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Sample records for neural crest-like human

  1. Properties of Neural Crest-Like Cells Differentiated from Human Embryonic Stem Cells

    Czech Academy of Sciences Publication Activity Database

    Křivánek, J.; Švandová, Eva; Králik, J.; Hajda, S.; Fedr, Radek; Vinařský, V.; Jaroš, J.; Souček, Karel

    2014-01-01

    Roč. 60, č. 2014 (2014), s. 30-38 ISSN 0015-5500 R&D Projects: GA ČR(CZ) GAP304/11/1418 Institutional support: RVO:68081707 Keywords : stem cell differentiation * neural crest * odontogenesis Subject RIV: BO - Biophysics; ED - Physiology (UZFG-Y) Impact factor: 1.000, year: 2014

  2. Cell reprogramming by 3D bioprinting of human fibroblasts in polyurethane hydrogel for fabrication of neural-like constructs.

    Science.gov (United States)

    Ho, Lin; Hsu, Shan-Hui

    2018-04-01

    reprogrammed into neural crest-like stem cells by 3D bioprinting with the gel, and the reprogrammed cells underwent neural differentiation in the printed structure after induction. The neural-like tissue engineering constructs fabricated by 3D bioprinting from human fibroblasts may be applied for neuroregeneration or further developed as mini-brain for basic research and drug screening. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  3. Neural networks of human nature and nurture

    Directory of Open Access Journals (Sweden)

    Daniel S. Levine

    2009-11-01

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

  4. Artificial neural network detects human uncertainty

    Science.gov (United States)

    Hramov, Alexander E.; Frolov, Nikita S.; Maksimenko, Vladimir A.; Makarov, Vladimir V.; Koronovskii, Alexey A.; Garcia-Prieto, Juan; Antón-Toro, Luis Fernando; Maestú, Fernando; Pisarchik, Alexander N.

    2018-03-01

    Artificial neural networks (ANNs) are known to be a powerful tool for data analysis. They are used in social science, robotics, and neurophysiology for solving tasks of classification, forecasting, pattern recognition, etc. In neuroscience, ANNs allow the recognition of specific forms of brain activity from multichannel EEG or MEG data. This makes the ANN an efficient computational core for brain-machine systems. However, despite significant achievements of artificial intelligence in recognition and classification of well-reproducible patterns of neural activity, the use of ANNs for recognition and classification of patterns in neural networks still requires additional attention, especially in ambiguous situations. According to this, in this research, we demonstrate the efficiency of application of the ANN for classification of human MEG trials corresponding to the perception of bistable visual stimuli with different degrees of ambiguity. We show that along with classification of brain states associated with multistable image interpretations, in the case of significant ambiguity, the ANN can detect an uncertain state when the observer doubts about the image interpretation. With the obtained results, we describe the possible application of ANNs for detection of bistable brain activity associated with difficulties in the decision-making process.

  5. Harmine stimulates proliferation of human neural progenitors

    Directory of Open Access Journals (Sweden)

    Vanja Dakic

    2016-12-01

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

  6. Differential neural network configuration during human path integration

    Science.gov (United States)

    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

  7. Neural networks for perception human and machine perception

    CERN Document Server

    Wechsler, Harry

    1991-01-01

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

  8. Neural Signatures of Trust During Human-Automation Interactions

    Science.gov (United States)

    2016-04-01

    also automated devices such as a Global Positioning System. For instance, to provide advanced safety measures, the Transportation Safety...AFRL-AFOSR-VA-TR-2016-0160 Neural Signatures of Trust during Human- Automation Interactions Frank Krueger GEORGE MASON UNIVERSITY Final Report 04/01...SUBTITLE Neural Signatures of Trust during Human- Automation Interactions 5a. CONTRACT NUMBER FA9550-13-1-0017 5b. GRANT NUMBER 5c. PROGRAM ELEMENT

  9. Engineering Human Neural Tissue by 3D Bioprinting.

    Science.gov (United States)

    Gu, Qi; Tomaskovic-Crook, Eva; Wallace, Gordon G; Crook, Jeremy M

    2018-01-01

    Bioprinting provides an opportunity to produce three-dimensional (3D) tissues for biomedical research and translational drug discovery, toxicology, and tissue replacement. Here we describe a method for fabricating human neural tissue by 3D printing human neural stem cells with a bioink, and subsequent gelation of the bioink for cell encapsulation, support, and differentiation to functional neurons and supporting neuroglia. The bioink uniquely comprises the polysaccharides alginate, water-soluble carboxymethyl-chitosan, and agarose. Importantly, the method could be adapted to fabricate neural and nonneural tissues from other cell types, with the potential to be applied for both research and clinical product development.

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

    Science.gov (United States)

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

    2017-10-01

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

  11. Human Face Recognition Using Convolutional Neural Networks

    Directory of Open Access Journals (Sweden)

    Răzvan-Daniel Albu

    2009-10-01

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

  12. Static human face recognition using artificial neural networks

    International Nuclear Information System (INIS)

    Qamar, R.; Shah, S.H.; Javed-ur-Rehman

    2003-01-01

    This paper presents a novel method of human face recognition using digital computers. A digital PC camera is used to take the BMP images of the human faces. An artificial neural network using Back Propagation Algorithm is developed as a recognition engine. The BMP images of the faces serve as the input patterns for this engine. A software 'Face Recognition' has been developed to recognize the human faces for which it is trained. Once the neural network is trained for patterns of the faces, the software is able to detect and recognize them with success rate of about 97%. (author)

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

    Science.gov (United States)

    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.

  14. Neural correlate of human reciprocity in social interactions

    Directory of Open Access Journals (Sweden)

    Shiro eSakaiya

    2013-12-01

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

  15. Neural correlate of human reciprocity in social interactions.

    Science.gov (United States)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Hayato Fukusumi

    2016-01-01

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

  17. Function of FEZF1 during early neural differentiation of human embryonic stem cells.

    Science.gov (United States)

    Liu, Xin; Su, Pei; Lu, Lisha; Feng, Zicen; Wang, Hongtao; Zhou, Jiaxi

    2018-01-01

    The understanding of the mechanism underlying human neural development has been hampered due to lack of a cellular system and complicated ethical issues. Human embryonic stem cells (hESCs) provide an invaluable model for dissecting human development because of unlimited self-renewal and the capacity to differentiate into nearly all cell types in the human body. In this study, using a chemical defined neural induction protocol and molecular profiling, we identified Fez family zinc finger 1 (FEZF1) as a potential regulator of early human neural development. FEZF1 is rapidly up-regulated during neural differentiation in hESCs and expressed before PAX6, a well-established marker of early human neural induction. We generated FEZF1-knockout H1 hESC lines using CRISPR-CAS9 technology and found that depletion of FEZF1 abrogates neural differentiation of hESCs. Moreover, loss of FEZF1 impairs the pluripotency exit of hESCs during neural specification, which partially explains the neural induction defect caused by FEZF1 deletion. However, enforced expression of FEZF1 itself fails to drive neural differentiation in hESCs, suggesting that FEZF1 is necessary but not sufficient for neural differentiation from hESCs. Taken together, our findings identify one of the earliest regulators expressed upon neural induction and provide insight into early neural development in human.

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

    OpenAIRE

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

    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 hiPS...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Leonardo D'Aiuto

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

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

    Science.gov (United States)

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

    2017-08-01

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

  2. Intranasal oxytocin modulates neural functional connectivity during human social interaction.

    Science.gov (United States)

    Rilling, James K; Chen, Xiangchuan; Chen, Xu; Haroon, Ebrahim

    2018-02-10

    Oxytocin (OT) modulates social behavior in primates and many other vertebrate species. Studies in non-primate animals have demonstrated that, in addition to influencing activity within individual brain areas, OT influences functional connectivity across networks of areas involved in social behavior. Previously, we used fMRI to image brain function in human subjects during a dyadic social interaction task following administration of either intranasal oxytocin (INOT) or placebo, and analyzed the data with a standard general linear model. Here, we conduct an extensive re-analysis of these data to explore how OT modulates functional connectivity across a neural network that animal studies implicate in social behavior. OT induced widespread increases in functional connectivity in response to positive social interactions among men and widespread decreases in functional connectivity in response to negative social interactions among women. Nucleus basalis of Meynert, an important regulator of selective attention and motivation with a particularly high density of OT receptors, had the largest number of OT-modulated connections. Regions known to receive mesolimbic dopamine projections such as the nucleus accumbens and lateral septum were also hubs for OT effects on functional connectivity. Our results suggest that the neural mechanism by which OT influences primate social cognition may include changes in patterns of activity across neural networks that regulate social behavior in other animals. © 2018 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    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.

  4. Neural correlates of heat-evoked pain memory in humans.

    Science.gov (United States)

    Wang, Liping; Gui, Peng; Li, Lei; Ku, Yixuan; Bodner, Mark; Fan, Gaojie; Zhou, Yong-Di; Dong, Xiao-Wei

    2016-03-01

    The neural processes underlying pain memory are not well understood. To explore these processes, contact heat-evoked potentials (CHEPs) were recorded in humans with electroencephalography (EEG) technique during a delayed matching-to-sample task, a working memory task involving presentations of two successive painful heat stimuli (S-1 and S-2) with different intensities separated by a 2-s interval (the memorization period). At the end of the task, the subject was required to discriminate the stimuli by indicating which (S-1 or S-2) induced more pain. A control task was used, in which no active discrimination was required between stimuli. All event-related potential (ERP) analysis was aligned to the onset of S-1. EEG activity exhibited two successive CHEPs: an N2-P2 complex (∼400 ms after onset of S-1) and an ultralate component (ULC, ∼900 ms). The amplitude of the N2-P2 at vertex, but not the ULC, was significantly correlated with stimulus intensity in these two tasks, suggesting that the N2-P2 represents neural coding of pain intensity. A late negative component (LNC) in the frontal recording region was observed only in the memory task during a 500-ms period before onset of S-2. LNC amplitude differed between stimulus intensities and exhibited significant correlations with the N2-P2 complex. These indicate that the frontal LNC is involved in maintenance of intensity of pain in working memory. Furthermore, alpha-band oscillations observed in parietal recording regions during the late delay displayed significant power differences between tasks. This study provides in the temporal domain previously unidentified neural evidence showing the neural processes involved in working memory of painful stimuli. Copyright © 2016 the American Physiological Society.

  5. Deep Recurrent Neural Networks for Human Activity Recognition

    Directory of Open Access Journals (Sweden)

    Abdulmajid Murad

    2017-11-01

    Full Text Available Adopting deep learning methods for human activity recognition has been effective in extracting discriminative features from raw input sequences acquired from body-worn sensors. Although human movements are encoded in a sequence of successive samples in time, typical machine learning methods perform recognition tasks without exploiting the temporal correlations between input data samples. Convolutional neural networks (CNNs address this issue by using convolutions across a one-dimensional temporal sequence to capture dependencies among input data. However, the size of convolutional kernels restricts the captured range of dependencies between data samples. As a result, typical models are unadaptable to a wide range of activity-recognition configurations and require fixed-length input windows. In this paper, we propose the use of deep recurrent neural networks (DRNNs for building recognition models that are capable of capturing long-range dependencies in variable-length input sequences. We present unidirectional, bidirectional, and cascaded architectures based on long short-term memory (LSTM DRNNs and evaluate their effectiveness on miscellaneous benchmark datasets. Experimental results show that our proposed models outperform methods employing conventional machine learning, such as support vector machine (SVM and k-nearest neighbors (KNN. Additionally, the proposed models yield better performance than other deep learning techniques, such as deep believe networks (DBNs and CNNs.

  6. Multiscale neural connectivity during human sensory processing in the brain

    Science.gov (United States)

    Maksimenko, Vladimir A.; Runnova, Anastasia E.; Frolov, Nikita S.; Makarov, Vladimir V.; Nedaivozov, Vladimir; Koronovskii, Alexey A.; Pisarchik, Alexander; Hramov, Alexander E.

    2018-05-01

    Stimulus-related brain activity is considered using wavelet-based analysis of neural interactions between occipital and parietal brain areas in alpha (8-12 Hz) and beta (15-30 Hz) frequency bands. We show that human sensory processing related to the visual stimuli perception induces brain response resulted in different ways of parieto-occipital interactions in these bands. In the alpha frequency band the parieto-occipital neuronal network is characterized by homogeneous increase of the interaction between all interconnected areas both within occipital and parietal lobes and between them. In the beta frequency band the occipital lobe starts to play a leading role in the dynamics of the occipital-parietal network: The perception of visual stimuli excites the visual center in the occipital area and then, due to the increase of parieto-occipital interactions, such excitation is transferred to the parietal area, where the attentional center takes place. In the case when stimuli are characterized by a high degree of ambiguity, we find greater increase of the interaction between interconnected areas in the parietal lobe due to the increase of human attention. Based on revealed mechanisms, we describe the complex response of the parieto-occipital brain neuronal network during the perception and primary processing of the visual stimuli. The results can serve as an essential complement to the existing theory of neural aspects of visual stimuli processing.

  7. Deep Recurrent Neural Networks for Human Activity Recognition.

    Science.gov (United States)

    Murad, Abdulmajid; Pyun, Jae-Young

    2017-11-06

    Adopting deep learning methods for human activity recognition has been effective in extracting discriminative features from raw input sequences acquired from body-worn sensors. Although human movements are encoded in a sequence of successive samples in time, typical machine learning methods perform recognition tasks without exploiting the temporal correlations between input data samples. Convolutional neural networks (CNNs) address this issue by using convolutions across a one-dimensional temporal sequence to capture dependencies among input data. However, the size of convolutional kernels restricts the captured range of dependencies between data samples. As a result, typical models are unadaptable to a wide range of activity-recognition configurations and require fixed-length input windows. In this paper, we propose the use of deep recurrent neural networks (DRNNs) for building recognition models that are capable of capturing long-range dependencies in variable-length input sequences. We present unidirectional, bidirectional, and cascaded architectures based on long short-term memory (LSTM) DRNNs and evaluate their effectiveness on miscellaneous benchmark datasets. Experimental results show that our proposed models outperform methods employing conventional machine learning, such as support vector machine (SVM) and k-nearest neighbors (KNN). Additionally, the proposed models yield better performance than other deep learning techniques, such as deep believe networks (DBNs) and CNNs.

  8. Signs of noise-induced neural degeneration in humans

    DEFF Research Database (Denmark)

    Holtegaard, Pernille; Olsen, Steen Østergaard

    2015-01-01

    of background noise, while leaving the processing of low-level stimuli unaffected. The purpose of this study was to investigate if signs of such primary neural damage from noise-exposure could also be found in noiseexposed human individuals. It was investigated: (1) if noise-exposed listeners with hearing......Animal studies demonstrated that noise exposure causes a primary and selective loss of auditory-nerve fibres with low spontaneous firing rate. This neuronal impairment, if also present in humans, can be assumed to affect the processing of supra-threshold stimuli, especially in the presence...... thresholds within the “normal” range perform poorer, in terms of their speech recognition threshold in noise (SRTN), and (2) if auditory brainstem responses (ABR) reveal lower amplitude of wave I in the noise-exposed listeners. A test group of noise/music-exposed individuals and a control group were...

  9. Test of neural inertia in humans during general anaesthesia.

    Science.gov (United States)

    Kuizenga, M H; Colin, P J; Reyntjens, K M E M; Touw, D J; Nalbat, H; Knotnerus, F H; Vereecke, H E M; Struys, M M R F

    2018-03-01

    Neural inertia is defined as the tendency of the central nervous system to resist transitions between arousal states. This phenomenon has been observed in mice and Drosophila anaesthetized with volatile anaesthetics: the effect-site concentration required to induce anaesthesia in 50% of the population (C 50 ) was significantly higher than the effect-site concentration for 50% of the population to recover from anaesthesia. We evaluated this phenomenon in humans using propofol or sevoflurane (both with or without remifentanil) as anaesthetic agents. Thirty-six healthy volunteers received four sessions of anaesthesia with different drug combinations in a step-up/step-down design. Propofol or sevoflurane was administered with or without remifentanil. Serum concentrations of propofol and remifentanil were measured from arterial blood samples. Loss and return of responsiveness (LOR-ROR), response to pain (PAIN), Patient State Index (PSI) and spectral edge frequency (SEF) were modeled with NONMEM®. For propofol, the C 50 for induction and recovery of anaesthesia was not significantly different across the different endpoints. For sevoflurane, for all endpoints except SEF, significant differences were found. For some endpoints (LOR and PAIN) the difference was significant only when sevoflurane was combined with remifentanil. Our results nuance earlier findings with volatile anaesthetics in mice and Drosophila. Methodological aspects of the study, such as the measured endpoint, influence the detection of neural inertia. A more thorough definition of neural inertia, with a robust methodological framework for clinical studies is required to advance our knowledge of this phenomenon. NCT 02043938. Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

  10. Neural mechanisms underlying human consensus decision-making.

    Science.gov (United States)

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

    2015-04-22

    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 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 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. GBM secretome induces transient transformation of human neural precursor cells.

    Science.gov (United States)

    Venugopal, Chitra; Wang, X Simon; Manoranjan, Branavan; McFarlane, Nicole; Nolte, Sara; Li, Meredith; Murty, Naresh; Siu, K W Michael; Singh, Sheila K

    2012-09-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor in humans, with a uniformly poor prognosis. The tumor microenvironment is composed of both supportive cellular substrates and exogenous factors. We hypothesize that exogenous factors secreted by brain tumor initiating cells (BTICs) could predispose normal neural precursor cells (NPCs) to transformation. When NPCs are grown in GBM-conditioned media, and designated as "tumor-conditioned NPCs" (tcNPCs), they become highly proliferative and exhibit increased stem cell self-renewal, or the unique ability of stem cells to asymmetrically generate another stem cell and a daughter cell. tcNPCs also show an increased transcript level of stem cell markers such as CD133 and ALDH and growth factor receptors such as VEGFR1, VEGFR2, EGFR and PDGFRα. Media analysis by ELISA of GBM-conditioned media reveals an elevated secretion of growth factors such as EGF, VEGF and PDGF-AA when compared to normal neural stem cell-conditioned media. We also demonstrate that tcNPCs require prolonged or continuous exposure to the GBM secretome in vitro to retain GBM BTIC characteristics. Our in vivo studies reveal that tcNPCs are unable to form tumors, confirming that irreversible transformation events may require sustained or prolonged presence of the GBM secretome. Analysis of GBM-conditioned media by mass spectrometry reveals the presence of secreted proteins Chitinase-3-like 1 (CHI3L1) and H2A histone family member H2AX. Collectively, our data suggest that GBM-secreted factors are capable of transiently altering normal NPCs, although for retention of the transformed phenotype, sustained or prolonged secretome exposure or additional transformation events are likely necessary.

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

    Science.gov (United States)

    Blangero, Annabelle; Kelly, Simon P

    2017-11-01

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

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

    Directory of Open Access Journals (Sweden)

    Piya Prajumwongs

    2016-01-01

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

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

    Science.gov (United States)

    Han, Shihui; Northoff, Georg

    2008-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Maucksch C

    2012-01-01

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

  16. Analysis of Neural Stem Cells from Human Cortical Brain Structures In Vitro.

    Science.gov (United States)

    Aleksandrova, M A; Poltavtseva, R A; Marei, M V; Sukhikh, G T

    2016-05-01

    Comparative immunohistochemical analysis of the neocortex from human fetuses showed that neural stem and progenitor cells are present in the brain throughout the gestation period, at least from week 8 through 26. At the same time, neural stem cells from the first and second trimester fetuses differed by the distribution, morphology, growth, and quantity. Immunocytochemical analysis of neural stem cells derived from fetuses at different gestation terms and cultured under different conditions showed their differentiation capacity. Detailed analysis of neural stem cell populations derived from fetuses on gestation weeks 8-9, 18-20, and 26 expressing Lex/SSEA1 was performed.

  17. Isolation and characterization of neural stem cells from human fetal striatum

    International Nuclear Information System (INIS)

    Li Xiaoxia; Xu Jinchong; Bai Yun; Wang Xuan; Dai Xin; Liu Yinan; Zhang Jun; Zou Junhua; Shen Li; Li Lingsong

    2005-01-01

    This paper described that neural stem cells (hsNSCs) were isolated and expanded rapidly from human fetal striatum in adherent culture. The population was serum- and growth factor-dependent and expressed neural stem cell markers. They were capable of multi-differentiation into neurons, astrocytes, and oligodendrocytes. When plated in the dopaminergic neuron inducing medium, human striatum neural stem cells could differentiate into tyrosine hydroxylase positive neurons. hsNSCs were morphologically homogeneous and possessed high proliferation ability. The population doubled every 44.28 h and until now it has divided for more than 82 generations in vitro. Normal human diploid karyotype was unchanged throughout the in vitro culture period. Together, this study has exploited a method for continuous and rapid expansion of human neural stem cells as pure population, which maintained the capacity to generate almost fifty percent neurons. The availability of such cells may hold great interest for basic and applied neuroscience

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

    Directory of Open Access Journals (Sweden)

    Cecilie Jonsgar Sandberg

    Full Text Available 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

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Jasminka Majdandžić

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

  1. Feedforward neural control of toe walking in humans.

    Science.gov (United States)

    Lorentzen, Jakob; Willerslev-Olsen, Maria; Hüche Larsen, Helle; Svane, Christian; Forman, Christian; Frisk, Rasmus; Farmer, Simon Francis; Kersting, Uwe; Nielsen, Jens Bo

    2018-03-23

    Activation of ankle muscles at ground contact during toe walking is unaltered when sensory feedback is blocked or the ground is suddenly dropped. Responses in the soleus muscle to transcranial magnetic stimulation, but not peripheral nerve stimulation, are facilitated at ground contact during toe walking. We argue that toe walking is supported by feedforward control at ground contact. Toe walking requires careful control of the ankle muscles in order to absorb the impact of ground contact and maintain a stable position of the joint. The present study aimed to clarify the peripheral and central neural mechanisms involved. Fifteen healthy adults walked on a treadmill (3.0 km h -1 ). Tibialis anterior (TA) and soleus (Sol) EMG, knee and ankle joint angles, and gastrocnemius-soleus muscle fascicle lengths were recorded. Peripheral and central contributions to the EMG activity were assessed by afferent blockade, H-reflex testing, transcranial magnetic brain stimulation (TMS) and sudden unloading of the planter flexor muscle-tendon complex. Sol EMG activity started prior to ground contact and remained high throughout stance. TA EMG activity, which is normally seen around ground contact during heel strike walking, was absent. Although stretch of the Achilles tendon-muscle complex was observed after ground contact, this was not associated with lengthening of the ankle plantar flexor muscle fascicles. Sol EMG around ground contact was not affected by ischaemic blockade of large-diameter sensory afferents, or the sudden removal of ground support shortly after toe contact. Soleus motor-evoked potentials elicited by TMS were facilitated immediately after ground contact, whereas Sol H-reflexes were not. These findings indicate that at the crucial time of ankle stabilization following ground contact, toe walking is governed by centrally mediated motor drive rather than sensory driven reflex mechanisms. These findings have implications for our understanding of the control of

  2. Modeling initiation of Ewing sarcoma in human neural crest cells.

    Directory of Open Access Journals (Sweden)

    Cornelia von Levetzow

    2011-04-01

    Full Text Available Ewing sarcoma family tumors (ESFT are aggressive bone and soft tissue tumors that express EWS-ETS fusion genes as driver mutations. Although the histogenesis of ESFT is controversial, mesenchymal (MSC and/or neural crest (NCSC stem cells have been implicated as cells of origin. For the current study we evaluated the consequences of EWS-FLI1 expression in human embryonic stem cell-derived NCSC (hNCSC. Ectopic expression of EWS-FLI1 in undifferentiated hNCSC and their neuro-mesenchymal stem cell (hNC-MSC progeny was readily tolerated and led to altered expression of both well established as well as novel EWS-FLI1 target genes. Importantly, whole genome expression profiling studies revealed that the molecular signature of established ESFT is more similar to hNCSC than any other normal tissue, including MSC, indicating that maintenance or reactivation of the NCSC program is a feature of ESFT pathogenesis. Consistent with this hypothesis, EWS-FLI1 induced hNCSC genes as well as the polycomb proteins BMI-1 and EZH2 in hNC-MSC. In addition, up-regulation of BMI-1 was associated with avoidance of cellular senescence and reversible silencing of p16. Together these studies confirm that, unlike terminally differentiated cells but consistent with bone marrow-derived MSC, NCSC tolerate expression of EWS-FLI1 and ectopic expression of the oncogene initiates transition to an ESFT-like state. In addition, to our knowledge this is the first demonstration that EWS-FLI1-mediated induction of BMI-1 and epigenetic silencing of p16 might be critical early initiating events in ESFT tumorigenesis.

