectors preferentially transduce neurons and have an impressive level of axonal retrograde transport in vivo. Our model provides a practical and versatile in vitro approach to study the CNS in a 3D cellular context. With the successful differentiation and subsequent genetic modification of neurospheres we are increasing the collection of tools available for neuroscience research and contributing for the implementation and widespread utilization of 3D cellular CNS models. These can be applied to study neurodegenerative diseases such as Parkinson's disease; to study the interaction of viral vectors of

  8. 3D cultures of human neural progenitor cells: dopaminergic differentiation and genetic modification. [corrected].

    PubMed

    Brito, Catarina; Simão, Daniel; Costa, Inês; Malpique, Rita; Pereira, Cristina I; Fernandes, Paulo; Serra, Margarida; Schwarz, Sigrid C; Schwarz, Johannes; Kremer, Eric J; Alves, Paula M

    2012-03-01

    Central nervous system (CNS) disorders remain a formidable challenge for the development of efficient therapies. Cell and gene therapy approaches are promising alternatives that can have a tremendous impact by treating the causes of the disease rather than the symptoms, providing specific targeting and prolonged duration of action. Hampering translation of gene-based therapeutic treatments of neurodegenerative diseases from experimental to clinical gene therapy is the lack of valid and reliable pre-clinical models that can contribute to evaluate feasibility and safety. Herein we describe a robust and reproducible methodology for the generation of 3D in vitro models of the human CNS following a systematic technological approach based on stirred culture systems. We took advantage of human midbrain-derived neural progenitor cells (hmNPCs) capability to differentiate into the various neural phenotypes and of their commitment to the dopaminergic lineage to generate differentiated neurospheres enriched in dopaminergic neurons. Furthermore, we describe a protocol for efficient gene transfer into differentiated neurospheres using CAV-2 viral vectors and stable expression of the transgene for at least 10 days. CAV-2 vectors, derived from canine adenovirus type 2, are promising tools to understand and treat neurodegenerative diseases, in particular Parkinson's disease. CAV-2 vectors preferentially transduce neurons and have an impressive level of axonal retrograde transport in vivo. Our model provides a practical and versatile in vitro approach to study the CNS in a 3D cellular context. With the successful differentiation and subsequent genetic modification of neurospheres we are increasing the collection of tools available for neuroscience research and contributing for the implementation and widespread utilization of 3D cellular CNS models. These can be applied to study neurodegenerative diseases such as Parkinson's disease; to study the interaction of viral vectors of

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

    SciTech Connect

    Manceur, Aziza P.; Tseng, Michael; Holowacz, Tamara; Witterick, Ian; Weksberg, Rosanna; McCurdy, Richard D.; Warsh, Jerry J.; Audet, Julie

    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.

  10. Improved Method for Ex Ovo-Cultivation of Developing Chicken Embryos for Human Stem Cell Xenografts

    PubMed Central

    Schomann, Timo; Qunneis, Firas; Widera, Darius; Kaltschmidt, Christian; Kaltschmidt, Barbara

    2013-01-01

    The characterization of human stem cells for the usability in regenerative medicine is particularly based on investigations regarding their differentiation potential in vivo. In this regard, the chicken embryo model represents an ideal model organism. However, the access to the chicken embryo is only achievable by windowing the eggshell resulting in limited visibility and accessibility in subsequent experiments. On the contrary, ex ovo-culture systems avoid such negative side effects. Here, we present an improved ex ovo-cultivation method enabling the embryos to survive 13 days in vitro. Optimized cultivation of chicken embryos resulted in a normal development regarding their size and weight. Our ex ovo-approach closely resembles the development of chicken embryos in ovo, as demonstrated by properly developed nervous system, bones, and cartilage at expected time points. Finally, we investigated the usability of our method for trans-species transplantation of adult stem cells by injecting human neural crest-derived stem cells into late Hamburger and Hamilton stages (HH26–HH28/E5—E6) of ex ovo-incubated embryos. We demonstrated the integration of human cells allowing experimentally easy investigation of the differentiation potential in the proper developmental context. Taken together, this ex ovo-method supports the prolonged cultivation of properly developing chicken embryos enabling integration studies of xenografted mammalian stem cells at late developmental stages. PMID:23554818

  11. 3D Normal Human Neural Progenitor Tissue-Like Assemblies: A Model of Persistent VZV Infection

    NASA Technical Reports Server (NTRS)

    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.

  12. Disentangling neural representations of value and salience in the human brain.

    PubMed

    Kahnt, Thorsten; Park, Soyoung Q; Haynes, John-Dylan; Tobler, Philippe N

    2014-04-01

    A large body of evidence has implicated the posterior parietal and orbitofrontal cortex in the processing of value. However, value correlates perfectly with salience when appetitive stimuli are investigated in isolation. Accordingly, considerable uncertainty has remained about the precise nature of the previously identified signals. In particular, recent evidence suggests that neurons in the primate parietal cortex signal salience instead of value. To investigate neural signatures of value and salience, here we apply multivariate (pattern-based) analyses to human functional MRI data acquired during a noninstrumental outcome-prediction task involving appetitive and aversive outcomes. Reaction time data indicated additive and independent effects of value and salience. Critically, we show that multivoxel ensemble activity in the posterior parietal cortex encodes predicted value and salience in superior and inferior compartments, respectively. These findings reinforce the earlier reports of parietal value signals and reconcile them with the recent salience report. Moreover, we find that multivoxel patterns in the orbitofrontal cortex correlate with value. Importantly, the patterns coding for the predicted value of appetitive and aversive outcomes are similar, indicating a common neural scale for appetite and aversive values in the orbitofrontal cortex. Thus orbitofrontal activity patterns satisfy a basic requirement for a neural value signal.

  13. Functional Magnetic Resonance Imaging for Imaging Neural Activity in the Human Brain: The Annual Progress

    PubMed Central

    Chen, Shengyong; Li, Xiaoli

    2012-01-01

    Functional magnetic resonance imaging (fMRI) is recently developed and applied to measure the hemodynamic response related to neural activity. The fMRI can not only noninvasively record brain signals without risks of ionising radiation inherent in other scanning methods, such as CT or PET scans, but also record signal from all regions of the brain, unlike EEG/MEG which are biased towards the cortical surface. This paper introduces the fundamental principles and summarizes the research progress of the last year for imaging neural activity in the human brain. Aims of functional analysis of neural activity from fMRI include biological findings, functional connectivity, vision and hearing research, emotional research, neurosurgical planning, pain management, and many others. Besides formulations and basic processing methods, models and strategies of processing technology are introduced, including general linear model, nonlinear model, generative model, spatial pattern analysis, statistical analysis, correlation analysis, and multimodal combination. This paper provides readers the most recent representative contributions in the area. PMID:22319550

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

    PubMed

    Zirra, Alexandra; Wiethoff, Sarah; Patani, Rickie

    2016-01-01

    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. PMID:27069483

  15. Transplantation of Defined Populations of Differentiated Human Neural Stem Cell Progeny

    PubMed Central

    Fortin, Jeff M.; Azari, Hassan; Zheng, Tong; Darioosh, Roya P.; Schmoll, Michael E.; Vedam-Mai, Vinata; Deleyrolle, Loic P.; Reynolds, Brent A.

    2016-01-01

    Many neurological injuries are likely too extensive for the limited repair capacity of endogenous neural stem cells (NSCs). An alternative is to isolate NSCs from a donor, and expand them in vitro as transplantation material. Numerous groups have already transplanted neural stem and precursor cells. A caveat to this approach is the undefined phenotypic distribution of the donor cells, which has three principle drawbacks: (1) Stem-like cells retain the capacity to proliferate in vivo. (2) There is little control over the cells’ terminal differentiation, e.g., a graft intended to replace neurons might choose a predominantly glial fate. (3) There is limited ability of researchers to alter the combination of cell types in pursuit of a precise treatment. We demonstrate a procedure for differentiating human neural precursor cells (hNPCs) in vitro, followed by isolation of the neuronal progeny. We transplanted undifferentiated hNPCs or a defined concentration of hNPC-derived neurons into mice, then compared these two groups with regard to their survival, proliferation and phenotypic fate. We present evidence suggesting that in vitro-differentiated-and-purified neurons survive as well in vivo as their undifferentiated progenitors, and undergo less proliferation and less astrocytic differentiation. We also describe techniques for optimizing low-temperature cell preservation and portability. PMID:27030542

  16. Behavioral and genetic correlates of the neural response to infant crying among human fathers

    PubMed Central

    Mascaro, Jennifer S.; Hackett, Patrick D.; Gouzoules, Harold; Lori, Adriana

    2014-01-01

    Although evolution has shaped human infant crying and the corresponding response from caregivers, there is marked variation in paternal involvement and caretaking behavior, highlighting the importance of understanding the neurobiology supporting optimal paternal responses to cries. We explored the neural response to infant cries in fathers of children aged 1–2, and its relationship with hormone levels, variation in the androgen receptor (AR) gene, parental attitudes and parental behavior. Although number of AR CAG trinucleotide repeats was positively correlated with neural activity in brain regions important for empathy (anterior insula and inferior frontal gyrus), restrictive attitudes were inversely correlated with neural activity in these regions and with regions involved with emotion regulation (orbitofrontal cortex). Anterior insula activity had a non-linear relationship with paternal caregiving, such that fathers with intermediate activation were most involved. These results suggest that restrictive attitudes may be associated with decreased empathy and emotion regulation in response to a child in distress, and that moderate anterior insula activity reflects an optimal level of arousal that supports engaged fathering. PMID:24336349

  17. Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin.

    PubMed Central

    Barber, A J; Lieth, E; Khin, S A; Antonetti, D A; Buchanan, A G; Gardner, T W

    1998-01-01

    This study determined whether retinal degeneration during diabetes includes retinal neural cell apoptosis. Image analysis of retinal sections from streptozotocin (STZ) diabetic rats after 7.5 months of STZ diabetes identified 22% and 14% reductions in the thickness of the inner plexiform and inner nuclear layers, respectively (P < 0. 001). The number of surviving ganglion cells was also reduced by 10% compared to controls (P < 0.001). In situ end labeling of DNA terminal dUTP nick end labeling (TUNEL) identified a 10-fold increase in the frequency of retinal apoptosis in whole-mounted rat retinas after 1, 3, 6, and 12 months of diabetes (P < 0.001, P < 0. 001, P < 0.01, and P < 0.01, respectively). Most TUNEL-positive cells were not associated with blood vessels and did not colocalize with the endothelial cell-specific antigen, von Willebrand factor. Insulin implants significantly reduced the number of TUNEL-positive cells (P < 0.05). The number of TUNEL-positive cells was also increased in retinas from humans with diabetes. These data indicate that retinal neural cell death occurs early in diabetes. This is the first quantitative report of an increase in neural cell apoptosis in the retina during diabetes, and indicates that neurodegeneration is an important component of diabetic retinopathy. PMID:9710447

  18. Functional magnetic resonance imaging for imaging neural activity in the human brain: the annual progress.

    PubMed

    Chen, Shengyong; Li, Xiaoli

    2012-01-01

    Functional magnetic resonance imaging (fMRI) is recently developed and applied to measure the hemodynamic response related to neural activity. The fMRI can not only noninvasively record brain signals without risks of ionising radiation inherent in other scanning methods, such as CT or PET scans, but also record signal from all regions of the brain, unlike EEG/MEG which are biased towards the cortical surface. This paper introduces the fundamental principles and summarizes the research progress of the last year for imaging neural activity in the human brain. Aims of functional analysis of neural activity from fMRI include biological findings, functional connectivity, vision and hearing research, emotional research, neurosurgical planning, pain management, and many others. Besides formulations and basic processing methods, models and strategies of processing technology are introduced, including general linear model, nonlinear model, generative model, spatial pattern analysis, statistical analysis, correlation analysis, and multimodal combination. This paper provides readers the most recent representative contributions in the area.

  19. Human endometrial stem cells as a new source for programming to neural cells.

    PubMed

    Mobarakeh, Zahra Taherian; Ai, Jafar; Yazdani, Farzad; Sorkhabadi, Seyed Mahdi Rezayat; Ghanbari, Zinat; Javidan, Abbas Noroozi; Mortazavi-Tabatabaei, Seyed Abdolreza; Massumi, Mohammad; Barough, Somayeh Ebrahimi

    2012-04-26

    Human EnSC (endometrial-derived stem cell) is an abundant and easily available source for cell replacement therapy. Many investigations have shown the potency of the cells to differentiate into several mesoderm-derived cell lineages, including osteocytes and adipocytes. Here, the potency of EnSC in neural differentiation has been investigated. Flow cytometric analysis showed that they were positive for CD90, CD105, OCT4, CD44 and negative for CD31, CD34, CD133. The characterized cells were induced into neural differentiation by bFGF (basic fibroblast growth factor), PDGF (platelet-derived growth factor) and EGF (epidermal growth factor) signalling molecules, respectively in a sequential protocol, and differentiated cells were analysed for expression of neuronal markers by RT-PCR (reverse transcription-PCR) and immunocytochemistry, including Nestin, GABA (γ-aminobutyric acid), MAP2 (microtubule-associated protein 2), β3-tub (class III β-tubulin) and NF-L (neurofilament-light) at the level of their mRNAs. The expression of MAP2, β3-tub and NF-L proteins in EnSC was confirmed 28 days PT (post-treatment) by immunocytochemistry. In conclusion, EnSC can respond to signalling molecules that are usually used as standards in neural differentiation and can programme neuronal cells, making these cells worth considering as a unique source for cell therapy in neurodegenerative disease.

  20. Neural differentiation of novel multipotent progenitor cells from cryopreserved human umbilical cord blood

    SciTech Connect

    Lee, Myoung Woo; Moon, Young Joon; Yang, Mal Sook; Kim, Sun Kyung; Jang, In Keun; Eom, Young-woo; Park, Joon Seong; Kim, Hugh C.; Song, Kye Yong; Park, Soon Cheol; Lim, Hwan Sub; Kim, Young Jin . E-mail: jin@lifecord.co.kr

    2007-06-29

    Umbilical cord blood (UCB) is a rich source of hematopoietic stem cells, with practical and ethical advantages. To date, the presence of other stem cells in UCB remains to be established. We investigated whether other stem cells are present in cryopreserved UCB. Seeded mononuclear cells formed adherent colonized cells in optimized culture conditions. Over a 4- to 6-week culture period, colonized cells gradually developed into adherent mono-layer cells, which exhibited homogeneous fibroblast-like morphology and immunophenotypes, and were highly proliferative. Isolated cells were designated 'multipotent progenitor cells (MPCs)'. Under appropriate conditions for 2 weeks, MPCs differentiated into neural tissue-specific cell types, including neuron, astrocyte, and oligodendrocyte. Differentiated cells presented their respective markers, specifically, NF-L and NSE for neurons, GFAP for astrocytes, and myelin/oligodendrocyte for oligodendrocytes. In this study, we successfully isolated MPCs from cryopreserved UCB, which differentiated into the neural tissue-specific cell types. These findings suggest that cryopreserved human UCB is a useful alternative source of neural progenitor cells, such as MPCs, for experimental and therapeutic applications.

  1. Neural Summation in Human Motor Cortex by Subthreshold Transcranial Magnetic Stimulations

    PubMed Central

    Du, Xiaoming; Choa, Fow-Sen; Summerfelt, Ann; Tagamets, Malle A.; Rowland, Laura M.; Kochunov, Peter; Shepard, Paul; Hong, L. Elliot

    2014-01-01

    Integration of diverse synaptic inputs is a basic neuronal operation that relies on many neurocomputational principles, one of which is neural summation. However, we lack empirical understanding of neuronal summation in the human brains in vivo. Here we explored the effect of neural summation in the motor cortex using two subthreshold pulses of transcranial magnetic stimulation (TMS), each with intensities ranging from 60% - 95% of the resting motor threshold (RMT) and interstimulus intervals (ISI) varying from 1 – 25 ms. We found that two subthreshold TMS pulses can produce supra threshold motor response when ISIs were less than 10 ms, most prominent at 1, 1.5 and 3 ms. This facilitatory, above threshold response was evident when the intensity of the subthreshold pulses were above 80% of RMT but was absent as the intensity was 70% or below. Modeling of the summation data across intensity suggested that they followed an exponential function with excellent model fitting. Understanding the constraints for inducing summation of subthreshold stimulations to generate above threshold response may have implications in modeling neural operations and potential clinical applications. PMID:25399245

  2. Is Avoiding an Aversive Outcome Rewarding? Neural Substrates of Avoidance Learning in the Human Brain

    PubMed Central

    Kim, Hackjin; Shimojo, Shinsuke

    2006-01-01

    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. PMID:16802856

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

    PubMed Central

    Zirra, Alexandra; Wiethoff, Sarah; Patani, Rickie

    2016-01-01

    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. PMID:27069483

  4. Disentangling neural representations of value and salience in the human brain.

    PubMed

    Kahnt, Thorsten; Park, Soyoung Q; Haynes, John-Dylan; Tobler, Philippe N

    2014-04-01

    A large body of evidence has implicated the posterior parietal and orbitofrontal cortex in the processing of value. However, value correlates perfectly with salience when appetitive stimuli are investigated in isolation. Accordingly, considerable uncertainty has remained about the precise nature of the previously identified signals. In particular, recent evidence suggests that neurons in the primate parietal cortex signal salience instead of value. To investigate neural signatures of value and salience, here we apply multivariate (pattern-based) analyses to human functional MRI data acquired during a noninstrumental outcome-prediction task involving appetitive and aversive outcomes. Reaction time data indicated additive and independent effects of value and salience. Critically, we show that multivoxel ensemble activity in the posterior parietal cortex encodes predicted value and salience in superior and inferior compartments, respectively. These findings reinforce the earlier reports of parietal value signals and reconcile them with the recent salience report. Moreover, we find that multivoxel patterns in the orbitofrontal cortex correlate with value. Importantly, the patterns coding for the predicted value of appetitive and aversive outcomes are similar, indicating a common neural scale for appetite and aversive values in the orbitofrontal cortex. Thus orbitofrontal activity patterns satisfy a basic requirement for a neural value signal. PMID:24639493

  5. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth.

    PubMed

    Tang, Hengli; Hammack, Christy; Ogden, Sarah C; Wen, Zhexing; Qian, Xuyu; Li, Yujing; Yao, Bing; Shin, Jaehoon; Zhang, Feiran; Lee, Emily M; Christian, Kimberly M; Didier, Ruth A; Jin, Peng; Song, Hongjun; Ming, Guo-Li

    2016-05-01

    The suspected link between infection by Zika virus (ZIKV), a re-emerging flavivirus, and microcephaly is an urgent global health concern. The direct target cells of ZIKV in the developing human fetus are not clear. Here we show that a strain of the ZIKV, MR766, serially passaged in monkey and mosquito cells efficiently infects human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells. Infected hNPCs further release infectious ZIKV particles. Importantly, ZIKV infection increases cell death and dysregulates cell-cycle progression, resulting in attenuated hNPC growth. Global gene expression analysis of infected hNPCs reveals transcriptional dysregulation, notably of cell-cycle-related pathways. Our results identify hNPCs as a direct ZIKV target. In addition, we establish a tractable experimental model system to investigate the impact and mechanism of ZIKV on human brain development and provide a platform to screen therapeutic compounds.

  6. Distinct gene expression responses of two anticonvulsant drugs in a novel human embryonic stem cell based neural differentiation assay protocol.

    PubMed

    Schulpen, Sjors H W; de Jong, Esther; de la Fonteyne, Liset J J; de Klerk, Arja; Piersma, Aldert H

    2015-04-01

    Hazard assessment of chemicals and pharmaceuticals is increasingly gaining from knowledge about molecular mechanisms of toxic action acquired in dedicated in vitro assays. We have developed an efficient human embryonic stem cell neural differentiation test (hESTn) that allows the study of the molecular interaction of compounds with the neural differentiation process. Within the 11-day differentiation protocol of the assay, embryonic stem cells lost their pluripotency, evidenced by the reduced expression of stem cell markers Pou5F1 and Nanog. Moreover, stem cells differentiated into neural cells, with morphologically visible neural structures together with increased expression of neural differentiation-related genes such as βIII-tubulin, Map2, Neurogin1, Mapt and Reelin. Valproic acid (VPA) and carbamazepine (CBZ) exposure during hESTn differentiation led to concentration-dependent reduced expression of βIII-tubulin, Neurogin1 and Reelin. In parallel VPA caused an increased gene expression of Map2 and Mapt which is possibly related to the neural protective effect of VPA. These findings illustrate the added value of gene expression analysis for detecting compound specific effects in hESTn. Our findings were in line with and could explain effects observed in animal studies. This study demonstrates the potential of this assay protocol for mechanistic analysis of specific compound-induced inhibition of human neural cell differentiation.

  7. A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts.

    PubMed

    Reamon-Buettner, Stella Marie; Ciribilli, Yari; Inga, Alberto; Borlak, Juergen

    2008-05-15

    Hypoplasia of the human heart is the most severe form of congenital heart disease (CHD) and usually lethal during early infancy. It is a leading cause of neonatal loss, especially in infants diagnosed with hypoplastic left heart syndrome (HLHS), a condition where the left side of the heart including the aorta, aortic valve, left ventricle (LV) and mitral valve are underdeveloped. The molecular causes of HLHS are unclear, but the basic helix-loop-helix (bHLH) transcription factor heart and neural crest derivatives expressed 1 (Hand1), may be a candidate culprit for this condition. The absence of Hand1 in mice resulted in the failure of rightward looping of the heart tube, a severely hypoplastic LV and outflow tract abnormalities. Nonetheless, no HAND1 mutations associated with human CHD have been reported so far. We sequenced the human HAND1 gene in heart tissues derived from 31 unrelated patients diagnosed with hypoplastic hearts. We detected in 24 of 31 hypoplastic ventricles, a common frameshift mutation (A126fs) in the bHLH domain, which is necessary for DNA binding and combinatorial interactions. The resulting mutant protein, unlike wild-type (wt) HAND1, was unable to modulate transcription of reporter constructs containing specific DNA-binding sites. Thus, in hypoplastic human hearts HAND1 function is impaired.

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

    PubMed

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

    2015-02-01

    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. PMID:25653384

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

    PubMed

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

    2015-02-01

    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.

  10. Evolutionary Basis of Human Running and Its Impact on Neural Function.

    PubMed

    Schulkin, Jay

    2016-01-01

    Running is not unique to humans, but it is seemingly a basic human capacity. This article addresses the evolutionary origins of humans running long distances, the basic physical capability of running, and the neurogenesis of aerobic fitness. This article more specifically speaks to the conditions that set the stage for the act of running, and then looks at brain expression, and longer-term consequences of running within a context of specific morphological features and diverse information molecules that participate in our capacity for running and sport. While causal factors are not known, we do know that physiological factors are involved in running and underlie neural function. Multiple themes about running are discussed in this article, including neurogenesis, neural plasticity, and memory enhancement. Aerobic exercise increases anterior hippocampus size. This expansion is linked to the improvement of memory, which reflects the improvement of learning as a function of running activity in animal studies. Higher fitness is associated with greater expansion, not only of the hippocampus, but of several other brain regions. PMID:27462208

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

    PubMed Central

    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

  12. Evolutionary Basis of Human Running and Its Impact on Neural Function

    PubMed Central

    Schulkin, Jay

    2016-01-01

    Running is not unique to humans, but it is seemingly a basic human capacity. This article addresses the evolutionary origins of humans running long distances, the basic physical capability of running, and the neurogenesis of aerobic fitness. This article more specifically speaks to the conditions that set the stage for the act of running, and then looks at brain expression, and longer-term consequences of running within a context of specific morphological features and diverse information molecules that participate in our capacity for running and sport. While causal factors are not known, we do know that physiological factors are involved in running and underlie neural function. Multiple themes about running are discussed in this article, including neurogenesis, neural plasticity, and memory enhancement. Aerobic exercise increases anterior hippocampus size. This expansion is linked to the improvement of memory, which reflects the improvement of learning as a function of running activity in animal studies. Higher fitness is associated with greater expansion, not only of the hippocampus, but of several other brain regions. PMID:27462208

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

    PubMed Central

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

    2010-01-01

    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. PMID:19015583

  14. Neural Mechanisms Underlying Contextual Dependency of Subjective Values: Converging Evidence from Monkeys and Humans

    PubMed Central

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

    2015-01-01

    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. PMID:25653384

  15. Learning of new sound categories shapes neural response patterns in human auditory cortex.

    PubMed

    Ley, Anke; Vroomen, Jean; Hausfeld, Lars; Valente, Giancarlo; De Weerd, Peter; Formisano, Elia

    2012-09-19

    The formation of new sound categories is fundamental to everyday goal-directed behavior. Categorization requires the abstraction of discrete classes from continuous physical features as required by context and task. Electrophysiology in animals has shown that learning to categorize novel sounds alters their spatiotemporal neural representation at the level of early auditory cortex. However, functional magnetic resonance imaging (fMRI) studies so far did not yield insight into the effects of category learning on sound representations in human auditory cortex. This may be due to the use of overlearned speech-like categories and fMRI subtraction paradigms, leading to insufficient sensitivity to distinguish the responses to learning-induced, novel sound categories. Here, we used fMRI pattern analysis to investigate changes in human auditory cortical response patterns induced by category learning. We created complex novel sound categories and analyzed distributed activation patterns during passive listening to a sound continuum before and after category learning. We show that only after training, sound categories could be successfully decoded from early auditory areas and that learning-induced pattern changes were specific to the category-distinctive sound feature (i.e., pitch). Notably, the similarity between fMRI response patterns for the sound continuum mirrored the sigmoid shape of the behavioral category identification function. Our results indicate that perceptual representations of novel sound categories emerge from neural changes at early levels of the human auditory processing hierarchy.

  16. Human facial neural activities and gesture recognition for machine-interfacing applications.

    PubMed

    Hamedi, M; Salleh, Sh-Hussain; Tan, T S; Ismail, K; Ali, J; Dee-Uam, C; Pavaganun, C; Yupapin, P P

    2011-01-01

    The authors present a new method of recognizing different human facial gestures through their neural activities and muscle movements, which can be used in machine-interfacing applications. Human-machine interface (HMI) technology utilizes human neural activities as input controllers for the machine. Recently, much work has been done on the specific application of facial electromyography (EMG)-based HMI, which have used limited and fixed numbers of facial gestures. In this work, a multipurpose interface is suggested that can support 2-11 control commands that can be applied to various HMI systems. The significance of this work is finding the most accurate facial gestures for any application with a maximum of eleven control commands. Eleven facial gesture EMGs are recorded from ten volunteers. Detected EMGs are passed through a band-pass filter and root mean square features are extracted. Various combinations of gestures with a different number of gestures in each group are made from the existing facial gestures. Finally, all combinations are trained and classified by a Fuzzy c-means classifier. In conclusion, combinations with the highest recognition accuracy in each group are chosen. An average accuracy >90% of chosen combinations proved their ability to be used as command controllers.

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

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

    2015-01-01

    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 nonspecific marker of brain activation. Here, 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 unprecedented spatial and temporal precision. PMID:25279772

  19. Kinesin Light Chain 1 Suppression Impairs Human Embryonic Stem Cell Neural Differentiation and Amyloid Precursor Protein Metabolism

    PubMed Central

    Killian, Rhiannon L.; Flippin, Jessica D.; Herrera, Cheryl M.; Almenar-Queralt, Angels; Goldstein, Lawrence S. B.