  3. The use of artificial neural network to evaluate the effects of human ...

    African Journals Online (AJOL)

    The use of artificial neural network to evaluate the effects of human and physiographic factors on forest stock volume. ... stock volume and human factors in certain topography conditions and provides useful information for the acceptable amount of standing inventory using the present human population in future experiment.

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

    Science.gov (United States)

    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

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

    DEFF Research Database (Denmark)

    Chandrasekaran, Abinaya; Avci, Hasan; Ochalek, Anna

    2017-01-01

    Neural progenitor cells (NPCs) from human induced pluripotent stem cells (hiPSCs) are frequently induced using 3D culture methodologies however, it is unknown whether spheroid-based (3D) neural induction is actually superior to monolayer (2D) neural induction. Our aim was to compare the efficiency......), cortical layer (TBR1, CUX1) and glial markers (SOX9, GFAP, AQP4). Electron microscopy demonstrated that both methods resulted in morphologically similar neural rosettes. However, quantification of NPCs derived from 3D neural induction exhibited an increase in the number of PAX6/NESTIN double positive cells...... the electrophysiological properties between the two induction methods. In conclusion, 3D neural induction increases the yield of PAX6+/NESTIN+ cells and gives rise to neurons with longer neurites, which might be an advantage for the production of forebrain cortical neurons, highlighting the potential of 3D neural...

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

    Science.gov (United States)

    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. © The Author (2015). Published by Oxford University Press.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2018-04-01

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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Stem cells are unspecialized cells capable of self-renewal and to differentiate into the large variety of cells in the body. The possibility to differentiate these cells into neural precursors and neural cells in vitro provides the opportunity to study neural development, nerve cell biology, neur...... differentiation from pluripotent stem cells. Moreover, some of the challenges in stem cell biology, differentiation, and proteomics/PTMomics that are not exclusive to neural development will be discussed.......Stem cells are unspecialized cells capable of self-renewal and to differentiate into the large variety of cells in the body. The possibility to differentiate these cells into neural precursors and neural cells in vitro provides the opportunity to study neural development, nerve cell biology...... the understanding of molecular processes in cells. Substantial advances in PTM enrichment methods and mass spectrometry has allowed the characterization of a subset of PTMs in large-scale studies. This review focuses on the current state-of-the-art of proteomic, as well as PTMomic studies related to human neural...

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    differentiation, we co-cultured cells from a human neural forebrain-derived stem cell line (hNS1) with rat striatal brain slices. In brief, coronal slices of neonatal rat striatum were cultured on semiporous membrane inserts placed in six-well trays overlying monolayers of hNS1 cells. After 12 days of co......Properly committed neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. To establish a setting for identification of secreted neural compounds promoting dopaminergic...

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

    Directory of Open Access Journals (Sweden)

    Callihan Phillip

    2008-12-01

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

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

    NARCIS (Netherlands)

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

    2008-01-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

  14. Neural basis of preference for human social hierarchy versus egalitarianism.

    Science.gov (United States)

    Chiao, Joan Y; Mathur, Vani A; Harada, Tokiko; Lipke, Trixie

    2009-06-01

    A fundamental way that individuals differ is in the degree to which they prefer social dominance hierarchy over egalitarianism as a guiding principle of societal structure, a phenomenon known as social dominance orientation. Here we show that preference for hierarchical rather than egalitarian social relations varies as a function of neural responses within left anterior insula and anterior cingulate cortices. Our findings provide novel evidence that preference for social dominance hierarchy is associated with neural functioning within brain regions that are associated with the ability to share and feel concern for the pain of others; this suggests a neurobiological basis for social and political attitudes. Implications of these findings for research on the social neuroscience of fairness, justice, and intergroup relations are discussed.

  15. Heparan Sulfate Proteoglycans as Drivers of Neural Progenitors Derived From Human Mesenchymal Stem Cells.

    Science.gov (United States)

    Okolicsanyi, Rachel K; Oikari, Lotta E; Yu, Chieh; Griffiths, Lyn R; Haupt, Larisa M

    2018-01-01

    Background: Due to their relative ease of isolation and their high ex vivo and in vitro expansive potential, human mesenchymal stem cells (hMSCs) are an attractive candidate for therapeutic applications in the treatment of brain injury and neurological diseases. Heparan sulfate proteoglycans (HSPGs) are a family of ubiquitous proteins involved in a number of vital cellular processes including proliferation and stem cell lineage differentiation. Methods: Following the determination that hMSCs maintain neural potential throughout extended in vitro expansion, we examined the role of HSPGs in mediating the neural potential of hMSCs. hMSCs cultured in basal conditions (undifferentiated monolayer cultures) were found to co-express neural markers and HSPGs throughout expansion with modulation of the in vitro niche through the addition of exogenous HS influencing cellular HSPG and neural marker expression. Results: Conversion of hMSCs into hMSC Induced Neurospheres (hMSC IN) identified distinctly localized HSPG staining within the spheres along with altered gene expression of HSPG core protein and biosynthetic enzymes when compared to undifferentiated hMSCs. Conclusion: Comparison of markers of pluripotency, neural self-renewal and neural lineage specification between hMSC IN, hMSC and human neural stem cell (hNSC H9) cultures suggest that in vitro generated hMSC IN may represent an intermediary neurogenic cell type, similar to a common neural progenitor cell. In addition, this data demonstrates HSPGs and their biosynthesis machinery, are associated with hMSC IN formation. The identification of specific HSPGs driving hMSC lineage-specification will likely provide new markers to allow better use of hMSCs in therapeutic applications and improve our understanding of human neurogenesis.

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

    Directory of Open Access Journals (Sweden)

    Shingo Kanao

    2017-01-01

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

  17. In vitro characterization of a human neural progenitor cell coexpressing SSEA4 and CD133

    DEFF Research Database (Denmark)

    Barraud, Perrine; Stott, Simon; Møllgård, Kjeld

    2007-01-01

    The stage-specific embryonic antigen 4 (SSEA4) is commonly used as a cell surface marker to identify the pluripotent human embryonic stem (ES) cells. Immunohistochemistry on human embryonic central nervous system revealed that SSEA4 is detectable in the early neuroepithelium, and its expression....... Therefore, we propose that SSEA4 associated with CD133 can be used for both the positive selection and the enrichment of neural stem/progenitor cells from human embryonic forebrain....... decreases as development proceeds. Flow cytometry analysis of forebrain-derived cells demonstrated that the SSEA4-expressing cells are enriched in the neural stem/progenitor cell fraction (CD133(+)), but are rarely codetected with the neural stem cell (NSC) marker CD15. Using a sphere-forming assay, we...

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

    Directory of Open Access Journals (Sweden)

    Ilyas Singec

    2016-09-01

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

  19. Cardiorespiratory interactions in neural circulatory control in humans.

    Science.gov (United States)

    Shamsuzzaman, A S; Somers, V K

    2001-06-01

    The reflex mechanisms and interactions described in this overview provide some explanation for the range of neural circulatory responses evident during changes in breathing. The effects described represent the integrated responses to activation of several reflex mechanisms, including peripheral and central chemoreflexes, arterial baroreflexes, pulmonary stretch receptors, and ventricular mechanoreceptors. These interactions occur on a dynamic basis and the transfer characteristics of any single interaction are, in all likelihood, also highly dynamic. Nevertheless, it is only by attempting to understand individual reflexes and their modulating influences that a more thorough understanding of the responses to complex phenomena such as hyperventilation, apnea, and obstructive sleep apnea can be better understood.

  20. Neural correlates of socioeconomic status in the developing human brain.

    Science.gov (United States)

    Noble, Kimberly G; Houston, Suzanne M; Kan, Eric; Sowell, Elizabeth R

    2012-07-01

    Socioeconomic disparities in childhood are associated with remarkable differences in cognitive and socio-emotional development during a time when dramatic changes are occurring in the brain. Yet, the neurobiological pathways through which socioeconomic status (SES) shapes development remain poorly understood. Behavioral evidence suggests that language, memory, social-emotional processing, and cognitive control exhibit relatively large differences across SES. Here we investigated whether volumetric differences could be observed across SES in several neural regions that support these skills. In a sample of 60 socioeconomically diverse children, highly significant SES differences in regional brain volume were observed in the hippocampus and the amygdala. In addition, SES × age interactions were observed in the left superior temporal gyrus and left inferior frontal gyrus, suggesting increasing SES differences with age in these regions. These results were not explained by differences in gender, race or IQ. Likely mechanisms include differences in the home linguistic environment and exposure to stress, which may serve as targets for intervention at a time of high neural plasticity. © 2012 Blackwell Publishing Ltd.

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    . 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......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...... 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....

  2. Prolonged Expansion Induces Spontaneous Neural Progenitor Differentiation from Human Gingiva-Derived Mesenchymal Stem Cells.

    Science.gov (United States)

    Rajan, Thangavelu Soundara; Scionti, Domenico; Diomede, Francesca; Piattelli, Adriano; Bramanti, Placido; Mazzon, Emanuela; Trubiani, Oriana

    2017-12-01

    Neural crest-derived mesenchymal stem cells (MSCs) obtained from dental tissues received considerable interest in regenerative medicine, particularly in nerve regeneration owing to their embryonic origin and ease of harvest. Proliferation efficacy and differentiation capacity into diverse cell lineages propose dental MSCs as an in vitro tool for disease modeling. In this study, we investigated the spontaneous differentiation efficiency of dental MSCs obtained from human gingiva tissue (hGMSCs) into neural progenitor cells after extended passaging. At passage 41, the morphology of hGMSCs changed from typical fibroblast-like shape into sphere-shaped cells with extending processes. Next-generation transcriptomics sequencing showed increased expression of neural progenitor markers such as NES, MEIS2, and MEST. In addition, de novo expression of neural precursor genes, such as NRN1, PHOX2B, VANGL2, and NTRK3, was noticed in passage 41. Immunocytochemistry results showed suppression of neurogenesis repressors TP53 and p21, whereas Western blot results revealed the expression of neurotrophic factors BDNF and NT3 at passage 41. Our results showed the spontaneous efficacy of hGMSCs to differentiate into neural precursor cells over prolonged passages and that these cells may assist in producing novel in vitro disease models that are associated with neural development.

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

    Science.gov (United States)

    Witoonchart, Peerajak; Chongstitvatana, Prabhas

    2017-08-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    by Lempel-Ziv complexity (LZc), a measure shown to track arousal in sleep and anesthesia. Neural activity related to the semantic content of stimuli was conserved in light non-rapid eye movement (NREM) sleep. However, these processes were suppressed in deep NREM sleep and, importantly, also in REM sleep...... could be related to modulation in sleep depth. InREMsleep, however, this relationship was reversed.Wetherefore propose that, in REM sleep, endogenously generated processes compete with the processing of external input. Sleep can thus be seen as a self-regulated process in which external information can...... be processed in lighter stages but suppressed in deeper stages. Last, our results suggest drastically different gating mechanisms in NREM and REM sleep....

  5. The neural representation of human versus nonhuman bipeds and quadrupeds

    OpenAIRE

    Papeo, Liuba; Wurm, Moritz F.; Oosterhof, Nikolaas N.; Caramazza, Alfonso

    2017-01-01

    How do humans recognize humans among other creatures? Recent studies suggest that a preference for conspecifics may emerge already in perceptual processing, in regions such as the right posterior superior temporal sulcus (pSTS), implicated in visual perception of biological motion. In the current functional MRI study, participants viewed point-light displays of human and nonhuman creatures moving in their typical bipedal (man and chicken) or quadrupedal mode (crawling-baby and cat). Stronger ...

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

    Energy Technology Data Exchange (ETDEWEB)

    Harrill, Joshua A.; Freudenrich, Theresa M.; Robinette, Brian L.; Mundy, William R., E-mail: mundy.william@epa.gov

    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

  7. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall

    Science.gov (United States)

    Hampson, Robert E.; Song, Dong; Robinson, Brian S.; Fetterhoff, Dustin; Dakos, Alexander S.; Roeder, Brent M.; She, Xiwei; Wicks, Robert T.; Witcher, Mark R.; Couture, Daniel E.; Laxton, Adrian W.; Munger-Clary, Heidi; Popli, Gautam; Sollman, Myriam J.; Whitlow, Christopher T.; Marmarelis, Vasilis Z.; Berger, Theodore W.; Deadwyler, Sam A.

    2018-06-01

    Objective. We demonstrate here the first successful implementation in humans of a proof-of-concept system for restoring and improving memory function via facilitation of memory encoding using the patient’s own hippocampal spatiotemporal neural codes for memory. Memory in humans is subject to disruption by drugs, disease and brain injury, yet previous attempts to restore or rescue memory function in humans typically involved only nonspecific, modulation of brain areas and neural systems related to memory retrieval. Approach. We have constructed a model of processes by which the hippocampus encodes memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of short-term memory. A nonlinear multi-input, multi-output (MIMO) model of hippocampal CA3 and CA1 neural firing is computed that predicts activation patterns of CA1 neurons during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results. MIMO model-derived electrical stimulation delivered to the same CA1 locations during the sample phase of DMS trials facilitated short-term/working memory by 37% during the task. Longer term memory retention was also tested in the same human subjects with a delayed recognition (DR) task that utilized images from the DMS task, along with images that were not from the task. Across the subjects, the stimulated trials exhibited significant improvement (35%) in both short-term and long-term retention of visual information. Significance. These results demonstrate the facilitation of memory encoding which is an important feature for the construction of an implantable neural prosthetic to improve human memory.

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

    International Nuclear Information System (INIS)

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

    2011-01-01

    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

  9. In vitro differentiation of neural cells from human adipose tissue derived stromal cells.

    Science.gov (United States)

    Dave, Shruti D; Patel, Chetan N; Vanikar, Aruna V; Trivedi, Hargovind L

    2018-01-01

    Stem cells, including neural stem cells (NSCs), are endowed with self-renewal capability and hence hold great opportunity for the institution of replacement/protective therapy. We propose a method for in vitro generation of stromal cells from human adipose tissue and their differentiation into neural cells. Ten grams of donor adipose tissue was surgically resected from the abdominal wall of the human donor after the participants' informed consents. The resected adipose tissue was minced and incubated for 1 hour in the presence of an enzyme (collagenase-type I) at 37 0 C followed by its centrifugation. After centrifugation, the supernatant and pellets were separated and cultured in a medium for proliferation at 37 0 C with 5% CO2 for 9-10 days in separate tissue culture dishes for generation of mesenchymal stromal cells (MSC). At the end of the culture, MSC were harvested and analyzed. The harvested MSC were subjected for further culture for their differentiation into neural cells for 5-7 days using differentiation medium mainly comprising of neurobasal medium. At the end of the procedure, culture cells were isolated and studied for expression of transcriptional factor proteins: orthodenticle homolog-2 (OTX-2), beta-III-tubulin (β3-Tubulin), glial-fibrillary acid protein (GFAP) and synaptophysin-β2. In total, 50 neural cells-lines were generated. In vitro generated MSC differentiated neural cells' mean quantum was 5.4 ± 6.9 ml with the mean cell count being, 5.27 ± 2.65 × 10 3/ μl. All of them showed the presence of OTX-2, β3-Tubulin, GFAP, synaptophysin-β2. Neural cells can be differentiated in vitro from MSC safely and effectively. In vitro generated neural cells represent a potential therapy for recovery from spinal cord injuries and neurodegenerative disease.

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    To investigate the feasibility of transplanting human neural progenitor cells (hNPCs) to the retina of nonimmunosuppressed pigs, cultured hNPCs were injected into the subretinal space of 5 adult pigs after laser burns were applied to promote donor cell integration. Postoperatively, the retinal ve...

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    To investigate the feasibility of transplanting human neural progenitor cells (hNPCs) to the retina of nonimmunosuppressed pigs, cultured hNPCs were injected into the subretinal space of 5 adult pigs after laser burns were applied to promote donor cell integration. Postoperatively, the retinal ve...... that modulation of host immunity is likely necessary for prolonged xenograft survival in this model....

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

    DEFF Research Database (Denmark)

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

    2017-01-01

    We compare a set of convolutional neural network (CNN) architectures for the task of segmenting and detecting human sperm cells in an image taken from a semen sample. In contrast to previous work, samples are not stained or washed to allow for full sperm quality analysis, making analysis harder due...

  13. Convolutional Neural Networks for Human Activity Recognition Using Body-Worn Sensors

    Directory of Open Access Journals (Sweden)

    Fernando Moya Rueda

    2018-05-01

    Full Text Available Human activity recognition (HAR is a classification task for recognizing human movements. Methods of HAR are of great interest as they have become tools for measuring occurrences and durations of human actions, which are the basis of smart assistive technologies and manual processes analysis. Recently, deep neural networks have been deployed for HAR in the context of activities of daily living using multichannel time-series. These time-series are acquired from body-worn devices, which are composed of different types of sensors. The deep architectures process these measurements for finding basic and complex features in human corporal movements, and for classifying them into a set of human actions. As the devices are worn at different parts of the human body, we propose a novel deep neural network for HAR. This network handles sequence measurements from different body-worn devices separately. An evaluation of the architecture is performed on three datasets, the Oportunity, Pamap2, and an industrial dataset, outperforming the state-of-the-art. In addition, different network configurations will also be evaluated. We find that applying convolutions per sensor channel and per body-worn device improves the capabilities of convolutional neural network (CNNs.

  14. The neural representation of human versus nonhuman bipeds and quadrupeds.

    Science.gov (United States)

    Papeo, Liuba; Wurm, Moritz F; Oosterhof, Nikolaas N; Caramazza, Alfonso

    2017-10-25

    How do humans recognize humans among other creatures? Recent studies suggest that a preference for conspecifics may emerge already in perceptual processing, in regions such as the right posterior superior temporal sulcus (pSTS), implicated in visual perception of biological motion. In the current functional MRI study, participants viewed point-light displays of human and nonhuman creatures moving in their typical bipedal (man and chicken) or quadrupedal mode (crawling-baby and cat). Stronger activity for man and chicken versus baby and cat was found in the right pSTS responsive to biological motion. The novel effect of pedalism suggests that, if right pSTS contributes to recognizing of conspecifics, it does so by detecting perceptual features (e.g. bipedal motion) that reliably correlate with their appearance. A searchlight multivariate pattern analysis could decode humans and nonhumans across pedalism in the left pSTS and bilateral posterior cingulate cortex. This result implies a categorical human-nonhuman distinction, independent from within-category physical/perceptual variation. Thus, recognizing conspecifics involves visual classification based on perceptual features that most frequently co-occur with humans, such as bipedalism, and retrieval of information that determines category membership above and beyond visual appearance. The current findings show that these processes are at work in separate brain networks.

  15. Human Splice-Site Prediction with Deep Neural Networks.

    Science.gov (United States)

    Naito, Tatsuhiko

    2018-04-18

    Accurate splice-site prediction is essential to delineate gene structures from sequence data. Several computational techniques have been applied to create a system to predict canonical splice sites. For classification tasks, deep neural networks (DNNs) have achieved record-breaking results and often outperformed other supervised learning techniques. In this study, a new method of splice-site prediction using DNNs was proposed. The proposed system receives an input sequence data and returns an answer as to whether it is splice site. The length of input is 140 nucleotides, with the consensus sequence (i.e., "GT" and "AG" for the donor and acceptor sites, respectively) in the middle. Each input sequence model is applied to the pretrained DNN model that determines the probability that an input is a splice site. The model consists of convolutional layers and bidirectional long short-term memory network layers. The pretraining and validation were conducted using the data set tested in previously reported methods. The performance evaluation results showed that the proposed method can outperform the previous methods. In addition, the pattern learned by the DNNs was visualized as position frequency matrices (PFMs). Some of PFMs were very similar to the consensus sequence. The trained DNN model and the brief source code for the prediction system are uploaded. Further improvement will be achieved following the further development of DNNs.

  16. Neural correlates of gesture processing across human development.

    Science.gov (United States)

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

    2013-01-01

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

  17. Dynamics of scene representations in the human brain revealed by magnetoencephalography and deep neural networks

    Science.gov (United States)

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

    2017-01-01

    Human scene recognition is a rapid multistep process evolving over time from single scene image to spatial layout processing. We used multivariate pattern analyses on magnetoencephalography (MEG) data to unravel the time course of this cortical process. Following an early signal for lower-level visual analysis of single scenes at ~100 ms, we found a marker of real-world scene size, i.e. spatial layout processing, at ~250 ms indexing neural representations robust to changes in unrelated scene properties and viewing conditions. For a quantitative model of how scene size representations may arise in the brain, we compared MEG data to a deep neural network model trained on scene classification. Representations of scene size emerged intrinsically in the model, and resolved emerging neural scene size representation. Together our data provide a first description of an electrophysiological signal for layout processing in humans, and suggest that deep neural networks are a promising framework to investigate how spatial layout representations emerge in the human brain. PMID:27039703

  18. Neural prediction errors reveal a risk-sensitive reinforcement-learning process in the human brain.

    Science.gov (United States)

    Niv, Yael; Edlund, Jeffrey A; Dayan, Peter; O'Doherty, John P

    2012-01-11

    Humans and animals are exquisitely, though idiosyncratically, sensitive to risk or variance in the outcomes of their actions. Economic, psychological, and neural aspects of this are well studied when information about risk is provided explicitly. However, we must normally learn about outcomes from experience, through trial and error. Traditional models of such reinforcement learning focus on learning about the mean reward value of cues and ignore higher order moments such as variance. We used fMRI to test whether the neural correlates of human reinforcement learning are sensitive to experienced risk. Our analysis focused on anatomically delineated regions of a priori interest in the nucleus accumbens, where blood oxygenation level-dependent (BOLD) signals have been suggested as correlating with quantities derived from reinforcement learning. We first provide unbiased evidence that the raw BOLD signal in these regions corresponds closely to a reward prediction error. We then derive from this signal the learned values of cues that predict rewards of equal mean but different variance and show that these values are indeed modulated by experienced risk. Moreover, a close neurometric-psychometric coupling exists between the fluctuations of the experience-based evaluations of risky options that we measured neurally and the fluctuations in behavioral risk aversion. This suggests that risk sensitivity is integral to human learning, illuminating economic models of choice, neuroscientific models of affective learning, and the workings of the underlying neural mechanisms.

  19. Neural representations of social status hierarchy in human inferior parietal cortex.

    Science.gov (United States)

    Chiao, Joan Y; Harada, Tokiko; Oby, Emily R; Li, Zhang; Parrish, Todd; Bridge, Donna J

    2009-01-01

    Mental representations of social status hierarchy share properties with that of numbers. Previous neuroimaging studies have shown that the neural representation of numerical magnitude lies within a network of regions within inferior parietal cortex. However the neural basis of social status hierarchy remains unknown. Using fMRI, we studied subjects while they compared social status magnitude of people, objects and symbols, as well as numerical magnitude. Both social status and number comparisons recruited bilateral intraparietal sulci. We also observed a semantic distance effect whereby neural activity within bilateral intraparietal sulci increased for semantically close relative to far numerical and social status comparisons. These results demonstrate that social status and number comparisons recruit distinct and overlapping neuronal representations within human inferior parietal cortex.

  20. Hierarchical graphical-based human pose estimation via local multi-resolution convolutional neural network

    Science.gov (United States)

    Zhu, Aichun; Wang, Tian; Snoussi, Hichem

    2018-03-01

    This paper addresses the problems of the graphical-based human pose estimation in still images, including the diversity of appearances and confounding background clutter. We present a new architecture for estimating human pose using a Convolutional Neural Network (CNN). Firstly, a Relative Mixture Deformable Model (RMDM) is defined by each pair of connected parts to compute the relative spatial information in the graphical model. Secondly, a Local Multi-Resolution Convolutional Neural Network (LMR-CNN) is proposed to train and learn the multi-scale representation of each body parts by combining different levels of part context. Thirdly, a LMR-CNN based hierarchical model is defined to explore the context information of limb parts. Finally, the experimental results demonstrate the effectiveness of the proposed deep learning approach for human pose estimation.

  1. Hierarchical graphical-based human pose estimation via local multi-resolution convolutional neural network

    Directory of Open Access Journals (Sweden)

    Aichun Zhu

    2018-03-01

    Full Text Available This paper addresses the problems of the graphical-based human pose estimation in still images, including the diversity of appearances and confounding background clutter. We present a new architecture for estimating human pose using a Convolutional Neural Network (CNN. Firstly, a Relative Mixture Deformable Model (RMDM is defined by each pair of connected parts to compute the relative spatial information in the graphical model. Secondly, a Local Multi-Resolution Convolutional Neural Network (LMR-CNN is proposed to train and learn the multi-scale representation of each body parts by combining different levels of part context. Thirdly, a LMR-CNN based hierarchical model is defined to explore the context information of limb parts. Finally, the experimental results demonstrate the effectiveness of the proposed deep learning approach for human pose estimation.

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

    Science.gov (United States)

    Krajíček, Jiří

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

  3. Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells

    Science.gov (United States)

    Chen, Song; Zhang, Wei; Wang, Ji-Ming; Duan, Hong-Tao; Kong, Jia-Hui; Wang, Yue-Xin; Dong, Meng; Bi, Xue; Song, Jian

    2016-01-01

    AIM To investigate whether umbilical cord human mesenchymal stem cell (UC-MSC) was able to differentiate into neural stem cell and neuron in vitro. METHODS The umbilical cords were obtained from pregnant women with their written consent and the approval of the Clinic Ethnics Committee. UC-MSC were isolated by adherent culture in the medium contains 20% fetal bovine serum (FBS), then they were maintained in the medium contain 10% FBS and induced to neural cells in neural differentiation medium. We investigated whether UC-MSC was able to differentiate into neural stem cell and neuron in vitro by using flow cytometry, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence (IF) analyzes. RESULTS A substantial number of UC-MSC was harvested using the tissue explants adherent method at about 2wk. Flow cytometric study revealed that these cells expressed common markers of MSCs, such as CD105 (SH2), CD73 (SH3) and CD90. After induction of differentiation of neural stem cells, the cells began to form clusters; RT-PCR and IF showed that the neuron specific enolase (NSE) and neurogenic differentiation 1-positive cells reached 87.3%±14.7% and 72.6%±11.8%, respectively. Cells showed neuronal cell differentiation after induced, including neuron-like protrusions, plump cell body, obviously and stronger refraction. RT-PCR and IF analysis showed that microtubule-associated protein 2 (MAP2) and nuclear factor-M-positive cells reached 43.1%±10.3% and 69.4%±19.5%, respectively. CONCLUSION Human umbilical cord derived MSCs can be cultured and proliferated in vitro and differentiate into neural stem cells, which may be a valuable source for cell therapy of neurodegenerative eye diseases. PMID:26949608

  4. Differentiation of isolated human umbilical cord mesenchymal stem cells into neural stem cells

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    Song Chen

    2016-01-01

    Full Text Available AIM: To investigate whether umbilical cord human mesenchymal stem cell (UC-MSC was able to differentiate into neural stem cell and neuron in vitro. METHODS: The umbilical cords were obtained from pregnant women with their written consent and the approval of the Clinic Ethnics Committee. UC-MSC were isolated by adherent culture in the medium contains 20% fetal bovine serum (FBS, then they were maintained in the medium contain 10% FBS and induced to neural cells in neural differentiation medium. We investigated whether UC-MSC was able to differentiate into neural stem cell and neuron in vitro by using flow cytometry, reverse transcriptase-polymerase chain reaction (RT-PCR and immunofluorescence (IF analyzes. RESULTS: A substantial number of UC-MSC was harvested using the tissue explants adherent method at about 2wk. Flow cytometric study revealed that these cells expressed common markers of MSCs, such as CD105 (SH2, CD73 (SH3 and CD90. After induction of differentiation of neural stem cells, the cells began to form clusters; RT-PCR and IF showed that the neuron specific enolase (NSE and neurogenic differentiation 1-positive cells reached 87.3%±14.7% and 72.6%±11.8%, respectively. Cells showed neuronal cell differentiation after induced, including neuron-like protrusions, plump cell body, obviously and stronger refraction. RT-PCR and IF analysis showed that microtubule-associated protein 2 (MAP2 and nuclear factor-M-positive cells reached 43.1%±10.3% and 69.4%±19.5%, respectively. CONCLUSION: Human umbilical cord derived MSCs can be cultured and proliferated in vitro and differentiate into neural stem cells, which may be a valuable source for cell therapy of neurodegenerative eye diseases.

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

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    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.

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

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    Mohammad S. Islam

    2017-01-01

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

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

    OpenAIRE

    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; Vemuri, Mohan C.

    2013-01-01

    This study developed a highly efficient serum-free pluripotent stem cell (PSC) neural induction medium that can induce human PSCs into primitive neural stem cells (NSCs) in 7 days, obviating the need for time-consuming, laborious embryoid body generation or rosette picking. This method of primitive NSC derivation sets the stage for the scalable production of clinically relevant neural cells for cell therapy applications in good manufacturing practice conditions.

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

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    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

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

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

    2017-07-01

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

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

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    Daniela Sánchez

    2017-01-01

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

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

    Science.gov (United States)

    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. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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

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

    2015-09-15

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

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

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    Patrick eHecht

    2015-10-01

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

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

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    Yirui Sun

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

  15. Deleterious effect of Usutu virus on human neural cells.

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    Sara Salinas

    2017-09-01

    Full Text Available In the last decade, the number of emerging Flaviviruses described worldwide has increased considerably. Among them Zika virus (ZIKV and Usutu virus (USUV are African mosquito-borne viruses that recently emerged. Recently, ZIKV has been intensely studied due to major outbreaks associated with neonatal death and birth defects, as well as neurological symptoms. USUV pathogenesis remains largely unexplored, despite significant human and veterinary associated disorders. Circulation of USUV in Africa was documented more than 50 years ago, and it emerged in Europe two decades ago, causing massive bird mortality. More recently, USUV has been described to be associated with neurological disorders in humans such as encephalitis and meningoencephalitis, highlighting USUV as a potential health threat. The aim of this study was to evaluate the ability of USUV to infect neuronal cells. Our results indicate that USUV efficiently infects neurons, astrocytes, microglia and IPSc-derived human neuronal stem cells. When compared to ZIKV, USUV led to a higher infection rate, viral production, as well as stronger cell death and anti-viral response. Our results highlight the need to better characterize the physiopathology related to USUV infection in order to anticipate the potential threat of USUV emergence.

  16. The organization and neural substrates of human memory.

    Science.gov (United States)

    Squire, L R

    The neurology of memory has been illuminated by parallel studies of patients with circumscribed memory impairment and animal models of human amnesia. Human amnesia can occur as an isolated cognitive deficit that impairs the ability to learn new facts and episodes. In addition, memory can be affected for material learned many years prior to the onset of amnesia. The finding that some memory abilities are intact in amnesia (e.g., skill learning, word priming, and adaptation-level effects) has suggested that memory can be divided into two or more separate processes. Declarative memory affords the ability to store information explicitly and to retrieve it later as a conscious recollection. This form of memory depends on the integrity of the structures damaged in amnesia. Other, non-declarative kinds of memory afford the ability to change as the result of experience, but the information is available only through performance. Recent studies of a favorable human case provided strong evidence that the hippocampus is a critical component of the declarative memory system. Extensive convergent and divergent projections link the hippocampus to many areas of neocortex where processing and storage of new information is likely to occur. It is perhaps by way of these connections that the hippocampus operates upon and participates in declarative representations.

  17. Generation of Oligodendrogenic Spinal Neural Progenitor Cells From Human Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Khazaei, Mohamad; Ahuja, Christopher S; Fehlings, Michael G

    2017-08-14

    This unit describes protocols for the efficient generation of oligodendrogenic neural progenitor cells (o-NPCs) from human induced pluripotent stem cells (hiPSCs). Specifically, detailed methods are provided for the maintenance and differentiation of hiPSCs, human induced pluripotent stem cell-derived neural progenitor cells (hiPS-NPCs), and human induced pluripotent stem cell-oligodendrogenic neural progenitor cells (hiPSC-o-NPCs) with the final products being suitable for in vitro experimentation or in vivo transplantation. Throughout, cell exposure to growth factors and patterning morphogens has been optimized for both concentration and timing, based on the literature and empirical experience, resulting in a robust and highly efficient protocol. Using this derivation procedure, it is possible to obtain millions of oligodendrogenic-NPCs within 40 days of initial cell plating which is substantially shorter than other protocols for similar cell types. This protocol has also been optimized to use translationally relevant human iPSCs as the parent cell line. The resultant cells have been extensively characterized both in vitro and in vivo and express key markers of an oligodendrogenic lineage. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley and Sons, Inc.

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

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    Shong Lau

    2014-12-01

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

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

    Science.gov (United States)

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

    2017-12-01

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

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

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    Montzka Katrin

    2009-03-01

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

  1. Factor Analysis for Finding Invariant Neural Descriptors of Human Emotions

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    Vitor Pereira

    2018-01-01

    Full Text Available A major challenge in decoding human emotions from electroencephalogram (EEG data is finding representations that are invariant to inter- and intrasubject differences. Most of the previous studies are focused in building an individual discrimination model for every subject (subject dependent model. Building subject-independent models is a harder problem due to the high data variability between different subjects and different experiments with the same subject. This paper explores, for the first time, the Factor Analysis as an efficient technique to extract temporal and spatial EEG features suitable to build brain-computer interface for decoding human emotions across various subjects. Our findings show that early waves (temporal window of 200–400 ms after the stimulus onset carry more information about the valence of the emotion. Also, spatial location of features, with a stronger impact on the emotional valence, occurs in the parietal and occipital regions of the brain. All discrimination models (NN, SVM, kNN, and RF demonstrate better discrimination rate of the positive valence. These results match closely experimental psychology hypothesis that, during early periods after the stimulus presentation, the brain response—to images with highly positive valence—is stronger.

  2. What is adapted in face adaptation? The neural representations of expression in the human visual system.

    Science.gov (United States)

    Fox, Christopher J; Barton, Jason J S

    2007-01-05

    The neural representation of facial expression within the human visual system is not well defined. Using an adaptation paradigm, we examined aftereffects on expression perception produced by various stimuli. Adapting to a face, which was used to create morphs between two expressions, substantially biased expression perception within the morphed faces away from the adapting expression. This adaptation was not based on low-level image properties, as a different image of the same person displaying that expression produced equally robust aftereffects. Smaller but significant aftereffects were generated by images of different individuals, irrespective of gender. Non-face visual, auditory, or verbal representations of emotion did not generate significant aftereffects. These results suggest that adaptation affects at least two neural representations of expression: one specific to the individual (not the image), and one that represents expression across different facial identities. The identity-independent aftereffect suggests the existence of a 'visual semantic' for facial expression in the human visual system.

  3. The neural encoding of guesses in the human brain.

    Science.gov (United States)

    Bode, Stefan; Bogler, Carsten; Soon, Chun Siong; Haynes, John-Dylan

    2012-01-16

    Human perception depends heavily on the quality of sensory information. When objects are hard to see we often believe ourselves to be purely guessing. Here we investigated whether such guesses use brain networks involved in perceptual decision making or independent networks. We used a combination of fMRI and pattern classification to test how visibility affects the signals, which determine choices. We found that decisions regarding clearly visible objects are predicted by signals in sensory brain regions, whereas different regions in parietal cortex became predictive when subjects were shown invisible objects and believed themselves to be purely guessing. This parietal network was highly overlapping with regions, which have previously been shown to encode free decisions. Thus, the brain might use a dedicated network for determining choices when insufficient sensory information is available. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Neural influences on human intestinal epithelium in vitro.

    Science.gov (United States)

    Krueger, Dagmar; Michel, Klaus; Zeller, Florian; Demir, Ihsan E; Ceyhan, Güralp O; Slotta-Huspenina, Julia; Schemann, Michael

    2016-01-15

    We present the first systematic and, up to now, most comprehensive evaluation of the basic features of epithelial functions, such as basal and nerve-evoked secretion, as well as tissue resistance, in over 2200 surgical specimens of human small and large intestine. We found no evidence for impaired nerve-evoked epithelial secretion or tissue resistance with age or disease pathologies (stomach, pancreas or colon cancer, polyps, diverticulitis, stoma reversal). This indicates the validity of future studies on epithelial secretion or resistance that are based on data from a variety of surgical specimens. ACh mainly mediated nerve-evoked and basal secretion in the small intestine, whereas vasoactive intestinal peptide and nitric oxide were the primary pro-secretory transmitters in the large intestine. The results of the present study revealed novel insights into regional differences in nerve-mediated secretion in the human intestine and comprise the basis by which to more specifically target impaired epithelial functions in the diseased gut. Knowledge on basic features of epithelial functions in the human intestine is scarce. We used Ussing chamber techniques to record basal tissue resistance (R-basal) and short circuit currents (ISC; secretion) under basal conditions (ISC-basal) and after electrical field stimulation (ISC-EFS) of nerves in 2221 resectates from 435 patients. ISC-EFS was TTX-sensitive and of comparable magnitude in the small and large intestine. ISC-EFS or R-basal were not influenced by the patients' age, sex or disease pathologies (cancer, polyps, diverticulitis). Ion substitution, bumetanide or adenylate cyclase inhibition studies suggested that ISC-EFS depended on epithelial cAMP-driven chloride and bicarbonate secretion but not on amiloride-sensitive sodium absorption. Although atropine-sensitive cholinergic components prevailed for ISC-EFS of the duodenum, jejunum and ileum, PG97-269-sensitive [vasoactive intestinal peptide (VIP) receptor 1

  5. Differential expression of the neural cell adhesion molecule NCAM 140 in human pituitary tumors

    OpenAIRE

    Aletsee-Ufrecht, M. C.; Langley, O. K.; Gratzl, O.; Gratzl, Manfred

    1990-01-01

    We have analyzed the expression of the intracellular marker protein neuron specific enolase (NSE), synaptophysin (SYN) and of the cell surface marker NCAM (neural cell adhesion molecule) in both normal human hypophysis and in pituitary adenomas in order to explore their potential use as diagnostic tools. All adenomas (4 prolactinomas, 3 growth hormone (GH) producing adenomas and 4 inactive adenomas) showed SYN and NSE immunoreactivity on tissue sections and this was confirmed by immunoblots. ...

  6. The neural code for face orientation in the human fusiform face area.

    Science.gov (United States)

    Ramírez, Fernando M; Cichy, Radoslaw M; Allefeld, Carsten; Haynes, John-Dylan

    2014-09-03

    Humans recognize faces and objects with high speed and accuracy regardless of their orientation. Recent studies have proposed that orientation invariance in face recognition involves an intermediate representation where neural responses are similar for mirror-symmetric views. Here, we used fMRI, multivariate pattern analysis, and computational modeling to investigate the neural encoding of faces and vehicles at different rotational angles. Corroborating previous studies, we demonstrate a representation of face orientation in the fusiform face-selective area (FFA). We go beyond these studies by showing that this representation is category-selective and tolerant to retinal translation. Critically, by controlling for low-level confounds, we found the representation of orientation in FFA to be compatible with a linear angle code. Aspects of mirror-symmetric coding cannot be ruled out when FFA mean activity levels are considered as a dimension of coding. Finally, we used a parametric family of computational models, involving a biased sampling of view-tuned neuronal clusters, to compare different face angle encoding models. The best fitting model exhibited a predominance of neuronal clusters tuned to frontal views of faces. In sum, our findings suggest a category-selective and monotonic code of face orientation in the human FFA, in line with primate electrophysiology studies that observed mirror-symmetric tuning of neural responses at higher stages of the visual system, beyond the putative homolog of human FFA. Copyright © 2014 the authors 0270-6474/14/3412155-13$15.00/0.

  7. Differentiation of insulin-producing cells from human neural progenitor cells.

    Directory of Open Access Journals (Sweden)

    Yuichi Hori

    2005-04-01

    Full Text Available BACKGROUND: Success in islet-transplantation-based therapies for type 1 diabetes, coupled with a worldwide shortage of transplant-ready islets, has motivated efforts to develop renewable sources of islet-replacement tissue. Islets and neurons share features, including common developmental programs, and in some species brain neurons are the principal source of systemic insulin. METHODS AND FINDINGS: Here we show that brain-derived human neural progenitor cells, exposed to a series of signals that regulate in vivo pancreatic islet development, form clusters of glucose-responsive insulin-producing cells (IPCs. During in vitro differentiation of neural progenitor cells with this novel method, genes encoding essential known in vivo regulators of pancreatic islet development were expressed. Following transplantation into immunocompromised mice, IPCs released insulin C-peptide upon glucose challenge, remained differentiated, and did not form detectable tumors. CONCLUSION: Production of IPCs solely through extracellular factor modulation in the absence of genetic manipulations may promote strategies to derive transplantable islet-replacement tissues from human neural progenitor cells and other types of multipotent human stem cells.

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

    Directory of Open Access Journals (Sweden)

    Hao Huang

    2010-01-01

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

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

    Science.gov (United States)

    Slone, Edward; Burles, Ford; Iaria, Giuseppe

    2016-05-01

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

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  12. Explaining neural signals in human visual cortex with an associative learning model.

    Science.gov (United States)

    Jiang, Jiefeng; Schmajuk, Nestor; Egner, Tobias

    2012-08-01

    "Predictive coding" models posit a key role for associative learning in visual cognition, viewing perceptual inference as a process of matching (learned) top-down predictions (or expectations) against bottom-up sensory evidence. At the neural level, these models propose that each region along the visual processing hierarchy entails one set of processing units encoding predictions of bottom-up input, and another set computing mismatches (prediction error or surprise) between predictions and evidence. This contrasts with traditional views of visual neurons operating purely as bottom-up feature detectors. In support of the predictive coding hypothesis, a recent human neuroimaging study (Egner, Monti, & Summerfield, 2010) showed that neural population responses to expected and unexpected face and house stimuli in the "fusiform face area" (FFA) could be well-described as a summation of hypothetical face-expectation and -surprise signals, but not by feature detector responses. Here, we used computer simulations to test whether these imaging data could be formally explained within the broader framework of a mathematical neural network model of associative learning (Schmajuk, Gray, & Lam, 1996). Results show that FFA responses could be fit very closely by model variables coding for conditional predictions (and their violations) of stimuli that unconditionally activate the FFA. These data document that neural population signals in the ventral visual stream that deviate from classic feature detection responses can formally be explained by associative prediction and surprise signals.