    2012-01-01

    The etiology of sporadic Alzheimer disease (AD) is largely unknown, although evidence implicates the pathological hallmark molecules amyloid beta (Aβ) and phosphorylated Tau. Work in animal models suggests that altered axonal transport caused by Kinesin-1 dysfunction perturbs levels of both Aβ and phosphorylated Tau in neural tissues, but the relevance of Kinesin-1 dependent functions to the human disease is unknown. To begin to address this issue, we generated human embryonic stem cells (hESC) expressing reduced levels of the kinesin light chain 1 (KLC1) Kinesin-1 subunit to use as a source of human neural cultures. Despite reduction of KLC1, undifferentiated hESC exhibited apparently normal colony morphology and pluripotency marker expression. Differentiated neural cultures derived from KLC1-suppressed hESC contained neural rosettes but further differentiation revealed obvious morphological changes along with reduced levels of microtubule-associated neural proteins, including Tau and less secreted Aβ, supporting the previously established connection between KLC1, Tau and Aβ. Intriguingly, KLC1-suppressed neural precursors (NPs), isolated using a cell surface marker signature known to identify cells that give rise to neurons and glia, unlike control cells, failed to proliferate. We suggest that KLC1 is required for normal human neural differentiation, ensuring proper metabolism of AD-associated molecules APP and Tau and for proliferation of NPs. Because impaired APP metabolism is linked to AD, this human cell culture model system will not only be a useful tool for understanding the role of KLC1 in regulating the production, transport and turnover of APP and Tau in neurons, but also in defining the essential function(s) of KLC1 in NPs and their progeny. This knowledge should have important implications for human neurodevelopmental and neurodegenerative diseases. PMID:22272245

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

    PubMed Central

    Lemon, Christian H.

    2015-01-01

    Introduction This mini-review discusses some of the parallels between rodent neurophysiological and human psychophysical data concerning temperature effects on sweet taste. Methods and Purpose “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. Results and Conclusions 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. PMID:26388965

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

    NASA Astrophysics Data System (ADS)

    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.

  2. Detection of whale calls in noise: performance comparison between a beluga whale, human listeners, and a neural network.

    PubMed

    Erbe, C

    2000-07-01

    This article examines the masking by anthropogenic noise of beluga whale calls. Results from human masking experiments and a software backpropagation neural network are compared to the performance of a trained beluga whale. The goal was to find an accurate, reliable, and fast model to replace lengthy and expensive animal experiments. A beluga call was masked by three types of noise, an icebreaker's bubbler system and propeller noise, and ambient arctic ice-cracking noise. Both the human experiment and the neural network successfully modeled the beluga data in the sense that they classified the noises in the same order from strongest to weakest masking as the whale and with similar call-detection thresholds. The neural network slightly outperformed the humans. Both models were then used to predict the masking of a fourth type of noise, Gaussian white noise. Their prediction ability was judged by returning to the aquarium to measure masked-hearing thresholds of a beluga in white noise. Both models and the whale identified bubbler noise as the strongest masker, followed by ramming, then white noise. Natural ice-cracking noise masked the least. However, the humans and the neural network slightly overpredicted the amount of masking for white noise. This is neglecting individual variation in belugas, because only one animal could be trained. Comparing the human model to the neural network model, the latter has the advantage of objectivity, reproducibility of results, and efficiency, particularly if the interference of a large number of signals and noise is to be examined.

  3. Human epidermal neural crest stem cells as a source of Schwann cells

    PubMed Central

    Sakaue, Motoharu; Sieber-Blum, Maya

    2015-01-01

    We show that highly pure populations of human Schwann cells can be derived rapidly and in a straightforward way, without the need for genetic manipulation, from human epidermal neural crest stem cells [hEPI-NCSC(s)] present in the bulge of hair follicles. These human Schwann cells promise to be a useful tool for cell-based therapies, disease modelling and drug discovery. Schwann cells are glia that support axons of peripheral nerves and are direct descendants of the embryonic neural crest. Peripheral nerves are damaged in various conditions, including through trauma or tumour-related surgery, and Schwann cells are required for their repair and regeneration. Schwann cells also promise to be useful for treating spinal cord injuries. Ex vivo expansion of hEPI-NCSC isolated from hair bulge explants, manipulating the WNT, sonic hedgehog and TGFβ signalling pathways, and exposure of the cells to pertinent growth factors led to the expression of the Schwann cell markers SOX10, KROX20 (EGR2), p75NTR (NGFR), MBP and S100B by day 4 in virtually all cells, and maturation was completed by 2 weeks of differentiation. Gene expression profiling demonstrated expression of transcripts for neurotrophic and angiogenic factors, as well as JUN, all of which are essential for nerve regeneration. Co-culture of hEPI-NCSC-derived human Schwann cells with rodent dorsal root ganglia showed interaction of the Schwann cells with axons, providing evidence of Schwann cell functionality. We conclude that hEPI-NCSCs are a biologically relevant source for generating large and highly pure populations of human Schwann cells. PMID:26251357

  4. Tripartite containing motif 32 modulates proliferation of human neural precursor cells in HIV-1 neurodegeneration

    PubMed Central

    Fatima, M; Kumari, R; Schwamborn, J C; Mahadevan, A; Shankar, S K; Raja, R; Seth, P

    2016-01-01

    In addition to glial cells, HIV-1 infection occurs in multipotent human neural precursor cells (hNPCs) and induces quiescence in NPCs. HIV-1 infection of the brain alters hNPC stemness, leading to perturbed endogenous neurorestoration of the CNS following brain damage by HIV-1, compounding the severity of dementia in adult neuroAIDS cases. In pediatric neuroAIDS cases, HIV-1 infection of neural stem cell can lead to delayed developmental milestones and impaired cognition. Using primary cultures of human fetal brain-derived hNPCs, we gained novel insights into the role of a neural stem cell determinant, tripartite containing motif 32 (TRIM32), in HIV-1 Tat-induced quiescence of NPCs. Acute HIV-1 Tat treatment of hNPCs resulted in proliferation arrest but did not induce differentiation. Cellular localization and levels of TRIM32 are critical regulators of stemness of NPCs. HIV-1 Tat exposure increased nuclear localization and levels of TRIM32 in hNPCs. The in vitro findings were validated by studying TRIM32 localization and levels in frontal cortex of HIV-1-seropositive adult patients collected at post mortem as well as by infection of hNPCs by HIV-1. We observed increased percentage of cells with nuclear localization of TRIM32 in the subventricular zone (SVZ) as compared with age-matched controls. Our quest for probing into the mechanisms revealed that TRIM32 is targeted by miR-155 as downregulation of miR-155 by HIV-1 Tat resulted in upregulation of TRIM32 levels. Furthermore, miR-155 or siRNA against TRIM32 rescued HIV-1 Tat-induced quiescence in NPCs. Our findings suggest a novel molecular cascade involving miR-155 and TRIM32 leading to HIV-1 Tat-induced attenuated proliferation of hNPCs. The study also uncovered an unidentified role for miR-155 in modulating human neural stem cell proliferation, helping in better understanding of hNPCs and diseased brain. PMID:26586575

  5. Neural Mechanisms of Human Perceptual Learning: Electrophysiological Evidence for a Two-Stage Process

    PubMed Central

    Hamamé, Carlos M.; Cosmelli, Diego; Henriquez, Rodrigo; Aboitiz, Francisco

    2011-01-01

    Background Humans and other animals change the way they perceive the world due to experience. This process has been labeled as perceptual learning, and implies that adult nervous systems can adaptively modify the way in which they process sensory stimulation. However, the mechanisms by which the brain modifies this capacity have not been sufficiently analyzed. Methodology/Principal Findings We studied the neural mechanisms of human perceptual learning by combining electroencephalographic (EEG) recordings of brain activity and the assessment of psychophysical performance during training in a visual search task. All participants improved their perceptual performance as reflected by an increase in sensitivity (d') and a decrease in reaction time. The EEG signal was acquired throughout the entire experiment revealing amplitude increments, specific and unspecific to the trained stimulus, in event-related potential (ERP) components N2pc and P3 respectively. P3 unspecific modification can be related to context or task-based learning, while N2pc may be reflecting a more specific attentional-related boosting of target detection. Moreover, bell and U-shaped profiles of oscillatory brain activity in gamma (30–60 Hz) and alpha (8–14 Hz) frequency bands may suggest the existence of two phases for learning acquisition, which can be understood as distinctive optimization mechanisms in stimulus processing. Conclusions/Significance We conclude that there are reorganizations in several neural processes that contribute differently to perceptual learning in a visual search task. We propose an integrative model of neural activity reorganization, whereby perceptual learning takes place as a two-stage phenomenon including perceptual, attentional and contextual processes. PMID:21541280

  6. Unsupervised Decoding of Long-Term, Naturalistic Human Neural Recordings with Automated Video and Audio Annotations.

    PubMed

    Wang, Nancy X R; Olson, Jared D; Ojemann, Jeffrey G; Rao, Rajesh P N; Brunton, Bingni W

    2016-01-01

    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. PMID:27148018

  7. Intermittent high oxygen influences the formation of neural retinal tissue from human embryonic stem cells.

    PubMed

    Gao, Lixiong; Chen, Xi; Zeng, Yuxiao; Li, Qiyou; Zou, Ting; Chen, Siyu; Wu, Qian; Fu, Caiyun; Xu, Haiwei; Yin, Zheng Qin

    2016-01-01

    The vertebrate retina is a highly multilayered nervous tissue with a large diversity of cellular components. With the development of stem cell technologies, human retinas can be generated in three-dimensional (3-D) culture in vitro. However, understanding the factors modulating key productive processes and the way that they influence development are far from clear. Oxygen, as the most essential element participating in metabolism, is a critical factor regulating organic development. In this study, using 3-D culture of human stem cells, we examined the effect of intermittent high oxygen treatment (40% O2) on the formation and cellular behavior of neural retinas (NR) in the embryonic body (EB). The volume of EB and number of proliferating cells increased significantly under 40% O2 on day 38, 50, and 62. Additionally, the ratio of PAX6+ cells within NR was significantly increased. The neural rosettes could only develop with correct apical-basal polarity under 40% O2. In addition, the generation, migration and maturation of retinal ganglion cells were enhanced under 40% O2. All of these results illustrated that 40% O2 strengthened the formation of NR in EB with characteristics similar to the in vivo state, suggesting that the hyperoxic state facilitated the retinal development in vitro. PMID:27435522

  8. Neuro-immune interactions of neural stem cell transplants: from animal disease models to human trials.

    PubMed

    Giusto, Elena; Donegà, Matteo; Cossetti, Chiara; Pluchino, Stefano

    2014-10-01

    Stem cell technology is a promising branch of regenerative medicine that is aimed at developing new approaches for the treatment of severely debilitating human diseases, including those affecting the central nervous system (CNS). Despite the increasing understanding of the mechanisms governing their biology, the application of stem cell therapeutics remains challenging. The initial idea that stem cell transplants work in vivo via the replacement of endogenous cells lost or damaged owing to disease has been challenged by accumulating evidence of their therapeutic plasticity. This new concept covers the remarkable immune regulatory and tissue trophic effects that transplanted stem cells exert at the level of the neural microenvironment to promote tissue healing via combination of immune modulatory and tissue protective actions, while retaining predominantly undifferentiated features. Among a number of promising candidate stem cell sources, neural stem/precursor cells (NPCs) are under extensive investigation with regard to their therapeutic plasticity after transplantation. The significant impact in vivo of experimental NPC therapies in animal models of inflammatory CNS diseases has raised great expectations that these stem cells, or the manipulation of the mechanisms behind their therapeutic impact, could soon be translated to human studies. This review aims to provide an update on the most recent evidence of therapeutically-relevant neuro-immune interactions following NPC transplants in animal models of multiple sclerosis, cerebral stroke and traumas of the spinal cord, and consideration of the forthcoming challenges related to the early translation of some of these exciting experimental outcomes into clinical medicines.

  9. Intermittent high oxygen influences the formation of neural retinal tissue from human embryonic stem cells

    PubMed Central

    Gao, Lixiong; Chen, Xi; Zeng, Yuxiao; Li, Qiyou; Zou, Ting; Chen, Siyu; Wu, Qian; Fu, Caiyun; Xu, Haiwei; Yin, Zheng Qin

    2016-01-01

    The vertebrate retina is a highly multilayered nervous tissue with a large diversity of cellular components. With the development of stem cell technologies, human retinas can be generated in three-dimensional (3-D) culture in vitro. However, understanding the factors modulating key productive processes and the way that they influence development are far from clear. Oxygen, as the most essential element participating in metabolism, is a critical factor regulating organic development. In this study, using 3-D culture of human stem cells, we examined the effect of intermittent high oxygen treatment (40% O2) on the formation and cellular behavior of neural retinas (NR) in the embryonic body (EB). The volume of EB and number of proliferating cells increased significantly under 40% O2 on day 38, 50, and 62. Additionally, the ratio of PAX6+ cells within NR was significantly increased. The neural rosettes could only develop with correct apical-basal polarity under 40% O2. In addition, the generation, migration and maturation of retinal ganglion cells were enhanced under 40% O2. All of these results illustrated that 40% O2 strengthened the formation of NR in EB with characteristics similar to the in vivo state, suggesting that the hyperoxic state facilitated the retinal development in vitro. PMID:27435522

  10. Neural correlates of spatial and nonspatial attention determined using intracranial electroencephalographic signals in humans.

    PubMed

    Park, Ga Young; Kim, Taekyung; Park, Jinsick; Lee, Eun Mi; Ryu, Han Uk; Kim, Sun I; Kim, In Young; Kang, Joong Koo; Jang, Dong Pyo; Husain, Masud

    2016-08-01

    Few studies have directly compared the neural correlates of spatial attention (i.e., attention to a particular location) and nonspatial attention (i.e., attention to a feature in the visual scene) using well-controlled tasks. Here, we investigated the neural correlates of spatial and nonspatial attention in humans using intracranial electroencephalography. The topography and number of electrodes showing significant event-related desynchronization (ERD) or event-related synchronization (ERS) in different frequency bands were studied in 13 epileptic patients. Performance was not significantly different between the two conditions. In both conditions, ERD in the low-frequency bands and ERS in the high-frequency bands were present bilaterally in the parietal cortex (prominently on the right hemisphere) and frontal regions. In addition to these common changes, spatial attention involved right-lateralized activity that was maximal in the right superior parietal lobule (SPL), whereas nonspatial attention involved wider brain networks including the bilateral parietal, frontal, and temporal regions, but still had maximal activity in the right parietal lobe. Within the parietal lobe, spatial attention involved ERD or ERS in the right SPL, whereas nonspatial attention involved ERD or ERS in the right inferior parietal lobule. These findings reveal that common as well as different brain networks are engaged in spatial and nonspatial attention. Hum Brain Mapp 37:3041-3054, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:27125904

  11. A neural network model of the inferior colliculus with modifiable lateral inhibitory synapses for human echolocation.

    PubMed

    Hoshino, Osamu; Kuroiwa, Kazuharu

    2002-03-01

    We propose a neural network model of the inferior colliculus (IC) for human echolocation. Neuronal mechanisms for human echolocation were investigated by simulating the model. The model consists of the neural networks of the central nucleus (ICc) and external nucleus (ICx) of the inferior colliculus. The neurons of the ICc receive interaural sound stimuli via multiple contralateral delay lines and a single ipsilateral delay line. The neurons of the ICc send output signals to the neurons of the ICx in a convergent manner. We stimulated the ICc with pairs of a direct sound (a sonar sound) and an echo sound (the reflection from an object). Information about the distance between the model and the object is expressed by the delay time of the echo sound with respect to the direct sound. The results presented here show that neurons of the ICc responsive to interaural onset time differences contribute to the creation of an auditory distance map in the ICx. We trained the model with various pairs of direct-echo sounds and modified synaptic connection strengths of the networks according to the Hebbian rule. It is shown that self-organized long-term depression of lateral inhibitory synaptic connections plays an important role in enhancing echolocation skills.

  12. Unsupervised Decoding of Long-Term, Naturalistic Human Neural Recordings with Automated Video and Audio Annotations

    PubMed Central

    Wang, Nancy X. R.; Olson, Jared D.; Ojemann, Jeffrey G.; Rao, Rajesh P. N.; Brunton, Bingni W.

    2016-01-01

    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. PMID:27148018

  13. Neural correlates of spatial and nonspatial attention determined using intracranial electroencephalographic signals in humans

    PubMed Central

    Park, Ga Young; Kim, Taekyung; Park, Jinsick; Lee, Eun Mi; Ryu, Han Uk; Kim, Sun I.; Kim, In Young; Husain, Masud

    2016-01-01

    Abstract Few studies have directly compared the neural correlates of spatial attention (i.e., attention to a particular location) and nonspatial attention (i.e., attention to a feature in the visual scene) using well‐controlled tasks. Here, we investigated the neural correlates of spatial and nonspatial attention in humans using intracranial electroencephalography. The topography and number of electrodes showing significant event‐related desynchronization (ERD) or event‐related synchronization (ERS) in different frequency bands were studied in 13 epileptic patients. Performance was not significantly different between the two conditions. In both conditions, ERD in the low‐frequency bands and ERS in the high‐frequency bands were present bilaterally in the parietal cortex (prominently on the right hemisphere) and frontal regions. In addition to these common changes, spatial attention involved right‐lateralized activity that was maximal in the right superior parietal lobule (SPL), whereas nonspatial attention involved wider brain networks including the bilateral parietal, frontal, and temporal regions, but still had maximal activity in the right parietal lobe. Within the parietal lobe, spatial attention involved ERD or ERS in the right SPL, whereas nonspatial attention involved ERD or ERS in the right inferior parietal lobule. These findings reveal that common as well as different brain networks are engaged in spatial and nonspatial attention. Hum Brain Mapp 37:3041–3054, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:27125904

  14. Predict human body indentation lying on a spring mattress using a neural network approach.

    PubMed

    Zhong, Shilu; Shen, Liming; Zhou, Lijuan; Guan, Zhongwei

    2014-08-01

    This article presents a method to predict and assess the interaction between a human body and a spring mattress. A three-layer artificial neural network model was developed to simulate and predict an indentation curve of human spine, characterized with the depth of lumbar lordosis and four inclination angles: cervicothoracic, thoracolumbar, lumbosacral and the back-hip (β). By comparing the spinal indentation curves described by the optimal evaluation parameters (depth of lumbar lordosis, cervicothoracic, thoracolumbar and lumbosacral), a better design of five-zone spring mattresses was obtained for individuals to have an effective support to the main part of the body. Using such approach, an operating process was further introduced, in which appropriate stiffness proportions were proposed to design mattress for the normal body types of Chinese young women. Finally, case studies were undertaken, which show that the method developed is feasible and practical. PMID:25150192

  15. Predict human body indentation lying on a spring mattress using a neural network approach.

    PubMed

    Zhong, Shilu; Shen, Liming; Zhou, Lijuan; Guan, Zhongwei

    2014-08-01

    This article presents a method to predict and assess the interaction between a human body and a spring mattress. A three-layer artificial neural network model was developed to simulate and predict an indentation curve of human spine, characterized with the depth of lumbar lordosis and four inclination angles: cervicothoracic, thoracolumbar, lumbosacral and the back-hip (β). By comparing the spinal indentation curves described by the optimal evaluation parameters (depth of lumbar lordosis, cervicothoracic, thoracolumbar and lumbosacral), a better design of five-zone spring mattresses was obtained for individuals to have an effective support to the main part of the body. Using such approach, an operating process was further introduced, in which appropriate stiffness proportions were proposed to design mattress for the normal body types of Chinese young women. Finally, case studies were undertaken, which show that the method developed is feasible and practical.

  16. Label-free nonlinear optical microscopy detects early markers for osteogenic differentiation of human stem cells

    NASA Astrophysics Data System (ADS)

    Hofemeier, Arne D.; Hachmeister, Henning; Pilger, Christian; Schürmann, Matthias; Greiner, Johannes F. W.; Nolte, Lena; Sudhoff, Holger; Kaltschmidt, Christian; Huser, Thomas; Kaltschmidt, Barbara

    2016-05-01

    Tissue engineering by stem cell differentiation is a novel treatment option for bone regeneration. Most approaches for the detection of osteogenic differentiation are invasive or destructive and not compatible with live cell analysis. Here, non-destructive and label-free approaches of Raman spectroscopy, coherent anti-Stokes Raman scattering (CARS) and second harmonic generation (SHG) microscopy were used to detect and image osteogenic differentiation of human neural crest-derived inferior turbinate stem cells (ITSCs). Combined CARS and SHG microscopy was able to detect markers of osteogenesis within 14 days after osteogenic induction. This process increased during continued differentiation. Furthermore, Raman spectroscopy showed significant increases of the PO43‑ symmetric stretch vibrations at 959 cm‑1 assigned to calcium hydroxyapatite between days 14 and 21. Additionally, CARS microscopy was able to image calcium hydroxyapatite deposits within 14 days following osteogenic induction, which was confirmed by Alizarin Red-Staining and RT- PCR. Taken together, the multimodal label-free analysis methods Raman spectroscopy, CARS and SHG microscopy can monitor osteogenic differentiation of adult human stem cells into osteoblasts with high sensitivity and spatial resolution in three dimensions. Our findings suggest a great potential of these optical detection methods for clinical applications including in vivo observation of bone tissue–implant-interfaces or disease diagnosis.

  17. Label-free nonlinear optical microscopy detects early markers for osteogenic differentiation of human stem cells

    PubMed Central

    Hofemeier, Arne D.; Hachmeister, Henning; Pilger, Christian; Schürmann, Matthias; Greiner, Johannes F. W.; Nolte, Lena; Sudhoff, Holger; Kaltschmidt, Christian; Huser, Thomas; Kaltschmidt, Barbara

    2016-01-01

    Tissue engineering by stem cell differentiation is a novel treatment option for bone regeneration. Most approaches for the detection of osteogenic differentiation are invasive or destructive and not compatible with live cell analysis. Here, non-destructive and label-free approaches of Raman spectroscopy, coherent anti-Stokes Raman scattering (CARS) and second harmonic generation (SHG) microscopy were used to detect and image osteogenic differentiation of human neural crest-derived inferior turbinate stem cells (ITSCs). Combined CARS and SHG microscopy was able to detect markers of osteogenesis within 14 days after osteogenic induction. This process increased during continued differentiation. Furthermore, Raman spectroscopy showed significant increases of the PO43− symmetric stretch vibrations at 959 cm−1 assigned to calcium hydroxyapatite between days 14 and 21. Additionally, CARS microscopy was able to image calcium hydroxyapatite deposits within 14 days following osteogenic induction, which was confirmed by Alizarin Red-Staining and RT- PCR. Taken together, the multimodal label-free analysis methods Raman spectroscopy, CARS and SHG microscopy can monitor osteogenic differentiation of adult human stem cells into osteoblasts with high sensitivity and spatial resolution in three dimensions. Our findings suggest a great potential of these optical detection methods for clinical applications including in vivo observation of bone tissue–implant-interfaces or disease diagnosis. PMID:27225821

  18. Generation of human cortical neurons from a new immortal fetal neural stem cell line

    SciTech Connect

    Cacci, E.; Villa, A.; Parmar, M.; Cavallaro, M.; Mandahl, N.; Lindvall, O.; Martinez-Serrano, A.; Kokaia, Z. . E-mail: Zaal.Kokaia@med.lu.se

    2007-02-01

    Isolation and expansion of neural stem cells (NSCs) of human origin are crucial for successful development of cell therapy approaches in neurodegenerative diseases. Different epigenetic and genetic immortalization strategies have been established for long-term maintenance and expansion of these cells in vitro. Here we report the generation of a new, clonal NSC (hc-NSC) line, derived from human fetal cortical tissue, based on v-myc immortalization. Using immunocytochemistry, we show that these cells retain the characteristics of NSCs after more than 50 passages. Under proliferation conditions, when supplemented with epidermal and basic fibroblast growth factors, the hc-NSCs expressed neural stem/progenitor cell markers like nestin, vimentin and Sox2. When growth factors were withdrawn, proliferation and expression of v-myc and telomerase were dramatically reduced, and the hc-NSCs differentiated into glia and neurons (mostly glutamatergic and GABAergic, as well as tyrosine hydroxylase-positive, presumably dopaminergic neurons). RT-PCR analysis showed that the hc-NSCs retained expression of Pax6, Emx2 and Neurogenin2, which are genes associated with regionalization and cell commitment in cortical precursors during brain development. Our data indicate that this hc-NSC line could be useful for exploring the potential of human NSCs to replace dead or damaged cortical cells in animal models of acute and chronic neurodegenerative diseases. Taking advantage of its clonality and homogeneity, this cell line will also be a valuable experimental tool to study the regulatory role of intrinsic and extrinsic factors in human NSC biology.

  19. Human recognition based on head-shoulder contour extraction and BP neural network

    NASA Astrophysics Data System (ADS)

    Kong, Xiao-fang; Wang, Xiu-qin; Gu, Guohua; Chen, Qian; Qian, Wei-xian

    2014-11-01

    In practical application scenarios like video surveillance and human-computer interaction, human body movements are uncertain because the human body is a non-rigid object. Based on the fact that the head-shoulder part of human body can be less affected by the movement, and will seldom be obscured by other objects, in human detection and recognition, a head-shoulder model with its stable characteristics can be applied as a detection feature to describe the human body. In order to extract the head-shoulder contour accurately, a head-shoulder model establish method with combination of edge detection and the mean-shift algorithm in image clustering has been proposed in this paper. First, an adaptive method of mixture Gaussian background update has been used to extract targets from the video sequence. Second, edge detection has been used to extract the contour of moving objects, and the mean-shift algorithm has been combined to cluster parts of target's contour. Third, the head-shoulder model can be established, according to the width and height ratio of human head-shoulder combined with the projection histogram of the binary image, and the eigenvectors of the head-shoulder contour can be acquired. Finally, the relationship between head-shoulder contour eigenvectors and the moving objects will be formed by the training of back-propagation (BP) neural network classifier, and the human head-shoulder model can be clustered for human detection and recognition. Experiments have shown that the method combined with edge detection and mean-shift algorithm proposed in this paper can extract the complete head-shoulder contour, with low calculating complexity and high efficiency.

  20. A robust method to derive functional neural crest cells from human pluripotent stem cells.

    PubMed

    Kreitzer, Faith R; Salomonis, Nathan; Sheehan, Alice; Huang, Miller; Park, Jason S; Spindler, Matthew J; Lizarraga, Paweena; Weiss, William A; So, Po-Lin; Conklin, Bruce R

    2013-01-01

    Neural crest (NC) cells contribute to the development of many complex tissues of all three germ layers during embryogenesis, and its abnormal development accounts for several congenital birth defects. Generating NC cells-including specific subpopulations such as cranial, cardiac, and trunk NC cells-from human pluripotent stem cells will provide a valuable model system to study human development and disease. Here, we describe a rapid and robust NC differentiation method called "LSB-short" that is based on dual SMAD pathway inhibition. This protocol yields high percentages of NC cell populations from multiple human induced pluripotent stem and human embryonic stem cell lines in 8 days. The resulting cells can be propagated easily, retain NC marker expression over multiple passages, and can spontaneously differentiate into several NC-derived cell lineages, including smooth muscle cells, peripheral neurons, and Schwann cells. NC cells generated by this method represent cranial, cardiac and trunk NC subpopulations based on global gene expression analyses, are similar to in vivo analogues, and express a common set of NC alternative isoforms. Functionally, they are also able to migrate appropriately in response to chemoattractants such as SDF-1, FGF8b, and Wnt3a. By yielding NC cells that likely represent all NC subpopulations in a shorter time frame than other published methods, our LSB-short method provides an ideal model system for further studies of human NC development and disease.