  13. Consent: a Cartesian ideal? Human neural transplantation in Parkinson's disease.

    Science.gov (United States)

    Lopes, Manuel; Meningaud, Jean-Paul; Behin, Anthony; Hervé, Christian

    2003-01-01

    The grafting of human embryonic cells in Parkinson's disease is an innovative and hopefully useful therapeutic approach. However, it still concerns a very small number of patients and is only suggested as a research protocol. We present here a study of the problems of information and consent to research within the framework of this disease in which the efficacy of medical treatment is shortlived. The only French center to use this treatment (Hôpital H. Mondor in Créteil) has received authorization from the Comité Consultatif National d'Ethique (Consultative National Committee on Ethics). Eleven patients were treated between 1991 and 1998. The study of the results of a questionnaire sent to those patients showed the difficulties met in evaluating the perception of information despite intact intellectual capacities in people "prepared to risk everything." In France, the duty to inform patients during research procedures is regulated by the Huriet Act. However, it is not easy to guarantee genuine consent when preliminary information is given to patients psychologically impaired by the slow and ineluctable course of their disease. In these borderline cases, a valid consent seems to be a myth in terms of pure autonomy when considered with the Cartesian aim of elimination of uncertainty. The relevance of this concept of genuine consent probably makes more sense as aiming at a Cartesian ideal which is perhaps more in the spirit rather than in the letter. It is in that same spirit that, from the outset, we propose to define t he practical ways of answering the patients' request for information, even sometimes after consent has been given.

  14. Neural Integration of Information Specifying Human Structure from Form, Motion, and Depth

    Science.gov (United States)

    Jackson, Stuart; Blake, Randolph

    2010-01-01

    Recent computational models of biological motion perception operate on ambiguous two-dimensional representations of the body (e.g., snapshots, posture templates) and contain no explicit means for disambiguating the three-dimensional orientation of a perceived human figure. Are there neural mechanisms in the visual system that represent a moving human figure’s orientation in three dimensions? To isolate and characterize the neural mechanisms mediating perception of biological motion, we used an adaptation paradigm together with bistable point-light (PL) animations whose perceived direction of heading fluctuates over time. After exposure to a PL walker with a particular stereoscopically defined heading direction, observers experienced a consistent aftereffect: a bistable PL walker, which could be perceived in the adapted orientation or reversed in depth, was perceived predominantly reversed in depth. A phase-scrambled adaptor produced no aftereffect, yet when adapting and test walkers differed in size or appeared on opposite sides of fixation aftereffects did occur. Thus, this heading direction aftereffect cannot be explained by local, disparity-specific motion adaptation, and the properties of scale and position invariance imply higher-level origins of neural adaptation. Nor is disparity essential for producing adaptation: when suspended on top of a stereoscopically defined, rotating globe, a context-disambiguated “globetrotter” was sufficient to bias the bistable walker’s direction, as were full-body adaptors. In sum, these results imply that the neural signals supporting biomotion perception integrate information on the form, motion, and three-dimensional depth orientation of the moving human figure. Models of biomotion perception should incorporate mechanisms to disambiguate depth ambiguities in two-dimensional body representations. PMID:20089892

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

    Directory of Open Access Journals (Sweden)

    Xinxin Han

    2017-01-01

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

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

    Science.gov (United States)

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

    2015-10-01

    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. 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. 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. 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.

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

    Directory of Open Access Journals (Sweden)

    Philipp Capetian

    2016-10-01

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

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

    Science.gov (United States)

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

    2015-10-01

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

  19. ERK-dependent and -independent pathways trigger human neural progenitor cell migration

    International Nuclear Information System (INIS)

    Moors, Michaela; Cline, Jason E.; Abel, Josef; Fritsche, Ellen

    2007-01-01

    Besides differentiation and apoptosis, cell migration is a basic process in brain development in which neural cells migrate several centimeters within the developing brain before reaching their proper positions and forming the right connections. For identifying signaling events that control neural migration and are therefore potential targets of chemicals to disturb normal brain development, we developed a human neurosphere-based migration assay based on normal human neural progenitor (NHNP) cells, in which the distance is measured that cells wander over time. Applying this assay, we investigated the role of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the regulation of NHNP cell migration. Exposure to model substances like ethanol or phorbol 12-myristate 13-acetate (PMA) revealed a correlation between ERK1/2 activation and cell migration. The participation of phospho-(P-) ERK1/2 was confirmed by exposure of the cells to the MEK inhibitor PD98059, which directly prohibits ERK1/2 phosphorylation and inhibited cell migration. We identified protein kinase C (PKC) and epidermal growth factor receptor (EGFR) as upstream signaling kinases governing ERK1/2 activation, thereby controlling NHNP cell migration. Additionally, treatments with src kinase inhibitors led to a diminished cell migration without affecting ERK1/2 phosphorylation. Based on these results, we postulate that migration of NHNP cells is controlled via ERK1/2-dependent and -independent pathways

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2009-07-01

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

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

    Directory of Open Access Journals (Sweden)

    Misako Komatsu

    2017-09-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  3. A scale out approach towards neural induction of human induced pluripotent stem cells for neurodevelopmental toxicity studies.

    Science.gov (United States)

    Miranda, Cláudia C; Fernandes, Tiago G; Pinto, Sandra N; Prieto, Manuel; Diogo, M Margarida; Cabral, Joaquim M S

    2018-05-21

    Stem cell's unique properties confer them a multitude of potential applications in the fields of cellular therapy, disease modelling and drug screening fields. In particular, the ability to differentiate neural progenitors (NP) from human induced pluripotent stem cells (hiPSCs) using chemically-defined conditions provides an opportunity to create a simple and straightforward culture platform for application in these fields. Here, we demonstrated that hiPSCs are capable of undergoing neural commitment inside microwells, forming characteristic neural structures resembling neural rosettes and further give rise to glial and neuronal cells. Furthermore, this platform can be applied towards the study of the effect of neurotoxic molecules that impair normal embryonic development. As a proof of concept, the neural teratogenic potential of the antiepileptic drug valproic acid (VPA) was analyzed. It was verified that exposure to VPA, close to typical dosage values (0.3 to 0.75 mM), led to a prevalence of NP structures over neuronal differentiation, as confirmed by analysis of the expression of neural cell adhesion molecule, as well as neural rosette number and morphology assessment. The methodology proposed herein for the generation and neural differentiation of hiPSC aggregates can potentially complement current toxicity tests such as the humanized embryonic stem cell test for the detection of teratogenic compounds that can interfere with normal embryonic development. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Nonstimulated human uncommitted mesenchymal stem cells express cell markers of mesenchymal and neural lineages.

    Science.gov (United States)

    Minguell, José J; Fierro, Fernando A; Epuñan, María J; Erices, Alejandro A; Sierralta, Walter D

    2005-08-01

    Ex vivo cultures of human bone marrow-derived mesenchymal stem cells (MSCs) contain subsets of progenitors exhibiting dissimilar properties. One of these subsets comprises uncommitted progenitors displaying distinctive features, such as morphology, a quiescent condition, growth factor production, and restricted tissue biodistribution after transplantation. In this study, we assessed the competence of these cells to express, in the absence of differentiation stimuli, markers of mesoderm and ectodermic (neural) cell lineages. Fluorescence microscopy analysis showed a unique pattern of expression of osteogenic, chondrogenic, muscle, and neural markers. The depicted "molecular signature" of these early uncommitted progenitors, in the absence of differentiation stimuli, is consistent with their multipotentiality and plasticity as suggested by several in vitro and in vivo studies.

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

    DEFF Research Database (Denmark)

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

    2017-01-01

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

  6. Purification of human induced pluripotent stem cell-derived neural precursors using magnetic activated cell sorting.

    Science.gov (United States)

    Rodrigues, Gonçalo M C; Fernandes, Tiago G; Rodrigues, Carlos A V; Cabral, Joaquim M S; Diogo, Maria Margarida

    2015-01-01

    Neural precursor (NP) cells derived from human induced pluripotent stem cells (hiPSCs), and their neuronal progeny, will play an important role in disease modeling, drug screening tests, central nervous system development studies, and may even become valuable for regenerative medicine treatments. Nonetheless, it is challenging to obtain homogeneous and synchronously differentiated NP populations from hiPSCs, and after neural commitment many pluripotent stem cells remain in the differentiated cultures. Here, we describe an efficient and simple protocol to differentiate hiPSC-derived NPs in 12 days, and we include a final purification stage where Tra-1-60+ pluripotent stem cells (PSCs) are removed using magnetic activated cell sorting (MACS), leaving the NP population nearly free of PSCs.

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

    Science.gov (United States)

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

    2014-01-01

    The development of three dimensional (3D) cell cultures represents a big step for the better understanding of cell behavior and disease in a more natural like environment, providing not only single but multiple cell type interactions in a complex 3D matrix, highly resembling physiological conditions. Light sheet fluorescence microscopy (LSFM) is becoming an excellent tool for fast imaging of such 3D biological structures. We demonstrate the potential of this technique for the imaging of human differentiated 3D neural aggregates in fixed and live samples, namely calcium imaging and cell death processes, showing the power of imaging modality compared with traditional microscopy. The combination of light sheet microscopy and 3D neural cultures will open the door to more challenging experiments involving drug testing at large scale as well as a better understanding of relevant biological processes in a more realistic environment. PMID:25161607

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

    Directory of Open Access Journals (Sweden)

    Emilio J Gualda

    2014-08-01

    Full Text Available The development of three dimensional 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 three dimensional matrix, highly resembling physiological conditions. Light sheet fluorescence microscopy is becoming an excellent tool for fast imaging of such three-dimensional 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.

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

    Directory of Open Access Journals (Sweden)

    Yongxin Li

    2016-01-01

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

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

    KAUST Repository

    Harrou, Fouzi; Zerrouki, Nabil; Sun, Ying; Houacine, Amrane

    2017-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Jinah Han

    2015-02-01

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

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

    KAUST Repository

    Harrou, Fouzi

    2017-01-05

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

  13. Long-Term Expandable SOX9+ Chondrogenic Ectomesenchymal Cells from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Katsutsugu Umeda

    2015-04-01

    Full Text Available Here we report the successful generation and long-term expansion of SOX9-expressing CD271+PDGFRα+CD73+ chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1−CD271hiPDGFRαloCD73− neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ inhibitor and fibroblast growth factor (FGF. When “primed” with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice. The ectomesenchymal cells were expandable without loss of chondrogenic potential for at least 16 passages. They maintained normal karyotype for at least 10 passages and expressed genes representing embryonic progenitors (SOX4/12, LIN28A/B, cranial mesenchyme (ALX1/3/4, and chondroprogenitors (SOX9, COL2A1 of neural crest origin (SOX8/9, NGFR, NES. Ectomesenchyme is a source of many craniofacial bone and cartilage structures. The method we describe for obtaining a large quantity of human ectomesenchymal cells will help to model craniofacial disorders in vitro and potentially provide cells for the repair of craniofacial damage.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-21

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

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

    Directory of Open Access Journals (Sweden)

    Zhibin Yu

    2017-08-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-09-10

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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

    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.

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

    Science.gov (United States)

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

    2017-12-01

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

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

    Science.gov (United States)

    Dasgupta, Hirak

    2016-12-01

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

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

    International Nuclear Information System (INIS)

    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

    2007-01-01

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Alexandra Zirra

    2016-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2006-02-01

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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  6. DEVELOPMENT OF WEARABLE HUMAN FALL DETECTION SYSTEM USING MULTILAYER PERCEPTRON NEURAL NETWORK

    Directory of Open Access Journals (Sweden)

    Hamideh Kerdegari

    2013-02-01

    Full Text Available This paper presents an accurate wearable fall detection system which can identify the occurrence of falls among elderly population. A waist worn tri-axial accelerometer was used to capture the movement signals of human body. A set of laboratory-based falls and activities of daily living (ADL were performed by volunteers with different physical characteristics. The collected acceleration patterns were classified precisely to fall and ADL using multilayer perceptron (MLP neural network. This work was resulted to a high accuracy wearable fall-detection system with the accuracy of 91.6%.

  7. Effect of 3D-scaffold formation on differentiation and survival in human neural progenitor cells.

    Science.gov (United States)

    Ortinau, Stefanie; Schmich, Jürgen; Block, Stephan; Liedmann, Andrea; Jonas, Ludwig; Weiss, Dieter G; Helm, Christiane A; Rolfs, Arndt; Frech, Moritz J

    2010-11-11

    3D-scaffolds have been shown to direct cell growth and differentiation in many different cell types, with the formation and functionalisation of the 3D-microenviroment being important in determining the fate of the embedded cells. Here we used a hydrogel-based scaffold to investigate the influences of matrix concentration and functionalisation with laminin on the formation of the scaffolds, and the effect of these scaffolds on human neural progenitor cells cultured within them. In this study we used different concentrations of the hydrogel-based matrix PuraMatrix. In some experiments we functionalised the matrix with laminin I. The impact of concentration and treatment with laminin on the formation of the scaffold was examined with atomic force microscopy. Cells from a human fetal neural progenitor cell line were cultured in the different matrices, as well as in a 2D culture system, and were subsequently analysed with antibody stainings against neuronal markers. In parallel, the survival rate of the cells was determined by a live/dead assay. Atomic force microscopy measurements demonstrated that the matrices are formed by networks of isolated PuraMatrix fibres and aggregates of fibres. An increase of the hydrogel concentration led to a decrease in the mesh size of the scaffolds and functionalisation with laminin promoted aggregation of the fibres (bundle formation), which further reduces the density of isolated fibres. We showed that laminin-functionalisation is essential for human neural progenitor cells to build up 3D-growth patterns, and that proliferation of the cells is also affected by the concentration of matrix. In addition we found that 3D-cultures enhanced neuronal differentiation and the survival rate of the cells compared to 2D-cultures. Taken together, we have demonstrated a direct influence of the 3D-scaffold formation on the survival and neuronal differentiation of human neural progenitor cells. These findings emphasize the importance of optimizing 3

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

    Czech Academy of Sciences Publication Activity Database

    Amemori, Takashi; Romanyuk, Nataliya; Jendelová, Pavla; Herynek, V.; Turnovcová, Karolína; Procházka, Pavel; Kapcalová, Miroslava; Cocks, G.; Price, J.; Syková, Eva

    2013-01-01

    Roč. 4, č. 3 (2013), s. 68 ISSN 1757-6512 R&D Projects: GA ČR(CZ) GAP304/12/1370; GA ČR GA13-00939S; GA MŠk LH12024; GA ČR(CZ) GBP304/12/G069 Grant - others:GA MZd(CZ) 00023001IKEM Institutional support: RVO:68378041 Keywords : human fetal neural stem cells * spinal cord injury * motor neuron differentiation Subject RIV: FH - Neurology Impact factor: 4.634, year: 2013

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

    Science.gov (United States)

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

    2016-12-01

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

  10. Immortalization of human neural stem cells with the c-myc mutant T58A.

    Directory of Open Access Journals (Sweden)

    Lidia De Filippis

    Full Text Available Human neural stem cells (hNSC represent an essential source of renewable brain cells for both experimental studies and cell replacement therapies. Their relatively slow rate of proliferation and physiological senescence in culture make their use cumbersome under some experimental and pre-clinical settings. The immortalization of hNSC with the v-myc gene (v-IhNSC has been shown to generate stem cells endowed with enhanced proliferative capacity, which greatly facilitates the study of hNSCs, both in vitro and in vivo. Despite the excellent safety properties displayed by v-IhNSCs--which do not transform in vitro and are not tumorigenic in vivo--the v-myc gene contains several mutations and recombination elements, whose role(s and effects remains to be elucidated, yielding unresolved safety concerns. To address this issue, we used a c-myc T58A retroviral vector to establish an immortal cell line (T-IhNSC from the same hNSCs used to generate the original v-IhNSCs and compared their characteristics with the latter, with hNSC and with hNSC immortalized using c-myc wt (c-IhNSC. T-IhNSCs displayed an enhanced self-renewal ability, with their proliferative capacity and clonogenic potential being remarkably comparable to those of v-IhNSC and higher than wild type hNSCs and c-IhNSCs. Upon growth factors removal, T-IhNSC promptly gave rise to well-differentiated neurons, astrocytes and most importantly, to a heretofore undocumented high percentage of human oligodendrocytes (up to 23%. Persistent growth-factor dependence, steady functional properties, lack of ability to generate colonies in soft-agar colony-forming assay and to establish tumors upon orthotopic transplantation, point to the fact that immortalization by c-myc T58A does not bring about tumorigenicity in hNSCs. Hence, this work describes a novel and continuous cell line of immortalized human multipotent neural stem cells, in which the immortalizing agent is represented by a single gene which, in

  11. Protection of visual functions by human neural progenitors in a rat model of retinal disease.

    Directory of Open Access Journals (Sweden)

    David M Gamm

    2007-03-01

    Full Text Available A promising clinical application for stem and progenitor cell transplantation is in rescue therapy for degenerative diseases. This strategy seeks to preserve rather than restore host tissue function by taking advantage of unique properties often displayed by these versatile cells. In studies using different neurodegenerative disease models, transplanted human neural progenitor cells (hNPC protected dying host neurons within both the brain and spinal cord. Based on these reports, we explored the potential of hNPC transplantation to rescue visual function in an animal model of retinal degeneration, the Royal College of Surgeons rat.Animals received unilateral subretinal injections of hNPC or medium alone at an age preceding major photoreceptor loss. Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus. At 90-100 days postnatal, a time point when untreated rats exhibit little or no retinal or visual function, hNPC-treated eyes retained substantial retinal electrical activity and visual field with near-normal visual acuity. Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor. Histological examination at 150 days postnatal showed hNPC had formed a nearly continuous pigmented layer between the neural retina and retinal pigment epithelium, as well as distributed within the inner retina. A concomitant preservation of host cone photoreceptors was also observed.Wild type and genetically modified human neural progenitor cells survive for prolonged periods, migrate extensively, secrete growth factors and rescue visual functions following subretinal transplantation in the Royal College of Surgeons rat. These results underscore the potential therapeutic utility of hNPC in the treatment of retinal degenerative diseases and suggest potential mechanisms underlying their effect in

  12. Neural mechanisms of human perceptual learning: electrophysiological evidence for a two-stage process.

    Science.gov (United States)

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

    2011-04-26

    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. 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. 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.

  13. A comparative transcriptomic analysis of astrocytes differentiation from human neural progenitor cells.

    Science.gov (United States)

    Magistri, Marco; Khoury, Nathalie; Mazza, Emilia Maria Cristina; Velmeshev, Dmitry; Lee, Jae K; Bicciato, Silvio; Tsoulfas, Pantelis; Faghihi, Mohammad Ali

    2016-11-01

    Astrocytes are a morphologically and functionally heterogeneous population of cells that play critical roles in neurodevelopment and in the regulation of central nervous system homeostasis. Studies of human astrocytes have been hampered by the lack of specific molecular markers and by the difficulties associated with purifying and culturing astrocytes from adult human brains. Human neural progenitor cells (NPCs) with self-renewal and multipotent properties represent an appealing model system to gain insight into the developmental genetics and function of human astrocytes, but a comprehensive molecular characterization that confirms the validity of this cellular system is still missing. Here we used an unbiased transcriptomic analysis to characterize in vitro culture of human NPCs and to define the gene expression programs activated during the differentiation of these cells into astrocytes using FBS or the combination of CNTF and BMP4. Our results demonstrate that in vitro cultures of human NPCs isolated during the gliogenic phase of neurodevelopment mainly consist of radial glial cells (RGCs) and glia-restricted progenitor cells. In these cells the combination of CNTF and BMP4 activates the JAK/STAT and SMAD signaling cascades, leading to the inhibition of oligodendrocytes lineage commitment and activation of astrocytes differentiation. On the other hand, FBS-derived astrocytes have properties of reactive astrocytes. Our work suggests that in vitro culture of human NPCs represents a valuable cellular system to study human disorders characterized by impairment of astrocytes development and function. Our datasets represent an important resource for researchers studying human astrocytes development and might set the basis for the discovery of novel human-specific astrocyte markers. © 2016 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  14. Multispectral embedding-based deep neural network for three-dimensional human pose recovery

    Science.gov (United States)

    Yu, Jialin; Sun, Jifeng

    2018-01-01

    Monocular image-based three-dimensional (3-D) human pose recovery aims to retrieve 3-D poses using the corresponding two-dimensional image features. Therefore, the pose recovery performance highly depends on the image representations. We propose a multispectral embedding-based deep neural network (MSEDNN) to automatically obtain the most discriminative features from multiple deep convolutional neural networks and then embed their penultimate fully connected layers into a low-dimensional manifold. This compact manifold can explore not only the optimum output from multiple deep networks but also the complementary properties of them. Furthermore, the distribution of each hierarchy discriminative manifold is sufficiently smooth so that the training process of our MSEDNN can be effectively implemented only using few labeled data. Our proposed network contains a body joint detector and a human pose regressor that are jointly trained. Extensive experiments conducted on four databases show that our proposed MSEDNN can achieve the best recovery performance compared with the state-of-the-art methods.

  15. Laminin enhances the growth of human neural stem cells in defined culture media

    Directory of Open Access Journals (Sweden)

    Lathia Justin D

    2008-07-01

    Full Text Available Abstract Background Human neural stem cells (hNSC have the potential to provide novel cell-based therapies for neurodegenerative conditions such as multiple sclerosis and Parkinson's disease. In order to realise this goal, protocols need to be developed that allow for large quantities of hNSC to be cultured efficiently. As such, it is important to identify factors which enhance the growth of hNSC. In vivo, stem cells reside in distinct microenvironments or niches that are responsible for the maintenance of stem cell populations. A common feature of niches is the presence of the extracellular matrix molecule, laminin. Therefore, this study investigated the effect of exogenous laminin on hNSC growth. Results To measure hNSC growth, we established culture conditions using B27-supplemented medium that enable neurospheres to grow from human neural cells plated at clonal densities. Limiting dilution assays confirmed that neurospheres were derived from single cells at these densities. Laminin was found to increase hNSC numbers as measured by this neurosphere formation. The effect of laminin was to augment the proliferation/survival of the hNSC, rather than promoting the undifferentiated state. In agreement, apoptosis was reduced in dissociated neurospheres by laminin in an integrin β1-dependent manner. Conclusion The addition of laminin to the culture medium enhances the growth of hNSC, and may therefore aid their large-scale production.

  16. Protein Kinase-A Inhibition Is Sufficient to Support Human Neural Stem Cells Self-Renewal.

    Science.gov (United States)

    Georges, Pauline; Boissart, Claire; Poulet, Aurélie; Peschanski, Marc; Benchoua, Alexandra

    2015-12-01

    Human pluripotent stem cell-derived neural stem cells offer unprecedented opportunities for producing specific types of neurons for several biomedical applications. However, to achieve it, protocols of production and amplification of human neural stem cells need to be standardized, cost effective, and safe. This means that small molecules should progressively replace the use of media containing cocktails of protein-based growth factors. Here we have conducted a phenotypical screening to identify pathways involved in the regulation of hNSC self-renewal. We analyzed 80 small molecules acting as kinase inhibitors and identified compounds of the 5-isoquinolinesulfonamide family, described as protein kinase A (PKA) and protein kinase G inhibitors, as candidates to support hNSC self-renewal. Investigating the mode of action of these compounds, we found that modulation of PKA activity was central in controlling the choice between self-renewal or terminal neuronal differentiation of hNSC. We finally demonstrated that the pharmacological inhibition of PKA using the small molecule HA1004 was sufficient to support the full derivation, propagation, and long-term maintenance of stable hNSC in absence of any other extrinsic signals. Our results indicated that tuning of PKA activity is a core mechanism regulating hNSC self-renewal and differentiation and delineate the minimal culture media requirement to maintain undifferentiated hNSC in vitro. © 2015 AlphaMed Press.

  17. Increasing Human Neural Stem Cell Transplantation Dose Alters Oligodendroglial and Neuronal Differentiation after Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Katja M. Piltti

    2017-06-01

    Full Text Available Multipotent human central nervous system-derived neural stem cells transplanted at doses ranging from 10,000 (low to 500,000 (very high cells differentiated predominantly into the oligodendroglial lineage. However, while the number of engrafted cells increased linearly in relationship to increasing dose, the proportion of oligodendrocytic cells declined. Increasing dose resulted in a plateau of engraftment, enhanced neuronal differentiation, and increased distal migration caudal to the transplantation sites. Dose had no effect on terminal sensory recovery or open-field locomotor scores. However, total human cell number and decreased oligodendroglial proportion were correlated with hindlimb girdle coupling errors. Conversely, greater oligodendroglial proportion was correlated with increased Ab step pattern, decreased swing speed, and increased paw intensity, consistent with improved recovery. These data suggest that transplant dose, and/or target niche parameters can regulate donor cell engraftment, differentiation/maturation, and lineage-specific migration profiles.

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

    International Nuclear Information System (INIS)

    Cacci, E.; Villa, A.; Parmar, M.; Cavallaro, M.; Mandahl, N.; Lindvall, O.; Martinez-Serrano, A.; Kokaia, Z.

    2007-01-01

    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. Multimodal neural correlates of cognitive control in the Human Connectome Project.

    Science.gov (United States)

    Lerman-Sinkoff, Dov B; Sui, Jing; Rachakonda, Srinivas; Kandala, Sridhar; Calhoun, Vince D; Barch, Deanna M

    2017-12-01

    Cognitive control is a construct that refers to the set of functions that enable decision-making and task performance through the representation of task states, goals, and rules. The neural correlates of cognitive control have been studied in humans using a wide variety of neuroimaging modalities, including structural MRI, resting-state fMRI, and task-based fMRI. The results from each of these modalities independently have implicated the involvement of a number of brain regions in cognitive control, including dorsal prefrontal cortex, and frontal parietal and cingulo-opercular brain networks. However, it is not clear how the results from a single modality relate to results in other modalities. Recent developments in multimodal image analysis methods provide an avenue for answering such questions and could yield more integrated models of the neural correlates of cognitive control. In this study, we used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) to identify multimodal patterns of variation related to cognitive control. We used two independent cohorts of participants from the Human Connectome Project, each of which had data from four imaging modalities. We replicated the findings from the first cohort in the second cohort using both independent and predictive analyses. The independent analyses identified a component in each cohort that was highly similar to the other and significantly correlated with cognitive control performance. The replication by prediction analyses identified two independent components that were significantly correlated with cognitive control performance in the first cohort and significantly predictive of performance in the second cohort. These components identified positive relationships across the modalities in neural regions related to both dynamic and stable aspects of task control, including regions in both the frontal-parietal and cingulo-opercular networks, as well as regions

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

    Science.gov (United States)

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

    2017-12-07

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

  1. Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD.

    Directory of Open Access Journals (Sweden)

    Yuanquan Song

    2009-12-01

    Full Text Available In humans, mutations in electron transfer flavoprotein (ETF or electron transfer flavoprotein dehydrogenase (ETFDH lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.

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

    Directory of Open Access Journals (Sweden)

    Ying Liu

    2017-03-01

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

  3. Human Episodic Memory Retrieval Is Accompanied by a Neural Contiguity Effect.

    Science.gov (United States)

    Folkerts, Sarah; Rutishauser, Ueli; Howard, Marc W

    2018-04-25

    Cognitive psychologists have long hypothesized that experiences are encoded in a temporal context that changes gradually over time. When an episodic memory is retrieved, the state of context is recovered-a jump back in time. We recorded from single units in the medial temporal lobe of epilepsy patients performing an item recognition task. The population vector changed gradually over minutes during presentation of the list. When a probe from the list was remembered with high confidence, the population vector reinstated the temporal context of the original presentation of that probe during study, a neural contiguity effect that provides a possible mechanism for behavioral contiguity effects. This pattern was only observed for well remembered probes; old probes that were not well remembered showed an anti-contiguity effect. These results constitute the first direct evidence that recovery of an episodic memory in humans is associated with retrieval of a gradually changing state of temporal context, a neural "jump back in time" that parallels the act of remembering. SIGNIFICANCE STATEMENT Episodic memory is the ability to relive a specific experience from one's life. For decades, researchers have hypothesized that, unlike other forms of memory that can be described as simple associations between stimuli, episodic memory depends on the recovery of a neural representation of spatiotemporal context. During study of a sequence of stimuli, the brain state of epilepsy patients changed slowly over at least a minute. When the participant remembered a particular event from the list, this gradually changing state was recovered. This provides direct confirmation of the prediction from computational models of episodic memory. The resolution of this point means that the study of episodic memory can focus on the mechanisms by which this representation of spatiotemporal context is maintained and sometimes recovered. Copyright © 2018 the authors 0270-6474/18/384200-12$15.00/0.

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

    Science.gov (United States)

    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. © 2014 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2015-08-01

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

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

    Science.gov (United States)

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

    2015-12-01

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

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

    DEFF Research Database (Denmark)

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

    2009-01-01

    as an absence of sweating and cutaneous vasodilatation during a whole-body heat stress. Upon this confirmation, adenosine was perfused through one of the microdialysis probes to increase skin blood flow similar to that of the unblocked site. After internal temperature increased approximately 0.7 degrees C......During heat stress, isometric handgrip (IHG) exercise causes cutaneous vasoconstriction, but it remains controversial whether neural mechanisms are responsible for this observation. The objective of this study was to test the hypothesis that cutaneous vasoconstriction during IHG exercise in heat...... stressed individuals occurs via a neural mechanism. An axillary nerve blockade was performed to block efferent nerve traffic to the left forearm in seven healthy subjects. Two intradermal microdialysis probes were placed within forearm skin of the blocked area. Forearm skin blood flow was measured by laser...

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

    Directory of Open Access Journals (Sweden)

    Adrian G Guggisberg

    2008-03-01

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

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

    Science.gov (United States)

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

    2017-06-15

    Nonpluripotent neural progenitor cells (NPCs) derived from the human fetal central nervous system were found to express a number of messenger RNA (mRNA) species associated with pluripotency, such as NANOG, REX1, and OCT4. The expression was restricted to small subpopulations of NPCs. In contrast to pluripotent stem cells, there was no coexpression of the pluripotency-associated genes studied. Although the expression of these genes rapidly declined during the in vitro differentiation of NPCs, we found no evidence that the discrete expression was associated with the markers of multipotent neural stem cells (CD133 + /CD24 lo ), the capacity of sphere formation, or high cell proliferation rates. The rate of cell death among NPCs expressing pluripotency-associated genes was also similar to that of other NPCs. Live cell imaging showed that NANOG- and REX1-expressing NPCs continuously changed morphology, as did the nonexpressing cells. Depletion experiments showed that after the complete removal of the subpopulations of NANOG- and REX1-expressing NPCs, the expression of these genes appeared in other NPCs within a few days. The percentage of NANOG- and REX1-expressing cells returned to that observed before depletion. Our results are best explained by a model in which there is stochastic transient expression of pluripotency-associated genes in proliferating NPCs.

  10. [Biological and neural bases of partner preferences in rodents: models to understand human pair bonds].

    Science.gov (United States)

    Coria-Avila, G A; Hernández-Aguilar, M E; Toledo-Cárdenas, R; García-Hernández, L I; Manzo, J; Pacheco, P; Miquel, M; Pfaus, J G

    To analyse the biological and neural bases of partner preference formation in rodents as models to understand human pair bonding. Rodents are social individuals, capable of forming short- or long-lasting partner preferences that develop slowly by stimuli like cohabitation, or rapidly by stimuli like sex and stress. Dopamine, corticosteroids, oxytocin, vasopressin, and opioids form the neurochemical substrate for pair bonding in areas like the nucleus accumbens, the prefrontal cortex, the piriform cortex, the medial preoptic area, the ventral tegmental area and the medial amygdala, among others. Additional areas may participate depending on the nature of the conditioned stimuli by which and individual recognizes a preferred partner. Animal models help us understand that the capacity of an individual to display long-lasting and selective preferences depends on neural bases, selected throughout evolution. The challenge in neuroscience is to use this knowledge to create new solutions for mental problems associated with the incapacity of an individual to display a social bond, keep one, or cope with the disruption of a consolidated one.

  11. Neural Determinants of Task Performance during Feature-Based Attention in Human Cortex

    Science.gov (United States)

    Gong, Mengyuan

    2018-01-01

    Abstract Studies of feature-based attention have associated activity in a dorsal frontoparietal network with putative attentional priority signals. Yet, how this neural activity mediates attentional selection and whether it guides behavior are fundamental questions that require investigation. We reasoned that endogenous fluctuations in the quality of attentional priority should influence task performance. Human subjects detected a speed increment while viewing clockwise (CW) or counterclockwise (CCW) motion (baseline task) or while attending to either direction amid distracters (attention task). In an fMRI experiment, direction-specific neural pattern similarity between the baseline task and the attention task revealed a higher level of similarity for correct than incorrect trials in frontoparietal regions. Using transcranial magnetic stimulation (TMS), we disrupted posterior parietal cortex (PPC) and found a selective deficit in the attention task, but not in the baseline task, demonstrating the necessity of this cortical area during feature-based attention. These results reveal that frontoparietal areas maintain attentional priority that facilitates successful behavioral selection. PMID:29497703

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

    Science.gov (United States)

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

    2017-05-08

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

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

    Directory of Open Access Journals (Sweden)

    Jong Hyun Kim

    2017-05-01

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

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

    OpenAIRE

    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 ...

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

    Directory of Open Access Journals (Sweden)

    Dana M. Cairns

    2016-09-01

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

  16. High purity of human oligodendrocyte progenitor cells obtained from neural stem cells: suitable for clinical application.

    Science.gov (United States)

    Wang, Caiying; Luan, Zuo; Yang, Yinxiang; Wang, Zhaoyan; Wang, Qian; Lu, Yabin; Du, Qingan

    2015-01-30

    Recent studies have suggested that the transplantation of oligodendrocyte progenitor cells (OPCs) may be a promising potential therapeutic strategy for a broad range of diseases affecting myelin, such as multiple sclerosis, periventricular leukomalacia, and spinal cord injury. Clinical interest arose from the potential of human stem cells to be directed to OPCs for the clinical application of treating these diseases since large quantities of high quality OPCs are needed. However, to date, there have been precious few studies about OPC induction from human neural stem cells (NSCs). Here we successfully directed human fetal NSCs into highly pure OPCs using a cocktail of basic fibroblast growth factor, platelet-derived growth factor, and neurotrophic factor-3. These cells had typical morphology of OPCs, and 80-90% of them expressed specific OPC markers such as A2B5, O4, Sox10 and PDGF-αR. When exposed to differentiation medium, 90% of the cells differentiated into oligodendrocytes. The OPCs could be amplified in our culture medium and passaged at least 10 times. Compared to a recent published method, this protocol had much higher stability and repeatability, and OPCs could be obtained from NSCs from passage 5 to 38. It also obtained more highly pure OPCs (80-90%) via simpler and more convenient manipulation. This study provided an easy and efficient method to obtain large quantities of high-quality human OPCs to meet clinical demand. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2016-09-15

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

  18. Zika Virus Strains Potentially Display Different Infectious Profiles in Human Neural Cells

    Directory of Open Access Journals (Sweden)

    Yannick Simonin

    2016-10-01

    Full Text Available The recent Zika virus (ZIKV epidemic has highlighted the poor knowledge on its physiopathology. Recent studies showed that ZIKV of the Asian lineage, responsible for this international outbreak, causes neuropathology in vitro and in vivo. However, two African lineages exist and the virus is currently found circulating in Africa. The original African strain was also suggested to be neurovirulent but its laboratory usage has been criticized due to its multiple passages. In this study, we compared the French Polynesian (Asian ZIKV strain to an African strain isolated in Central African Republic and show a difference in infectivity and cellular response between both strains in human neural stem cells and astrocytes. Consistently, this African strain led to a higher infection rate and viral production, as well as stronger cell death and anti-viral response. Our results highlight the need to better characterize the physiopathology and predict neurological impairment associated with African ZIKV.

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

    DEFF Research Database (Denmark)

    Dreyer-Andersen, Nanna; Almeida, Ana Sofia; Jensen, Pia

    2018-01-01

    cells constitute an alternative source of cells for transplantation in Parkinson's disease, but efficient protocols for controlled dopaminergic differentiation need to be developed. Short-term, low-level carbon monoxide (CO) exposure has been shown to affect signaling in several tissues, resulting...... in both protection and generation of reactive oxygen species. The present study investigated the effect of CO produced by a novel CO-releasing molecule on dopaminergic differentiation of human neural stem cells. Short-term exposure to 25 ppm CO at days 0 and 4 significantly increased the relative content...... of β-tubulin III-immunoreactive immature neurons and tyrosine hydroxylase expressing catecholaminergic neurons, as assessed 6 days after differentiation. Also the number of microtubule associated protein 2-positive mature neurons had increased significantly. Moreover, the content of apoptotic cells...

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

    Directory of Open Access Journals (Sweden)

    Tomoko Horikiri

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

  1. Amniotic fluid promotes the appearance of neural retinal progenitors and neurons in human RPE cell cultures.

    Science.gov (United States)

    Davari, Maliheh; Soheili, Zahra-Soheila; Ahmadieh, Hamid; Sanie-Jahromi, Fateme; Ghaderi, Shima; Kanavi, Mozhgan Rezaei; Samiei, Shahram; Akrami, Hassan; Haghighi, Massoud; Javidi-Azad, Fahimeh

    2013-01-01

    Retinal pigment epithelial (RPE) cells are capable of differentiating into retinal neurons when induced by the appropriate growth factors. Amniotic fluid contains a variety of growth factors that are crucial for the development of a fetus. In this study, the effects of human amniotic fluid (HAF) on primary RPE cell cultures were evaluated. RPE cells were isolated from the globes of postnatal human cadavers. The isolated cells were plated and grown in DMEM/F12 with 10% fetal bovine serum. To confirm the RPE identity of the cultured cells, they were immunocytochemically examined for the presence of the RPE cell-specific marker RPE65. RPE cultures obtained from passages 2-7 were treated with HAF and examined morphologically for 1 month. To determine whether retinal neurons or progenitors developed in the treated cultures, specific markers for bipolar (protein kinase C isomer α, PKCα), amacrine (cellular retinoic acid-binding protein I, CRABPI), and neural progenitor (NESTIN) cells were sought, and the amount of mRNA was quantified using real-time PCR. Treating RPE cells with HAF led to a significant decrease in the number of RPE65-positive cells, while PKCα- and CRABPI-positive cells were detected in the cultures. Compared with the fetal bovine serum-treated cultures, the levels of mRNAs quantitatively increased by 2-, 20- and 22-fold for NESTIN, PKCα, and CRABPI, respectively. The RPE cultures treated with HAF established spheres containing both pigmented and nonpigmented cells, which expressed neural progenitor markers such as NESTIN. This study showed that HAF can induce RPE cells to transdifferentiate into retinal neurons and progenitor cells, and that it provides a potential source for cell-based therapies to treat retinal diseases.

  2. Spontaneous calcium transients in human neural progenitor cells mediated by transient receptor potential channels.

    Science.gov (United States)

    Morgan, Peter J; Hübner, Rayk; Rolfs, Arndt; Frech, Moritz J

    2013-09-15

    Calcium signals affect many developmental processes, including proliferation, migration, survival, and apoptosis, processes that are of particular importance in stem cells intended for cell replacement therapies. The mechanisms underlying Ca(2+) signals, therefore, have a role in determining how stem cells respond to their environment, and how these responses might be controlled in vitro. In this study, we examined the spontaneous Ca(2+) activity in human neural progenitor cells during proliferation and differentiation. Pharmacological characterization indicates that in proliferating cells, most activity is the result of transient receptor potential (TRP) channels that are sensitive to Gd(3+) and La(3+), with the more subtype selective antagonist Ruthenium red also reducing activity, suggesting the involvement of transient receptor potential vanilloid (TRPV) channels. In differentiating cells, Gd(3+) and La(3+)-sensitive TRP channels also appear to underlie the spontaneous activity; however, no sub-type-specific antagonists had any effect. Protein levels of TRPV2 and TRPV3 decreased in differentiated cells, which is demonstrated by western blot. Thus, it appears that TRP channels represent the main route of Ca(2+) entry in human neural progenitor cells (hNPCs), but the responsible channel types are subject to substitution under differentiating conditions. The level of spontaneous activity could be increased and decreased by lowering and raising the extracellular K(+) concentration. Proliferating cells in low K(+) slowed the cell cycle, with a disproportionate increased percentage of cells in G1 phase and a reduction in S phase. Taken together, these results suggest a link between external K(+) concentration, spontaneous Ca(2+) transients, and cell cycle distribution, which is able to influence the fate of stem and progenitor cells.

  3. The Postischemic Environment Differentially Impacts Teratoma or Tumor Formation After Transplantation of Human Embryonic Stem Cell-Derived Neural Progenitors

    Czech Academy of Sciences Publication Activity Database

    Seminatore, CH.; Polentes, J.; Ellman, D.; Kozubenko, Nataliya; Itier, V.; Tine, S.; Tritschler, L.; Brenot, M.; Guidou, E.; Blondeau, J.; Lhuillier, M.; Bugi, A.; Aubry, L.; Jendelová, Pavla; Syková, Eva; Perrier, A. L.; Finsen, B.; Onteniente, B.

    2010-01-01

    Roč. 41, č. 1 (2010), s. 153-159 ISSN 0039-2499 Institutional research plan: CEZ:AV0Z50390703 Keywords : brain transplantation * human embryonic stem cells * neural differentiation Subject RIV: FH - Neurology Impact factor: 5.756, year: 2010

  4. Alternative splicing events identified in human embryonic stem cells and neural progenitors.

    Directory of Open Access Journals (Sweden)

    Gene W Yeo

    2007-10-01

    Full Text Available Human embryonic stem cells (hESCs and neural progenitor (NP cells are excellent models for recapitulating early neuronal development in vitro, and are key to establishing strategies for the treatment of degenerative disorders. While much effort had been undertaken to analyze transcriptional and epigenetic differences during the transition of hESC to NP, very little work has been performed to understand post-transcriptional changes during neuronal differentiation. Alternative RNA splicing (AS, a major form of post-transcriptional gene regulation, is important in mammalian development and neuronal function. Human ESC, hESC-derived NP, and human central nervous system stem cells were compared using Affymetrix exon arrays. We introduced an outlier detection approach, REAP (Regression-based Exon Array Protocol, to identify 1,737 internal exons that are predicted to undergo AS in NP compared to hESC. Experimental validation of REAP-predicted AS events indicated a threshold-dependent sensitivity ranging from 56% to 69%, at a specificity of 77% to 96%. REAP predictions significantly overlapped sets of alternative events identified using expressed sequence tags and evolutionarily conserved AS events. Our results also reveal that focusing on differentially expressed genes between hESC and NP will overlook 14% of potential AS genes. In addition, we found that REAP predictions are enriched in genes encoding serine/threonine kinase and helicase activities. An example is a REAP-predicted alternative exon in the SLK (serine/threonine kinase 2 gene that is differentially included in hESC, but skipped in NP as well as in other differentiated tissues. Lastly, comparative sequence analysis revealed conserved intronic cis-regulatory elements such as the FOX1/2 binding site GCAUG as being proximal to candidate AS exons, suggesting that FOX1/2 may participate in the regulation of AS in NP and hESC. In summary, a new methodology for exon array analysis was introduced

  5. Perianal implantation of bioengineered human internal anal sphincter constructs intrinsically innervated with human neural progenitor cells.