  1. Decoding movement intent from human premotor cortex neurons for neural prosthetic applications

    PubMed Central

    Ojakangas, Catherine L.; Shaikhouni, Ammar; Friehs, Gerhard M.; Caplan, Abraham H.; Serruya, Mijail D.; Saleh, Maryam; Morris, Daniel S.; Donoghue, John P.

    2006-01-01

    Summary Primary motor cortex (MI), a key region for voluntary motor control, has been considered a first choice as the source of neural signals to control prosthetic devices for humans with paralysis. Less is known about the potential for other areas of frontal cortex as prosthesis signal sources. The frontal cortex is widely engaged in voluntary behavior. Single neuron recordings in monkey frontal cortex beyond MI have readily identified activity related to planning and initiating movement direction, remembering movement instructions over delays, or mixtures of these features (Kurata & Wise, 1988; Boussaoud & Wise, 1993; Crammond & Kalaska, 1994, 2000). Human functional imaging and lesion studies also support this role (Toni et al., 1999; Simon et al., 2002). Intraoperative mapping during deep brain stimulator placement in humans (Benabid et al., 1989) provides a unique opportunity to evaluate potential prosthesis control signals derived from non-primary areas and to expand our understanding of frontal lobe function and its role in movement disorders. Here we show that recordings from small groups of human prefrontal/premotor cortex neurons can provide information about movement planning, production and decision making sufficient to decode the planned direction of movement. Thus, additional frontal areas, beyond M1, may be valuable signal sources for human neuromotor prostheses. PMID:17143147

  2. A robust method to derive functional neural crest cells from human pluripotent stem cells.

    PubMed

    Kreitzer, Faith R; Salomonis, Nathan; Sheehan, Alice; Huang, Miller; Park, Jason S; Spindler, Matthew J; Lizarraga, Paweena; Weiss, William A; So, Po-Lin; Conklin, Bruce R

    2013-01-01

    Neural crest (NC) cells contribute to the development of many complex tissues of all three germ layers during embryogenesis, and its abnormal development accounts for several congenital birth defects. Generating NC cells-including specific subpopulations such as cranial, cardiac, and trunk NC cells-from human pluripotent stem cells will provide a valuable model system to study human development and disease. Here, we describe a rapid and robust NC differentiation method called "LSB-short" that is based on dual SMAD pathway inhibition. This protocol yields high percentages of NC cell populations from multiple human induced pluripotent stem and human embryonic stem cell lines in 8 days. The resulting cells can be propagated easily, retain NC marker expression over multiple passages, and can spontaneously differentiate into several NC-derived cell lineages, including smooth muscle cells, peripheral neurons, and Schwann cells. NC cells generated by this method represent cranial, cardiac and trunk NC subpopulations based on global gene expression analyses, are similar to in vivo analogues, and express a common set of NC alternative isoforms. Functionally, they are also able to migrate appropriately in response to chemoattractants such as SDF-1, FGF8b, and Wnt3a. By yielding NC cells that likely represent all NC subpopulations in a shorter time frame than other published methods, our LSB-short method provides an ideal model system for further studies of human NC development and disease. PMID:23862100

  3. Genetically Engineered Plant Viral Nanoparticles Direct Neural Cells Differentiation and Orientation.

    PubMed

    Feng, Sheng; Lu, Lin; Zan, Xingjie; Wu, Yehong; Lin, Yuan; Wang, Qian

    2015-09-01

    An important aim of tissue engineering is to design biomimetic materials with specific cell binding motifs and precisely controlled structural organization, thereby providing biochemical and physical cues for desired cellular behaviors. Previously, our group generated genetically modified tobacco mosaic virus (TMV) displaying integrin binding motifs, RGD1, RGD7, PSHRN3, P15, and DGEA. The resulting rod-like virus particles displaying integrin binding motifs were biocompatible with Neuro 2A (N2a), a mouse neural crest-derived cell line, and could promote the neurite outgrowth of N2a. The genetically modified viruses could be assembled with aligned orientation in the capillary by applying a shear force. The resulting aligned substrates were able to dictate directional neurite outgrowth of N2a cells. Therefore, this method could be potentially applied for neural tissue engineering, as a neural conduit for repairing peripheral nerve injuries. PMID:26247572

  4. Regulation of viability, differentiation and death of human melanoma cells carrying neural stem cell biomarkers: a possibility for neural trans-differentiation.

    PubMed

    Ivanov, Vladimir N; Hei, Tom K

    2015-07-01

    During embryonic development, melanoblasts, the precursors of melanocytes, emerge from a subpopulation of the neural crest stem cells and migrate to colonize skin. Melanomas arise during melanoblast differentiation into melanocytes and from young proliferating melanocytes through somatic mutagenesis and epigenetic regulations. In the present study, we used several human melanoma cell lines from the sequential phases of melanoma development (radial growth phase, vertical growth phase and metastatic phase) to compare: (i) the frequency and efficiency of the induction of cell death via apoptosis and necroptosis; (ii) the presence of neural and cancer stem cell biomarkers as well as death receptors, DR5 and FAS, in both adherent and spheroid cultures of melanoma cells; (iii) anti-apoptotic effects of the endogenous production of cytokines and (iv) the ability of melanoma cells to perform neural trans-differentiation. We demonstrated that programed necrosis or necroptosis, could be induced in two metastatic melanoma lines, FEMX and OM431, while the mitochondrial pathway of apoptosis was prevalent in a vast majority of melanoma lines. All melanoma lines used in the current study expressed substantial levels of pluripotency markers, SOX2 and NANOG. There was a trend for increasing expression of Nestin, an early neuroprogenitor marker, during melanoma progression. Most of the melanoma lines, including WM35, FEMX and A375, can grow as a spheroid culture in serum-free media with supplements. It was possible to induce neural trans-differentiation of 1205Lu and OM431 melanoma cells in serum-free media supplemented with insulin. This was confirmed by the expression of neuronal markers, doublecortin and β3-Tubulin, by significant growth of neurites and by the negative regulation of this process by a dominant-negative Rac1N17. These results suggest a relative plasticity of differentiated melanoma cells and a possibility for their neural trans-differentiation without the

  5. Operational point of neural cardiovascular regulation in humans up to 6 months in space.

    PubMed

    Verheyden, B; Liu, J; Beckers, F; Aubert, A E

    2010-03-01

    Entering weightlessness affects central circulation in humans by enhancing venous return and cardiac output. We tested whether the operational point of neural cardiovascular regulation in space sets accordingly to adopt a level close to that found in the ground-based horizontal position. Heart rate (HR), finger blood and brachial blood pressure (BP), and respiratory frequency were collected in 11 astronauts from nine space missions. Recordings were made in supine and standing positions at least 10 days before launch and during spaceflight (days 5-19, 45-67, 77-116, 146-180). Cross-correlation analyses of HR and systolic BP were used to measure three complementary aspects of cardiac baroreflex modulation: 1) baroreflex sensitivity, 2) number of effective baroreflex estimates, and 3) baroreflex time delay. A fixed breathing protocol was performed to measure respiratory sinus arrhythmia and low-frequency power of systolic BP variability. We found that HR and mean arterial pressure did not differ from preflight supine values for up to 6 mo in space. Respiration frequency tended to decrease during prolonged spaceflight. Concerning neural markers of cardiovascular regulation, we observed in-flight adaptations toward homeostatic conditions similar to those found in the ground-based supine position. Surprisingly, this was not the case for baroreflex time delay distribution, which had somewhat longer latencies in space. Except for this finding, our results confirm that the operational point of neural cardiovascular regulation in space sets to a level close to that of an Earth-based supine position. This adaptation level suggests that circulation is chronically relaxed for at least 6 mo in space. PMID:20075261

  6. The Effect of Chronic Cannabinoids on Broadband EEG Neural Oscillations in Humans

    PubMed Central

    Skosnik, Patrick D; D'Souza, Deepak C; Steinmetz, Adam B; Edwards, Chad R; Vollmer, Jennifer M; Hetrick, William P; O'Donnell, Brian F

    2012-01-01

    Animal and cellular work has shown that central cannabinoid-1 receptors modulate neural oscillations in the gamma range (40 Hz), which may be important for normal perceptual and cognitive processes. In order to assess the effect of cannabinoids on broadband-frequency neural oscillations in humans, the current study examined the effect of chronic cannabis use on auditory steady-state responses (ASSRs) utilizing electroencephalography (EEG). Passive ASSRs were assessed using varying rates of binaural stimulation (auditory click-trains; 10–50 Hz in increments of 5 Hz; 80 dB SPL) in carefully screened cannabis users and controls. Chronic cannabis users (n=22; 12 h abstinence before study; positive 11-nor-9-carboxy-delta-9-tetrahydrocannabinol urine levels) and cannabis naïve controls (n=24) were evaluated. Time X frequency analyses on EEG data were performed using Fourier-based mean trial power (MTP) and phase-locking (inter-trial coherence; ITC). Transient ERPs to stimulus onset (auditory N100 components) were also evaluated. As predicted, a decrease in spectral power (MTP) at 40 Hz was observed in the cannabis group (p<0.018). No effects on phase-locking (ITC) or the N100 were observed. Further, within the cannabis group, lower 40 Hz power correlated with an earlier age of onset of cannabis use (p<0.04). These data suggest that chronic exposure to exogenous cannabinoids can alter the ability to generate neural oscillations, particularly in the gamma range. This is consistent with preclinical animal and cellular data, which may have implications for understanding the short- and long-term psychopharmacological effects of cannabis. PMID:22713908

  7. Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease.

    PubMed

    Marei, Hany E S; Lashen, Samah; Farag, Amany; Althani, Asmaa; Afifi, Nahla; A, Abd-Elmaksoud; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

    2015-07-01

    Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease.

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

    PubMed

    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. PMID:25709097

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

    PubMed

    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. Genetic Programming Neural Networks: A Powerful Bioinformatics Tool for Human Genetics

    PubMed Central

    Ritchie, Marylyn D; Motsinger, Alison A.; Bush, William S; Coffey, Christopher S; Moore, Jason H

    2010-01-01

    The identification of genes that influence the risk of common, complex disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. This challenge is partly due to the limitations of parametric statistical methods for detecting genetic effects that are dependent solely or partially on interactions. We have previously introduced a genetic programming neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of genetic and gene-environment combinations associated with disease risk. Previous empirical studies suggest GPNN has excellent power for identifying gene-gene and gene-environment interactions. The goal of this study was to compare the power of GPNN to stepwise logistic regression (SLR) and classification and regression trees (CART) for identifying gene-gene and gene-environment interactions. SLR and CART are standard methods of analysis for genetic association studies. Using simulated data, we show that GPNN has higher power to identify gene-gene and gene-environment interactions than SLR and CART. These results indicate that GPNN may be a useful pattern recognition approach for detecting gene-gene and gene-environment interactions in studies of human disease. PMID:20948988

  11. Controllability modulates the neural response to predictable but not unpredictable threat in humans.

    PubMed

    Wood, Kimberly H; Wheelock, Muriah D; Shumen, Joshua R; Bowen, Kenton H; Ver Hoef, Lawrence W; Knight, David C

    2015-10-01

    Stress resilience is mediated, in part, by our ability to predict and control threats within our environment. Therefore, determining the neural mechanisms that regulate the emotional response to predictable and controllable threats may provide important new insight into the processes that mediate resilience to emotional dysfunction and guide the future development of interventions for anxiety disorders. To better understand the effect of predictability and controllability on threat-related brain activity in humans, two groups of healthy volunteers participated in a yoked Pavlovian fear conditioning study during functional magnetic resonance imaging (fMRI). Threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or by presenting the UCS alone (i.e., unpredictable). Similar to animal model research that has employed yoked fear conditioning procedures, one group (controllable condition; CC), but not the other group (uncontrollable condition; UC) was able to terminate the UCS. The fMRI signal response within the dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and posterior cingulate was diminished during predictable compared to unpredictable threat (i.e., UCS). In addition, threat-related activity within the ventromedial PFC and bilateral hippocampus was diminished only to threats that were both predictable and controllable. These findings provide insight into how threat predictability and controllability affects the activity of brain regions (i.e., ventromedial PFC and hippocampus) involved in emotion regulation, and may have important implications for better understanding neural processes that mediate emotional resilience to stress.

  12. Human cord blood-derived neural stem cell line--possible implementation in studying neurotoxicity.

    PubMed

    Buzańska, L; Habich, A; Jurga, M; Sypecka, J; Domańska-Janik, K

    2005-10-01

    Neural stem cell line developed from human umbilical cord blood (HUCB-NSC) [Buzańska et al., 2003. Journal of Neurochemistry 85, 33] is an ethically uncontroversial source of stem cells, able to differentiate into neuronal, astrocytic and oligodendroglial lineages. Developmental fate decisions of HUCB-NSC can be experimentally manipulated in vitro by the presence of trophic factors, mitogenes and neuromorphogenes, but can also be influenced by neurotoxins. In this report two-dimensional (2-D) and three-dimensional (3-D) HUCB-NSC cultures are introduced as useful models for testing developmental neurotoxicity. For 2-D culture models we established a standardized method for the assessment of the growth rate and cell differentiation in 96-well plates. The proliferative capacity of the HUCB-NSC was monitored by the MTT test while their ability to differentiate into neural-like cells by immunocytochemistry of beta-tubulin III and MAP-2 for neurons, GFAP and S-100beta for astrocytes and GalC for oligodendrocytes. The 3-D culture of HUCB-NSC is represented by neurospheres. Proliferation and migration of the intermediate precursors from attached neurospheres are shown to be controlled and altered by various growth factors and further modulated by the extracellular matrix component-fibronectin. Thus, neurospheres derived from the HUCB-NSC line can represent a suitable model of the activation of dormant stem cells residing in their niche, and can be used for neurotoxic studies. PMID:16084685

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

    PubMed

    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.

  14. Neural substrates of human facial expression of pleasant emotion induced by comic films: a PET Study.

    PubMed

    Iwase, Masao; Ouchi, Yasuomi; Okada, Hiroyuki; Yokoyama, Chihiro; Nobezawa, Shuji; Yoshikawa, Etsuji; Tsukada, Hideo; Takeda, Masaki; Yamashita, Ko; Takeda, Masatoshi; Yamaguti, Kouzi; Kuratsune, Hirohiko; Shimizu, Akira; Watanabe, Yasuyoshi

    2002-10-01

    Laughter or smile is one of the emotional expressions of pleasantness with characteristic contraction of the facial muscles, of which the neural substrate remains to be explored. This currently described study is the first to investigate the generation of human facial expression of pleasant emotion using positron emission tomography and H(2)(15)O. Regional cerebral blood flow (rCBF) during laughter/smile induced by visual comics and the magnitude of laughter/smile indicated significant correlation in the bilateral supplementary motor area (SMA) and left putamen (P < 0.05, corrected), but no correlation in the primary motor area (M1). In the voluntary facial movement, significant correlation between rCBF and the magnitude of EMG was found in the face area of bilateral M1 and the SMA (P < 0.001, uncorrected). Laughter/smile, as opposed to voluntary movement, activated the visual association areas, left anterior temporal cortex, left uncus, and orbitofrontal and medial prefrontal cortices (P < 0.05, corrected), whereas voluntary facial movement generated by mimicking a laughing/smiling face activated the face area of the left M1 and bilateral SMA, compared with laughter/smile (P < 0.05, corrected). We demonstrated distinct neural substrates of emotional and volitional facial expression and defined cognitive and experiential processes of a pleasant emotion, laughter/smile.

  15. Biocompatibility of nanostructured boron doped diamond for the attachment and proliferation of human neural stem cells

    NASA Astrophysics Data System (ADS)

    Taylor, Alice C.; Vagaska, Barbora; Edgington, Robert; Hébert, Clément; Ferretti, Patrizia; Bergonzo, Philippe; Jackman, Richard B.

    2015-12-01

    Objective. We quantitatively investigate the biocompatibility of chemical vapour deposited (CVD) nanocrystalline diamond (NCD) after the inclusion of boron, with and without nanostructuring. The nanostructuring method involves a novel approach of growing NCD over carbon nanotubes (CNTs) that act as a 3D scaffold. This nanostructuring of BNCD leads to a material with increased capacitance, and this along with wide electrochemical window makes BNCD an ideal material for neural interface applications, and thus it is essential that their biocompatibility is investigated. Approach. Biocompatibility was assessed by observing the interaction of human neural stem cells (hNSCs) with a variety of NCD substrates including un-doped ones, and NCD doped with boron, which are both planar, and nanostructured. hNSCs were chosen due to their sensitivity, and various methods including cell population and confluency were used to quantify biocompatibility. Main results. Boron inclusion into NCD film was shown to have no observable effect on hNSC attachment, proliferation and viability. Furthermore, the biocompatibility of nanostructured boron-doped NCD is increased upon nanostructuring, potentially due to the increased surface area. Significance. Diamond is an attractive material for supporting the attachment and development of cells as it can show exceptional biocompatibility. When boron is used as a dopant within diamond it becomes a p-type semiconductor, and at high concentrations the diamond becomes quasi-metallic, offering the prospect of a direct electrical device-cell interfacing system.

  16. Genetic Programming Neural Networks: A Powerful Bioinformatics Tool for Human Genetics.

    PubMed

    Ritchie, Marylyn D; Motsinger, Alison A; Bush, William S; Coffey, Christopher S; Moore, Jason H

    2007-01-01

    The identification of genes that influence the risk of common, complex disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. This challenge is partly due to the limitations of parametric statistical methods for detecting genetic effects that are dependent solely or partially on interactions. We have previously introduced a genetic programming neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of genetic and gene-environment combinations associated with disease risk. Previous empirical studies suggest GPNN has excellent power for identifying gene-gene and gene-environment interactions. The goal of this study was to compare the power of GPNN to stepwise logistic regression (SLR) and classification and regression trees (CART) for identifying gene-gene and gene-environment interactions. SLR and CART are standard methods of analysis for genetic association studies. Using simulated data, we show that GPNN has higher power to identify gene-gene and gene-environment interactions than SLR and CART. These results indicate that GPNN may be a useful pattern recognition approach for detecting gene-gene and gene-environment interactions in studies of human disease.

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

    NASA Astrophysics Data System (ADS)

    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.

  18. Neural representations of faces and body parts in macaque and human cortex: a comparative FMRI study.

    PubMed

    Pinsk, Mark A; Arcaro, Michael; Weiner, Kevin S; Kalkus, Jan F; Inati, Souheil J; Gross, Charles G; Kastner, Sabine

    2009-05-01

    Single-cell studies in the macaque have reported selective neural responses evoked by visual presentations of faces and bodies. Consistent with these findings, functional magnetic resonance imaging studies in humans and monkeys indicate that regions in temporal cortex respond preferentially to faces and bodies. However, it is not clear how these areas correspond across the two species. Here, we directly compared category-selective areas in macaques and humans using virtually identical techniques. In the macaque, several face- and body part-selective areas were found located along the superior temporal sulcus (STS) and middle temporal gyrus (MTG). In the human, similar to previous studies, face-selective areas were found in ventral occipital and temporal cortex and an additional face-selective area was found in the anterior temporal cortex. Face-selective areas were also found in lateral temporal cortex, including the previously reported posterior STS area. Body part-selective areas were identified in the human fusiform gyrus and lateral occipitotemporal cortex. In a first experiment, both monkey and human subjects were presented with pictures of faces, body parts, foods, scenes, and man-made objects, to examine the response profiles of each category-selective area to the five stimulus types. In a second experiment, face processing was examined by presenting upright and inverted faces. By comparing the responses and spatial relationships of the areas, we propose potential correspondences across species. Adjacent and overlapping areas in the macaque anterior STS/MTG responded strongly to both faces and body parts, similar to areas in the human fusiform gyrus and posterior STS. Furthermore, face-selective areas on the ventral bank of the STS/MTG discriminated both upright and inverted faces from objects, similar to areas in the human ventral temporal cortex. Overall, our findings demonstrate commonalities and differences in the wide-scale brain organization between

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

    PubMed

    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. PMID:27191382

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

    PubMed Central

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

    2016-01-01

    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 R2 = 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 R2 = 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. PMID:27191382

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

    PubMed

    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.

  2. GDNF is required for neural colonization of the pancreas.

    PubMed

    Muñoz-Bravo, José Luis; Hidalgo-Figueroa, María; Pascual, Alberto; López-Barneo, José; Leal-Cerro, Alfonso; Cano, David A

    2013-09-01

    The mammalian pancreas is densely innervated by both the sympathetic and parasympathetic nervous systems, which control exocrine and endocrine secretion. During embryonic development, neural crest cells migrating in a rostrocaudal direction populate the gut, giving rise to neural progenitor cells. Recent studies in mice have shown that neural crest cells enter the pancreatic epithelium at E11.5. However, the cues that guide the migration of neural progenitors into the pancreas are poorly defined. In this study we identify glial cell line-derived neurotrophic factor (GDNF) as a key player in this process. GDNF displays a dynamic expression pattern during embryonic development that parallels the chronology of migration and differentiation of neural crest derivatives in the pancreas. Conditional inactivation of Gdnf in the pancreatic epithelium results in a dramatic loss of neuronal and glial cells and in reduced parasympathetic innervation in the pancreas. Importantly, the innervation of other regions of the gut remains unaffected. Analysis of Gdnf mutant mouse embryos and ex vivo experiments indicate that GDNF produced in the pancreas acts as a neurotrophic factor for gut-resident neural progenitor cells. Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas.

  3. MicroRNAs as markers for neurally committed CD133+/CD34+ stem cells derived from human umbilical cord blood.

    PubMed

    Hafizi, Maryam; Atashi, Amir; Bakhshandeh, Behnaz; Kabiri, Mahboubeh; Nadri, Samad; Hosseini, Reza Haji; Soleimani, Masoud

    2013-04-01

    Neural differentiation of the CD133+/CD34+ subpopulation of human umbilical cord blood stem cells was investigated, and neuro-miR (mir-9 and mir-124) expression was examined. An efficient induction protocol for neural differentiation of hematopoietic stem cells together with the exclusion of retinoic acid in this process was also studied. Transcription of some neural markers such as microtubule-associated protein-2, beta-tubulin III, and neuron-specific enolase was evaluated by real-time PCR, immunocytochemistry, and western blotting. Increased expression of neural indicators in the treated cells confirmed the appropriate neural differentiation, which supported the high efficiency of our defined neuronal induction protocol. Verified high expression of neuro-miRNAs along with neuronal specific proteins not only strengthens the regulatory role of miRNAs in determining stem cell fate but also introduces these miRNAs as novel indicators of neural differentiation. These data highlight the prominent therapeutic potential of hematopoietic stem cells for use in cell therapy of neurodegenerative diseases.

  4. Nature of the coupling between neural drive and force-generating capacity in the human quadriceps muscle.

    PubMed

    Hug, François; Goupille, Clément; Baum, Daniel; Raiteri, Brent J; Hodges, Paul W; Tucker, Kylie

    2015-11-22

    The force produced by a muscle depends on both the neural drive it receives and several biomechanical factors. When multiple muscles act on a single joint, the nature of the relationship between the neural drive and force-generating capacity of the synergistic muscles is largely unknown. This study aimed to determine the relationship between the ratio of neural drive and the ratio of muscle force-generating capacity between two synergist muscles (vastus lateralis (VL) and vastus medialis (VM)) in humans. Twenty-one participants performed isometric knee extensions at 20 and 50% of maximal voluntary contractions (MVC). Myoelectric activity (surface electromyography (EMG)) provided an index of neural drive. Physiological cross-sectional area (PCSA) was estimated from measurements of muscle volume (magnetic resonance imaging) and muscle fascicle length (three-dimensional ultrasound imaging) to represent the muscles' force-generating capacities. Neither PCSA nor neural drive was balanced between VL and VM. There was a large (r = 0.68) and moderate (r = 0.43) correlation between the ratio of VL/VM EMG amplitude and the ratio of VL/VM PCSA at 20 and 50% of MVC, respectively. This study provides evidence that neural drive is biased by muscle force-generating capacity, the greater the force-generating capacity of VL compared with VM, the stronger bias of drive to the VL.

  5. Molecular signatures associated with ZIKV exposure in human cortical neural progenitors

    PubMed Central

    Zhang, Feiran; Hammack, Christy; Ogden, Sarah C.; Cheng, Yichen; Lee, Emily M.; Wen, Zhexing; Qian, Xuyu; Nguyen, Ha Nam; Li, Yujing; Yao, Bing; Xu, Miao; Xu, Tianlei; Chen, Li; Wang, Zhiqin; Feng, Hao; Huang, Wei-Kai; Yoon, Ki-jun; Shan, Chao; Huang, Luoxiu; Qin, Zhaohui; Christian, Kimberly M.; Shi, Pei-Yong; Xu, Mingjiang; Xia, Menghang; Zheng, Wei; Wu, Hao; Song, Hongjun; Tang, Hengli; Ming, Guo-Li; Jin, Peng

    2016-01-01

    Zika virus (ZIKV) infection causes microcephaly and has been linked to other brain abnormalities. How ZIKV impairs brain development and function is unclear. Here we systematically profiled transcriptomes of human neural progenitor cells exposed to Asian ZIKVC, African ZIKVM, and dengue virus (DENV). In contrast to the robust global transcriptome changes induced by DENV, ZIKV has a more selective and larger impact on expression of genes involved in DNA replication and repair. While overall expression profiles are similar, ZIKVC, but not ZIKVM, induces upregulation of viral response genes and TP53. P53 inhibitors can block the apoptosis induced by both ZIKVC and ZIKVM in hNPCs, with higher potency against ZIKVC-induced apoptosis. Our analyses reveal virus- and strain-specific molecular signatures associated with ZIKV infection. These datasets will help to investigate ZIKV-host interactions and identify neurovirulence determinants of ZIKV. PMID:27580721

  6. Anchoring the neural compass: coding of local spatial reference frames in human medial parietal lobe.

    PubMed

    Marchette, Steven A; Vass, Lindsay K; Ryan, Jack; Epstein, Russell A

    2014-11-01

    The neural systems that code for location and facing direction during spatial navigation have been investigated extensively; however, the mechanisms by which these quantities are referenced to external features of the world are not well understood. To address this issue, we examined behavioral priming and functional magnetic resonance imaging activity patterns while human subjects recalled spatial views from a recently learned virtual environment. Behavioral results indicated that imagined location and facing direction were represented during this task, and multivoxel pattern analyses indicated that the retrosplenial complex (RSC) was the anatomical locus of these spatial codes. Critically, in both cases, location and direction were defined on the basis of fixed elements of the local environment and generalized across geometrically similar local environments. These results suggest that RSC anchors internal spatial representations to local topographical features, thus allowing us to stay oriented while we navigate and retrieve from memory the experience of being in a particular place. PMID:25282616

  7. Dissociating cognitive and sensory neural plasticity in human superior temporal cortex.

    PubMed

    Cardin, Velia; Orfanidou, Eleni; Rönnberg, Jerker; Capek, Cheryl M; Rudner, Mary; Woll, Bencie

    2013-01-01

    Disentangling the effects of sensory and cognitive factors on neural reorganization is fundamental for establishing the relationship between plasticity and functional specialization. Auditory deprivation in humans provides a unique insight into this problem, because the origin of the anatomical and functional changes observed in deaf individuals is not only sensory, but also cognitive, owing to the implementation of visual communication strategies such as sign language and speechreading. Here, we describe a functional magnetic resonance imaging study of individuals with different auditory deprivation and sign language experience. We find that sensory and cognitive experience cause plasticity in anatomically and functionally distinguishable substrates. This suggests that after plastic reorganization, cortical regions adapt to process a different type of input signal, but preserve the nature of the computation they perform, both at a sensory and cognitive level.

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

    PubMed Central

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

    2016-01-01

    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. SIGNIFICANCE STATEMENT 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

  9. EVALUATION OF HUMAN NEURAL PROGENITOR CELLS FOR DEVELOPMENTAL NEUROTOXICITY SCREENING: TIME COURSE OF EFFECTS ON CELL PROLIFERATION AND VIABILITY.

    EPA Science Inventory

    Current testing methods for developmental neurotoxicity (DNT) make evaluation of the effects of large numbers of chemicals impractical and prohibitively expensive. As such, we are evaluating human neural progenitor cells (NPCs) as a screen for DNT. ReNcell CX (ReN CX) cells are a...

  10. Micropatterned, clickable culture substrates enable in situ spatiotemporal control of human PSC-derived neural tissue morphology.

    PubMed

    Knight, G T; Sha, J; Ashton, R S

    2015-03-28

    We describe a modular culture platform that enables spatiotemporal control of the morphology of 2D neural tissues derived from human pluripotent stem cells (hPSCs) by simply adding clickable peptides to the media. It should be widely applicable for elucidating how spatiotemporal changes in morphology and substrate biochemistry regulate tissue morphogenesis. PMID:25688384

  11. MycN Is Critical for the Maintenance of Human Embryonic Stem Cell-Derived Neural Crest Stem Cells.

    PubMed

    Zhang, Jie Ting; Weng, Zhi Hui; Tsang, Kam Sze; Tsang, Lai Ling; Chan, Hsiao Chang; Jiang, Xiao Hua

    2016-01-01

    The biologic studies of human neural crest stem cells (hNCSCs) are extremely challenging due to the limited source of hNCSCs as well as ethical and technical issues surrounding isolation of early human embryonic tissues. On the other hand, vast majority of studies on MycN have been conducted in human tumor cells, thus, the role of MycN in normal human neural crest development is completely unknown. In the present study, we determined the role of MycN in hNCSCs isolated from in vitro-differentiating human embryonic stem cells (hESCs). For the first time, we show that suppression of MycN in hNCSCs inhibits cell growth and cell cycle progression. Knockdown of MycN in hNCSCs increases the expression of Cdkn1a, Cdkn2a and Cdkn2b, which encodes the cyclin-dependent kinases p21CIP1, p16 INK4a and p15INK4b. In addition, MycN is involved in the regulation of human sympathetic neurogenesis, as knockdown of MycN enhances the expression of key transcription factors involved in sympathetic neuron differentiation, including Phox2a, Phox2b, Mash1, Hand2 and Gata3. We propose that unlimited source of hNCSCs provides an invaluable platform for the studies of human neural crest development and diseases.

  12. Chaos-Entropy Analysis and Acquisition of Individuality and Proficiency of Human Operator's Skill Using a Neural Controller

    NASA Astrophysics Data System (ADS)

    Kawazoe, Yoshihiko; Ikura, Yoshiaki; Uchiyama, Keiji; Kaise, Toru

    The emergence of intelligence in an autonomous robot exists in the dexterity of humans or creatures as complex systems and research and development procedures along this approach seems necessary for realization of an intellectual robot. However, although strict judgment is required during stabilizing control of an unstable system, such as an inverted pendulum on a cart by human operators, it is assumed that human operators exhibit complex behavior intermittently. A previous paper investigated the skill of a human operator and investigated the formation of a complex system in the learning process of human operators with objects difficult to control. It also considered the mechanism of robustness of human operators against such a disturbance. The current paper shows that the neural network controller identified from time series data of each trial of several operators exhibits the human-generated decision-making characteristics with the chaos and a large amount of disorder. It also confirms that the estimated degrees of freedom of motion increases and the estimated amount of disorder decreases with an increase of proficiency. In addision, this paper shows that the agreement between the neural control simulation and the experimental results of neural control for the degrees of freedom of motion and the entropy ratio is particularly good when the simulated wave form and the measured wave form are similar in appearance.

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

    PubMed

    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.

  14. Human Adult Dental Pulp Stem Cells Enhance Poststroke Functional Recovery Through Non-Neural Replacement Mechanisms

    PubMed Central

    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

    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. In this study, we demonstrate that the intracerebral transplantation of human DPSCs 24 hours following focal cerebral ischemia in a rodent model resulted in significant improvement in forelimb sensorimotor function at 4 weeks post-treatment. At this time, 2.3 ± 0.7% of engrafted cells had survived in the poststroke brain and demonstrated targeted migration toward the stroke lesion. In the peri-infarct striatum, transplanted DPSCs differentiated into astrocytes in preference to neurons. Our data suggest that the dominant mechanism of action underlying DPSC treatment that resulted in enhanced functional recovery is unlikely to be due to neural replacement. Functional improvement is more likely to be mediated through DPSC-dependent paracrine effects. This study provides preclinical evidence for the future use of human DPSCs in cell therapy to improve outcome in stroke patients. PMID:23197777

  15. Neural signatures for sustaining object representations attributed to others in preverbal human infants

    PubMed Central

    Kampis, Dora; Parise, Eugenio; Csibra, Gergely; Kovács, Ágnes Melinda

    2015-01-01

    A major feat of social beings is to encode what their conspecifics see, know or believe. While various non-human animals show precursors of these abilities, humans perform uniquely sophisticated inferences about other people's mental states. However, it is still unclear how these possibly human-specific capacities develop and whether preverbal infants, similarly to adults, form representations of other agents' mental states, specifically metarepresentations. We explored the neurocognitive bases of eight-month-olds' ability to encode the world from another person's perspective, using gamma-band electroencephalographic activity over the temporal lobes, an established neural signature for sustained object representation after occlusion. We observed such gamma-band activity when an object was occluded from the infants' perspective, as well as when it was occluded only from the other person (study 1), and also when subsequently the object disappeared, but the person falsely believed the object to be present (study 2). These findings suggest that the cognitive systems involved in representing the world from infants' own perspective are also recruited for encoding others' beliefs. Such results point to an early-developing, powerful apparatus suitable to deal with multiple concurrent representations, and suggest that infants can have a metarepresentational understanding of other minds even before the onset of language. PMID:26559949

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

    PubMed

    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. PMID:26905451

  17. Neural signatures for sustaining object representations attributed to others in preverbal human infants.

    PubMed

    Kampis, Dora; Parise, Eugenio; Csibra, Gergely; Kovács, Ágnes Melinda

    2015-11-22

    A major feat of social beings is to encode what their conspecifics see, know or believe. While various non-human animals show precursors of these abilities, humans perform uniquely sophisticated inferences about other people's mental states. However, it is still unclear how these possibly human-specific capacities develop and whether preverbal infants, similarly to adults, form representations of other agents' mental states, specifically metarepresentations. We explored the neurocognitive bases of eight-month-olds' ability to encode the world from another person's perspective, using gamma-band electroencephalographic activity over the temporal lobes, an established neural signature for sustained object representation after occlusion. We observed such gamma-band activity when an object was occluded from the infants' perspective, as well as when it was occluded only from the other person (study 1), and also when subsequently the object disappeared, but the person falsely believed the object to be present (study 2). These findings suggest that the cognitive systems involved in representing the world from infants' own perspective are also recruited for encoding others' beliefs. Such results point to an early-developing, powerful apparatus suitable to deal with multiple concurrent representations, and suggest that infants can have a metarepresentational understanding of other minds even before the onset of language. PMID:26559949

  18. Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development

    PubMed Central

    Nicholas, Cory R.; Chen, Jiadong; Tang, Yunshuo; Southwell, Derek G.; Chalmers, Nadine; Vogt, Daniel; Arnold, Christine M.; Chen, Ying-Jiun J.; Stanley, Edouard G.; Elefanty, Andrew G.; Sasai, Yoshiki; Alvarez-Buylla, Arturo; Rubenstein, John L.R.; Kriegstein, Arnold R.

    2013-01-01

    SUMMARY Directed differentiation from human pluripotent stem cells (hPSCs) has seen significant progress in recent years. Most differentiated populations, however, exhibit immature properties of an early embryonic stage, raising concerns about their ability to model and treat disease. Here, we report the directed differentiation of hPSCs into medial ganglionic eminence (MGE)-like progenitors and their maturation into forebrain type interneurons. We find that early stage progenitors progress via a radial glial-like stem cell enriched in the human fetal brain. Both in vitro and post-transplantation into the rodent cortex, the MGE-like cells develop into GABAergic interneuron subtypes with mature physiological properties along a prolonged intrinsic timeline of up to seven months, mimicking endogenous human neural development. MGE-derived cortical interneuron deficiencies are implicated in a broad range of neurodevelopmental and degenerative disorders, highlighting the importance of these results for modeling human neural development and disease. PMID:23642366

  19. Perfusion Stirred-Tank Bioreactors for 3D Differentiation of Human Neural Stem Cells.

    PubMed

    Simão, Daniel; Arez, Francisca; Terasso, Ana P; Pinto, Catarina; Sousa, Marcos F Q; Brito, Catarina; Alves, Paula M

    2016-01-01

    Therapeutic breakthroughs in neurological disorders have been hampered by the lack of accurate central nervous system (CNS) models. The development of these models allows the study of the disease onset/progression mechanisms and the preclinical evaluation of new therapeutics. This has traditionally relied on genetically engineered animal models that often diverge considerably from the human phenotype (developmental, anatomic, and physiological) and 2D in vitro cell models, which fail to recapitulate the characteristics of the target tissue (cell-cell and cell-matrix interactions, cell polarity, etc.). Recapitulation of CNS phenotypic and functional features in vitro requires the implementation of advanced culture strategies, such as 3D culture systems, which enable to mimic the in vivo structural and molecular complexity. Models based on differentiation of human neural stem cells (hNSC) in 3D cultures have great potential as complementary tools in preclinical research, bridging the gap between human clinical studies and animal models. The development of robust and scalable processes for the 3D differentiation of hNSC can improve the accuracy of early stage development in preclinical research. In this context, the use of software-controlled stirred-tank bioreactors (STB) provides an efficient technological platform for hNSC aggregation and differentiation. This system enables to monitor and control important physicochemical parameters for hNSC culture, such as dissolved oxygen. Importantly, the adoption of a perfusion operation mode allows a stable flow of nutrients and differentiation/neurotrophic factors, while clearing the toxic by-products. This contributes to a setting closer to the physiological, by mimicking the in vivo microenvironment. In this chapter, we address the technical requirements and procedures for the implementation of 3D differentiation strategies of hNSC, by operating STB under perfusion mode for long-term cultures. This strategy is suitable

  20. Perfusion Stirred-Tank Bioreactors for 3D Differentiation of Human Neural Stem Cells.

    PubMed

    Simão, Daniel; Arez, Francisca; Terasso, Ana P; Pinto, Catarina; Sousa, Marcos F Q; Brito, Catarina; Alves, Paula M

    2016-01-01

    Therapeutic breakthroughs in neurological disorders have been hampered by the lack of accurate central nervous system (CNS) models. The development of these models allows the study of the disease onset/progression mechanisms and the preclinical evaluation of new therapeutics. This has traditionally relied on genetically engineered animal models that often diverge considerably from the human phenotype (developmental, anatomic, and physiological) and 2D in vitro cell models, which fail to recapitulate the characteristics of the target tissue (cell-cell and cell-matrix interactions, cell polarity, etc.). Recapitulation of CNS phenotypic and functional features in vitro requires the implementation of advanced culture strategies, such as 3D culture systems, which enable to mimic the in vivo structural and molecular complexity. Models based on differentiation of human neural stem cells (hNSC) in 3D cultures have great potential as complementary tools in preclinical research, bridging the gap between human clinical studies and animal models. The development of robust and scalable processes for the 3D differentiation of hNSC can improve the accuracy of early stage development in preclinical research. In this context, the use of software-controlled stirred-tank bioreactors (STB) provides an efficient technological platform for hNSC aggregation and differentiation. This system enables to monitor and control important physicochemical parameters for hNSC culture, such as dissolved oxygen. Importantly, the adoption of a perfusion operation mode allows a stable flow of nutrients and differentiation/neurotrophic factors, while clearing the toxic by-products. This contributes to a setting closer to the physiological, by mimicking the in vivo microenvironment. In this chapter, we address the technical requirements and procedures for the implementation of 3D differentiation strategies of hNSC, by operating STB under perfusion mode for long-term cultures. This strategy is suitable

  1. Cell line differences in replication timing of human glutamate receptor genes and other large genes associated with neural disease

    PubMed Central

    Watanabe, Yoshihisa; Shibata, Kiyoshi; Maekawa, Masato

    2014-01-01

    There is considerable current interest in the function of epigenetic mechanisms in neuroplasticity with regard to learning and memory formation and to a range of neural diseases. Previously, we described replication timing on human chromosome 21q in the THP-1 human cell line (2n = 46, XY) and showed that several genes associated with neural diseases, such as the neuronal glutamate receptor subunit GluR-5 (GRIK1) and amyloid precursor protein (APP), were located in regions where replication timing transitioned from early to late S phase. Here, we compared replication timing of all known human glutamate receptor genes (26 genes in total) and APP in 6 different human cell lines including human neuron-related cell lines. Replication timings were obtained by integrating our previously reported data with new data generated here and information from the online database ReplicationDomain. We found that many of the glutamate receptor genes were clearly located in replication timing transition zones in neural precursor cells, but this relationship was less clear in embryonic stem cells before neural differentiation; in the latter, the genes were often located in later replication timing zones that displayed DNA hypermethylation. Analysis of selected large glutamate receptor genes (>200 kb), and of APP, showed that their precise replication timing patterns differed among the cell lines. We propose that the transition zones of DNA replication timing are altered by epigenetic mechanisms, and that these changes may affect the neuroplasticity that is important to memory and learning, and may also have a role in the development of neural diseases. PMID:25437050

  2. Analysis of neural activity in human motor cortex -- Towards brain machine interface system

    NASA Astrophysics Data System (ADS)

    Secundo, Lavi

    , the correlation of ECoG activity to kinematic parameters of arm movement is context-dependent, an important constraint to consider in future development of BMI systems. The third chapter delves into a fundamental organizational principle of the primate motor system---cortical control of contralateral limb movements. However, ipsilateral motor areas also appear to play a role in the control of ipsilateral limb movements. Several studies in monkeys have shown that individual neurons in ipsilateral primary motor cortex (M1) may represent, on average, the direction of movements of the ipsilateral arm. Given the increasing body of evidence demonstrating that neural ensembles can reliably represent information with a high temporal resolution, here we characterize the distributed neural representation of ipsilateral upper limb kinematics in both monkey and man. In two macaque monkeys trained to perform center-out reaching movements, we found that the ensemble spiking activity in M1 could continuously represent ipsilateral limb position. We also recorded cortical field potentials from three human subjects and also consistently found evidence of a neural representation for ipsilateral movement parameters. Together, our results demonstrate the presence of a high-fidelity neural representation for ipsilateral movement and illustrates that it can be successfully incorporated into a brain-machine interface.

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

    PubMed Central

    Alsalman, Ola; Ost, Jan; Vanspauwen, Robby; Blaivie, Catherine; De Ridder, Dirk; Vanneste, Sven

    2016-01-01

    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 symptoms of vertigo

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

    PubMed

    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.

  5. Foraging under competition: the neural basis of input-matching in humans.

    PubMed

    Mobbs, Dean; Hassabis, Demis; Yu, Rongjun; Chu, Carlton; Rushworth, Matthew; Boorman, Erie; Dalgleish, Tim

    2013-06-01

    Input-matching is a key mechanism by which animals optimally distribute themselves across habitats to maximize net gains based on the changing input values of food supply rate and competition. To examine the neural systems that underlie this rule in humans, we created a continuous-input foraging task where subjects had to decide to stay or switch between two habitats presented on the left and right of the screen. The subject's decision to stay or switch was based on changing input values of reward-token supply rate and competition density. High density of competition or low-reward token rate was associated with decreased chance of winning. Therefore, subjects attempted to maximize their gains by switching to habitats that possessed low competition density and higher token rate. When it was increasingly disadvantageous to be in a habitat, we observed increased activity in brain regions that underlie preparatory motor actions, including the dorsal anterior cingulate cortex and the supplementary motor area, as well as the insula, which we speculate may be involved in the conscious urge to switch habitats. Conversely, being in an advantageous habitat is associated with activity in the reward systems, namely the striatum and medial prefrontal cortex. Moreover, amygdala and dorsal putamen activity steered interindividual preferences in competition avoidance and pursuing reward. Our results suggest that input-matching decisions are made as a net function of activity in a distributed set of neural systems. Furthermore, we speculate that switching behaviors are related to individual differences in competition avoidance and reward drive.

  6. Remembering forward: Neural correlates of memory and prediction in human motor adaptation

    PubMed Central

    Scheidt, Robert A; Zimbelman, Janice L; Salowitz, Nicole M G; Suminski, Aaron J; Mosier, Kristine M; Houk, James; Simo, Lucia

    2011-01-01

    We used functional MR imaging (FMRI), a robotic manipulandum and systems identification techniques to examine neural correlates of predictive compensation for spring-like loads during goal-directed wrist movements in neurologically-intact humans. Although load changed unpredictably from one trial to the next, subjects nevertheless used sensorimotor memories from recent movements to predict and compensate upcoming loads. Prediction enabled subjects to adapt performance so that the task was accomplished with minimum effort. Population analyses of functional images revealed a distributed, bilateral network of cortical and subcortical activity supporting predictive load compensation during visual target capture. Cortical regions - including prefrontal, parietal and hippocampal cortices - exhibited trial-by-trial fluctuations in BOLD signal consistent with the storage and recall of sensorimotor memories or “states” important for spatial working memory. Bilateral activations in associative regions of the striatum demonstrated temporal correlation with the magnitude of kinematic performance error (a signal that could drive reward-optimizing reinforcement learning and the prospective scaling of previously learned motor programs). BOLD signal correlations with load prediction were observed in the cerebellar cortex and red nuclei (consistent with the idea that these structures generate adaptive fusimotor signals facilitating cancellation of expected proprioceptive feedback, as required for conditional feedback adjustments to ongoing motor commands and feedback error learning). Analysis of single subject images revealed that predictive activity was at least as likely to be observed in more than one of these neural systems as in just one. We conclude therefore that motor adaptation is mediated by predictive compensations supported by multiple, distributed, cortical and subcortical structures. PMID:21840405

  7. Effects of topography on the functional development of human neural progenitor cells.

    PubMed

    Wu, Ze-Zhi; Kisaalita, William S; Wang, Lina; Zachman, Angela L; Zhao, Yiping; Hasneen, Kowser; Machacek, Dave; Stice, Steven L

    2010-07-01

    We have fabricated a topographical substrate with a packed polystyrene bead array for the development of cell-based assay systems targeting voltage-gated calcium channels (VGCCs). Human neural progenitor cells (H945RB.3) cultured on both flat and topographical substrates were analyzed in terms of morphological spreading, neuronal commitment, resting membrane potential (V(m)) establishment and VGCC function development. We found, by SEM imaging, that arrayed substrates, formed with both sub-micrometer (of 0.51 microm in mean diameter) and micrometer (of 1.98 microm in mean diameter) beads, were capable of promoting the spreading of the progenitor cells as compared with the flat polystyrene surfaces. With the micrometer beads, it was found that arrayed substrates facilitated the neural progenitor cells' maintenance of less negative V(m) values upon differentiation with bFGF starvation, which favored predominant neuronal commitment. Almost all the progenitor cells were responsive to 50 mM K(+) depolarization with an increase in [Ca(2+)](i) either before or upon differentiation, suggesting the expression of functional VGCCs. Compared to the flat polystyrene surfaces, microbead arrayed substrates facilitated the development of higher VGCC responsiveness by the progenitor cells upon differentiation. The enhancement of both VGCC responsiveness and cell spreading by arrays of micrometer beads was most significant on day 14 into differentiation, which was the latest time point of measurement in this study. This study thus rationalized the possibility for future substrate topography engineering to manipulate ion channel function and to meet the challenge of low VGCC responsiveness found in early drug discovery. PMID:20198656

  8. Controllability modulates the neural response to predictable but not unpredictable threat in humans.

    PubMed

    Wood, Kimberly H; Wheelock, Muriah D; Shumen, Joshua R; Bowen, Kenton H; Ver Hoef, Lawrence W; Knight, David C

    2015-10-01

    Stress resilience is mediated, in part, by our ability to predict and control threats within our environment. Therefore, determining the neural mechanisms that regulate the emotional response to predictable and controllable threats may provide important new insight into the processes that mediate resilience to emotional dysfunction and guide the future development of interventions for anxiety disorders. To better understand the effect of predictability and controllability on threat-related brain activity in humans, two groups of healthy volunteers participated in a yoked Pavlovian fear conditioning study during functional magnetic resonance imaging (fMRI). Threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or by presenting the UCS alone (i.e., unpredictable). Similar to animal model research that has employed yoked fear conditioning procedures, one group (controllable condition; CC), but not the other group (uncontrollable condition; UC) was able to terminate the UCS. The fMRI signal response within the dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and posterior cingulate was diminished during predictable compared to unpredictable threat (i.e., UCS). In addition, threat-related activity within the ventromedial PFC and bilateral hippocampus was diminished only to threats that were both predictable and controllable. These findings provide insight into how threat predictability and controllability affects the activity of brain regions (i.e., ventromedial PFC and hippocampus) involved in emotion regulation, and may have important implications for better understanding neural processes that mediate emotional resilience to stress. PMID:26149610

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

    PubMed

    Baulch, Janet E; Craver, Brianna M; Tran, Katherine K; Yu, Liping; Chmielewski, Nicole; Allen, Barrett D; Limoli, Charles L

    2015-08-01

    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. PMID:25800120

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

    PubMed

    Iidaka, Tetsuya; Harada, Tokiko; Sadato, Norihiro

    2014-12-01

    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.

  11. Controllability Modulates the Neural Response to Predictable but not Unpredictable Threat in Humans

    PubMed Central

    Wood, Kimberly H.; Wheelock, Muriah D.; Shumen, Joshua R.; Bowen, Kenton H.; Ver Hoef, Lawrence W.; Knight, David C.

    2015-01-01

    Stress resilience is mediated, in part, by our ability to predict and control threats within our environment. Therefore, determining the neural mechanisms that regulate the emotional response to predictable and controllable threat may provide important new insight into the processes that mediate resilience to emotional dysfunction and guide the future development of interventions for anxiety disorders. To better understand the effect of predictability and controllability on threat-related brain activity in humans, two groups of healthy volunteers participated in a yoked Pavlovian fear conditioning study during functional magnetic resonance imaging (fMRI). Threat predictability was manipulated by presenting an aversive unconditioned stimulus (UCS) that was either preceded by a conditioned stimulus (i.e., predictable) or by presenting the UCS alone (i.e., unpredictable). Similar to animal model research that has employed yoked fear conditioning procedures, one group (Controllable Condition; CC), but not the other group (Uncontrollable Condition; UC) was able to terminate the UCS. The fMRI signal response within the dorsolateral prefrontal cortex (PFC), dorsomedial PFC, ventromedial PFC, and posterior cingulate was diminished during predictable compared to unpredictable threat (i.e., UCS). In addition, threat-related activity within the ventromedial PFC and bilateral hippocampus was diminished only to threats that were both predictable and controllable. These findings provide insight into how threat predictability and controllability affects the activity of brain regions (i.e., ventromedial PFC and hippocampus) involved in emotion regulation, and may have important implications for better understanding neural processes that mediate emotional resilience to stress. PMID:26149610

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

    PubMed

    Alsalman, Ola; Ost, Jan; Vanspauwen, Robby; Blaivie, Catherine; De Ridder, Dirk; Vanneste, Sven

    2016-01-01

    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 symptoms of vertigo

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

    PubMed

    Alsalman, Ola; Ost, Jan; Vanspauwen, Robby; Blaivie, Catherine; De Ridder, Dirk; Vanneste, Sven

    2016-01-01

    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 symptoms of vertigo

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

    PubMed Central

    Baulch, Janet E.; Craver, Brianna M.; Tran, Katherine K.; Yu, Liping; Chmielewski, Nicole; Allen, Barrett D.; Limoli, Charles L.

    2015-01-01

    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. PMID:25800120

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

    SciTech Connect

    Zhang, Yun; Wang, Jing; Chen, Guian; Fan, Dongsheng; Deng, Min

    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.

  16. Dynamical Integration of Language and Behavior in a Recurrent Neural Network for Human-Robot Interaction.

    PubMed

    Yamada, Tatsuro; Murata, Shingo; Arie, Hiroaki; Ogata, Tetsuya

    2016-01-01

    To work cooperatively with humans by using language, robots must not only acquire a mapping between language and their behavior but also autonomously utilize the mapping in appropriate contexts of interactive tasks online. To this end, we propose a novel learning method linking language to robot behavior by means of a recurrent neural network. In this method, the network learns from correct examples of the imposed task that are given not as explicitly separated sets of language and behavior but as sequential data constructed from the actual temporal flow of the task. By doing this, the internal dynamics of the network models both language-behavior relationships and the temporal patterns of interaction. Here, "internal dynamics" refers to the time development of the system defined on the fixed-dimensional space of the internal states of the context layer. Thus, in the execution phase, by constantly representing where in the interaction context it is as its current state, the network autonomously switches between recognition and generation phases without any explicit signs and utilizes the acquired mapping in appropriate contexts. To evaluate our method, we conducted an experiment in which a robot generates appropriate behavior responding to a human's linguistic instruction. After learning, the network actually formed the attractor structure representing both language-behavior relationships and the task's temporal pattern in its internal dynamics. In the dynamics, language-behavior mapping was achieved by the branching structure. Repetition of human's instruction and robot's behavioral response was represented as the cyclic structure, and besides, waiting to a subsequent instruction was represented as the fixed-point attractor. Thanks to this structure, the robot was able to interact online with a human concerning the given task by autonomously switching phases.

  17. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.

    PubMed

    Liu, Guang-Hui; Qu, Jing; Suzuki, Keiichiro; Nivet, Emmanuel; Li, Mo; Montserrat, Nuria; Yi, Fei; Xu, Xiuling; Ruiz, Sergio; Zhang, Weiqi; Wagner, Ulrich; Kim, Audrey; Ren, Bing; Li, Ying; Goebl, April; Kim, Jessica; Soligalla, Rupa Devi; Dubova, Ilir; Thompson, James; Yates, John; Esteban, Concepcion Rodriguez; Sancho-Martinez, Ignacio; Izpisua Belmonte, Juan Carlos

    2012-11-22

    Nuclear-architecture defects have been shown to correlate with the manifestation of a number of human diseases as well as ageing. It is therefore plausible that diseases whose manifestations correlate with ageing might be connected to the appearance of nuclear aberrations over time. We decided to evaluate nuclear organization in the context of ageing-associated disorders by focusing on a leucine-rich repeat kinase 2 (LRRK2) dominant mutation (G2019S; glycine-to-serine substitution at amino acid 2019), which is associated with familial and sporadic Parkinson's disease as well as impairment of adult neurogenesis in mice. Here we report on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson's disease patients and the implications of LRRK2(G2019S) mutation in human neural-stem-cell (NSC) populations. Mutant NSCs showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear-envelope organization, clonal expansion and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2(G2019S) mutation with its wild-type counterpart in Parkinson's disease iPSCs and were recapitulated after targeted knock-in of the LRRK2(G2019S) mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear-envelope impairment in clinically diagnosed Parkinson's disease patients. Together, our results identify the nucleus as a previously unknown cellular organelle in Parkinson's disease pathology and may help to open new avenues for Parkinson's disease diagnoses as well as for the potential development of therapeutics targeting this fundamental cell structure.