    Science.gov (United States)

    Raghavan, Shreya; Miyasaka, Eiichi A; Gilmont, Robert R; Somara, Sita; Teitelbaum, Daniel H; Bitar, Khalil N

    2014-04-01

    The internal anal sphincter (IAS) is a major contributing factor to pressure within the anal canal and is required for maintenance of rectoanal continence. IAS damage or weakening results in fecal incontinence. We have demonstrated that bioengineered, intrinsically innervated, human IAS tissue replacements possess key aspects of IAS physiology, such as the generation of spontaneous basal tone and contraction/relaxation in response to neurotransmitters. The objective of this study is to demonstrate the feasibility of implantation of bioengineered IAS constructs in the perianal region of athymic rats. Human IAS tissue constructs were bioengineered from isolated human IAS circular smooth muscle cells and human enteric neuronal progenitor cells. After maturation of the bioengineered constructs in culture, they were implanted operatively into the perianal region of athymic rats. Platelet-derived growth factor was delivered to the implanted constructs through a microosmotic pump. Implanted constructs were retrieved from the animals 4 weeks postimplantation. Animals tolerated the implantation well, and there were no early postoperative complications. Normal stooling was observed during the implantation period. At harvest, implanted constructs were adherent to the perirectal rat tissue and appeared healthy and pink. Immunohistochemical analysis revealed neovascularization. Implanted smooth muscle cells maintained contractile phenotype. Bioengineered constructs responded in vitro in a tissue chamber to neuronally evoked relaxation in response to electrical field stimulation and vasoactive intestinal peptide, indicating the preservation of neuronal networks. Our results indicate that bioengineered innervated IAS constructs can be used to augment IAS function in an animal model. This is a regenerative medicine based therapy for fecal incontinence that would directly address the dysfunction of the IAS muscle. Copyright © 2014 Mosby, Inc. All rights reserved.

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

    DEFF Research Database (Denmark)

    Seminatore, Christine; Polentes, Jerome; Ellman, Ditte

    2010-01-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    Iidaka, Tetsuya; Harada, Tokiko; Sadato, Norihiro

    2014-12-03

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

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Ola Alsalman

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

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

    Science.gov (United States)

    Rice, Katherine; Redcay, Elizabeth

    2016-04-01

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

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

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

    2017-12-06

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-01-14

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

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

    International Nuclear Information System (INIS)

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

    2011-01-01

    Research highlights: → Nicotinamide inhibit Sirt1. → MASH1 and Ngn2 activation. → Increase the expression of HB9. → 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 βIII-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 μM) or inhibitor nicotinamide (100 μM). 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. Do neural tube defects lead to structural alterations in the human bladder?

    Science.gov (United States)

    Pazos, Helena M F; Lobo, Márcio Luiz de P; Costa, Waldemar S; Sampaio, Francisco J B; Cardoso, Luis Eduardo M; Favorito, Luciano Alves

    2011-05-01

    Anencephaly is the most severe neural tube defect in human fetuses. The objective of this paper is to analyze the structure of the bladder in anencephalic human fetuses. We studied 40 bladders of normal human fetuses (20 male and 20 female, aged 14 to 23 WPC) and 12 bladders of anencephalic fetuses (5 male and 7 female, aged 18 to 22 WPC). The bladders were removed and processed by routine histological techniques. Stereological analysis of collagen, elastic system fibers and smooth muscle was performed in sections. Data were expressed as volumetric density (Vv-%). The images were captured with Olympus BX51 microscopy and Olympus DP70 camera. The stereological analysis was done using the software Image Pro and Image J. For biochemical analysis, samples were fixed in acetone, and collagen concentrations were expressed as micrograms of hydroxyproline per mg of dry tissue. Means were statistically compared using the unpaired t-test (p<0.05). We observed a significant increase (p<0.0001) in the Vv of collagen in the bladders of anencephalic fetuses (69.71%) when compared to normal fetuses (52.74%), and a significant decrease (p<0.0001) in the Vv of smooth muscle cells in the bladders of anencephalic fetuses (23.96%) when compared to normal fetuses (38.35%). The biochemical analyses showed a higher concentration of total collagen in the bladders of anencephalic fetuses (37354 µg/mg) when compared to normal fetuses (48117 µg/mg, p<0.02). The structural alterations of the bladder found in this study may suggest the existence of functional alterations in the bladder of anencephalic human fetuses.

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

    Science.gov (United States)

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

    2017-08-01

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

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

    Directory of Open Access Journals (Sweden)

    Tatsuro Yamada

    2016-07-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

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

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    Erica L. McGrath

    2017-03-01

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

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

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    Samuel McLenachan

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

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

    2013-01-01

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

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Kyungha Shin

    2016-01-01

    Full Text Available 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.

  6. Micro-Doppler Based Classification of Human Aquatic Activities via Transfer Learning of Convolutional Neural Networks

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    Jinhee Park

    2016-11-01

    Full Text Available Accurate classification of human aquatic activities using radar has a variety of potential applications such as rescue operations and border patrols. Nevertheless, the classification of activities on water using radar has not been extensively studied, unlike the case on dry ground, due to its unique challenge. Namely, not only is the radar cross section of a human on water small, but the micro-Doppler signatures are much noisier due to water drops and waves. In this paper, we first investigate whether discriminative signatures could be obtained for activities on water through a simulation study. Then, we show how we can effectively achieve high classification accuracy by applying deep convolutional neural networks (DCNN directly to the spectrogram of real measurement data. From the five-fold cross-validation on our dataset, which consists of five aquatic activities, we report that the conventional feature-based scheme only achieves an accuracy of 45.1%. In contrast, the DCNN trained using only the collected data attains 66.7%, and the transfer learned DCNN, which takes a DCNN pre-trained on a RGB image dataset and fine-tunes the parameters using the collected data, achieves a much higher 80.3%, which is a significant performance boost.

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

    Science.gov (United States)

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

    2017-03-14

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

  8. Evolutionary Design of Convolutional Neural Networks for Human Activity Recognition in Sensor-Rich Environments

    Science.gov (United States)

    2018-01-01

    Human activity recognition is a challenging problem for context-aware systems and applications. It is gaining interest due to the ubiquity of different sensor sources, wearable smart objects, ambient sensors, etc. This task is usually approached as a supervised machine learning problem, where a label is to be predicted given some input data, such as the signals retrieved from different sensors. For tackling the human activity recognition problem in sensor network environments, in this paper we propose the use of deep learning (convolutional neural networks) to perform activity recognition using the publicly available OPPORTUNITY dataset. Instead of manually choosing a suitable topology, we will let an evolutionary algorithm design the optimal topology in order to maximize the classification F1 score. After that, we will also explore the performance of committees of the models resulting from the evolutionary process. Results analysis indicates that the proposed model was able to perform activity recognition within a heterogeneous sensor network environment, achieving very high accuracies when tested with new sensor data. Based on all conducted experiments, the proposed neuroevolutionary system has proved to be able to systematically find a classification model which is capable of outperforming previous results reported in the state-of-the-art, showing that this approach is useful and improves upon previously manually-designed architectures. PMID:29690587

  9. Evolutionary Design of Convolutional Neural Networks for Human Activity Recognition in Sensor-Rich Environments

    Directory of Open Access Journals (Sweden)

    Alejandro Baldominos

    2018-04-01

    Full Text Available Human activity recognition is a challenging problem for context-aware systems and applications. It is gaining interest due to the ubiquity of different sensor sources, wearable smart objects, ambient sensors, etc. This task is usually approached as a supervised machine learning problem, where a label is to be predicted given some input data, such as the signals retrieved from different sensors. For tackling the human activity recognition problem in sensor network environments, in this paper we propose the use of deep learning (convolutional neural networks to perform activity recognition using the publicly available OPPORTUNITY dataset. Instead of manually choosing a suitable topology, we will let an evolutionary algorithm design the optimal topology in order to maximize the classification F1 score. After that, we will also explore the performance of committees of the models resulting from the evolutionary process. Results analysis indicates that the proposed model was able to perform activity recognition within a heterogeneous sensor network environment, achieving very high accuracies when tested with new sensor data. Based on all conducted experiments, the proposed neuroevolutionary system has proved to be able to systematically find a classification model which is capable of outperforming previous results reported in the state-of-the-art, showing that this approach is useful and improves upon previously manually-designed architectures.

  10. Evolutionary Design of Convolutional Neural Networks for Human Activity Recognition in Sensor-Rich Environments.

    Science.gov (United States)

    Baldominos, Alejandro; Saez, Yago; Isasi, Pedro

    2018-04-23

    Human activity recognition is a challenging problem for context-aware systems and applications. It is gaining interest due to the ubiquity of different sensor sources, wearable smart objects, ambient sensors, etc. This task is usually approached as a supervised machine learning problem, where a label is to be predicted given some input data, such as the signals retrieved from different sensors. For tackling the human activity recognition problem in sensor network environments, in this paper we propose the use of deep learning (convolutional neural networks) to perform activity recognition using the publicly available OPPORTUNITY dataset. Instead of manually choosing a suitable topology, we will let an evolutionary algorithm design the optimal topology in order to maximize the classification F1 score. After that, we will also explore the performance of committees of the models resulting from the evolutionary process. Results analysis indicates that the proposed model was able to perform activity recognition within a heterogeneous sensor network environment, achieving very high accuracies when tested with new sensor data. Based on all conducted experiments, the proposed neuroevolutionary system has proved to be able to systematically find a classification model which is capable of outperforming previous results reported in the state-of-the-art, showing that this approach is useful and improves upon previously manually-designed architectures.

  11. Efficient and rapid derivation of primitive neural stem cells and generation of brain subtype neurons from human pluripotent stem cells.

    Science.gov (United States)

    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; Vemuri, Mohan C

    2013-11-01

    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.

  12. Shades of grey; Assessing the contribution of the magno- and parvocellular systems to neural processing of the retinal input in the human visual system from the influence of neural population size and its discharge activity on the VEP.

    Science.gov (United States)

    Marcar, Valentine L; Baselgia, Silvana; Lüthi-Eisenegger, Barbara; Jäncke, Lutz

    2018-03-01

    Retinal input processing in the human visual system involves a phasic and tonic neural response. We investigated the role of the magno- and parvocellular systems by comparing the influence of the active neural population size and its discharge activity on the amplitude and latency of four VEP components. We recorded the scalp electric potential of 20 human volunteers viewing a series of dartboard images presented as a pattern reversing and pattern on-/offset stimulus. These patterns were designed to vary both neural population size coding the temporal- and spatial luminance contrast property and the discharge activity of the population involved in a systematic manner. When the VEP amplitude reflected the size of the neural population coding the temporal luminance contrast property of the image, the influence of luminance contrast followed the contrast response function of the parvocellular system. When the VEP amplitude reflected the size of the neural population responding to the spatial luminance contrast property the image, the influence of luminance contrast followed the contrast response function of the magnocellular system. The latencies of the VEP components examined exhibited the same behavior across our stimulus series. This investigation demonstrates the complex interplay of the magno- and parvocellular systems on the neural response as captured by the VEP. It also demonstrates a linear relationship between stimulus property, neural response, and the VEP and reveals the importance of feedback projections in modulating the ongoing neural response. In doing so, it corroborates the conclusions of our previous study.

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

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    Takayuki Kondo

    2014-08-01

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

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

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    Agnete Kirkeby

    2012-06-01

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

  15. GABA and Gap Junctions in the Development of Synchronized Activity in Human Pluripotent Stem Cell-Derived Neural Networks

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    Meeri Eeva-Liisa Mäkinen

    2018-03-01

    Full Text Available The electrical activity of the brain arises from single neurons communicating with each other. However, how single neurons interact during early development to give rise to neural network activity remains poorly understood. We studied the emergence of synchronous neural activity in human pluripotent stem cell (hPSC-derived neural networks simultaneously on a single-neuron level and network level. The contribution of gamma-aminobutyric acid (GABA and gap junctions to the development of synchronous activity in hPSC-derived neural networks was studied with GABA agonist and antagonist and by blocking gap junctional communication, respectively. We characterized the dynamics of the network-wide synchrony in hPSC-derived neural networks with high spatial resolution (calcium imaging and temporal resolution microelectrode array (MEA. We found that the emergence of synchrony correlates with a decrease in very strong GABA excitation. However, the synchronous network was found to consist of a heterogeneous mixture of synchronously active cells with variable responses to GABA, GABA agonists and gap junction blockers. Furthermore, we show how single-cell distributions give rise to the network effect of GABA, GABA agonists and gap junction blockers. Finally, based on our observations, we suggest that the earliest form of synchronous neuronal activity depends on gap junctions and a decrease in GABA induced depolarization but not on GABAA mediated signaling.

  16. GABA and Gap Junctions in the Development of Synchronized Activity in Human Pluripotent Stem Cell-Derived Neural Networks

    Science.gov (United States)

    Mäkinen, Meeri Eeva-Liisa; Ylä-Outinen, Laura; Narkilahti, Susanna

    2018-01-01

    The electrical activity of the brain arises from single neurons communicating with each other. However, how single neurons interact during early development to give rise to neural network activity remains poorly understood. We studied the emergence of synchronous neural activity in human pluripotent stem cell (hPSC)-derived neural networks simultaneously on a single-neuron level and network level. The contribution of gamma-aminobutyric acid (GABA) and gap junctions to the development of synchronous activity in hPSC-derived neural networks was studied with GABA agonist and antagonist and by blocking gap junctional communication, respectively. We characterized the dynamics of the network-wide synchrony in hPSC-derived neural networks with high spatial resolution (calcium imaging) and temporal resolution microelectrode array (MEA). We found that the emergence of synchrony correlates with a decrease in very strong GABA excitation. However, the synchronous network was found to consist of a heterogeneous mixture of synchronously active cells with variable responses to GABA, GABA agonists and gap junction blockers. Furthermore, we show how single-cell distributions give rise to the network effect of GABA, GABA agonists and gap junction blockers. Finally, based on our observations, we suggest that the earliest form of synchronous neuronal activity depends on gap junctions and a decrease in GABA induced depolarization but not on GABAA mediated signaling. PMID:29559893

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

    International Nuclear Information System (INIS)

    Colleoni, Silvia; Galli, Cesare; Giannelli, Serena G.; Armentero, Marie-Therese; Blandini, Fabio; Broccoli, Vania; Lazzari, Giovanna

    2010-01-01

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-04-15

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

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

    Science.gov (United States)

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

    2016-12-01

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

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

    Directory of Open Access Journals (Sweden)

    Xihe Tang

    2016-03-01

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

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

    Science.gov (United States)

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

  2. State of expectancy modulates the neural response to visual food stimuli in humans.

    Science.gov (United States)

    Malik, Saima; McGlone, Francis; Dagher, Alain

    2011-04-01

    Human brain imaging studies demonstrate distributed activation of limbic, paralimbic and sensory systems to food and food-associated cues. Activity in this circuit may be modulated by internal factors, such as hunger, and cognitive factors. Anticipation to eat is one such factor, which likely impacts consummatory behavior. Here, the neural substrates of food expectancy were identified in 10 healthy male participants who underwent two whole-brain functional Magnetic Resonance Imaging scans on separate days. Fasted subjects viewed images of food and scenery, in two counterbalanced states. During one condition, subjects were 'expecting' to eat right after the scan and during the other they were 'not expecting' to eat for 1 h after the scan. Food pictures compared with scenery yielded bilateral activation in visual areas as well as in the left insula and amygdala in both conditions. The left dorsolateral prefrontal cortex, hippocampus and putamen were additionally activated in the 'not expecting' condition while right orbitofrontal cortex activity was enhanced in the 'expecting' condition. These data suggest that cognitive manipulations affect the response to food cues in the prefrontal cortex, in areas involved in the planning and control of motivated behaviors, while the amygdala and insula responded equally in both conditions, consistent with a more basic role in homeostatically driven appetitive behavior. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Silencing of CXCR4 inhibits tumor cell proliferation and neural invasion in human hilar cholangiocarcinoma.

    Science.gov (United States)

    Tan, Xin-Yu; Chang, Shi; Liu, Wei; Tang, Hui-Huan

    2014-03-01

    To evaluate the expression of CXC motif chemokine receptor 4 (CXCR4) in the tissues of patients with hilar cholangiocarcinoma (hilar-CCA) and to investigate the cell proliferation and frequency of neural invasion (NI) influenced by RNAi-mediated CXCR4 silencing. An immunohistochemical technique was used to detect the expression of CXCR4 in 41 clinical tissues, including hilar-CCA, cholangitis, and normal bile duct tissues. The effects of small interference RNA (siRNA)-mediated CXCR4 silencing were detected in the hilar-CCA cell line QBC939. Cell proliferation was determined by MTT. Expression of CXCR4 was monitored by quantitative real time polymerase chain reaction and Western blot analysis. The NI ability of hilar-CCA cells was evaluated using a perineural cell and hilar-CCA cell coculture migration assay. The expression of CXCR4 was significantly induced in clinical hilar-CCA tissue. There was a positive correlation between the expression of CXCR4 and lymph node metastasis/NI in hilar-CCA patients (philar-CCA. CXCR4 is involved in the invasion and proliferation of human hilar-CCA cell line QBC939, indicating that CXCR4 could be a promising therapeutic target for hilar-CCA.

  4. Neural mechanisms of human perceptual choice under focused and divided attention.

    Science.gov (United States)

    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. Copyright © 2015 the authors 0270-6474/15/353485-14$15.00/0.

  5. Human Neural Stem Cell Aging Is Counteracted by α-Glycerylphosphorylethanolamine.

    Science.gov (United States)

    Daniele, Simona; Da Pozzo, Eleonora; Iofrida, Caterina; Martini, Claudia

    2016-07-20

    Neural stem cells (NSCs) represent a subpopulation of cells, located in specific regions of the adult mammalian brain, with the ability of self-renewing and generating neurons and glia. In aged NSCs, modifications in the amount and composition of membrane proteins/lipids, which lead to a reduction in membrane fluidity and cholinergic activities, have been reported. In this respect, molecules that are effective at normalizing the membrane composition and cholinergic signaling could counteract stem cell aging. α-Glycerylphosphorylethanolamine (GPE), a nootropic drug, plays a role in phospholipid biosynthesis and acetylcholine release. Herein, GPE was assayed on human NSC cultures and on hydroxyurea-aged cells. Using cell counting, colorimetric, and fluorimetric analyses, immunoenzymatic assays, and real time PCR experiments, NSC culture proliferation, senescence, reactive oxygen species, and ADP/ATP levels were assessed. Aged NSCs exhibited cellular senescence, decreased proliferation, and an impairment in mitochondrial metabolism. These changes included a substantial induction in the nuclear factor NF-κB, a key inflammatory mediator. GPE cell treatment significantly protected the redox state and functional integrity of mitochondria, and counteracted senescence and NF-κB activation. In conclusion, our data show the beneficial properties of GPE in this model of stem cell aging.

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

    Directory of Open Access Journals (Sweden)

    Tetsuro Yasui

    2017-06-01

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

  7. Lesion-induced increase in survival and migration of human neural progenitor cells releasing GDNF

    Science.gov (United States)

    Behrstock, Soshana; Ebert, Allison D.; Klein, Sandra; Schmitt, Melanie; Moore, Jeannette M.; Svendsen, Clive N.

    2009-01-01

    The use of human neural progenitor cells (hNPC) has been proposed to provide neuronal replacement or astrocytes delivering growth factors for brain disorders such as Parkinson’s and Huntington’s disease. Success in such studies likely requires migration from the site of transplantation and integration into host tissue in the face of ongoing damage. In the current study, hNPC modified to release glial cell line derived neurotrophic factor (hNPCGDNF) were transplanted into either intact or lesioned animals. GDNF release itself had no effect on the survival, migration or differentiation of the cells. The most robust migration and survival was found using a direct lesion of striatum (Huntington’s model) with indirect lesions of the dopamine system (Parkinson’s model) or intact animals showing successively less migration and survival. No lesion affected differentiation patterns. We conclude that the type of brain injury dictates migration and integration of hNPC which has important consequences when considering transplantation of these cells as a therapy for neurodegenerative diseases. PMID:19044202

  8. Cholinergic enhancement of visual attention and neural oscillations in the human brain.

    Science.gov (United States)

    Bauer, Markus; Kluge, Christian; Bach, Dominik; Bradbury, David; Heinze, Hans Jochen; Dolan, Raymond J; Driver, Jon

    2012-03-06

    Cognitive processes such as visual perception and selective attention induce specific patterns of brain oscillations. The neurochemical bases of these spectral changes in neural activity are largely unknown, but neuromodulators are thought to regulate processing. The cholinergic system is linked to attentional function in vivo, whereas separate in vitro studies show that cholinergic agonists induce high-frequency oscillations in slice preparations. This has led to theoretical proposals that cholinergic enhancement of visual attention might operate via gamma oscillations in visual cortex, although low-frequency alpha/beta modulation may also play a key role. Here we used MEG to record cortical oscillations in the context of administration of a cholinergic agonist (physostigmine) during a spatial visual attention task in humans. This cholinergic agonist enhanced spatial attention effects on low-frequency alpha/beta oscillations in visual cortex, an effect correlating with a drug-induced speeding of performance. By contrast, the cholinergic agonist did not alter high-frequency gamma oscillations in visual cortex. Thus, our findings show that cholinergic neuromodulation enhances attentional selection via an impact on oscillatory synchrony in visual cortex, for low rather than high frequencies. We discuss this dissociation between high- and low-frequency oscillations in relation to proposals that lower-frequency oscillations are generated by feedback pathways within visual cortex. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Elham Hashemi

    2017-01-01

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

  10. Lentiviral vector-mediated genetic modification of human neural progenitor cells for ex vivo gene therapy.

    Science.gov (United States)

    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.

  11. DeepFix: A Fully Convolutional Neural Network for Predicting Human Eye Fixations.

    Science.gov (United States)

    Kruthiventi, Srinivas S S; Ayush, Kumar; Babu, R Venkatesh

    2017-09-01

    Understanding and predicting the human visual attention mechanism is an active area of research in the fields of neuroscience and computer vision. In this paper, we propose DeepFix, a fully convolutional neural network, which models the bottom-up mechanism of visual attention via saliency prediction. Unlike classical works, which characterize the saliency map using various hand-crafted features, our model automatically learns features in a hierarchical fashion and predicts the saliency map in an end-to-end manner. DeepFix is designed to capture semantics at multiple scales while taking global context into account, by using network layers with very large receptive fields. Generally, fully convolutional nets are spatially invariant-this prevents them from modeling location-dependent patterns (e.g., centre-bias). Our network handles this by incorporating a novel location-biased convolutional layer. We evaluate our model on multiple challenging saliency data sets and show that it achieves the state-of-the-art results.

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

    Directory of Open Access Journals (Sweden)

    Meyer Anne K

    2009-06-01

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

  13. Neural mechanisms of human perceptual choice under focused and divided attention

    Science.gov (United States)

    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

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

    Science.gov (United States)

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

    2015-02-01

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

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

    Directory of Open Access Journals (Sweden)

    Lu Chen

    2014-06-01

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

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

    Science.gov (United States)

    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.