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

    PubMed

    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.

  19. The Evaluation of Nerve Growth Factor Over Expression on Neural Lineage Specific Genes in Human Mesenchymal Stem Cells

    PubMed Central

    Mortazavi, Yousef; Sheikhsaran, Fatemeh; Khamisipour, Gholamreza Khamisipour; Soleimani, Masoud; Teimuri, Ali; Shokri, Somayeh

    2016-01-01

    Objective Treatment and repair of neurodegenerative diseases such as brain tumors, spinal cord injuries, and functional disorders, including Alzheimer’s disease, are challenging problems. A common treatment approach for such disorders involves the use of mesenchymal stem cells (MSCs) as an alternative cell source to replace injured cells. However, use of these cells in hosts may potentially cause adverse outcomes such as tumorigenesis and uncontrolled differentiation. In attempt to generate mesenchymal derived neural cells, we have infected MSCs with recombinant lentiviruses that expressed nerve growth factor (NGF) and assessed their neural lineage genes. Materials and Methods In this experimental study, we cloned the NGF gene sequence into a helper dependent lentiviral vector that contained the green fluorescent protein (GFP) gene. The recombinant vector was amplified in DH5 bacterial cells. Recombinant viruses were generated in the human embryonic kidney 293 (HEK-293) packaging cell line with the helper vectors and analyzed under fluorescent microscopy. Bone marrow mesenchymal cells were infected by recombinant viruses for three days followed by assessment of neural differentiation. We evaluated expression of NGF through measurement of the NGF protein in culture medium by ELISA; neural specific genes were quantified by real-time polymerase chain reaction (PCR). Results We observed neural morphological changes after three days. Quantitative PCR showed that expressions of NESTIN, glial derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP) and Microtubule-associated protein 2 (MAP2) genes increased following induction of NGF overexpression, whereas expressions of endogenous NGF and brain derived neural growth factor (BDNF) genes reduced. Conclusion Ectopic expression of NGF can induce neurogenesis in MSCs. Direct injection of MSCs may cause tumorigenesis and an undesirable outcome. Therefore an alternative choice to overcome this obstacle may

  20. Efficient and Rapid Derivation of Primitive Neural Stem Cells and Generation of Brain Subtype Neurons From Human Pluripotent Stem Cells

    PubMed Central

    Yan, Yiping; Shin, Soojung; Jha, Balendu Shekhar; Liu, Qiuyue; Sheng, Jianting; Li, Fuhai; Zhan, Ming; Davis, Janine; Bharti, Kapil; Zeng, Xianmin; Rao, Mahendra; Malik, Nasir

    2013-01-01

    Human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, are unique cell sources for disease modeling, drug discovery screens, and cell therapy applications. The first step in producing neural lineages from hPSCs is the generation of neural stem cells (NSCs). Current methods of NSC derivation involve the time-consuming, labor-intensive steps of an embryoid body generation or coculture with stromal cell lines that result in low-efficiency derivation of NSCs. In this study, we report a highly efficient serum-free pluripotent stem cell neural induction medium that can induce hPSCs into primitive NSCs (pNSCs) in 7 days, obviating the need for time-consuming, laborious embryoid body generation or rosette picking. The pNSCs expressed the neural stem cell markers Pax6, Sox1, Sox2, and Nestin; were negative for Oct4; could be expanded for multiple passages; and could be differentiated into neurons, astrocytes, and oligodendrocytes, in addition to the brain region-specific neuronal subtypes GABAergic, dopaminergic, and motor neurons. Global gene expression of the transcripts of pNSCs was comparable to that of rosette-derived and human fetal-derived NSCs. This work demonstrates an efficient method to generate expandable pNSCs, which can be further differentiated into central nervous system neurons and glia with temporal, spatial, and positional cues of brain regional heterogeneity. This method of pNSC derivation sets the stage for the scalable production of clinically relevant neural cells for cell therapy applications in good manufacturing practice conditions. PMID:24113065

  1. PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype.

    PubMed

    Duan, Shunlei; Yuan, Guohong; Liu, Xiaomeng; Ren, Ruotong; Li, Jingyi; Zhang, Weizhou; Wu, Jun; Xu, Xiuling; Fu, Lina; Li, Ying; Yang, Jiping; Zhang, Weiqi; Bai, Ruijun; Yi, Fei; Suzuki, Keiichiro; Gao, Hua; Esteban, Concepcion Rodriguez; Zhang, Chuanbao; Izpisua Belmonte, Juan Carlos; Chen, Zhiguo; Wang, Xiaomin; Jiang, Tao; Qu, Jing; Tang, Fuchou; Liu, Guang-Hui

    2015-01-01

    PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma. PMID:26632666

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

    PubMed

    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. PMID:26811252

  3. Human Neural Stem Cells Overexpressing Choline Acetyltransferase Restore Unconditioned Fear in Rats with Amygdala Injury

    PubMed Central

    Shin, Kyungha; Cha, Yeseul; Kim, Kwang Sei; Choi, Ehn-Kyoung; Choi, Youngjin; Guo, Haiyu; Ban, Young-Hwan; Kim, Jong-Choon; Park, Dongsun; Kim, Yun-Bae

    2016-01-01

    Amygdala is involved in the fear memory that recognizes certain environmental cues predicting threatening events. Manipulation of neurotransmission within the amygdala affects the expression of conditioned and unconditioned emotional memories such as fear freezing behaviour. We previously demonstrated that F3.ChAT human neural stem cells (NSCs) overexpressing choline acetyltransferase (ChAT) improve cognitive function of Alzheimer's disease model rats with hippocampal or cholinergic nerve injuries by increasing acetylcholine (ACh) level. In the present study, we examined the effect of F3.ChAT cells on the deficit of unconditioned fear freezing. Rats given N-methyl-d-aspartate (NMDA) in their amygdala 2 weeks prior to cat odor exposure displayed very short resting (freezing) time compared to normal animals. NMDA induced neuronal degeneration in the amygdala, leading to a decreased ACh concentration in cerebrospinal fluid. However, intracerebroventricular transplantation of F3.ChAT cells attenuated amygdala lesions 4 weeks after transplantation. The transplanted cells were found in the NMDA-injury sites and produced ChAT protein. In addition, F3.ChAT-receiving rats recuperated freezing time staying remote from the cat odor source, according to the recovery of brain ACh concentration. The results indicate that human NSCs overexpressing ChAT may facilitate retrieval of unconditioned fear memory by increasing ACh level. PMID:27087745

  4. Modeling activity-dependent plasticity in BCM spiking neural networks with application to human behavior recognition.

    PubMed

    Meng, Yan; Jin, Yaochu; Yin, Jun

    2011-12-01

    Spiking neural networks (SNNs) are considered to be computationally more powerful than conventional NNs. However, the capability of SNNs in solving complex real-world problems remains to be demonstrated. In this paper, we propose a substantial extension of the Bienenstock, Cooper, and Munro (BCM) SNN model, in which the plasticity parameters are regulated by a gene regulatory network (GRN). Meanwhile, the dynamics of the GRN is dependent on the activation levels of the BCM neurons. We term the whole model "GRN-BCM." To demonstrate its computational power, we first compare the GRN-BCM with a standard BCM, a hidden Markov model, and a reservoir computing model on a complex time series classification problem. Simulation results indicate that the GRN-BCM significantly outperforms the compared models. The GRN-BCM is then applied to two widely used datasets for human behavior recognition. Comparative results on the two datasets suggest that the GRN-BCM is very promising for human behavior recognition, although the current experiments are still limited to the scenarios in which only one object is moving in the considered video sequences.

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

    PubMed

    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.

  6. Neural network analysis of the information content in population responses from human periodontal receptors

    NASA Astrophysics Data System (ADS)

    Edin, Benoni B.; Trulsson, Mats

    1992-07-01

    Understanding of the information processing in some sensory systems is hampered for several reasons. First, some of these systems may depend on several receptor types with different characteristics, and the crucial features of natural stimuli encoded by the receptors are rarely known with certainty. Second, the functional output of sensory processing is often not well defined. The human tooth is endowed with several types of sensory receptors. Among these, the mechanoreceptors located in the periodontal ligaments have been implicated in force encoding during chewing and biting. Individual receptors cannot, however, code unambiguously either the direction or the magnitude of the applied forces. Neuronal responses recorded in single human nerve fibers from periodontal receptors were fed to multi-layered feed-forward networks. The networks were trained with error back-propagation to identify specific features of the force stimuli that evoked the receptor responses. It was demonstrated that population responses in periodontal receptors contain information about both the point of attack and the direction of applied forces. It is concluded that networks may provide a powerful tool to investigate the information content in responses from biological receptor populations. As such, specific hypotheses with respect to information processing may be tested using neural networks also in sensory systems less well understood than, for instance, the visual system.

  7. V-Myc Immortalizes Human Neural Stem Cells in the Absence of Pluripotency-Associated Traits

    PubMed Central

    Pino-Barrio, María José; García-García, Elisa; Menéndez, Pablo; Martínez-Serrano, Alberto

    2015-01-01

    A better understanding of the molecular mechanisms governing stem cell self-renewal will foster the use of different types of stem cells in disease modeling and cell therapy strategies. Immortalization, understood as the capacity for indefinite expansion, is needed for the generation of any cell line. In the case of v-myc immortalized multipotent human Neural Stem Cells (hNSCs), we hypothesized that v-myc immortalization could induce a more de-differentiated state in v-myc hNSC lines. To test this, we investigated the expression of surface, biochemical and genetic markers of stemness and pluripotency in v-myc immortalized and control hNSCs (primary precursors, that is, neurospheres) and compared these two cell types to human Embryonic Stem Cells (hESCs) and fibroblasts. Using a Hierarchical Clustering method and a Principal Component Analysis (PCA), the v-myc hNSCs associated with their counterparts hNSCs (in the absence of v-myc) and displayed a differential expression pattern when compared to hESCs. Moreover, the expression analysis of pluripotency markers suggested no evidence supporting a reprogramming-like process despite the increment in telomerase expression. In conclusion, v-myc expression in hNSC lines ensures self-renewal through the activation of some genes involved in the maintenance of stem cell properties in multipotent cells but does not alter the expression of key pluripotency-associated genes. PMID:25764185

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

    PubMed Central

    Edmiston, Elliot Kale; Merkle, Kristen

    2015-01-01

    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. PMID:25552572

  9. Human Neural Stem Cells Overexpressing Choline Acetyltransferase Restore Unconditioned Fear in Rats with Amygdala Injury.

    PubMed

    Shin, Kyungha; Cha, Yeseul; Kim, Kwang Sei; Choi, Ehn-Kyoung; Choi, Youngjin; Guo, Haiyu; Ban, Young-Hwan; Kim, Jong-Choon; Park, Dongsun; Kim, Yun-Bae

    2016-01-01

    Amygdala is involved in the fear memory that recognizes certain environmental cues predicting threatening events. Manipulation of neurotransmission within the amygdala affects the expression of conditioned and unconditioned emotional memories such as fear freezing behaviour. We previously demonstrated that F3.ChAT human neural stem cells (NSCs) overexpressing choline acetyltransferase (ChAT) improve cognitive function of Alzheimer's disease model rats with hippocampal or cholinergic nerve injuries by increasing acetylcholine (ACh) level. In the present study, we examined the effect of F3.ChAT cells on the deficit of unconditioned fear freezing. Rats given N-methyl-d-aspartate (NMDA) in their amygdala 2 weeks prior to cat odor exposure displayed very short resting (freezing) time compared to normal animals. NMDA induced neuronal degeneration in the amygdala, leading to a decreased ACh concentration in cerebrospinal fluid. However, intracerebroventricular transplantation of F3.ChAT cells attenuated amygdala lesions 4 weeks after transplantation. The transplanted cells were found in the NMDA-injury sites and produced ChAT protein. In addition, F3.ChAT-receiving rats recuperated freezing time staying remote from the cat odor source, according to the recovery of brain ACh concentration. The results indicate that human NSCs overexpressing ChAT may facilitate retrieval of unconditioned fear memory by increasing ACh level. PMID:27087745

  10. PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype.

    PubMed

    Duan, Shunlei; Yuan, Guohong; Liu, Xiaomeng; Ren, Ruotong; Li, Jingyi; Zhang, Weizhou; Wu, Jun; Xu, Xiuling; Fu, Lina; Li, Ying; Yang, Jiping; Zhang, Weiqi; Bai, Ruijun; Yi, Fei; Suzuki, Keiichiro; Gao, Hua; Esteban, Concepcion Rodriguez; Zhang, Chuanbao; Izpisua Belmonte, Juan Carlos; Chen, Zhiguo; Wang, Xiaomin; Jiang, Tao; Qu, Jing; Tang, Fuchou; Liu, Guang-Hui

    2015-12-03

    PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.

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

    PubMed

    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.

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

    PubMed

    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. PMID:25552572

  13. A neural network simulating human reach-grasp coordination by continuous updating of vector positioning commands.

    PubMed

    Ulloa, Antonio; Bullock, Daniel

    2003-10-01

    We developed a neural network model to simulate temporal coordination of human reaching and grasping under variable initial grip apertures and perturbations of object size and object location/orientation. The proposed model computes reach-grasp trajectories by continuously updating vector positioning commands. The model hypotheses are (1) hand/wrist transport, grip aperture, and hand orientation control modules are coupled by a gating signal that fosters synchronous completion of the three sub-goals. (2) Coupling from transport and orientation velocities to aperture control causes maximum grip apertures that scale with these velocities and exceed object size. (3) Part of the aperture trajectory is attributable to an aperture-reducing passive biomechanical effect that is stronger for larger apertures. (4) Discrepancies between internal representations of targets partially inhibit the gating signal, leading to movement time increases that compensate for perturbations. Simulations of the model replicate key features of human reach-grasp kinematics observed under three experimental protocols. Our results indicate that no precomputation of component movement times is necessary for online temporal coordination of the components of reaching and grasping.

  14. Comparison of deep neural networks to spatio-temporal cortical dynamics of human visual object recognition reveals hierarchical correspondence

    PubMed Central

    Cichy, Radoslaw Martin; Khosla, Aditya; Pantazis, Dimitrios; Torralba, Antonio; Oliva, Aude

    2016-01-01

    The complex multi-stage architecture of cortical visual pathways provides the neural basis for efficient visual object recognition in humans. However, the stage-wise computations therein remain poorly understood. Here, we compared temporal (magnetoencephalography) and spatial (functional MRI) visual brain representations with representations in an artificial deep neural network (DNN) tuned to the statistics of real-world visual recognition. We showed that the DNN captured the stages of human visual processing in both time and space from early visual areas towards the dorsal and ventral streams. Further investigation of crucial DNN parameters revealed that while model architecture was important, training on real-world categorization was necessary to enforce spatio-temporal hierarchical relationships with the brain. Together our results provide an algorithmically informed view on the spatio-temporal dynamics of visual object recognition in the human visual brain. PMID:27282108

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

    SciTech Connect

    Colleoni, Silvia; Giannelli, Serena G.; Armentero, Marie-Therese; Blandini, Fabio; Broccoli, Vania; Lazzari, Giovanna

    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.

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

    PubMed Central

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

    2015-01-01

    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 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. PMID:24882167

  17. Cellular and molecular effects of high-LET radiation on human neural stem cells and neurons

    NASA Astrophysics Data System (ADS)

    Vazquez, M.; Guida, P.; Green, L.; Chang, P.; Otto, S.

    cells exposed to 5 GeV/n iron ions, we demonstrated a time and dose dependent increase in p53 protein levels. This induction occurred as early as 6 hours post-irradiation, and was detectable with a dose as low as 10 cGy. Meanwhile, the levels of the structural protein actin did not change in these cell samples, assuring accurate protein quantization and equal loading from sample to sample. We have also shown a time and dose dependent increase in p53 protein levels in terminally differentiated human neuronal (hNT) cells exposed to 1 GeV/n iron ions. Using a more detailed protocol of early harvesting times, we determined that p53 accumulated in these neuronal cells within 8 hours after irradiation. Our laboratory's demonstration that HZE radiation exposure results in a dose dependent induction of p53 protein, concomitant with our finding of a dose dependent induction of apoptosis in the neural stem (NT2) cells, strongly implies that p53 plays a major role in this HZE radiation-induced apoptosis response.

  18. Neural stem-like cells derived from human amnion tissue are effective in treating traumatic brain injury in rat.

    PubMed

    Yan, Zhong-Jie; Zhang, Peng; Hu, Yu-Qin; Zhang, Hong-Tian; Hong, Sun-Quan; Zhou, Hong-Long; Zhang, Mao-Ying; Xu, Ru-Xiang

    2013-05-01

    Although human amnion derived mesenchymal stem cells (AMSC) are a promising source of stem cells, their therapeutic potential for traumatic brain injury (TBI) has not been widely investigated. In this study, we evaluated the therapeutic potential of AMSC using a rat TBI model. AMSC were isolated from human amniotic membrane and characterized by flow cytometry. After induction, AMSC differentiated in vitro into neural stem-like cells (AM-NSC) that expressed higher levels of the neural stem cell markers, nestin, sox2 and musashi, in comparison to undifferentiated AMSC. Interestingly, the neurotrophic factors, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), glial cell derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) were markedly upregulated after neural stem cell induction. Following transplantation in a rat TBI model, significant improvements in neurological function, brain tissue morphology, and higher levels of BDNF, NGF, NT-3, GDNF and CNTF, were observed in the AM-NSC group compared with the AMSC and Matrigel groups. However, few grafted cells survived with minimal differentiation into neural-like cells. Together, our results suggest that transplantation of AM-NSC promotes functional rehabilitation of rats with TBI, with enhanced expression of neurotrophic factors a likely mechanistic pathway.

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

    PubMed

    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 (<10) of presynaptic inputs, whereas a small set of hub-like neurons have large numbers of synaptic connections (>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. PMID:26395144

  20. Thermogel nanofiber induces human endometrial-derived stromal cells to neural differentiation: In vitro and in vivo studies in rat.

    PubMed

    Tavakol, Shima; Aligholi, Hadi; Gorji, Ali; Eshaghabadi, Arezou; Hoveizi, Elham; Tavakol, Behnaz; Rezayat, Seyed Mahdi; Ai, Jafar

    2014-12-01

    Spinal cord injury (SCI) in humans remains a devastating and incurable disorder. The use of Matrigel, a hydrogel-mimicking extracellular matrix, has been suggested as a scaffold for spinal cord regeneration. Human endometrial-derived stromal cells (hEnSCs) are abundant and available in adult stem cells with low immunological incompatibility, which could be considered for cell replacement therapy. The purpose of this study was to investigate the role of Matrigel in neural differentiation of hEnSCs in vitro and assess the supportive effects of this hydrogel in an animal model of SCI. hEnSCs were isolated and encapsulated into nanofibrous thermogel and cell viability and cell membrane damage were assessed. Encapsulated hEnSCs into Matrigel were treated with neural differentiation medium for 21 days, and then neural genes and protein markers were analyzed using real time-PCR and immunocytochemistry. Matrigel was implanted into rats with SCI and followed for 42 days using a behavioral test. Our study revealed a higher cell viability and neural differentiation in the level of genes and proteins as well as lower cell membrane damage. Substantial recoveries of motor function were observed in animals receiving the Matrigel treatment. The treatment with Matrigel, nanofibrous scaffold, produced beneficial effects on functional recovery following SCI in rats, possibly via assimilation to cytoskeleton fiber, high surface/volume ratio, spatial interconnectivity and containing some adhesive molecules and growth factors, enhancement of anti-inflammation, anti-astrogliosis, neuronal extension, and neuronal regeneration effects.

  1. Significant expansion of the REST/NRSF cistrome in human versus mouse embryonic stem cells: potential implications for neural development.

    PubMed

    Rockowitz, Shira; Zheng, Deyou

    2015-07-13

    Recent studies have employed cross-species comparisons of transcription factor binding, reporting significant regulatory network 'rewiring' between species. Here, we address how a transcriptional repressor targets and regulates neural genes differentially between human and mouse embryonic stem cells (ESCs). We find that the transcription factor, Repressor Element 1 Silencing Transcription factor (REST; also called neuron restrictive silencer factor) binds to a core group of ∼1200 syntenic genomic regions in both species, with these conserved sites highly enriched with co-factors, selective histone modifications and DNA hypomethylation. Genes with conserved REST binding are enriched with neural functions and more likely to be upregulated upon REST depletion. Interestingly, we identified twice as many REST peaks in human ESCs compared to mouse ESCs. Human REST cistrome expansion involves additional peaks in genes targeted by REST in both species and human-specific gene targets. Genes with expanded REST occupancy in humans are enriched for learning or memory functions. Analysis of neurological disorder associated genes reveals that Amyotrophic Lateral Sclerosis and oxidative stress genes are particularly enriched with human-specific REST binding. Overall, our results demonstrate that there is substantial rewiring of human and mouse REST cistromes, and that REST may have human-specific roles in brain development and functions. PMID:25990720

  2. Significant expansion of the REST/NRSF cistrome in human versus mouse embryonic stem cells: potential implications for neural development

    PubMed Central

    Rockowitz, Shira; Zheng, Deyou

    2015-01-01

    Recent studies have employed cross-species comparisons of transcription factor binding, reporting significant regulatory network ‘rewiring’ between species. Here, we address how a transcriptional repressor targets and regulates neural genes differentially between human and mouse embryonic stem cells (ESCs). We find that the transcription factor, Repressor Element 1 Silencing Transcription factor (REST; also called neuron restrictive silencer factor) binds to a core group of ∼1200 syntenic genomic regions in both species, with these conserved sites highly enriched with co-factors, selective histone modifications and DNA hypomethylation. Genes with conserved REST binding are enriched with neural functions and more likely to be upregulated upon REST depletion. Interestingly, we identified twice as many REST peaks in human ESCs compared to mouse ESCs. Human REST cistrome expansion involves additional peaks in genes targeted by REST in both species and human-specific gene targets. Genes with expanded REST occupancy in humans are enriched for learning or memory functions. Analysis of neurological disorder associated genes reveals that Amyotrophic Lateral Sclerosis and oxidative stress genes are particularly enriched with human-specific REST binding. Overall, our results demonstrate that there is substantial rewiring of human and mouse REST cistromes, and that REST may have human-specific roles in brain development and functions. PMID:25990720

  3. The Interleukin 3 Gene (IL3) Contributes to Human Brain Volume Variation by Regulating Proliferation and Survival of Neural Progenitors

    PubMed Central

    Huang, Liang; Nho, Kwangsik; Deng, Min; Chen, Qiang; Weinberger, Daniel R.; Vasquez, Alejandro Arias; Rijpkema, Mark; Mattay, Venkata S.; Saykin, Andrew J.; Shen, Li; Fernández, Guillén; Franke, Barbara; Chen, Jing-chun; Chen, Xiang-ning; Wang, Jin-kai; Xiao, Xiao; Qi, Xue-bin; Xiang, Kun; Peng, Ying-Mei; Cao, Xiang-yu; Li, Yi; Shi, Xiao-dong; Gan, Lin; Su, Bing

    2012-01-01

    One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which alters the expression of IL3 by affecting the binding affinity of transcription factor SP1. Further analysis indicated that IL3 and its receptors are continuously expressed in the developing mouse brain, reaching highest levels at postnatal day 1–4. Furthermore, we found IL3 receptor alpha (IL3RA) was mainly expressed in neural progenitors and neurons, and IL3 could promote proliferation and survival of the neural progenitors. The expression level of IL3 thus played pivotal roles in the expansion and maintenance of the neural progenitor pool and the number of surviving neurons. Moreover, we found that IL3 activated both estrogen receptors, but estrogen didn’t directly regulate the expression of IL3. Our results demonstrate that genetic variation in the IL3 promoter regulates human brain volume and reveals novel roles of IL3 in regulating brain development. PMID:23226269

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

    PubMed

    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. PMID:27147262

  5. Lentiviral vector-mediated genetic modification of human neural progenitor cells for ex vivo gene therapy.

    PubMed

    Capowski, Elizabeth E; Schneider, Bernard L; Ebert, Allison D; Seehus, Corey R; Szulc, Jolanta; Zufferey, Romain; Aebischer, Patrick; Svendsen, Clive N

    2007-07-30

    Human neural progenitor cells (hNPC) hold great potential as an ex vivo system for delivery of therapeutic proteins to the central nervous system. When cultured as aggregates, termed neurospheres, hNPC are capable of significant in vitro expansion. In the current study, we present a robust method for lentiviral vector-mediated gene delivery into hNPC that maintains the differentiation and proliferative properties of neurosphere cultures while minimizing the amount of viral vector used and controlling the number of insertion sites per population. This method results in long-term, stable expression even after differentiation of the hNPC to neurons and astrocytes and allows for generation of equivalent transgenic populations of hNPC. In addition, the in vitro analysis presented predicts the behavior of transgenic lines in vivo when transplanted into a rodent model of Parkinson's disease. The methods presented provide a powerful tool for assessing the impact of factors such as promoter systems or different transgenes on the therapeutic utility of these cells.

  6. Characterization of Voltage-Gated Potassium Channels in Human Neural Progenitor Cells

    PubMed Central

    Schaarschmidt, Grit; Wegner, Florian; Schwarz, Sigrid C.; Schmidt, Hartmut; Schwarz, Johannes

    2009-01-01

    Background Voltage-gated potassium (Kv) channels are among the earliest ion channels to appear during brain development, suggesting a functional requirement for progenitor cell proliferation and/or differentiation. We tested this hypothesis, using human neural progenitor cells (hNPCs) as a model system. Methodology/Principal Findings In proliferating hNPCs a broad spectrum of Kv channel subtypes was identified using quantitative real-time PCR with a predominant expression of the A-type channel Kv4.2. In whole-cell patch-clamp recordings Kv currents were separated into a large transient component characteristic for fast-inactivating A-type potassium channels (IA) and a small, sustained component produced by delayed-rectifying channels (IK). During differentiation the expression of IA as well as A-type channel transcripts dramatically decreased, while IK producing delayed-rectifiers were upregulated. Both Kv currents were differentially inhibited by selective neurotoxins like phrixotoxin-1 and α-dendrotoxin as well as by antagonists like 4-aminopyridine, ammoniumchloride, tetraethylammonium chloride and quinidine. In viability and proliferation assays chronic inhibition of the A-type currents severely disturbed the cell cycle and precluded proper hNPC proliferation, while the blockade of delayed-rectifiers by α-dendrotoxin increased proliferation. Conclusions/Significance These findings suggest that A-type potassium currents are essential for proper proliferation of immature multipotent hNPCs. PMID:19584922

  7. Low oxygen alters mitochondrial function and response to oxidative stress in human neural progenitor cells.

    PubMed

    Lages, Yury M; Nascimento, Juliana M; Lemos, Gabriela A; Galina, Antonio; Castilho, Leda R; Rehen, Stevens K

    2015-01-01

    Oxygen concentration should be carefully regulated in all living tissues, beginning at the early embryonic stages. Unbalances in oxygen regulation can lead to cell death and disease. However, to date, few studies have investigated the consequences of variations in oxygen levels for fetal-like cells. Therefore, in the present work, human neural progenitor cells (NPCs) derived from pluripotent stem cells grown in 3% oxygen (v/v) were compared with NPCs cultured in 21% (v/v) oxygen. Low oxygen concentrations altered the mitochondrial content and oxidative functions of the cells, which led to improved ATP production, while reducing generation of reactive oxygen species (ROS). NPCs cultured in both conditions showed no differences in proliferation and glucose metabolism. Furthermore, antioxidant enzymatic activity was not altered in NPCs cultured in 3% oxygen under normal conditions, however, when exposed to external agents known to induce oxidative stress, greater susceptibility to DNA damage was observed. Our findings indicate that the management of oxygen levels should be considered for in vitro models of neuronal development and drug screening.