  17. Drive Control Scheme of Electric Power Assisted Wheelchair Based on Neural Network Learning of Human Wheelchair Operation Characteristics

    Science.gov (United States)

    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.

  18. Comprehensive quantitative comparison of the membrane proteome and PTM-ome of human embryonic stem cells and neural stem cells

    DEFF Research Database (Denmark)

    Braga, Marcella Nunes de Melo; Schulz, Melanie; Jakobsen, Lene

    Introduction: Human embryonic stem cells (hESCs) can differentiate into all three germ layers and self-renew. Due to its ability to differentiate in vitro into human neural stem cells (hNSCs), which can further be differentiated into motor neurons and dopaminergic neurons, these cells are potential...... identified phosphorylated and SA glycosylated proteins, respectively. This study allowed us to identify several significantly regulated proteins during the differentiation process, including proteins involved in the early embryonic development as well as in the neural development. In the latter group...... of proteins we could identify a number of proteins associated with synaptic vesicles, which are vesicles that store neurotransmitters in the nerve-terminals. An example of an upregulated protein in hESCs is the gap junction alpha 1 (GJA1), a phosphorylated protein which plays a crucial role in embryonic...

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

    Directory of Open Access Journals (Sweden)

    German Ignacio Parisi

    2015-06-01

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

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

    Science.gov (United States)

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

    2016-04-01

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

  1. Neurons from the adult human dentate nucleus: neural networks in the neuron classification.

    Science.gov (United States)

    Grbatinić, Ivan; Marić, Dušica L; Milošević, Nebojša T

    2015-04-07

    Topological (central vs. border neuron type) and morphological classification of adult human dentate nucleus neurons according to their quantified histomorphological properties using neural networks on real and virtual neuron samples. In the real sample 53.1% and 14.1% of central and border neurons, respectively, are classified correctly with total of 32.8% of misclassified neurons. The most important result present 62.2% of misclassified neurons in border neurons group which is even greater than number of correctly classified neurons (37.8%) in that group, showing obvious failure of network to classify neurons correctly based on computational parameters used in our study. On the virtual sample 97.3% of misclassified neurons in border neurons group which is much greater than number of correctly classified neurons (2.7%) in that group, again confirms obvious failure of network to classify neurons correctly. Statistical analysis shows that there is no statistically significant difference in between central and border neurons for each measured parameter (p>0.05). Total of 96.74% neurons are morphologically classified correctly by neural networks and each one belongs to one of the four histomorphological types: (a) neurons with small soma and short dendrites, (b) neurons with small soma and long dendrites, (c) neuron with large soma and short dendrites, (d) neurons with large soma and long dendrites. Statistical analysis supports these results (pneurons can be classified in four neuron types according to their quantitative histomorphological properties. These neuron types consist of two neuron sets, small and large ones with respect to their perykarions with subtypes differing in dendrite length i.e. neurons with short vs. long dendrites. Besides confirmation of neuron classification on small and large ones, already shown in literature, we found two new subtypes i.e. neurons with small soma and long dendrites and with large soma and short dendrites. These neurons are

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

    Science.gov (United States)

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

    2013-01-01

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

  3. Using repetitive transcranial magnetic stimulation to study the underlying neural mechanisms of human motor learning and memory.

    Science.gov (United States)

    Censor, Nitzan; Cohen, Leonardo G

    2011-01-01

    In the last two decades, there has been a rapid development in the research of the physiological brain mechanisms underlying human motor learning and memory. While conventional memory research performed on animal models uses intracellular recordings, microfusion of protein inhibitors to specific brain areas and direct induction of focal brain lesions, human research has so far utilized predominantly behavioural approaches and indirect measurements of neural activity. Repetitive transcranial magnetic stimulation (rTMS), a safe non-invasive brain stimulation technique, enables the study of the functional role of specific cortical areas by evaluating the behavioural consequences of selective modulation of activity (excitation or inhibition) on memory generation and consolidation, contributing to the understanding of the neural substrates of motor learning. Depending on the parameters of stimulation, rTMS can also facilitate learning processes, presumably through purposeful modulation of excitability in specific brain regions. rTMS has also been used to gain valuable knowledge regarding the timeline of motor memory formation, from initial encoding to stabilization and long-term retention. In this review, we summarize insights gained using rTMS on the physiological and neural mechanisms of human motor learning and memory. We conclude by suggesting possible future research directions, some with direct clinical implications.

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

    Directory of Open Access Journals (Sweden)

    Hong J Lee

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

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

    Directory of Open Access Journals (Sweden)

    Roman Bauer

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

  6. Neurally mediated airway constriction in human and other species: a comparative study using precision-cut lung slices (PCLS.

    Directory of Open Access Journals (Sweden)

    Marco Schlepütz

    Full Text Available The peripheral airway innervation of the lower respiratory tract of mammals is not completely functionally characterized. Recently, we have shown in rats that precision-cut lung slices (PCLS respond to electric field stimulation (EFS and provide a useful model to study neural airway responses in distal airways. Since airway responses are known to exhibit considerable species differences, here we examined the neural responses of PCLS prepared from mice, rats, guinea pigs, sheep, marmosets and humans. Peripheral neurons were activated either by EFS or by capsaicin. Bronchoconstriction in response to identical EFS conditions varied between species in magnitude. Frequency response curves did reveal further species-dependent differences of nerve activation in PCLS. Atropine antagonized the EFS-induced bronchoconstriction in human, guinea pig, sheep, rat and marmoset PCLS, showing cholinergic responses. Capsaicin (10 µM caused bronchoconstriction in human (4 from 7 and guinea pig lungs only, indicating excitatory non-adrenergic non-cholinergic responses (eNANC. However, this effect was notably smaller in human responder (30 ± 7.1% than in guinea pig (79 ± 5.1% PCLS. The transient receptor potential (TRP channel blockers SKF96365 and ruthenium red antagonized airway contractions after exposure to EFS or capsaicin in guinea pigs. In conclusion, the different species show distinct patterns of nerve-mediated bronchoconstriction. In the most common experimental animals, i.e. in mice and rats, these responses differ considerably from those in humans. On the other hand, guinea pig and marmoset monkey mimic human responses well and may thus serve as clinically relevant models to study neural airway responses.

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

    Science.gov (United States)

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

    2017-10-12

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

  8. Enhancement of human neural stem cell self-renewal in 3D hypoxic culture.

    Science.gov (United States)

    Ghourichaee, Sasan Sharee; Powell, Elizabeth M; Leach, Jennie B

    2017-05-01

    The pathology of neurological disorders is associated with the loss of neuronal and glial cells that results in functional impairments. Human neural stem cells (hNSCs), due to their self-renewing and multipotent characteristics, possess enormous tissue-specific regenerative potential. However, the efficacy of clinical applications is restricted due to the lack of standardized in vitro cell production methods with the capability of generating hNSC populations with well-defined cellular compositions. At any point, a population of hNSCs may include undifferentiated stem cells, intermediate and terminally differentiated progenies, and dead cells. Due to the plasticity of hNSCs, environmental cues play crucial roles in determining the cellular composition of hNSC cultures over time. Here, we investigated the independent and synergistic effect of three important environmental factors (i.e., culture dimensionality, oxygen concentration, and growth factors) on the survival, renewal potential, and differentiation of hNSCs. Our experimental design included two dimensional (2D) versus three dimensional (3D) cultures and normoxic (21% O 2 ) versus hypoxic (3% O 2 ) conditions in the presence and absence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). Additionally, we discuss the feasibility of mathematical models that predict hNSC growth and differentiation under these culture conditions by adopting a negative feedback regulatory term. Our results indicate that the synergistic effect of culture dimensionality and hypoxic oxygen concentration in the presence of growth factors enhances the proliferation of viable, undifferentiated hNSCs. Moreover, the same synergistic effect in the absence of growth factors promotes the differentiation of hNSCs. Biotechnol. Bioeng. 2017;114: 1096-1106. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    1999-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Methichit Wattanapanitch

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

  12. Neural Networks

    International Nuclear Information System (INIS)

    Smith, Patrick I.

    2003-01-01

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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    Human embryonic stem cells (hESCs) can differentiate into neural stem cells (NSCs), which can further be differentiated into neurons and glia cells. Therefore, these cells have huge potential as source for treatment of neurological diseases. Membrane-associated proteins are very important......ESCs and NSCs as well as to investigate potential new markers for these two cell stages, we performed large-scale quantitative membrane-proteomic of hESCs and NSCs. This approach employed membrane purification followed by peptide dimethyl labeling and peptide enrichment to study the membrane subproteome as well...... in which 78% of phosphopeptides were identified with ≥99% confidence in site assignment and 1810 unique formerly sialylated N-linked glycopeptides. Several proteins were identified as significantly regulated in hESCs and NSC, including proteins involved in the early embryonic and neural development...

  14. Distinct contributions of functional and deep neural network features to representational similarity of scenes in human brain and behavior.

    Science.gov (United States)

    Groen, Iris Ia; Greene, Michelle R; Baldassano, Christopher; Fei-Fei, Li; Beck, Diane M; Baker, Chris I

    2018-03-07

    Inherent correlations between visual and semantic features in real-world scenes make it difficult to determine how different scene properties contribute to neural representations. Here, we assessed the contributions of multiple properties to scene representation by partitioning the variance explained in human behavioral and brain measurements by three feature models whose inter-correlations were minimized a priori through stimulus preselection. Behavioral assessments of scene similarity reflected unique contributions from a functional feature model indicating potential actions in scenes as well as high-level visual features from a deep neural network (DNN). In contrast, similarity of cortical responses in scene-selective areas was uniquely explained by mid- and high-level DNN features only, while an object label model did not contribute uniquely to either domain. The striking dissociation between functional and DNN features in their contribution to behavioral and brain representations of scenes indicates that scene-selective cortex represents only a subset of behaviorally relevant scene information.

  15. Exposure to titanium dioxide and other metallic oxide nanoparticles induces cytotoxicity on human neural cells and fibroblasts

    Directory of Open Access Journals (Sweden)

    James C K Lai

    2008-12-01

    Full Text Available James C K Lai1, Maria B Lai1, Sirisha Jandhyam1, Vikas V Dukhande1, Alok Bhushan1, Christopher K Daniels1, Solomon W Leung21Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, and Biomedical Research Institute; 2Department of Civil and Environmental Engineering, College of Engineering and Biomedical Research Institute, Idaho State University, Pocatello, ID, USAAbstract: The use of titanium dioxide (TiO2 in various industrial applications (eg, production of paper, plastics, cosmetics, and paints has been expanding thereby increasing the occupational and other environmental exposure of these nanoparticles to humans and other species. However, the health effects of exposure to TiO2 nanoparticles have not been systematically assessed even though recent studies suggest that such exposure induces inflammatory responses in lung tissue and cells. Because the effects of such nanoparticles on human neural cells are unknown, we have determined the putative cytotoxic effects of these nanoparticles on human astrocytes-like astrocytoma U87 cells and compared their effects on normal human fibroblasts. We found that TiO2 micro- and nanoparticles induced cell death on both human cell types in a concentration-related manner. We further noted that zinc oxide (ZnO nanoparticles were the most effective, TiO2 nanoparticles the second most effective, and magnesium oxide (MgO nanoparticles the least effective in inducing cell death in U87 cells. The cell death mechanisms underlying the effects of TiO2 micro- and nanoparticles on U87 cells include apoptosis, necrosis, and possibly apoptosis-like and necrosis-like cell death types. Thus, our findings may have toxicological and other pathophysiological implications on exposure of humans and other mammalian species to metallic oxide nanoparticles.Keywords: cytotoxicity of titanium dioxide micro- and nanoparticles, cytotoxicity of zinc oxide and magnesium oxide nanoparticles, human neural cells

  16. Mapping face categorization in the human ventral occipitotemporal cortex with direct neural intracranial recordings.

    Science.gov (United States)

    Rossion, Bruno; Jacques, Corentin; Jonas, Jacques

    2018-02-26

    The neural basis of face categorization has been widely investigated with functional magnetic resonance imaging (fMRI), identifying a set of face-selective local regions in the ventral occipitotemporal cortex (VOTC). However, indirect recording of neural activity with fMRI is associated with large fluctuations of signal across regions, often underestimating face-selective responses in the anterior VOTC. While direct recording of neural activity with subdural grids of electrodes (electrocorticography, ECoG) or depth electrodes (stereotactic electroencephalography, SEEG) offers a unique opportunity to fill this gap in knowledge, these studies rather reveal widely distributed face-selective responses. Moreover, intracranial recordings are complicated by interindividual variability in neuroanatomy, ambiguity in definition, and quantification of responses of interest, as well as limited access to sulci with ECoG. Here, we propose to combine SEEG in large samples of individuals with fast periodic visual stimulation to objectively define, quantify, and characterize face categorization across the whole VOTC. This approach reconciles the wide distribution of neural face categorization responses with their (right) hemispheric and regional specialization, and reveals several face-selective regions in anterior VOTC sulci. We outline the challenges of this research program to understand the neural basis of face categorization and high-level visual recognition in general. © 2018 New York Academy of Sciences.

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    with reduced attention to fear. Erythropoietin additionally reduced recognition of fearful facial expressions without affecting recognition of other emotional expressions. These actions occurred in the absence of changes in hematological parameters. CONCLUSIONS: The present study demonstrates that Epo directly......) versus saline on the neural processing of happy and fearful faces in 23 healthy volunteers. Facial expression recognition was assessed outside the scanner. RESULTS: One week after administration, Epo reduced neural response to fearful versus neutral faces in the occipito-parietal cortex consistent...... study aimed to explore the effects of Epo on neural and behavioral measures of emotional processing relevant for depression and the effects of conventional antidepressant medication. METHODS: In the present study, we used functional magnetic resonance imaging to explore the effects of Epo (40,000 IU...

  18. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation.

    Directory of Open Access Journals (Sweden)

    Michael P Hefferan

    Full Text Available 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 SOD1(G93A 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 SOD1(G93A rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A animals.Presymptomatic SOD1(G93A 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 SOD1(G93A 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 SOD1(G93A 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 SOD1(G93A rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65% loss of large caliber descending motor axons.These data demonstrate that in order to achieve a more

  19. Emotional expectations influence neural sensitivity to fearful faces in humans:An event-related potential study

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The present study tested whether neural sensitivity to salient emotional facial expressions was influenced by emotional expectations induced by a cue that validly predicted the expression of a subsequently presented target face. Event-related potentials (ERPs) elicited by fearful and neutral faces were recorded while participants performed a gender discrimination task under cued (‘expected’) and uncued (‘unexpected’) conditions. The behavioral results revealed that accuracy was lower for fearful compared with neutral faces in the unexpected condition, while accuracy was similar for fearful and neutral faces in the expected condition. ERP data revealed increased amplitudes in the P2 component and 200–250 ms interval for unexpected fearful versus neutral faces. By contrast, ERP responses were similar for fearful and neutral faces in the expected condition. These findings indicate that human neural sensitivity to fearful faces is modulated by emotional expectations. Although the neural system is sensitive to unpredictable emotionally salient stimuli, sensitivity to salient stimuli is reduced when these stimuli are predictable.

  20. Generation of Regionally Specific Neural Progenitor Cells (NPCs) and Neurons from Human Pluripotent Stem Cells (hPSCs).

    Science.gov (United States)

    Cutts, Josh; Brookhouser, Nicholas; Brafman, David A

    2016-01-01

    Neural progenitor cells (NPCs) derived from human pluripotent stem cells (hPSCs) are a multipotent cell population capable of long-term expansion and differentiation into a variety of neuronal subtypes. As such, NPCs have tremendous potential for disease modeling, drug screening, and regenerative medicine. Current methods for the generation of NPCs results in cell populations homogenous for pan-neural markers such as SOX1 and SOX2 but heterogeneous with respect to regional identity. In order to use NPCs and their neuronal derivatives to investigate mechanisms of neurological disorders and develop more physiologically relevant disease models, methods for generation of regionally specific NPCs and neurons are needed. Here, we describe a protocol in which exogenous manipulation of WNT signaling, through either activation or inhibition, during neural differentiation of hPSCs, promotes the formation of regionally homogenous NPCs and neuronal cultures. In addition, we provide methods to monitor and characterize the efficiency of hPSC differentiation to these regionally specific cell identities.

  1. Effects of light emitting diode irradiation on neural differentiation of human umbilical cord-derived mesenchymal cells.

    Science.gov (United States)

    Dehghani-Soltani, Samereh; Shojaee, Mohammad; Jalalkamali, Mahshid; Babaee, Abdolreza; Nematollahi-Mahani, Seyed Noureddin

    2017-08-30

    Recently, light emitting diodes (LEDs) have been introduced as a potential physical factor for proliferation and differentiation of various stem cells. Among the mesenchymal stem cells human umbilical cord matrix-derived mesenchymal (hUCM) cells are easily propagated in the laboratory and their low immunogenicity make them more appropriate for regenerative medicine procedures. We aimed at this study to evaluate the effect of red and green light emitted from LED on the neural lineage differentiation of hUCM cells in the presence or absence of retinoic acid (RA). Harvested hUCM cells exhibited mesenchymal and stemness properties. Irradiation of these cells by green and red LED with or without RA pre-treatment successfully differentiated them into neural lineage when the morphology of the induced cells, gene expression pattern (nestin, β-tubulin III and Olig2) and protein synthesis (anti-nestin, anti-β-tubulin III, anti-GFAP and anti-O4 antibodies) was evaluated. These data point for the first time to the fact that LED irradiation and optogenetic technology may be applied for neural differentiation and neuronal repair in regenerative medicine.

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

    Directory of Open Access Journals (Sweden)

    Anh Vu Le

    2017-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

    Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ42). However, their effect on the physiologic functions of γ-secretase has not been tested in human model systems. γ-Secretase regulates fate determination of neural progenitor cells. Thus, we studied the impact of SGSMs on the neuronal differentiation of ReNcell VM (ReN) human neural progenitor cells (hNPCs). Quantitative PCR analysis showed that treatment of neurosphere-like ReN cell aggregate cultures with γ-secretase inhibitors (GSIs), but not SGSMs, induced a 2- to 4-fold increase in the expression of the neuronal markers Tuj1 and doublecortin. GSI treatment also induced neuronal marker protein expression, as shown by Western blot analysis. In the same conditions, SGSM treatment selectively reduced endogenous Aβ42 levels by ∼80%. Mechanistically, we found that Notch target gene expressions were selectively inhibited by a GSI, not by SGSM treatment. We can assert, for the first time, that SGSMs do not affect the neuronal differentiation of hNPCs while selectively decreasing endogenous Aβ42 levels in the same conditions. Our results suggest that our hNPC differentiation system can serve as a useful model to test the impact of GSIs and SGSMs on both endogenous Aβ levels and γ-secretase physiologic functions including endogenous Notch signaling.—D’Avanzo, C., Sliwinski, C., Wagner, S. L., Tanzi, R. E., Kim, D. Y., Kovacs, D. M. γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation. PMID:25903103

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

    Directory of Open Access Journals (Sweden)

    Ahmadi Majid

    2003-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Katja M. Piltti

    2015-09-01

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

  6. Beneficial effect of human induced pluripotent stem cell-derived neural precursors in spinal cord injury repair

    Czech Academy of Sciences Publication Activity Database

    Romanyuk, Nataliya; Amemori, Takashi; Turnovcová, Karolína; Procházka, Pavel; Onteniente, B.; Syková, Eva; Jendelová, Pavla

    2015-01-01

    Roč. 24, č. 9 (2015), s. 1781-1797 ISSN 0963-6897 R&D Projects: GA MŠk LH12024; GA ČR(CZ) GA13-00939S; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) ED1.1.00/02.0109; GA MŠk(CZ) LO1309 Institutional support: RVO:68378041 Keywords : human induced pluripotent stem cells * neural precursors * spinal cord injury Subject RIV: FH - Neurology Impact factor: 3.427, year: 2015

  7. Mechanical Design Of Prototype Exoskeleton Robotic System For Human Leg Movements And Implementation Of Gait Data With Neural Network

    Directory of Open Access Journals (Sweden)

    Evren Meltem Toygar

    2012-06-01

    Full Text Available Target of this study is designing a exoskeleton system for single lower extremity disabled person and controlling this exoskeleton system with neural network. Exoskeleton system is modeled by using SolidWorks. At the same time, gait data is acquired on human body and sole is divided four parts after that reaction forces are gauged during the walking. Distributions of strain and deformation are obtained by using experimental gait data. The walking is designed using the obtained data and walking data is derived for control stage. Power requirements of actuators are defined.

  8. Dissociable neural response signatures for slow amplitude and frequency modulation in human auditory cortex.

    Science.gov (United States)

    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.

  9. Neural ECM in laminar organization and connectivity development in healthy and diseased human brain

    NARCIS (Netherlands)

    Jovanov Milošević, Nataša; Judaš, Miloš; Aronica, Eleonora; Kostovic, Ivica

    2014-01-01

    The neural extracellular matrix (ECM) provides a supportive framework for differentiating cells and their processes and regulates morphogenetic events by spatially and temporally relevant localization of signaling molecules and by direct signaling via receptor and/or coreceptor-mediated action. The

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

    Science.gov (United States)

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

    2010-01-01

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

  11. Leukemia inhibitory factor (LIF) enhances MAP2 + and HUC/D + neurons and influences neurite extension during differentiation of neural progenitors derived from human embryonic stem cells.

    Science.gov (United States)

    Leukemia Inhibitory Factor (L1F), a member of the Interleukin 6 cytokine family, has a role in differentiation of Human Neural Progenitor (hNP) cells in vitro. hNP cells, derived from Human Embryonic Stem (hES) cells, have an unlimited capacity for self-renewal in monolayer cultu...