  8. Neural correlates of forward planning in a spatial decision task in humans.

    PubMed

    Simon, Dylan Alexander; Daw, Nathaniel D

    2011-04-01

    Although reinforcement learning (RL) theories have been influential in characterizing the mechanisms for reward-guided choice in the brain, the predominant temporal difference (TD) algorithm cannot explain many flexible or goal-directed actions that have been demonstrated behaviorally. We investigate such actions by contrasting an RL algorithm that is model based, in that it relies on learning a map or model of the task and planning within it, to traditional model-free TD learning. To distinguish these approaches in humans, we used functional magnetic resonance imaging in a continuous spatial navigation task, in which frequent changes to the layout of the maze forced subjects continually to relearn their favored routes, thereby exposing the RL mechanisms used. We sought evidence for the neural substrates of such mechanisms by comparing choice behavior and blood oxygen level-dependent (BOLD) signals to decision variables extracted from simulations of either algorithm. Both choices and value-related BOLD signals in striatum, although most often associated with TD learning, were better explained by the model-based theory. Furthermore, predecessor quantities for the model-based value computation were correlated with BOLD signals in the medial temporal lobe and frontal cortex. These results point to a significant extension of both the computational and anatomical substrates for RL in the brain.

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

    NASA Astrophysics Data System (ADS)

    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.

  10. Attomole quantification and global profile of RNA modifications: Epitranscriptome of human neural stem cells

    PubMed Central

    Basanta-Sanchez, Maria; Temple, Sally; Ansari, Suraiya A.; D'Amico, Anna; Agris, Paul F.

    2016-01-01

    Exploration of the epitranscriptome requires the development of highly sensitive and accurate technologies in order to elucidate the contributions of the more than 100 RNA modifications to cell processes. A highly sensitive and accurate ultra-high performance liquid chromatography—tandem mass spectrometry method was developed to simultaneously detect and quantify 28 modified and four major nucleosides in less than 20 min. Absolute concentrations were calculated using extinction coefficients of each of the RNA modifications studied. A comprehensive RNA modifications database of UV profiles and extinction coefficient is reported within a 2.3–5.2 % relative standard deviation. Excellent linearity was observed 0.99227–0.99999 and limit of detection values ranged from 63.75 attomoles to 1.21 femtomoles. The analytical performance was evaluated by analyzing RNA modifications from 100 ng of RNA from human pluripotent stem cell-derived neural cells. Modifications were detected at concentrations four orders of magnitude lower than the corresponding parental nucleosides, and as low as 23.01 femtograms, 64.09 attomoles. Direct and global quantitative analysis of RNA modifications are among the advantages of this new approach. PMID:26438536

  11. Neural Correlates of Natural Human Echolocation in Early and Late Blind Echolocation Experts

    PubMed Central

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

    2011-01-01

    Background 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. Results 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. Conclusions 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. PMID:21633496

  12. Neural mechanisms of human perceptual choice under focused and divided attention

    PubMed Central

    Wyart, Valentin; Myers, Nicholas E.; Summerfield, Christopher

    2015-01-01

    Perceptual decisions occur after evaluation and integration of momentary sensory inputs, and dividing attention between spatially disparate sources of information impairs decision performance. However, it remains unknown whether dividing attention degrades the precision of sensory signals, precludes their conversion into decision signals, or dampens the integration of decision information towards an appropriate response. Here we recorded human electroencephalographic (EEG) activity whilst participants categorised one of two simultaneous and independent streams of visual gratings according to their average tilt. By analyzing trial-by-trial correlations between EEG activity and the information offered by each sample, we obtained converging behavioural and neural evidence that dividing attention between left and right visual fields does not dampen the encoding of sensory or decision information. Under divided attention, momentary decision information from both visual streams was encoded in slow parietal signals without interference but was lost downstream during their integration as reflected in motor mu- and beta-band (10–30 Hz) signals, resulting in a ‘leaky’ accumulation process which conferred greater behavioural influence to more recent samples. By contrast, sensory inputs that were explicitly cued as irrelevant were not converted into decision signals. These findings reveal that a late cognitive bottleneck on information integration limits decision performance under divided attention, and place new capacity constraints on decision-theoretic models of information integration under cognitive load. PMID:25716848

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

    PubMed

    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. PMID:20735988

  14. Transcriptional consequences of schizophrenia candidate miR-137 manipulation in human neural progenitor cells.

    PubMed

    Hill, Matthew J; Donocik, Jacek G; Nuamah, Rosamond A; Mein, Charles A; Sainz-Fuertes, Ricardo; Bray, Nicholas J

    2014-03-01

    MIR137, transcribed as the microRNA miR-137, is one of the leading candidate schizophrenia susceptibility genes to arise from large genome-wide association studies (GWAS) of the disorder. Recent data suggest that miR-137 modulates the expression of other schizophrenia susceptibility genes. Although bioinformatic resources are available with which to predict genes regulated by individual microRNA, there has been a lack of empirical data on genome-wide gene expression changes following miR-137 manipulation. We have therefore performed a genome-wide assessment of transcriptional changes in a human neural progenitor cell line after miR-137 over-expression and inhibition in order to elucidate molecular pathways by which genetic perturbation of miR-137 could promote susceptibility to schizophrenia. Bioinformatically-predicted miR-137 targets showed a small but highly significant down-regulation following miR-137 over-expression. Genes that were significantly down-regulated in association with miR-137 over-expression were enriched for involvement in neuronal differentiation. Differentially expressed genes that were confirmed by qPCR included others at genome-wide significant risk loci for schizophrenia (MAD1L1 and DPYD) and BDNF. These data point to molecular pathways through which genetic variation at the MIR137 locus could confer risk for schizophrenia.

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

    PubMed Central

    Sontag, Christopher J.; Uchida, Nobuko; Cummings, Brian J.; Anderson, Aileen J.

    2014-01-01

    Summary 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. PMID:24936450

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

    PubMed

    Dou, Tingting; Yan, Mengling; Wang, Xinjin; Lu, Wen; Zhao, Lina; Lou, Dan; Wu, Chunhua; Chang, Xiuli; Zhou, Zhijun

    2016-01-01

    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. PMID:26649146

  17. Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks.

    PubMed

    Nebel, Rebecca A; Zhao, Dejian; Pedrosa, Erika; Kirschen, Jill; Lachman, Herbert M; Zheng, Deyou; Abrahams, Brett S

    2016-01-01

    Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation.

  18. Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks

    PubMed Central

    Nebel, Rebecca A.; Zhao, Dejian; Pedrosa, Erika; Kirschen, Jill; Lachman, Herbert M.; Zheng, Deyou; Abrahams, Brett S.

    2016-01-01

    Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation. PMID:26824476

  19. Classification of mammographic masses: comparison between Backpropagation Neural Network (BNN) and human readers

    NASA Astrophysics Data System (ADS)

    Arbach, Lina; Bennett, Darus L.; Reinhardt, Joseph M.; Fallouh, Ghassan

    2003-05-01

    PURPOSE: We compare mammographic mass classification performance between a backpropagation neural network (BNN), expert radiologists, and residents. Our goal is to reduce false negatives during routine reading of mammograms. METHODS: 160 cases from 3 different institutions were used. Each case contained at least one mass and had an accompanying biopsy result. Masses were extracted using region growing with seed locations identified by an expert radiologist. 10 texture and shape based features (area, perimeter, compactness, radial length, spiculation, mean/standard deviation of radial length, minimum/maximum axis, and boundary roughness) were used as inputs to a three-layer BNN. Shape features were computed on the boundary of the mass region; texture features were computed from the pixel values inside the mass. 140 cases were used for training the BNN and the remaining 20 cases were used for testing. The testing set was diagnosed by three expert radiologists, three residents, and the BNN. We evaluated the human readers and the BNN by computing the area under the ROC curve (AUC). RESULTS: The AUC was 0.923 for the BNN, 0.846 for the expert radiologists, and 0.648 for the residents. These results illustrate the promise of using BNN as a physician"s assistant for breast mass classification.

  20. Neural correlates of forward planning in a spatial decision task in humans

    PubMed Central

    Simon, Dylan Alexander; Daw, Nathaniel D.

    2011-01-01

    Although reinforcement learning (RL) theories have been influential in characterizing the brain’s mechanisms for reward-guided choice, the predominant temporal difference (TD) algorithm cannot explain many flexible or goal-directed actions that have been demonstrated behaviorally. We investigate such actions by contrasting an RL algorithm that is model-based, in that it relies on learning a map or model of the task and planning within it, to traditional model-free TD learning. To distinguish these approaches in humans, we used fMRI in a continuous spatial navigation task, in which frequent changes to the layout of the maze forced subjects continually to relearn their favored routes, thereby exposing the RL mechanisms employed. We sought evidence for the neural substrates of such mechanisms by comparing choice behavior and BOLD signals to decision variables extracted from simulations of either algorithm. Both choices and value-related BOLD signals in striatum, though most often associated with TD learning, were better explained by the model-based theory. Further, predecessor quantities for the model-based value computation were correlated with BOLD signals in the medial temporal lobe and frontal cortex. These results point to a significant extension of both the computational and anatomical substrates for RL in the brain. PMID:21471389

  1. Effects of silver nanoparticles on human and rat embryonic neural stem cells

    PubMed Central

    Liu, Fang; Mahmood, Meena; Xu, Yang; Watanabe, Fumiya; Biris, Alexandru S.; Hansen, Deborah K.; Inselman, Amy; Casciano, Daniel; Patterson, Tucker A.; Paule, Merle G.; Slikker, William; Wang, Cheng

    2015-01-01

    Silver nano-particles (Ag-NPs) are becoming increasingly prevalent in consumer products as antibacterial agents. The increased use of Ag NP-enhanced products will almost certainly increase environmental silver levels, resulting in increased exposures and the potential for increased adverse reactions including neurotoxic effects. In the present study, embryonic neural stem cells (NSCs) from human and rat fetuses (gestational day-16) were used to determine whether Ag-NPs are capable of causing developmental neurotoxicity. The NSCs were cultured in serum free medium supplemented with appropriate growth factors. On the eighth day in vitro (DIV 8), the cells were exposed to Ag-NPs at concentrations of 1, 5, 10, and 20 μg/ml for 24 h. The cultured cells then were characterized by NSC markers including nestin and SOX2 and a variety of assays were utilized to determine the effects of Ag-NPs on NSC proliferation and viability and the underlying mechanisms associated with these effects. The results indicate that mitochondrial viability (MTT metabolism) was substantially attenuated and LDH release was increased significantly in a dose-dependent manner. Ag-NPs-induced neurotoxicity was further confirmed by up-regulated Bax protein expression, an increased number of TUNEL-positively stained cells, and elevated reactive oxygen species (ROS). NSC proliferation was also significantly decreased by Ag-NPs. Co-administration of acetyl-L-carnitine, an antioxidant agent, effectively blocked the adverse effects associated with Ag-NP exposure. PMID:25904840

  2. Neural mechanisms of human perceptual choice under focused and divided attention.

    PubMed

    Wyart, Valentin; Myers, Nicholas E; Summerfield, Christopher

    2015-02-25

    Perceptual decisions occur after the evaluation and integration of momentary sensory inputs, and dividing attention between spatially disparate sources of information impairs decision performance. However, it remains unknown whether dividing attention degrades the precision of sensory signals, precludes their conversion into decision signals, or dampens the integration of decision information toward an appropriate response. Here we recorded human electroencephalographic (EEG) activity while participants categorized one of two simultaneous and independent streams of visual gratings according to their average tilt. By analyzing trial-by-trial correlations between EEG activity and the information offered by each sample, we obtained converging behavioral and neural evidence that dividing attention between left and right visual fields does not dampen the encoding of sensory or decision information. Under divided attention, momentary decision information from both visual streams was encoded in slow parietal signals without interference but was lost downstream during their integration as reflected in motor mu- and beta-band (10-30 Hz) signals, resulting in a "leaky" accumulation process that conferred greater behavioral influence to more recent samples. By contrast, sensory inputs that were explicitly cued as irrelevant were not converted into decision signals. These findings reveal that a late cognitive bottleneck on information integration limits decision performance under divided attention, and places new capacity constraints on decision-theoretic models of information integration under cognitive load.

  3. A nerve guidance conduit with topographical and biochemical cues: potential application using human neural stem cells

    NASA Astrophysics Data System (ADS)

    Jenkins, Phillip M.; Laughter, Melissa R.; Lee, David J.; Lee, Young M.; Freed, Curt R.; Park, Daewon

    2015-06-01

    Despite major advances in the pathophysiological understanding of peripheral nerve damage, the treatment of nerve injuries still remains an unmet medical need. Nerve guidance conduits present a promising treatment option by providing a growth-permissive environment that 1) promotes neuronal cell survival and axon growth and 2) directs axonal extension. To this end, we designed an electrospun nerve guidance conduit using a blend of polyurea and poly-caprolactone with both biochemical and topographical cues. Biochemical cues were integrated into the conduit by functionalizing the polyurea with RGD to improve cell attachment. Topographical cues that resemble natural nerve tissue were incorporated by introducing intraluminal microchannels aligned with nanofibers. We determined that electrospinning the polymer solution across a two electrode system with dissolvable sucrose fibers produced a polymer conduit with the appropriate biomimetic properties. Human neural stem cells were cultured on the conduit to evaluate its ability to promote neuronal growth and axonal extension. The nerve guidance conduit was shown to enhance cell survival, migration, and guide neurite extension.

  4. Effects of silver nanoparticles on human and rat embryonic neural stem cells.

    PubMed

    Liu, Fang; Mahmood, Meena; Xu, Yang; Watanabe, Fumiya; Biris, Alexandru S; Hansen, Deborah K; Inselman, Amy; Casciano, Daniel; Patterson, Tucker A; Paule, Merle G; Slikker, William; Wang, Cheng

    2015-01-01

    Silver nano-particles (Ag-NPs) are becoming increasingly prevalent in consumer products as antibacterial agents. The increased use of Ag NP-enhanced products will almost certainly increase environmental silver levels, resulting in increased exposures and the potential for increased adverse reactions including neurotoxic effects. In the present study, embryonic neural stem cells (NSCs) from human and rat fetuses (gestational day-16) were used to determine whether Ag-NPs are capable of causing developmental neurotoxicity. The NSCs were cultured in serum free medium supplemented with appropriate growth factors. On the eighth day in vitro (DIV 8), the cells were exposed to Ag-NPs at concentrations of 1, 5, 10, and 20 μg/ml for 24 h. The cultured cells then were characterized by NSC markers including nestin and SOX2 and a variety of assays were utilized to determine the effects of Ag-NPs on NSC proliferation and viability and the underlying mechanisms associated with these effects. The results indicate that mitochondrial viability (MTT metabolism) was substantially attenuated and LDH release was increased significantly in a dose-dependent manner. Ag-NPs-induced neurotoxicity was further confirmed by up-regulated Bax protein expression, an increased number of TUNEL-positively stained cells, and elevated reactive oxygen species (ROS). NSC proliferation was also significantly decreased by Ag-NPs. Co-administration of acetyl-L-carnitine, an antioxidant agent, effectively blocked the adverse effects associated with Ag-NP exposure. PMID:25904840

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

    PubMed

    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.

  6. Further assessment of neuropathology in retinal explants and neuroprotection by human neural progenitor cells

    NASA Astrophysics Data System (ADS)

    Mohlin, Camilla; Liljekvist-Soltic, Ingela; Johansson, Kjell

    2011-10-01

    Explanted rat retinas show progressive photoreceptor degeneration that appears to be caspase-12-dependent. Decrease in photoreceptor density eventually affects the inner retina, particularly in the bipolar cell population. Explantation and the induced photoreceptor degeneration are accompanied by activation of Müller and microglia cells. The goal of this study was to determine whether the presence of a feeder layer of human neural progenitor cells (hNPCs) could suppress the degenerative and reactive changes in the explants. Immunohistochemical analyses showed considerable sprouting of rod photoreceptor axon terminals into the inner retina and reduced densities of cone and rod bipolar cells. Both sprouting and bipolar cell degenerations were significantly lower in retinas cultured with feeder layer cells compared to cultured controls. A tendency toward reduced microglia activation in the retinal layers was also noted in the presence of feeder layer cells. These results indicate that hNPCs or factors produced by them can limit the loss of photoreceptors and secondary injuries in the inner retina. The latter may be a consequence of disrupted synaptic arrangement.

  7. Attomole quantification and global profile of RNA modifications: Epitranscriptome of human neural stem cells.

    PubMed

    Basanta-Sanchez, Maria; Temple, Sally; Ansari, Suraiya A; D'Amico, Anna; Agris, Paul F

    2016-02-18

    Exploration of the epitranscriptome requires the development of highly sensitive and accurate technologies in order to elucidate the contributions of the more than 100 RNA modifications to cell processes. A highly sensitive and accurate ultra-high performance liquid chromatography-tandem mass spectrometry method was developed to simultaneously detect and quantify 28 modified and four major nucleosides in less than 20 min. Absolute concentrations were calculated using extinction coefficients of each of the RNA modifications studied. A comprehensive RNA modifications database of UV profiles and extinction coefficient is reported within a 2.3-5.2 % relative standard deviation. Excellent linearity was observed 0.99227-0.99999 and limit of detection values ranged from 63.75 attomoles to 1.21 femtomoles. The analytical performance was evaluated by analyzing RNA modifications from 100 ng of RNA from human pluripotent stem cell-derived neural cells. Modifications were detected at concentrations four orders of magnitude lower than the corresponding parental nucleosides, and as low as 23.01 femtograms, 64.09 attomoles. Direct and global quantitative analysis of RNA modifications are among the advantages of this new approach.

  8. Human neural stem cell-induced endothelial morphogenesis requires autocrine/paracrine and juxtacrine signaling

    PubMed Central

    Chou, Chung-Hsing; Modo, Michel

    2016-01-01

    Transplanted neural stem cells (NSC) interact with the host brain microenvironment. A neovascularization is commonly observed in the vicinity of the cell deposit, which is correlated with behavioral improvements. To elucidate the signaling mechanisms between human NSCs and endothelial cells (ECs), these were cocultured in an in vitro model in which NSC-induced endothelial morphogenesis produced a neurovascular environment. Soluble (autocrine/paracrine) and contact–mediated (juxtacrine) signaling molecules were evaluated for two conditionally immortalized fetal NSC lines derived from the cortical anlage (CTXOE03) and ganglionic eminence (STROC05), as well as an adult EC line (D3) derived from the cerebral microvasculature of a hippocampal biopsy. STROC05 were 4 times as efficient to induce endothelial morphogenesis compared to CTXOE03. The cascade of reciprocal interactions between NSCs and ECs in this process was determined by quantifying soluble factors, receptor mapping, and immunocytochemistry for extracellular matrix molecules. The mechanistic significance of these was further evaluated by pharmacological blockade. The sequential cell-specific regulation of autocrine/paracrine and juxtacrine signaling accounted for the differential efficiency of NSCs to induce endothelial morphogenesis. These in vitro studies shed new light on the reciprocal interactions between NSCs and ECs, which are pivotal for our mechanistic understanding of the efficacy of NSC transplantation. PMID:27374240

  9. Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects

    PubMed Central

    Bosoi, Ciprian M.; Capra, Valeria; Allache, Redouane; Trinh, Vincent Quoc-Huy; De Marco, Patrizia; Merello, Elisa; Drapeau, Pierre; Bassuk, Alexander G.; Kibar, Zoha

    2011-01-01

    The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure and has been implicated in the pathogenesis of neural tube defects (NTDs) in animal models and human cohorts. In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified 7 rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of 5 PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations. PMID:21901791

  10. Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects.

    PubMed

    Bosoi, Ciprian M; Capra, Valeria; Allache, Redouane; Trinh, Vincent Quoc-Huy; De Marco, Patrizia; Merello, Elisa; Drapeau, Pierre; Bassuk, Alexander G; Kibar, Zoha

    2011-12-01

    The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure, and has been implicated in the pathogenesis of neural tube defects (NTDs) in animal models and human cohorts. In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified seven rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of five PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a (zpk1a) in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations.

  11. Drive Control Scheme of Electric Power Assisted Wheelchair Based on Neural Network Learning of Human Wheelchair Operation Characteristics

    NASA Astrophysics Data System (ADS)

    Tanohata, Naoki; Seki, Hirokazu

    This paper describes a novel drive control scheme of electric power assisted wheelchairs based on neural network learning of human wheelchair operation characteristics. “Electric power assisted wheelchair” which enhances the drive force of the operator by employing electric motors is expected to be widely used as a mobility support system for elderly and disabled people. However, some handicapped people with paralysis of the muscles of one side of the body cannot maneuver the wheelchair as desired because of the difference in the right and left input force. Therefore, this study proposes a neural network learning system of such human wheelchair operation characteristics and a drive control scheme with variable distribution and assistance ratios. Some driving experiments will be performed to confirm the effectiveness of the proposed control system.

  12. Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell–derived neural transplants

    PubMed Central

    Bieberich, Erhard; Silva, Jeane; Wang, Guanghu; Krishnamurthy, Kannan; Condie, Brian G.

    2004-01-01

    The formation of stem cell–derived tumors (teratomas) is observed when engrafting undifferentiated embryonic stem (ES) cells, embryoid body–derived cells (EBCs), or mammalian embryos and is a significant obstacle to stem cell therapy. We show that in tumors formed after engraftment of EBCs into mouse brain, expression of the pluripotency marker Oct-4 colocalized with that of prostate apoptosis response-4 (PAR-4), a protein mediating ceramide-induced apoptosis during neural differentiation of ES cells. We tested the ability of the novel ceramide analogue N-oleoyl serinol (S18) to eliminate mouse and human Oct-4(+)/PAR-4(+) cells and to increase the proportion of nestin(+) neuroprogenitors in EBC-derived cell cultures and grafts. S18-treated EBCs persisted in the hippocampal area and showed neuronal lineage differentiation as indicated by the expression of β-tubulin III. However, untreated cells formed numerous teratomas that contained derivatives of endoderm, mesoderm, and ectoderm. Our results show for the first time that ceramide-induced apoptosis eliminates residual, pluripotent EBCs, prevents teratoma formation, and enriches the EBCs for cells that undergo neural differentiation after transplantation. PMID:15545317

  13. Self-organizing neural integration of pose-motion features for human action recognition

    PubMed Central

    Parisi, German I.; Weber, Cornelius; Wermter, Stefan

    2015-01-01

    The visual recognition of complex, articulated human movements is fundamental for a wide range of artificial systems oriented toward 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 spatio-temporal 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 results for a public benchmark of domestic daily actions. PMID:26106323

  14. Self-organizing neural integration of pose-motion features for human action recognition.

    PubMed

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

    2015-01-01

    The visual recognition of complex, articulated human movements is fundamental for a wide range of artificial systems oriented toward 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 spatio-temporal 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 results for a public benchmark of domestic daily actions.

  15. Intravenous Administration of Human ES-derived Neural Precursor Cells Attenuates Cuprizone-induced CNS Demyelination

    PubMed Central

    Crocker, Stephen J.; Bajpai, Ruchi; Moore, Craig S.; Frausto, Ricardo F.; Brown, Graham D.; Pagarigan, Roberto R.; Whitton, J. Lindsay; Terskikh, Alexey V.

    2011-01-01

    Aims Previous studies have demonstrated the therapeutic potential for human embryonic stem cell-derived neural precursor cells (hES-NPCs) in autoimmune and genetic animal models of demyelinating diseases. Herein, we tested whether intravenous (i.v) administration of hES-NPCs would impact central nervous system (CNS) demyelination in a cuprizone model of demyelination. Methods C57Bl/6 mice were fed cuprizone (0.2%) for two weeks and then separated into two groups that either received an i.v. injection of hES-NPCs or i.v. administration of media without these cells. After an additional two weeks of dietary cuprizone treatment, CNS tissues were analyzed for detection of transplanted cells and differences in myelination in the region of the corpus callosum (CC). Results Cuprizone-induced demyelination in the CC was significantly reduced in mice treated with hES-NPCs compared with cuprizone-treated controls that did not receive stem cells. hES-NPCs were identified within the brain tissues of treated mice and revealed migration of transplanted cells into the CNS. A limited number of human cells were found to express the mature oligodendrocyte marker, O1, or the astrocyte marker, GFAP. Reduced apoptosis and attenuated microglial and astrocytic responses were also observed in the CC of hES-NPC-treated mice. Conclusions These findings indicated that systemically-administered hES-NPCs migrated from circulation into a demyelinated lesion within the CNS and effectively reduced demyelination. Observed reductions in astrocyte and microglial responses, and (c) the benefit of hES-NPC treatment in this model of myelin injury was not obviously accountable to tissue replacement by exogenously administered cells. PMID:21276029

  16. PPARγ Is Activated during Congenital Cytomegalovirus Infection and Inhibits Neuronogenesis from Human Neural Stem Cells

    PubMed Central

    Rolland, Maude; Li, Xiaojun; Perez-Berezo, Teresa; Rauwel, Benjamin; Benchoua, Alexandra; Bessières, Bettina; Aziza, Jacqueline; Cenac, Nicolas; Luo, Minhua; Casper, Charlotte; Peschanski, Marc; Gonzalez-Dunia, Daniel; Leruez-Ville, Marianne; Davrinche, Christian; Chavanas, Stéphane

    2016-01-01

    Congenital infection by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae of the central nervous system, including sensorineural deafness, cerebral palsies or devastating neurodevelopmental abnormalities (0.1% of all births). To gain insight on the impact of HCMV on neuronal development, we used both neural stem cells from human embryonic stem cells (NSC) and brain sections from infected fetuses and investigated the outcomes of infection on Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a transcription factor critical in the developing brain. We observed that HCMV infection dramatically impaired the rate of neuronogenesis and strongly increased PPARγ levels and activity. Consistent with these findings, levels of 9-hydroxyoctadecadienoic acid (9-HODE), a known PPARγ agonist, were significantly increased in infected NSCs. Likewise, exposure of uninfected NSCs to 9-HODE recapitulated the effect of infection on PPARγ activity. It also increased the rate of cells expressing the IE antigen in HCMV-infected NSCs. Further, we demonstrated that (1) pharmacological activation of ectopically expressed PPARγ was sufficient to induce impaired neuronogenesis of uninfected NSCs, (2) treatment of uninfected NSCs with 9-HODE impaired NSC differentiation and (3) treatment of HCMV-infected NSCs with the PPARγ inhibitor T0070907 restored a normal rate of differentiation. The role of PPARγ in the disease phenotype was strongly supported by the immunodetection of nuclear PPARγ in brain germinative zones of congenitally infected fetuses (N = 20), but not in control samples. Altogether, our findings reveal a key role for PPARγ in neurogenesis and in the pathophysiology of HCMV congenital infection. They also pave the way to the identification of PPARγ gene targets in the infected brain. PMID:27078877

  17. Self-organizing neural integration of pose-motion features for human action recognition.

    PubMed

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

    2015-01-01

    The visual recognition of complex, articulated human movements is fundamental for a wide range of artificial systems oriented toward 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 spatio-temporal 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 results for a public benchmark of domestic daily actions. PMID:26106323

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

    PubMed Central

    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

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

    PubMed

    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.

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

    PubMed

    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. PMID:24110386

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

    PubMed

    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. PMID:21805133

  2. Assistive technology and robotic control using motor cortex ensemble-based neural interface systems in humans with tetraplegia

    PubMed Central

    Donoghue, John P; Nurmikko, Arto; Black, Michael; Hochberg, Leigh R

    2007-01-01

    This review describes the rationale, early stage development, and initial human application of neural interface systems (NISs) for humans with paralysis. NISs are emerging medical devices designed to allow persons with paralysis to operate assistive technologies or to reanimate muscles based upon a command signal that is obtained directly from the brain. Such systems require the development of sensors to detect brain signals, decoders to transform neural activity signals into a useful command, and an interface for the user. We review initial pilot trial results of an NIS that is based on an intracortical microelectrode sensor that derives control signals from the motor cortex. We review recent findings showing, first, that neurons engaged by movement intentions persist in motor cortex years after injury or disease to the motor system, and second, that signals derived from motor cortex can be used by persons with paralysis to operate a range of devices. We suggest that, with further development, this form of NIS holds promise as a useful new neurotechnology for those with limited motor function or communication. We also discuss the additional potential for neural sensors to be used in the diagnosis and management of various neurological conditions and as a new way to learn about human brain function. PMID:17272345

  3. Effects of transforming growth factor beta1 (TGFbeta-1) and dentin non-collagenous proteins (DNCP) on human embryonic ectomesenchymal cells in a three-dimensional culture system.

    PubMed

    Deng, Manjing; Shi, Junnan; Smith, Anthony J; Jin, Yan

    2005-11-01

    Cranial neural crest-derived ectomesenchymal cells represent a population of pluripotent stem cells giving rise to many of the various oro-facial and dental tissues. The factors determining the terminal fate of these cells are still unclear. The potentiality of human embryonic ectomesenchymal cells from the first branchial arch have been investigated when isolated and grown in a three-dimensional (3D)-collagen gel culture system in the presence of dentin matrix-derived non-collagenous proteins (DNCP) and TGFbeta-1. Functional differentiation of cells showing some characteristics of odontoblast-like cells could be observed when the cells were cultured with DNCP+TGFbeta-1 or DNCP, however, only cytological differentiation was observed during culture with TGFbeta-1 alone. The characteristics of these cells was assessed by morphological appearance, expression of the odontoblast phenotype marker dentin sialophosphoprotein (DSPP), increased alkaline phosphatase levels and formation of mineralised nodules in vitro. The results indicate that these embryonic cells from the first branchial arch are capable of responding to the inductive stimulus of DNCP or DNCP+TGFbeta-1 when isolated and grown in the 3D collagen gel culture system. The capacity of the isolated cells to differentiate into mineralizing cells showing some characteristics of odontoblast-like cells under these growth conditions highlights the potential of such approaches for tissue engineering strategies for hard-tissue regeneration after injury. PMID:15871903

  4. Using an achiasmic human visual system to quantify the relationship between the fMRI BOLD signal and neural response.

    PubMed

    Bao, Pinglei; Purington, Christopher J; Tjan, Bosco S

    2015-01-01

    Achiasma in humans causes gross mis-wiring of the retinal-fugal projection, resulting in overlapped cortical representations of left and right visual hemifields. We show that in areas V1-V3 this overlap is due to two co-located but non-interacting populations of neurons, each with a receptive field serving only one hemifield. Importantly, the two populations share the same local vascular control, resulting in a unique organization useful for quantifying the relationship between neural and fMRI BOLD responses without direct measurement of neural activity. Specifically, we can non-invasively double local neural responses by stimulating both neuronal populations with identical stimuli presented symmetrically across the vertical meridian to both visual hemifields, versus one population by stimulating in one hemifield. Measurements from a series of such doubling experiments show that the amplitude of BOLD response is proportional to approximately 0.5 power of the underlying neural response. Reanalyzing published data shows that this inferred relationship is general.

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

    NASA Astrophysics Data System (ADS)

    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.

  6. The development of neural synchrony reflects late maturation and restructuring of functional networks in humans

    PubMed Central

    Uhlhaas, Peter J.; Roux, Frederic; Singer, Wolf; Haenschel, Corinna; Sireteanu, Ruxandra; Rodriguez, Eugenio

    2009-01-01

    Brain development is characterized by maturational processes that span the period from childhood through adolescence to adulthood, but little is known whether and how developmental processes differ during these phases. We analyzed the development of functional networks by measuring neural synchrony in EEG recordings during a Gestalt perception task in 68 participants ranging in age from 6 to 21 years. Until early adolescence, developmental improvements in cognitive performance were accompanied by increases in neural synchrony. This developmental phase was followed by an unexpected decrease in neural synchrony that occurred during late adolescence and was associated with reduced performance. After this period of destabilization, we observed a reorganization of synchronization patterns that was accompanied by pronounced increases in gamma-band power and in theta and beta phase synchrony. These findings provide evidence for the relationship between neural synchrony and late brain development that has important implications for the understanding of adolescence as a critical period of brain maturation. PMID:19478071

  7. Neural Networks

    SciTech Connect

    Smith, Patrick I.

    2003-09-23

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

  8. Infrared neural stimulation of primary visual cortex in non-human primates

    PubMed Central

    Cayce, Jonathan M.; Friedman, Robert M.; Chen, Gang; Jansen, E. Duco; Mahadevan-Jansen, Anita; Roe, Anna W.

    2014-01-01

    Infrared neural stimulation (INS) is an alternative neurostimulation modality that uses pulsed infrared light to evoke spatially precise neural activity that does not require direct contact with neural tissue. With these advantages INS has the potential to increase our understanding of specific neural pathways and impact current diagnostic and therapeutic clinical applications. In order to develop this technique, we investigate the feasibility of INS (λ = 1.875 μm, fiber diameter = 100–400 μm) to activate and modulate neural activity in primary visual cortex (V1) of Macaque monkeys. Infrared neural stimulation was found to evoke localized neural responses as evidenced by both electrophysiology and intrinsic signal optical imaging (OIS). Single unit recordings acquired during INS indicated statistically significant increases in neuron firing rates that demonstrate INS evoked excitatory neural activity. Consistent with this, INS stimulation led to focal intensity-dependent reflectance changes recorded with OIS. We also asked whether INS is capable of stimulating functionally specific domains in visual cortex and of modulating visually evoked activity in visual cortex. We found that application of INS via 100 μm or 200 μm fiber optics produced enhancement of visually evoked OIS response confined to the eye column where INS was applied and relative suppression of the other eye column. Stimulating the cortex with a 400 μm fiber, exceeding the ocular dominance width, led to relative suppression, consistent with involvement of inhibitory surrounds. This study is the first to demonstrate that INS can be used to either enhance or diminish visual cortical response and that this can be done in a functional domain specific manner. INS thus holds great potential for use as a safe, non-contact, focally specific brain stimulation technology in primate brains. PMID:23994125

  9. Dynamics and cortical distribution of neural responses to 2D and 3D motion in human.

    PubMed

    Cottereau, Benoit R; McKee, Suzanne P; Norcia, Anthony M

    2014-02-01

    The perception of motion-in-depth is important for avoiding collisions and for the control of vergence eye-movements and other motor actions. Previous psychophysical studies have suggested that sensitivity to motion-in-depth has a lower temporal processing limit than the perception of lateral motion. The present study used functional MRI-informed EEG source-imaging to study the spatiotemporal properties of the responses to lateral motion and motion-in-depth in human visual cortex. Lateral motion and motion-in-depth displays comprised stimuli whose only difference was interocular phase: monocular oscillatory motion was either in-phase in the two eyes (lateral motion) or in antiphase (motion-in-depth). Spectral analysis was used to break the steady-state visually evoked potentials responses down into even and odd harmonic components within five functionally defined regions of interest: V1, V4, lateral occipital complex, V3A, and hMT+. We also characterized the responses within two anatomically defined regions: the inferior and superior parietal cortex. Even harmonic components dominated the evoked responses and were a factor of approximately two larger for lateral motion than motion-in-depth. These responses were slower for motion-in-depth and were largely independent of absolute disparity. In each of our regions of interest, responses at odd-harmonics were relatively small, but were larger for motion-in-depth than lateral motion, especially in parietal cortex, and depended on absolute disparity. Taken together, our results suggest a plausible neural basis for reduced psychophysical sensitivity to rapid motion-in-depth.

  10. Neural correlates of changing intention in the human FEF and IPS.

    PubMed

    Astle, Duncan E; Nixon, Elena; Jackson, Stephen R; Jackson, Georgina M

    2012-02-01

    Previous research demonstrates that our apparent mental flexibility depends largely on the strength of our prior intention; changing our intention in advance enables a smooth transition from one task to another (e.g., Astle DE, Jackson GM, Swainson R. J Cogn Neurosci 20: 255-267, 2008; Duncan J, Emslie H, Williams P, Johnson R, Freer C. Cogn Psychol 30: 257-303, 1996; Husain M, Parton A, Hodgson TL, Mort D, Rees G. Nat Neurosci 6: 117-118, 2003). However, these necessarily rapid anticipatory mechanisms have been difficult to study in the human brain. We used EEG and magnetoencephalography, specifically event-related potentials and fields (ERPs and ERFs), respectively, to explore the neural correlates of this important aspect of mental flexibility. Subjects performed a manual version of a pro/antisaccade task using preparatory cues to switch between the pro- and antirules. When subjects switched their intention, we observed a positivity over central electrodes, which correlated significantly with our behavioral data; the greater the ERP effect, the stronger the subject's change of intention. ERFs, alongside subject-specific structural MRIs, were used to project into source space. When subjects switched their intention, they showed significantly elevated activity in the right frontal eye field and left intraparietal sulcus (IPS); the greater the left IPS activity on switch trials, the stronger the subject's change of intention. This network has previously been implicated in the top-down control of eye movements, but here we demonstrate its role in the top-down control of a task set, in particular, that it is recruited when we change the task that we intend to perform. PMID:22114156

  11. Neural Processes in the Human Temporoparietal Cortex Separated by Localized Independent Component Analysis.

    PubMed

    Igelström, Kajsa M; Webb, Taylor W; Graziano, Michael S A

    2015-06-24

    The human temporoparietal junction (TPJ) is a topic of intense research. Imaging studies have identified TPJ activation in association with many higher-order functions such as theory-of-mind, episodic memory, and attention, causing debate about the distribution of different processes. One major challenge is the lack of consensus about the anatomical location and extent of the TPJ. Here, we address this problem using data-driven analysis to test the hypothesis that the bilateral TPJ can be parcellated into subregions. We applied independent component analysis (ICA) to task-free fMRI data within a local region around the bilateral TPJ, iterating the ICA at multiple model orders and in several datasets. The localized analysis allowed finer separation of processes and the use of multiple dimensionalities provided qualitative information about lateralization. We identified four subdivisions that were bilaterally symmetrical and one that was right biased. To test whether the independent components (ICs) reflected true subdivisions, we performed functional connectivity analysis using the IC coordinates as seeds. This confirmed that the subdivisions belonged to distinct networks. The right-biased IC was connected with a network often associated with attentional processing. One bilateral subdivision was connected to sensorimotor regions and another was connected to auditory regions. One subdivision that presented as distinct left- and right-biased ICs was connected to frontoparietal regions. Another subdivision that also had left- and right-biased ICs was connected to social or default mode networks. Our results show that the TPJ in both hemispheres hosts multiple neural processes with connectivity patterns consistent with well developed specialization and lateralization. PMID:26109666

  12. Dynamics and cortical distribution of neural responses to 2D and 3D motion in human

    PubMed Central

    McKee, Suzanne P.; Norcia, Anthony M.

    2013-01-01

    The perception of motion-in-depth is important for avoiding collisions and for the control of vergence eye-movements and other motor actions. Previous psychophysical studies have suggested that sensitivity to motion-in-depth has a lower temporal processing limit than the perception of lateral motion. The present study used functional MRI-informed EEG source-imaging to study the spatiotemporal properties of the responses to lateral motion and motion-in-depth in human visual cortex. Lateral motion and motion-in-depth displays comprised stimuli whose only difference was interocular phase: monocular oscillatory motion was either in-phase in the two eyes (lateral motion) or in antiphase (motion-in-depth). Spectral analysis was used to break the steady-state visually evoked potentials responses down into even and odd harmonic components within five functionally defined regions of interest: V1, V4, lateral occipital complex, V3A, and hMT+. We also characterized the responses within two anatomically defined regions: the inferior and superior parietal cortex. Even harmonic components dominated the evoked responses and were a factor of approximately two larger for lateral motion than motion-in-depth. These responses were slower for motion-in-depth and were largely independent of absolute disparity. In each of our regions of interest, responses at odd-harmonics were relatively small, but were larger for motion-in-depth than lateral motion, especially in parietal cortex, and depended on absolute disparity. Taken together, our results suggest a plausible neural basis for reduced psychophysical sensitivity to rapid motion-in-depth. PMID:24198326

  13. Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats.

    PubMed

    Das, Melanie M; Avalos, Pablo; Suezaki, Patrick; Godoy, Marlesa; Garcia, Leslie; Chang, Christine D; Vit, Jean-Philippe; Shelley, Brandon; Gowing, Genevieve; Svendsen, Clive N

    2016-06-01

    Age-associated health decline presents a significant challenge to healthcare, although there are few animal models that can be used to test potential treatments. Here, we show that there is a significant reduction in both spinal cord motor neurons and motor function over time in the aging rat. One explanation for this motor neuron loss could be reduced support from surrounding aging astrocytes. Indeed, we have previously shown using in vitro models that aging rat astrocytes are less supportive to rat motor neuron function and survival over time. Here, we test whether rejuvenating the astrocyte niche can improve the survival of motor neurons in an aging spinal cord. We transplanted fetal-derived human neural progenitor cells (hNPCs) into the aging rat spinal cord and found that the cells survive and differentiate into astrocytes with a much higher efficiency than when transplanted into younger animals, suggesting that the aging environment stimulates astrocyte maturation. Importantly, the engrafted astrocytes were able to protect against motor neuron loss associated with aging, although this did not result in an increase in motor function based on behavioral assays. We also transplanted hNPCs genetically modified to secrete glial cell line-derived neurotrophic factor (GDNF) into the aging rat spinal cord, as this combination of cell and protein delivery can protect motor neurons in animal models of ALS. During aging, GDNF-expressing hNPCs protected motor neurons, though to the same extent as hNPCs alone, and again had no effect on motor function. We conclude that hNPCs can survive well in the aging spinal cord, protect motor neurons and mature faster into astrocytes when compared to transplantation into the young spinal cord. While there was no functional improvement, there were no functional deficits either, further supporting a good safety profile of hNPC transplantation even into the older patient population. PMID:27032721

  14. A neural basis for real-world visual search in human occipitotemporal cortex.

    PubMed

    Peelen, Marius V; Kastner, Sabine

    2011-07-19

    Mammals are highly skilled in rapidly detecting objects in cluttered natural environments, a skill necessary for survival. What are the neural mechanisms mediating detection of objects in natural scenes? Here, we use human brain imaging to address the role of top-down preparatory processes in the detection of familiar object categories in real-world environments. Brain activity was measured while participants were preparing to detect highly variable depictions of people or cars in natural scenes that were new to the participants. The preparation to detect objects of the target category, in the absence of visual input, evoked activity patterns in visual cortex that resembled the response to actual exemplars of the target category. Importantly, the selectivity of multivoxel preparatory activity patterns in object-selective cortex (OSC) predicted target detection performance. By contrast, preparatory activity in early visual cortex (V1) was negatively related to search performance. Additional behavioral results suggested that the dissociation between OSC and V1 reflected the use of different search strategies, linking OSC preparatory activity to relatively abstract search preparation and V1 to more specific imagery-like preparation. Finally, whole-brain searchlight analyses revealed that, in addition to OSC, response patterns in medial prefrontal cortex distinguished the target categories based on the search cues alone, suggesting that this region may constitute a top-down source of preparatory activity observed in visual cortex. These results indicate that in naturalistic situations, when the precise visual characteristics of target objects are not known in advance, preparatory activity at higher levels of the visual hierarchy selectively mediates visual search.

  15. Modulation of human visceral sensitivity by noninvasive magnetoelectrical neural stimulation in health and irritable bowel syndrome.

    PubMed

    Algladi, Tarig; Harris, Mary; Whorwell, Peter J; Paine, Peter; Hamdy, Shaheen

    2015-07-01

    Visceral pain is a particularly difficult symptom to manage in patients with irritable bowel syndrome (IBS). Our aim was to examine whether noninvasive neurostimulation applied to the motor cortex or lumbosacral region can modulate human visceral sensation. Sixteen healthy adult volunteers and 10 patients with IBS were evaluated. Single-pulse lumbosacral magnetic stimulation (LSMS) or transcranial magnetic stimulation (TMS) was used to assess spinal root and cortical excitability as well as the effect of neurostimulation on anorectal sensation and pain, which were provoked by a local electrical stimulus. Initially, healthy volunteers received 6 stimulation paradigms in a randomised order (3 repetitive LSMS [1 Hz, 10 Hz, and sham]) and 3 repetitive TMS (1 Hz, 10 Hz, and sham) to investigate the effects on neural function and visceral sensation over 1 hour. The most effective cortical and spinal interventions were then applied in patients with IBS. Only 1-Hz rLSMS altered healthy anal motor excitability, increasing spinal (58 ± 12.3 vs 38.5 ± 5.7 μV, P = 0.04) but not cortical responses. Both 1-Hz rLSMS and 10-Hz repetitive transcranial magnetic stimulation increased healthy rectal pain thresholds for up to an hour after intervention (P < 0.05). When applied to patients with IBS, rectal pain thresholds were increased across all time points after both 1-Hz rLSMS and 10-Hz repetitive transcranial magnetic stimulation (P < 0.05) compared with sham. The application of magnetoelectric stimuli to the cortical and lumbosacral areas modulates visceral sensation in healthy subjects and patients with IBS. This proof-of-concept study provides supportive evidence for neurostimulation in managing functional gastrointestinal disorders.

  16. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine.

    PubMed

    Marutle, Amelia; Ohmitsu, Masao; Nilbratt, Mats; Greig, Nigel H; Nordberg, Agneta; Sugaya, Kiminobu

    2007-07-24

    In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)-phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.

  17. Transplantation of neural differentiated human mesenchymal stem cells into the cochlea of an auditory-neuropathy guinea pig model.

    PubMed

    Cho, Yong-Bum; Cho, Hyong-Ho; Jang, Sujeong; Jeong, Han-Seong; Park, Jong-Seong

    2011-04-01

    The aim of this study was to determine the effects of transplanted neural differentiated human mesenchymal stem cells (hMSCs) in a guinea pig model of auditory neuropathy. In this study, hMSCs were pretreated with a neural-induction protocol and transplanted into the scala tympani of the guinea pig cochlea 7 days after ouabain injury. A control model was made by injection of Hanks balanced salt solution alone into the scala tympani of the guinea pig cochlea 7 days after ouabain injury. We established the auditory neuropathy guinea pig model using 1 mM ouabain application to the round window niche. After application of ouabain to the round window niche, degeneration of most spiral ganglion neurons (SGNs) without the loss of hair cells within the organ of Corti and increasing the auditory brain responses (ABR) threshold were found. After transplantation of neural differentiated hMSCs, the number of SGNs was increased, and some of the SGNs expressed immunoreactivity with human nuclear antibody under confocal laser scanning microscopy. ABR results showed mild hearing recovery after transplantation. Based on an auditory neuropathy animal model, these findings suggest that it may be possible to replace degenerated SGNs by grafting stem cells into the scala tympani. PMID:21468255

  18. Neural Signatures of Value Comparison in Human Cingulate Cortex during Decisions Requiring an Effort-Reward Trade-off

    PubMed Central

    Kennerley, Steven W.; Friston, Karl; Bestmann, Sven

    2016-01-01

    Integrating costs and benefits is crucial for optimal decision-making. Although much is known about decisions that involve outcome-related costs (e.g., delay, risk), many of our choices are attached to actions and require an evaluation of the associated motor costs. Yet how the brain incorporates motor costs into choices remains largely unclear. We used human fMRI during choices involving monetary reward and physical effort to identify brain regions that serve as a choice comparator for effort-reward trade-offs. By independently varying both options' effort and reward levels, we were able to identify the neural signature of a comparator mechanism. A network involving supplementary motor area and the caudal portion of dorsal anterior cingulate cortex encoded the difference in reward (positively) and effort levels (negatively) between chosen and unchosen choice options. We next modeled effort-discounted subjective values using a novel behavioral model. This revealed that the same network of regions involving dorsal anterior cingulate cortex and supplementary motor area encoded the difference between the chosen and unchosen options' subjective values, and that activity was best described using a concave model of effort-discounting. In addition, this signal reflected how precisely value determined participants' choices. By contrast, separate signals in supplementary motor area and ventromedial prefrontal cortex correlated with participants' tendency to avoid effort and seek reward, respectively. This suggests that the critical neural signature of decision-making for choices involving motor costs is found in human cingulate cortex and not ventromedial prefrontal cortex as typically reported for outcome-based choice. Furthermore, distinct frontal circuits seem to drive behavior toward reward maximization and effort minimization. SIGNIFICANCE STATEMENT The neural processes that govern the trade-off between expected benefits and motor costs remain largely unknown. This is

  19. Potential dynamics of the human striate cortex cerebrum realistic neural network under the influence of an external signal

    NASA Astrophysics Data System (ADS)

    Melnikov, Leonid A.; Novosselova, Anna V.; Blinova, Nadejda V.; Vinitsky, Sergey I.; Serov, Vladislav V.; Bakutkin, Valery V.; Camenskich, T. G.; Guileva, E. V.

    2000-03-01

    In this work the numerical investigations of a potential dynamics of a neural network as the non-linear system and dynamics of the visual nerve which connect the eye retina receptors with the striate cortex cerebrum as the answer to the through-skin excitement of the eye retina by the electrical signal were realized. The visual evoked potential is the answer and characterizes the human brain state over the structures retina state and the conduction of the visual nerve fibers. The results of these investigations were presented. Specific features of the neural network, such as the excitation and depression, we took into account too. The discussion about the model parameters, used at the time of the numerical investigation, was made. The comparative analysis of the retina potential data and the data of the external signal filing by the brain hemicerebrum visual centers was made too.

  20. Electrical stimulation using conductive polymer polypyrrole promotes differentiation of human neural stem cells: a biocompatible platform for translational neural tissue engineering.

    PubMed

    Stewart, Elise; Kobayashi, Nao R; Higgins, Michael J; Quigley, Anita F; Jamali, Sina; Moulton, Simon E; Kapsa, Robert M I; Wallace, Gordon G; Crook, Jeremy M

    2015-04-01

    Conductive polymers (CPs) are organic materials that hold great promise for biomedicine. Potential applications include in vitro or implantable electrodes for excitable cell recording and stimulation and conductive scaffolds for cell support and tissue engineering. In this study, we demonstrate the utility of electroactive CP polypyrrole (PPy) containing the anionic dopant dodecylbenzenesulfonate (DBS) to differentiate novel clinically relevant human neural stem cells (hNSCs). Electrical stimulation of PPy(DBS) induced hNSCs to predominantly β-III Tubulin (Tuj1) expressing neurons, with lower induction of glial fibrillary acidic protein (GFAP) expressing glial cells. In addition, stimulated cultures comprised nodes or clusters of neurons with longer neurites and greater branching than unstimulated cultures. Cell clusters showed a similar spatial distribution to regions of higher conductivity on the film surface. Our findings support the use of electrical stimulation to promote neuronal induction and the biocompatibility of PPy(DBS) with hNSCs and opens up the possibility of identifying novel mechanisms of fate determination of differentiating human stem cells for advanced in vitro modeling, translational drug discovery, and regenerative medicine.

  1. Differing Lectin Binding Profiles among Human Embryonic Stem Cells and Derivatives Aid in the Isolation of Neural Progenitor Cells

    PubMed Central

    Dodla, Mahesh C.; Young, Amber; Venable, Alison; Hasneen, Kowser; Rao, Raj R.; Machacek, David W.; Stice, Steven L.

    2011-01-01

    Human embryonic stem cells (hESCs) and their differentiated progeny allow for investigation of important changes/events during normal embryonic development. Currently most of the research is focused on proteinacous changes occurring as a result of differentiation of stem cells and little is known about changes in cell surface glycosylation patterns. Identification of cell lineage specific glycans can help in understanding their role in maintenance, proliferation and differentiation. Furthermore, these glycans can serve as markers for isolation of homogenous populations of cells. Using a panel of eight biotinylated lectins, the glycan expression of hESCs, hESCs-derived human neural progenitors (hNP) cells, and hESCs-derived mesenchymal progenitor (hMP) cells was investigated. Our goal was to identify glycans that are unique for hNP cells and use the corresponding lectins for cell isolation. Flow cytometry and immunocytochemistry were used to determine expression and localization of glycans, respectively, in each cell type. These results show that the glycan expression changes upon differentiation of hESCs and is different for neural and mesenchymal lineage. For example, binding of PHA-L lectin is low in hESCs (14±4.4%) but significantly higher in differentiated hNP cells (99±0.4%) and hMP cells (90±3%). Three lectins: VVA, DBA and LTL have low binding in hESCs and hMP cells, but significantly higher binding in hNP cells. Finally, VVA lectin binding was used to isolate hNP cells from a mixed population of hESCs, hNP cells and hMP cells. This is the first report that compares glycan expression across these human stem cell lineages and identifies significant differences. Also, this is the first study that uses VVA lectin for isolation for human neural progenitor cells. PMID:21850265

  2. Neural correlates of consonance, dissonance, and the hierarchy of musical pitch in the human brainstem.

    PubMed

    Bidelman, Gavin M; Krishnan, Ananthanarayan

    2009-10-21

    Consonant and dissonant pitch relationships in music provide the foundation of melody and harmony, the building blocks of Western tonal music. We hypothesized that phase-locked neural activity within the brainstem may preserve information relevant to these important perceptual attributes of music. To this end, we measured brainstem frequency-following responses (FFRs) from nonmusicians in response to the dichotic presentation of nine musical intervals that varied in their degree of consonance and dissonance. Neural pitch salience was computed for each response using temporally based autocorrelation and harmonic pitch sieve analyses. Brainstem responses to consonant intervals were more robust and yielded stronger pitch salience than those to dissonant intervals. In addition, the ordering of neural pitch salience across musical intervals followed the hierarchical arrangement of pitch stipulated by Western music theory. Finally, pitch salience derived from neural data showed high correspondence with behavioral consonance judgments (r = 0.81). These results suggest that brainstem neural mechanisms mediating pitch processing show preferential encoding of consonant musical relationships and, furthermore, preserve the hierarchical pitch relationships found in music, even for individuals without formal musical training. We infer that the basic pitch relationships governing music may be rooted in low-level sensory processing and that an encoding scheme that favors consonant pitch relationships may be one reason why such intervals are preferred behaviorally.

  3. Extracellular matrix-regulated neural differentiation of human multipotent marrow progenitor cells enhances functional recovery after spinal cord injury

    PubMed Central

    Deng, Win-Ping; Yang, Chi-Chiang; Yang, Liang-Yo; Chen, Chun-Wei D.; Chen, Wei-Hong; Yang, Charn-Bing; Chen, Yu-Hsin; Lai, Wen-Fu T.; Renshaw, Perry F.

    2015-01-01

    BACKGROUND CONTEXT Recent advanced studies have demonstrated that cytokines and extracellular matrix (ECM) could trigger various types of neural differentiation. However, the efficacy of differentiation and in vivo transplantation has not yet thoroughly been investigated. PURPOSE To highlight the current understanding of the effects of ECM on neural differentiation of human bone marrow-derived multipotent progenitor cells (MPCs), regarding state-of-art cure for the animal with acute spinal cord injury (SCI), and explore future treatments aimed at neural repair. STUDY DESIGN A selective overview of the literature pertaining to the neural differentiation of the MSCs and experimental animals aimed at improved repair of SCI. METHODS Extracellular matrix proteins, tenascin-cytotactin (TN-C), tenascin-restrictin (TN-R), and chondroitin sulfate (CS), with the cytokines, nerve growth factor (NGF)/brain-derived neurotrophic factor (BDNF)/retinoic acid (RA) (NBR), were incorporated to induce transdifferentiation of human MPCs. Cells were treated with NBR for 7 days, and then TN-C, TN-R, or CS was added for 2 days. The medium was changed every 2 days. Twenty-four animals were randomly assigned to four groups with six animals in each group: one experimental and three controls. Animals received two (bilateral) injections of vehicle, MPCs, NBR-induced MPCs, or NBR/TN-C-induced MPCs into the lesion sites after SCI. Functional assessment was measured using the Basso, Beattie, and Bresnahan locomotor rating score. Data were analyzed using analysis of variance followed by Student-Newman-Keuls (SNK) post hoc tests. RESULTS Results showed that MPCs with the transdifferentiation of human MPCs to neurons were associated with increased messenger-RNA (mRNA) expression of neuronal markers including nestin, microtubule-associated protein (MAP) 2, glial fibrillary acidic protein, βIII tubulin, and NGF. Greater amounts of neuronal morphology appeared in cultures incorporated with TN-C and TN

  4. Perspectives on the neural connectivity of the fornix in the human brain

    PubMed Central

    Jang, Sung Ho; Kwon, Hyeok Gyu

    2014-01-01

    The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural connectivity of the fornix. The anterior fornical body has high connectivity with the anterior commissure, and brain areas relevant to cholinergic nuclei (septal forebrain region and brainstem) and memory function (medial temporal lobe). In the normal subjects, by contrast, the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum. We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix. PMID:25317154

  5. Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss.

    PubMed

    Locher, Heiko; de Groot, John C M J; van Iperen, Liesbeth; Huisman, Margriet A; Frijns, Johan H M; Chuva de Sousa Lopes, Susana M

    2015-11-01

    Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9-W18) and show the cochlear expression dynamics of key potassium-regulating proteins. At W12, MITF+/SOX10+/KIT+ neural-crest-derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+-ATPase-positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. PMID:25663387

  6. Neural crest potential for tooth development in a urodele amphibian: developmental and evolutionary significance.

    PubMed

    Graveson, A C; Smith, M M; Hall, B K

    1997-08-01

    Tooth development in urodele amphibians occurs from a restricted region of anterior cranial neural crest. An in vitro culture system was used to test the odontogenic potential of more caudal regions of neural crest, including an "intermediate region" of neural folds which has never previously been tested for either fate or potential. Explants of different axial levels of neural crest with stomodaeal ectoderm and endoderm demonstrated that odontogenic potential extends not only further caudally than the axial level fated to produce teeth, but also beyond that with potential to produce cartilage. Our results show that chondrogenic potential is found only within the most rostral portion of the intermediate region, but that odontogenic potential extends to its most caudal limit. This separation of skeletogenic cell lineages in the neural crest necessitates a reevaluation of the designations of "cranial" and "trunk" and a reconsideration of the evolutionary implications of developmentally distinct crest-derived mesenchyme populations. The proposal that odontogenic potential extends into the trunk neural crest may be explained as conserved from a phylogenetically older, more extensive skeletogenic ability which produced the exoskeleton of more basal vertebrates. PMID:9245509

  7. Human Neural Stem Cell Replacement Therapy for Amyotrophic Lateral Sclerosis by Spinal Transplantation

    PubMed Central

    Hefferan, Michael P.; Galik, Jan; Kakinohana, Osamu; Sekerkova, Gabriela; Santucci, Camila; Marsala, Silvia; Navarro, Roman; Hruska-Plochan, Marian; Johe, Karl; Feldman, Eva; Cleveland, Don W.; Marsala, Martin

    2012-01-01

    Background Mutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1G93A rats leads to a moderate therapeutical effect as evidenced by local α-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1G93A animals. Methods/Principal Findings Presymptomatic SOD1G93A rats (60–65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1G93A rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1G93A rats protected α-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to α-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1G93A rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50–65%) loss of large caliber descending motor axons. Conclusions/Significance These data

  8. In our own image? Emotional and neural processing differences when observing human–human vs human–robot interactions

    PubMed Central

    Wang, Yin

    2015-01-01

    Notwithstanding the significant role that human–robot interactions (HRI) will play in the near future, limited research has explored the neural correlates of feeling eerie in response to social robots. To address this empirical lacuna, the current investigation examined brain activity using functional magnetic resonance imaging while a group of participants (n = 26) viewed a series of human–human interactions (HHI) and HRI. Although brain sites constituting the mentalizing network were found to respond to both types of interactions, systematic neural variation across sites signaled diverging social-cognitive strategies during HHI and HRI processing. Specifically, HHI elicited increased activity in the left temporal–parietal junction indicative of situation-specific mental state attributions, whereas HRI recruited the precuneus and the ventromedial prefrontal cortex (VMPFC) suggestive of script-based social reasoning. Activity in the VMPFC also tracked feelings of eeriness towards HRI in a parametric manner, revealing a potential neural correlate for a phenomenon known as the uncanny valley. By demonstrating how understanding social interactions depends on the kind of agents involved, this study highlights pivotal sub-routes of impression formation and identifies prominent challenges in the use of humanoid robots. PMID:25911418

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

    PubMed Central

    Raja, Waseem K.; Mungenast, Alison E.; Lin, Yuan-Ta; Ko, Tak; Abdurrob, Fatema; Seo, Jinsoo; Tsai, Li-Huei

    2016-01-01

    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. PMID:27622770

  10. Low-Dose Methylmercury-Induced Apoptosis and Mitochondrial DNA Mutation in Human Embryonic Neural Progenitor Cells.

    PubMed

    Wang, Xinjin; Yan, Mengling; Zhao, Lina; Wu, Qing; Wu, Chunhua; Chang, Xiuli; Zhou, Zhijun

    2016-01-01

    Methylmercury (MeHg) is a long-lasting organic pollutant primarily found in the aquatic environment. The developing brain is particularly sensitive to MeHg due to reduced proliferation of neural stem cell. Although several mechanisms of MeHg-induced apoptosis have been defined in culture models, it remains unclear whether mitochondrial DNA (mtDNA) mutation is involved in the toxic effect of MeHg, especially in the neural progenitor cells. In the present study, the ReNcell CX cell, a human neural progenitor cells (hNPCs) line, was exposed to nanomolar concentrations of MeHg (≤50 nM). We found that MeHg altered mitochondrial metabolic function and induced apoptosis. In addition, we observed that MeHg induced ROS production in a dose-dependent manner in hNPCs cells, which was associated with significantly increased expressions of ND1, Cytb, and ATP6. To elucidate the mechanism underlying MeHg toxicity on mitochondrial function, we examined the ATP content and mitochondrial membrane potential in MeHg-treated hNPCs. Our study showed that MeHg exposure led to decreased ATP content and reduced mitochondrial membrane potential, which failed to match the expansion in mtDNA copy number, suggesting impaired mtDNA. Collectively, these results demonstrated that MeHg induced toxicity in hNPCs through altering mitochondrial function and inducing oxidative damage to mtDNA. PMID:27525052

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

    PubMed

    Raja, Waseem K; Mungenast, Alison E; Lin, Yuan-Ta; Ko, Tak; Abdurrob, Fatema; Seo, Jinsoo; Tsai, Li-Huei

    2016-01-01

    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. PMID:27622770

  12. Dissociation between neural signatures of stimulus and choice in population activity of human V1 during perceptual decision-making.

    PubMed

    Choe, Kyoung Whan; Blake, Randolph; Lee, Sang-Hun

    2014-02-12

    Primary visual cortex (V1) forms the initial cortical representation of objects and events in our visual environment, and it distributes information about that representation to higher cortical areas within the visual hierarchy. Decades of work have established tight linkages between neural activity occurring in V1 and features comprising the retinal image, but it remains debatable how that activity relates to perceptual decisions. An actively debated question is the extent to which V1 responses determine, on a trial-by-trial basis, perceptual choices made by observers. By inspecting the population activity of V1 from human observers engaged in a difficult visual discrimination task, we tested one essential prediction of the deterministic view: choice-related activity, if it exists in V1, and stimulus-related activity should occur in the same neural ensemble of neurons at the same time. Our findings do not support this prediction: while cortical activity signifying the variability in choice behavior was indeed found in V1, that activity was dissociated from activity representing stimulus differences relevant to the task, being advanced in time and carried by a different neural ensemble. The spatiotemporal dynamics of population responses suggest that short-term priors, perhaps formed in higher cortical areas involved in perceptual inference, act to modulate V1 activity prior to stimulus onset without modifying subsequent activity that actually represents stimulus features within V1.

  13. Isolation and purification of self-renewable human neural stem cells for cell therapy in experimental model of ischemic stroke.

    PubMed

    Azevedo-Pereira, Ricardo L; Daadi, Marcel M

    2013-01-01

    Human embryonic stem cells (hESCs) are pluripotent with a strong self-renewable ability making them a virtually unlimited source of neural cells for structural repair in neurological disorders. Currently, hESCs are one of the most promising cell sources amenable for commercialization of off-shelf cell therapy products. However, along with this strong proliferative capacity of hESCs comes the tumorigenic potential of these cells after transplantation. Thus, the isolation and purification of a homogeneous, population of neural stem cells (hNSCs) are of paramount importance to avoid tumor formation in the host brain. This chapter describes the isolation, neuralization, and long-term perpetuation of hNSCs derived from hESCs through use of specific mitogenic growth factors and the preparation of hNSCs for transplantation in an experimental model of stroke. Additionally, we describe methods to analyze the stroke and size of grafts using magnetic resonance imaging and Osirix software, and neuroanatomical tracing procedures to study axonal remodeling after stroke and cell transplantation.

  14. Genome-Wide Definition of Promoter and Enhancer Usage during Neural Induction of Human Embryonic Stem Cells.

    PubMed

    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

    Genome-wide mapping of transcriptional regulatory elements is an essential tool for understanding the molecular events orchestrating self-renewal, commitment and differentiation of stem cells. We combined high-throughput identification of transcription start sites with genome-wide profiling of histones modifications to map active promoters and enhancers in embryonic stem cells (ESCs) induced to neuroepithelial-like stem cells (NESCs). Our analysis showed that most promoters are active in both cell types while approximately half of the enhancers 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. Interestingly, the majority of the promoters activated or up-regulated during neural induction have a "bivalent" histone modification signature in ESCs, suggesting that developmentally-regulated promoters are already poised for transcription in ESCs, which are apparently pre-committed to neuroectodermal differentiation. Overall, our study provides a collection of differentially used enhancers, promoters, transcription starts sites, protein-coding and non-coding RNAs in human ESCs and ESC-derived NESCs, and a broad, genome-wide description of promoter and enhancer usage and of gene expression programs characterizing the transition from a pluripotent to a neural-restricted cell fate.

  15. Neurally mediated propagating discrete clustered contractions superimposed on myogenic ripples in ex vivo segments of human ileum.

    PubMed

    Kuizenga, Merel H; Sia, Tiong C; Dodds, Kelsi N; Wiklendt, Lukasz; Arkwright, John W; Thomas, A; Brookes, Simon J; Spencer, Nick J; Wattchow, David A; Dinning, Phil G; Costa, Marcello

    2015-01-01

    Narrow muscle strips have been extensively used to study intestinal contractility. Larger specimens from laboratory animals have provided detailed understanding of mechanisms that underlie patterned intestinal motility. Despite progress in animal tissue, investigations of motor patterns in large, intact specimens of human gut ex vivo have been sparse. In this study, we tested whether neurally dependent motor patterns could be detected in isolated specimens of intact human ileum. Specimens (n = 14; 7-30 cm long) of terminal ileum were obtained with prior informed consent from patients undergoing colonic surgery for removal of carcinomas. Preparations were set up in an organ bath with an array of force transducers, a fiberoptic manometry catheter, and a video camera. Spontaneous and distension-evoked motor activity was recorded, and the effects of lidocaine, which inhibits neural activity, were studied. Myogenic contractions (ripples) occurred in all preparations (6.17 ± 0.36/min). They were of low amplitude and formed complex patterns by colliding and propagating in both directions along the specimen at anterograde velocities of 4.1 ± 0.3 mm/s and retrogradely at 4.9 ± 0.6 mm/s. In five specimens, larger amplitude clusters of contractions were seen (discrete clustered contractions), which propagated aborally at 1.05 ± 0.13 mm/s and orally at 1.07 ± 0.09 mm/s. These consisted of two to eight phasic contractions that aligned with ripples. These motor patterns were abolished by addition of lidocaine (0.3 mM). The ripples continued unchanged in the presence of this neural blocking agent. These results demonstrate that both myogenic and neurogenic motor patterns can be studied in isolated specimens of human small intestine.

  16. Neural signatures of human fear conditioning: an updated and extended meta-analysis of fMRI studies.

    PubMed

    Fullana, M A; Harrison, B J; Soriano-Mas, C; Vervliet, B; Cardoner, N; Àvila-Parcet, A; Radua, J

    2016-04-01

    Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the 'central autonomic-interoceptive network'. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations-a scarcely addressed dynamic in fMRI fear-conditioning studies-also suggests the existence of a coordinated brain response potentially underlying the 'safety signal' (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches.

  17. Induction of Neural Progenitor-Like Cells from Human Fibroblasts via a Genetic Material-Free Approach

    PubMed Central

    Mirakhori, Fahimeh; Zeynali, Bahman; Rassouli, Hassan; Shahbazi, Ebrahim; Hashemizadeh, Shiva; Kiani, Sahar; Salekdeh, Ghasem Hosseini; Baharvand, Hossein

    2015-01-01

    Background A number of studies generated induced neural progenitor cells (iNPCs) from human fibroblasts by viral delivering defined transcription factors. However, the potential risks associated with gene delivery systems have limited their clinical use. We propose it would be safer to induce neural progenitor-like cells from human adult fibroblasts via a direct non-genetic alternative approach. Methodology/Principal Findings Here, we have reported that seven rounds of TAT-SOX2 protein transduction in a defined chemical cocktail under a 3D sphere culture gradually morphed fibroblasts into neuroepithelial-like colonies. We were able to expand these cells for up to 20 passages. These cells could give rise to cells that expressed neurons and glia cell markers both in vitro and in vivo. Conclusions/Significance These results show that our approach is beneficial for the genetic material-free generation of iNPCs from human fibroblasts where small chemical molecules can provide a valuable, viable strategy to boost and improve induction in a 3D sphere culture. PMID:26266943

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

    PubMed Central

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

    2015-01-01

    The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell 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. PMID:26298025

  19. The study of neural tube defects after the Human Genome Project and folic acid fortification of foods.

    PubMed

    Graf, W D; Oleinik, O E

    2000-12-01

    The implementation of folic acid fortification will eliminate a proportion of neural tube defects (NTD). As a result, the etiologic and clinical profiles of the developmental disorder may both change. In the assessment of NTD as it evolves, the bioinformatics structure and content of the Human Genome Project will find vital application. One important development will be an enhanced understanding of the role of folic acid in global regulation of gene expression through epigenetic processes. In addition, bioinformatics will facilitate coordination of research in the basic sciences with clinical investigations to better define remaining etiologic factors.

  20. An “As Soon As Possible” Effect in Human Intertemporal Decision Making: Behavioral Evidence and Neural Mechanisms

    PubMed Central

    Glimcher, Paul W.

    2010-01-01

    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. PMID:20181737

  1. Neural Signatures of Number Processing in Human Infants: Evidence for Two Core Systems Underlying Numerical Cognition

    ERIC Educational Resources Information Center

    Hyde, Daniel C.; Spelke, Elizabeth S.

    2011-01-01

    Behavioral research suggests that two cognitive systems are at the foundations of numerical thinking: one for representing 1-3 objects in parallel and one for representing and comparing large, approximate numerical magnitudes. We tested for dissociable neural signatures of these systems in preverbal infants by recording event-related potentials…

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

    ERIC Educational Resources Information Center

    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…

  3. Dissociable Neural Response Signatures for Slow Amplitude and Frequency Modulation in Human Auditory Cortex

    PubMed Central

    Henry, Molly J.; Obleser, Jonas

    2013-01-01

    Natural auditory stimuli are characterized by slow fluctuations in amplitude and frequency. However, the degree to which the neural responses to slow amplitude modulation (AM) and frequency modulation (FM) are capable of conveying independent time-varying information, particularly with respect to speech communication, is unclear. In the current electroencephalography (EEG) study, participants listened to amplitude- and frequency-modulated narrow-band noises with a 3-Hz modulation rate, and the resulting neural responses were compared. Spectral analyses revealed similar spectral amplitude peaks for AM and FM at the stimulation frequency (3 Hz), but amplitude at the second harmonic frequency (6 Hz) was much higher for FM than for AM. Moreover, the phase delay of neural responses with respect to the full-band stimulus envelope was shorter for FM than for AM. Finally, the critical analysis involved classification of single trials as being in response to either AM or FM based on either phase or amplitude information. Time-varying phase, but not amplitude, was sufficient to accurately classify AM and FM stimuli based on single-trial neural responses. Taken together, the current results support the dissociable nature of cortical signatures of slow AM and FM. These cortical signatures potentially provide an efficient means to dissect simultaneously communicated slow temporal and spectral information in acoustic communication signals. PMID:24205309

  4. A functional genetic study identifies HAND1 mutations in septation defects of the human heart.

    PubMed

    Reamon-Buettner, Stella Marie; Ciribilli, Yari; Traverso, Ilaria; Kuhls, Beate; Inga, Alberto; Borlak, Juergen

    2009-10-01

    Heart and neural crest derivatives expressed 1 (HAND1) is a basic helix-loop-helix (bHLH) transcription factor essential for mammalian heart development. Absence of Hand1 in mice results in embryonal lethality, as well as in a wide spectrum of cardiac abnormalities including failed cardiac looping, defective chamber septation and impaired ventricular development. Therefore, Hand1 is a strong candidate for the many cardiac malformations observed in human congenital heart disease (CHD). Recently, we identified a loss-of-function frameshift mutation (p.A126fs) in the bHLH domain of HAND1 frequent in hypoplastic hearts. This finding prompted us to continue our search for HAND1 gene mutations in a different cohort of malformed hearts affected primarily by septation defects. Indeed, in tissue samples of septal defects, we detected 32 sequence alterations leading to amino acid change, of which 12 are in the bHLH domain of HAND1. Interestingly, 10 sequence alterations, such as p.L28H and p.L138P, had been identified earlier in hypoplastic hearts, but the frequent p.A126fs mutation was absent except in one aborted case with ventricular septal defect and outflow tract abnormalities. Functional studies in yeast and mammalian cells enabled translation of sequence alterations to HAND1 transcriptional activity, which was reduced or abolished by certain mutations, notably p.L138P. Our results suggest that HAND1 may also be affected in septation defects of the human hearts, and thus has a broader role in human heart development and CHD.

  5. 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.

    EPA Science Inventory

    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...

  6. Nanofiber Matrices Promote the Neuronal Differentiation of Human Embryonic Stem Cell-Derived Neural Precursors In Vitro

    PubMed Central

    Lim, Shawn H.; Christopherson, Gregory T.; Xu, Leyan; Nasonkin, Igor; Yu, Christopher; Mao, Hai-Quan; Koliatsos, Vassilis E.

    2011-01-01

    The potential of human embryonic stem (ES) cells as experimental therapies for neuronal replacement has recently received considerable attention. In view of the organization of the mature nervous system into distinct neural circuits, key challenges of such therapies are the directed differentiation of human ES cell-derived neural precursors (NPs) into specific neuronal types and the directional growth of axons along specified trajectories. In the present study, we cultured human NPs derived from the NIH-approved ES line BGO1 on polycaprolactone fiber matrices of different diameter (i.e., nanofibers and microfibers) and orientation (i.e., aligned and random); fibers were coated with poly-L-ornithine/laminin to mimic the extracellular matrix and support the adhesion, viability, and differentiation of NPs. On aligned fibrous meshes, human NPs adopt polarized cell morphology with processes extending along the axis of the fiber, whereas NPs on plain tissue culture surfaces or random fiber substrates form nonpolarized neurite networks. Under differentiation conditions, human NPs cultured on aligned fibrous substrates show a higher rate of neuronal differentiation than other matrices; 62% and 86% of NPs become TUJ1 (+) early neurons on aligned micro- and nanofibers, respectively, whereas only 32% and 27% of NPs acquire the same fate on random micro- and nanofibers. Metabolic cell activity/viability studies reveal that fiber alignment and diameter also have an effect on NP viability, but only in the presence of mitogens. Our findings demonstrate that fibrous substrates serve as an artificial extracellular matrix and provide a microenviroment that influences key aspects of the neuronal differentiation of ES-derived NPs. PMID:20973749

  7. Comparison of Neural Responses to Cat Meows and Human Vowels in the Anterior and Posterior Auditory Field of Awake Cats

    PubMed Central

    Ma, Hanlu; Qin, Ling; Dong, Chao; Zhong, Renjia; Sato, Yu

    2013-01-01

    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. PMID:23301004

  8. Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration.

    PubMed

    Pallocca, Giorgia; Grinberg, Marianna; Henry, Margit; Frickey, Tancred; Hengstler, Jan G; Waldmann, Tanja; Sachinidis, Agapios; Rahnenführer, Jörg; Leist, Marcel

    2016-01-01

    The in vitro test battery of the European research consortium ESNATS ('novel stem cell-based test systems') has been used to screen for potential human developmental toxicants. As part of this effort, the migration of neural crest (MINC) assay has been used to evaluate chemical effects on neural crest function. It identified some drug-like compounds in addition to known environmental toxicants. The hits included the HSP90 inhibitor geldanamycin, the chemotherapeutic arsenic trioxide, the flame-retardant PBDE-99, the pesticide triadimefon and the histone deacetylase inhibitors valproic acid and trichostatin A. Transcriptome changes triggered by these substances in human neural crest cells were recorded and analysed here to answer three questions: (1) can toxicants be individually identified based on their transcript profile; (2) how can the toxicity pattern reflected by transcript changes be compacted/dimensionality-reduced for practical regulatory use; (3) how can a reduced set of biomarkers be selected for large-scale follow-up? Transcript profiling allowed clear separation of different toxicants and the identification of toxicant types in a blinded test study. We also developed a diagrammatic system to visualize and compare toxicity patterns of a group of chemicals by giving a quantitative overview of altered superordinate biological processes (e.g. activation of KEGG pathways or overrepresentation of gene ontology terms). The transcript data were mined for potential markers of toxicity, and 39 transcripts were selected to either indicate general developmental toxicity or distinguish compounds with different modes-of-action in read-across. In summary, we found inclusion of transcriptome data to largely increase the information from the MINC phenotypic test. PMID:26705709

  9. Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration.

    PubMed

    Pallocca, Giorgia; Grinberg, Marianna; Henry, Margit; Frickey, Tancred; Hengstler, Jan G; Waldmann, Tanja; Sachinidis, Agapios; Rahnenführer, Jörg; Leist, Marcel

    2016-01-01

    The in vitro test battery of the European research consortium ESNATS ('novel stem cell-based test systems') has been used to screen for potential human developmental toxicants. As part of this effort, the migration of neural crest (MINC) assay has been used to evaluate chemical effects on neural crest function. It identified some drug-like compounds in addition to known environmental toxicants. The hits included the HSP90 inhibitor geldanamycin, the chemotherapeutic arsenic trioxide, the flame-retardant PBDE-99, the pesticide triadimefon and the histone deacetylase inhibitors valproic acid and trichostatin A. Transcriptome changes triggered by these substances in human neural crest cells were recorded and analysed here to answer three questions: (1) can toxicants be individually identified based on their transcript profile; (2) how can the toxicity pattern reflected by transcript changes be compacted/dimensionality-reduced for practical regulatory use; (3) how can a reduced set of biomarkers be selected for large-scale follow-up? Transcript profiling allowed clear separation of different toxicants and the identification of toxicant types in a blinded test study. We also developed a diagrammatic system to visualize and compare toxicity patterns of a group of chemicals by giving a quantitative overview of altered superordinate biological processes (e.g. activation of KEGG pathways or overrepresentation of gene ontology terms). The transcript data were mined for potential markers of toxicity, and 39 transcripts were selected to either indicate general developmental toxicity or distinguish compounds with different modes-of-action in read-across. In summary, we found inclusion of transcriptome data to largely increase the information from the MINC phenotypic test.

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

    PubMed Central

    Shahbazi, Ebrahim; Moradi, Sharif; Nemati, Shiva; Satarian, Leila; Basiri, Mohsen; Gourabi, Hamid; Zare Mehrjardi, Narges; Günther, Patrick; Lampert, Angelika; Händler, Kristian; Hatay, Firuze Fulya; Schmidt, Diana; Molcanyi, Marek; Hescheler, Jürgen; Schultze, Joachim L.; Saric, Tomo; Baharvand, Hossein

    2016-01-01

    Summary 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. PMID:27052315

  11. Identification of the Plant for Upright Stance in Humans: Multiple Movement Patterns From a Single Neural Strategy

    PubMed Central

    Kiemel, Tim; Elahi, Alexander J.; Jeka, John J.

    2008-01-01

    We determined properties of the plant during human upright stance using a closed-loop system identification method originally applied to human postural control by another group. To identify the plant, which was operationally defined as the mapping from muscle activation (rectified EMG signals) to body segment angles, we rotated the visual scene about the axis through the subject's ankles using a sum-of-sines stimulus signal. Because EMG signals from ankle muscles and from hip and lower trunk muscles showed similar responses to the visual perturbation across frequency, we combined EMG signals from all recorded muscles into a single plant input. Body kinematics were described by the trunk and leg angles in the sagittal plane. The phase responses of both angles to visual scene angle were similar at low frequencies and approached a difference of ∼150° at higher frequencies. Therefore we considered leg and trunk angles as separate plant outputs. We modeled the plant with a two-joint (ankle and hip) model of the body, a second-order low-pass filter from EMG activity to active joint torques, and intrinsic stiffness and damping at both joints. The results indicated that the in-phase (ankle) pattern was neurally generated, whereas the out-of-phase pattern was caused by plant dynamics. Thus a single neural strategy leads to multiple kinematic patterns. Moreover, estimated intrinsic stiffness in the model was insufficient to stabilize the plant. PMID:18829854