  12. Characterizing low dose and dose rate effects in rodent and human neural stem cells exposed to proton and gamma irradiation

    Directory of Open Access Journals (Sweden)

    Bertrand P. Tseng

    2013-01-01

    Full Text Available Past work has shown that exposure to gamma rays and protons elicit a persistent oxidative stress in rodent and human neural stem cells (hNSCs. We have now adapted these studies to more realistic exposure scenarios in space, using lower doses and dose rates of these radiation modalities, to further elucidate the role of radiation-induced oxidative stress in these cells. Rodent neural stem and precursor cells grown as neurospheres and human neural stem cells grown as monolayers were subjected to acute and multi-dosing paradigms at differing dose rates and analyzed for changes in reactive oxygen species (ROS, reactive nitrogen species (RNS, nitric oxide and superoxide for 2 days after irradiation. While acute exposures led to significant changes in both cell types, hNSCs in particular, exhibited marked and significant elevations in radiation-induced oxidative stress. Elevated oxidative stress was more significant in hNSCs as opposed to their rodent counterparts, and hNSCs were significantly more sensitive to low dose exposures in terms of survival. Combinations of protons and γ-rays delivered as lower priming or higher challenge doses elicited radioadaptive changes that were associated with improved survival, but in general, only under conditions where the levels of reactive species were suppressed compared to cells irradiated acutely. Protective radioadaptive effects on survival were eliminated in the presence of the antioxidant N-acetylcysteine, suggesting further that radiation-induced oxidative stress could activate pro-survival signaling pathways that were sensitive to redox state. Data corroborates much of our past work and shows that low dose and dose rate exposures elicit significant changes in oxidative stress that have functional consequences on survival.

  13. Investigation of Slow-wave Activity Saturation during Surgical Anesthesia Reveals a Signature of Neural Inertia in Humans.

    Science.gov (United States)

    Warnaby, Catherine E; Sleigh, Jamie W; Hight, Darren; Jbabdi, Saad; Tracey, Irene

    2017-10-01

    Previously, we showed experimentally that saturation of slow-wave activity provides a potentially individualized neurophysiologic endpoint for perception loss during anesthesia. Furthermore, it is clear that induction and emergence from anesthesia are not symmetrically reversible processes. The observed hysteresis is potentially underpinned by a neural inertia mechanism as proposed in animal studies. In an advanced secondary analysis of 393 individual electroencephalographic data sets, we used slow-wave activity dose-response relationships to parameterize slow-wave activity saturation during induction and emergence from surgical anesthesia. We determined whether neural inertia exists in humans by comparing slow-wave activity dose responses on induction and emergence. Slow-wave activity saturation occurs for different anesthetics and when opioids and muscle relaxants are used during surgery. There was wide interpatient variability in the hypnotic concentrations required to achieve slow-wave activity saturation. Age negatively correlated with power at slow-wave activity saturation. On emergence, we observed abrupt decreases in slow-wave activity dose responses coincident with recovery of behavioral responsiveness in ~33% individuals. These patients are more likely to have lower power at slow-wave activity saturation, be older, and suffer from short-term confusion on emergence. Slow-wave activity saturation during surgical anesthesia implies that large variability in dosing is required to achieve a targeted potential loss of perception in individual patients. A signature for neural inertia in humans is the maintenance of slow-wave activity even in the presence of very-low hypnotic concentrations during emergence from anesthesia.

  14. Glycoconjugates reveal diversity of human neural stem cells (hNSCs) derived from human induced pluripotent stem cells (hiPSCs).

    Science.gov (United States)

    Kandasamy, Majury; Roll, Lars; Langenstroth, Daniel; Brüstle, Oliver; Faissner, Andreas

    2017-06-01

    Neural stem cells (NSCs) have the ability to self-renew and to differentiate into various cell types of the central nervous system. This potential can be recapitulated by human induced pluripotent stem cells (hiPSCs) in vitro. The differentiation capacity of hiPSCs is characterized by several stages with distinct morphologies and the expression of various marker molecules. We used the monoclonal antibodies (mAbs) 487 LeX , 5750 LeX and 473HD to analyze the expression pattern of particular carbohydrate motifs as potential markers at six differentiation stages of hiPSCs. Mouse ESCs were used as a comparison. At the pluripotent stage, 487 LeX -, 5750 LeX - and 473HD-related glycans were differently expressed. Later, cells of the three germ layers in embryoid bodies (hEBs) and, even after neuralization of hEBs, subpopulations of cells were labeled with these surface antibodies. At the human rosette-stage of NSCs (hR-NSC), LeX- and 473HD-related epitopes showed antibody-specific expression patterns. We also found evidence that these surface antibodies could be used to distinguish the hR-NSCs from the hSR-NSCs stages. Characterization of hNSCs FGF-2/EGF derived from hSR-NSCs revealed that both LeX antibodies and the 473HD antibody labeled subpopulations of hNSCs FGF-2/EGF . Finally, we identified potential LeX carrier molecules that were spatiotemporally regulated in early and late stages of differentiation. Our study provides new insights into the regulation of glycoconjugates during early human stem cell development. The mAbs 487 LeX , 5750 LeX and 473HD are promising tools for identifying distinct stages during neural differentiation.

  15. A chemically defined substrate for the expansion and neuronal differentiation of human pluripotent stem cell-derived neural progenitor cells

    Directory of Open Access Journals (Sweden)

    Yihuan Tsai

    2015-07-01

    Full Text Available Due to the limitation of current pharmacological therapeutic strategies, stem cell therapies have emerged as a viable option for treating many incurable neurological disorders. Specifically, human pluripotent stem cell (hPSC-derived neural progenitor cells (hNPCs, a multipotent cell population that is capable of near indefinite expansion and subsequent differentiation into the various cell types that comprise the central nervous system (CNS, could provide an unlimited source of cells for such cell-based therapies. However the clinical application of these cells will require (i defined, xeno-free conditions for their expansion and neuronal differentiation and (ii scalable culture systems that enable their expansion and neuronal differentiation in numbers sufficient for regenerative medicine and drug screening purposes. Current extracellular matrix protein (ECMP-based substrates for the culture of hNPCs are expensive, difficult to isolate, subject to batch-to-batch variations, and, therefore, unsuitable for clinical application of hNPCs. Using a high-throughput array-based screening approach, we identified a synthetic polymer, poly(4-vinyl phenol (P4VP, that supported the long-term proliferation and self-renewal of hNPCs. The hNPCs cultured on P4VP maintained their characteristic morphology, expressed high levels of markers of multipotency, and retained their ability to differentiate into neurons. Such chemically defined substrates will eliminate critical roadblocks for the utilization of hNPCs for human neural regenerative repair, disease modeling, and drug discovery.

  16. Transcriptional profiling of MEF2-regulated genes in human neural progenitor cells derived from embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Shing Fai Chan

    2015-03-01

    Full Text Available The myocyte enhancer factor 2 (MEF2 family of transcription factors is highly expressed in the brain and constitutes a key determinant of neuronal survival, differentiation, and synaptic plasticity. However, genome-wide transcriptional profiling of MEF2-regulated genes has not yet been fully elucidated, particularly at the neural stem cell stage. Here we report the results of microarray analysis comparing mRNAs isolated from human neural progenitor/stem cells (hNPCs derived from embryonic stem cells expressing a control vector versus progenitors expressing a constitutively-active form of MEF2 (MEF2CA, which increases MEF2 activity. Microarray experiments were performed using the Illumina Human HT-12 V4.0 expression beadchip (GEO#: GSE57184. By comparing vector-control cells to MEF2CA cells, microarray analysis identified 1880 unique genes that were differentially expressed. Among these genes, 1121 genes were up-regulated and 759 genes were down-regulated. Our results provide a valuable resource for identifying transcriptional targets of MEF2 in hNPCs.

  17. In vitro culture and characterization of enteric neural precursor cells from human gut biopsy specimens using polymer scaffold.

    Science.gov (United States)

    Krishnamohan, Janardhanam; Senthilnathan, Venugopal S; Vaikundaraman, Tirunelveli Muthiah; Srinivasan, Thangavelu; Balamurugan, Madasamy; Iwasaki, Masaru; Preethy, Senthilkumar; Abraham, Samuel Jk

    2013-08-01

    In vitro expansion and characterization of neural precursor cells from human gut biopsy specimens with or without Hirschsprung's disease using a novel thermoreversible gelation polymer (TGP) is reported aiming at a possible future treatment. Gut biopsy samples were obtained from five patients undergoing gut resection for Hirschsprung's disease (n = 1) or gastrointestinal disorders (n = 4). Cells isolated from the smooth muscle layer and the myenteric plexus were cultured in two groups for 18 to 28 days; Group I: conventional culture as earlier reported and Group II: using TGP scaffold. Neurosphere like bodies (NLBs) were observed in the cultures between 8th to 12th day and H & E staining was positive for neural cells in both groups including aganglionic gut portion from the Hirschsprung's disease patient. Immunohistochemistry using S-100 and neuron specific enolase (NSE) was positive in both groups but the TGP group (Group II) showed more number of cells with intense cytoplasmic granular positivity for both NSE and S-100 compared to Group I. TGP supports the in vitro expansion of human gut derived neuronal cells with seemingly better quality NLBs. Animal Studies can be tried to validate their functional outcome by transplanting the NLBs with TGP scaffolds to see whether this can enhance the outcome of cell based therapies for Hirschsprung's disease.

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

    Directory of Open Access Journals (Sweden)

    Ebrahim Shahbazi

    2016-04-01

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

  19. Neuronal regeneration in injured rat spinal cord after human dental pulp derived neural crest stem cell transplantation.

    Science.gov (United States)

    Kabatas, S; Demir, C S; Civelek, E; Yilmaz, I; Kircelli, A; Yilmaz, C; Akyuva, Y; Karaoz, E

    2018-01-01

    This study aimed to analyze the effect of human Dental Pulp-Neural Crest Stem Cells (hDP-NCSCs) delivery on lesion site after spinal cord injury (SCI), and to observe the functional recovery after transplantation. Neural Crest Stem Cells (NCSCs) were isolated from human Dental Pulp (hDP). The experimental rat population was divided into four groups (n = 6/24). Their behavioral motility was scored regularly. After 4-weeks, rats were sacrificed, and their spinal cords were examined for Green Fluorescent Protein (GFP) labeled hDP-NCSCs by immunofluorescence (IF) staining. In early post-injury (p.i) period, the ultrastructure of spinal cord tissue was preserved in Group 4. The majority of cells forming the ependymal region around the central canal were found to be hDP-NCSCs. While the grey-and-white-matter around the ependymal region was composed of e.g. GFP cells, with astrocytic-like appearance. The scores showed significant motor recovery in hind limb functions in Group 4. However, no obvious change was observed in other groups. Cells e.g., mesenchymal (Vimentin+) which express GFP+ cells in the gray-and-white-matter around the ependymal region could indicate the potential to self-renewal and plasticity. Thus, transplantation of hDP-NCSCs might be an effective strategy to improve functional recovery following spinal cord trauma (Fig. 10, Ref. 32).

  20. Automatic delineation and 3D visualization of the human ventricular system using probabilistic neural networks

    Science.gov (United States)

    Hatfield, Fraser N.; Dehmeshki, Jamshid

    1998-09-01

    Neurosurgery is an extremely specialized area of medical practice, requiring many years of training. It has been suggested that virtual reality models of the complex structures within the brain may aid in the training of neurosurgeons as well as playing an important role in the preparation for surgery. This paper focuses on the application of a probabilistic neural network to the automatic segmentation of the ventricles from magnetic resonance images of the brain, and their three dimensional visualization.

  1. Neural Systems Responding to Degrees of Uncertainty in Human Decision-Making

    OpenAIRE

    Hsu, Ming; Bhatt, Meghana; Adolphs, Ralph; Tranel, Daniel; Camerer, Colin F.

    2005-01-01

    Much is known about how people make decisions under varying levels of probability (risk). Less is known about the neural basis of decision-making when probabilities are uncertain because of missing information (ambiguity). In decision theory, ambiguity about probabilities should not affect choices. Using functional brain imaging, we show that the level of ambiguity in choices correlates positively with activation in the amygdala and orbitofrontal cortex, and negatively with a striatal system....

  2. Neural responses during the anticipation and receipt of olfactory reward and punishment in human.

    Science.gov (United States)

    Zou, Lai-Quan; Zhou, Han-Yu; Zhuang, Yuan; van Hartevelt, Tim J; Lui, Simon S Y; Cheung, Eric F C; Møller, Arne; Kringelbach, Morten L; Chan, Raymond C K

    2018-03-01

    Pleasure experience is an important part of normal healthy life and is essential for general and mental well-being. Many neuroimaging studies have investigated the underlying neural processing of verbal and visual modalities of reward. However, how the brain processes rewards in the olfactory modality is not fully understood. This study aimed to examine the neural basis of olfactory rewards in 25 healthy participants using functional magnetic resonance imaging (fMRI). We developed an Olfactory Incentive Delay (OLID) imaging task distinguishing between the anticipation and receipt of olfactory rewards and punishments. We found that the pallidum was activated during the anticipation of both olfactory rewards and punishments. The bilateral insula was activated independently from the odours' hedonic valence during the receipt phase. In addition, right caudate activation during the anticipation of unpleasant odours was correlated with self-reported anticipatory hedonic traits, whereas bilateral insular activation during the receipt of pleasant odours was correlated with self-reported consummatory hedonic traits. These findings suggest that activity in the insula and the caudate may be biomarkers of anhedonia. These findings also highlight a useful and valid paradigm to study the neural circuitry underlying reward processing in people with anhedonia. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. Ferritin nanoparticles for improved self-renewal and differentiation of human neural stem cells.

    Science.gov (United States)

    Lee, Jung Seung; Yang, Kisuk; Cho, Ann-Na; Cho, Seung-Woo

    2018-01-01

    Biomaterials that promote the self-renewal ability and differentiation capacity of neural stem cells (NSCs) are desirable for improving stem cell therapy to treat neurodegenerative diseases. Incorporation of micro- and nanoparticles into stem cell culture has gained great attention for the control of stem cell behaviors, including proliferation and differentiation. In this study, ferritin, an iron-containing natural protein nanoparticle, was applied as a biomaterial to improve the self-renewal and differentiation of NSCs and neural progenitor cells (NPCs). Ferritin nanoparticles were added to NSC or NPC culture during cell growth, allowing for incorporation of ferritin nanoparticles during neurosphere formation. Compared to neurospheres without ferritin treatment, neurospheres with ferritin nanoparticles showed significantly promoted self-renewal and cell-cell interactions. When spontaneous differentiation of neurospheres was induced during culture without mitogenic factors, neuronal differentiation was enhanced in the ferritin-treated neurospheres. In conclusion, we found that natural nanoparticles can be used to improve the self-renewal ability and differentiation potential of NSCs and NPCs, which can be applied in neural tissue engineering and cell therapy for neurodegenerative diseases.

  4. Revocation of European patent for neural progenitors highlights patent challenges for inventions relating to human embryonic stem cells.

    Science.gov (United States)

    Rigby, Barbara

    2013-11-01

    Cells derived from human embryonic stem cells have great therapeutic potential. Patents are key to allowing companies that develop methods of generating such cells to recuperate their investment. However, in Europe, inventions relating to the use of human embryos for commercial purposes are excluded from patentability on moral grounds. The scope of this morality exclusion was recently tested before Germany's highest court and before the European Patent Office (EPO), with diverging results. The decision by the EPO's Opposition Division to revoke EP1040185 relating to neural precursors and methods for their generation has received a mixed reception. The decision has very recently been appealed, and the outcome of this Appeal should provide more definitive guidance on the scope of the morality exclusion.

  5. Persistent neural activity in auditory cortex is related to auditory working memory in humans and nonhuman primates.

    Science.gov (United States)

    Huang, Ying; Matysiak, Artur; Heil, Peter; König, Reinhard; Brosch, Michael

    2016-07-20

    Working memory is the cognitive capacity of short-term storage of information for goal-directed behaviors. Where and how this capacity is implemented in the brain are unresolved questions. We show that auditory cortex stores information by persistent changes of neural activity. We separated activity related to working memory from activity related to other mental processes by having humans and monkeys perform different tasks with varying working memory demands on the same sound sequences. Working memory was reflected in the spiking activity of individual neurons in auditory cortex and in the activity of neuronal populations, that is, in local field potentials and magnetic fields. Our results provide direct support for the idea that temporary storage of information recruits the same brain areas that also process the information. Because similar activity was observed in the two species, the cellular bases of some auditory working memory processes in humans can be studied in monkeys.

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

    Directory of Open Access Journals (Sweden)

    Hiroko Shimada

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

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

    Directory of Open Access Journals (Sweden)

    Gunnar Hargus

    2014-09-01

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

  8. Neural Differentiation of Human Pluripotent Stem Cells for Nontherapeutic Applications: Toxicology, Pharmacology, and In Vitro Disease Modeling

    Directory of Open Access Journals (Sweden)

    May Shin Yap

    2015-01-01

    Full Text Available Human pluripotent stem cells (hPSCs derived from either blastocyst stage embryos (hESCs or reprogrammed somatic cells (iPSCs can provide an abundant source of human neuronal lineages that were previously sourced from human cadavers, abortuses, and discarded surgical waste. In addition to the well-known potential therapeutic application of these cells in regenerative medicine, these are also various promising nontherapeutic applications in toxicological and pharmacological screening of neuroactive compounds, as well as for in vitro modeling of neurodegenerative and neurodevelopmental disorders. Compared to alternative research models based on laboratory animals and immortalized cancer-derived human neural cell lines, neuronal cells differentiated from hPSCs possess the advantages of species specificity together with genetic and physiological normality, which could more closely recapitulate in vivo conditions within the human central nervous system. This review critically examines the various potential nontherapeutic applications of hPSC-derived neuronal lineages and gives a brief overview of differentiation protocols utilized to generate these cells from hESCs and iPSCs.

  9. Human neural stem cells over-expressing choline acetyltransferase restore cognition in rat model of cognitive dysfunction.

    Science.gov (United States)

    Park, Dongsun; Lee, Hong Jun; Joo, Seong Soo; Bae, Dae-Kwon; Yang, Goeun; Yang, Yun-Hui; Lim, Inja; Matsuo, Akinori; Tooyama, Ikuo; Kim, Yun-Bae; Kim, Seung U

    2012-04-01

    A human neural stem cell (NSC) line over-expressing human choline acetyltransferase (ChAT) gene was generated and these F3.ChAT NSCs were transplanted into the brain of rat Alzheimer disease (AD) model which was induced by application of ethylcholine mustard aziridinium ion (AF64A) that specifically denatures cholinergic nerves and thereby leads to memory deficit as a salient feature of AD. Transplantation of F3.ChAT human NSCs fully recovered the learning and memory function of AF64A animals, and induced elevated levels of acetylcholine (ACh) in cerebrospinal fluid (CSF). Transplanted F3.ChAT human NSCs were found to migrate to various brain regions including cerebral cortex, hippocampus, striatum and septum, and differentiated into neurons and astrocytes. The present study demonstrates that brain transplantation of human NSCs over-expressing ChAT ameliorates complex learning and memory deficits in AF64A-cholinotoxin-induced AD rat model. Copyright © 2012 Elsevier Inc. All rights reserved.

  10. Identification of Noncanonical Wnt Receptors Required for Wnt-3a-Induced Early Differentiation of Human Neural Stem Cells.

    Science.gov (United States)

    Bengoa-Vergniory, Nora; Gorroño-Etxebarria, Irantzu; López-Sánchez, Inmaculada; Marra, Michele; Di Chiaro, Pierluigi; Kypta, Robert

    2017-10-01

    Wnt proteins preferentially activate either β-catenin-dependent or β-catenin-independent signals, but the activity of a particular Wnt also depends on cellular context and receptor availability. We previously reported that Wnt-3a induces neural differentiation of human embryonic stem cell-derived neural stem cells (NSCs) in a β-catenin-independent manner by activating a signal involving JNK and the AP-1 family member ATF-2. Here, we report the results of a gene silencing approach to identify the Wnt receptors that mediate this response to Wnt-3a. Silencing of ROR2 increased neuronal differentiation, as measured by expression of the genes DCX, NEUROD1, and NGN1, suggesting ROR2 signals normally prevent differentiation. Silencing of the other Wnt receptors singly did not affect Wnt-3a-induced neuronal differentiation. However, pairwise silencing of ROR1 and FZD4 or FZD5 and of LRP6 and FZD4 or FZD5 inhibited neuronal differentiation, as detected by reductions in the expression of neuronal genes and immunocytochemical detection of DCX, NEUROD1 and DCX. Ectopic expression of these receptors in HEK 293 cells increased ATF2-dependent transcription. In addition, ROR1 coimmunoprecipitated with FZD4 and LRP6 in transfected HEK 293 cells and colocalized with FZD4 and with LRP6 at the cell surface of transfected L cells. Wnt-3a did not appear to affect these interactions but did alter the interactions between LRP6 and FZD4/5. Together, these observations highlight roles for ROR1, LRP6, FZD4, and FZD5 in neural stem cell differentiation and provide support for a model in which dynamic interactions among these receptors mediate Wnt-3a activation of ATF2 signaling.

  11. Quantitative Live Imaging of Human Embryonic Stem Cell Derived Neural Rosettes Reveals Structure-Function Dynamics Coupled to Cortical Development.

    Science.gov (United States)

    Ziv, Omer; Zaritsky, Assaf; Yaffe, Yakey; Mutukula, Naresh; Edri, Reuven; Elkabetz, Yechiel

    2015-10-01

    Neural stem cells (NSCs) are progenitor cells for brain development, where cellular spatial composition (cytoarchitecture) and dynamics are hypothesized to be linked to critical NSC capabilities. However, understanding cytoarchitectural dynamics of this process has been limited by the difficulty to quantitatively image brain development in vivo. Here, we study NSC dynamics within Neural Rosettes--highly organized multicellular structures derived from human pluripotent stem cells. Neural rosettes contain NSCs with strong epithelial polarity and are expected to perform apical-basal interkinetic nuclear migration (INM)--a hallmark of cortical radial glial cell development. We developed a quantitative live imaging framework to characterize INM dynamics within rosettes. We first show that the tendency of cells to follow the INM orientation--a phenomenon we referred to as radial organization, is associated with rosette size, presumably via mechanical constraints of the confining structure. Second, early forming rosettes, which are abundant with founder NSCs and correspond to the early proliferative developing cortex, show fast motions and enhanced radial organization. In contrast, later derived rosettes, which are characterized by reduced NSC capacity and elevated numbers of differentiated neurons, and thus correspond to neurogenesis mode in the developing cortex, exhibit slower motions and decreased radial organization. Third, later derived rosettes are characterized by temporal instability in INM measures, in agreement with progressive loss in rosette integrity at later developmental stages. Finally, molecular perturbations of INM by inhibition of actin or non-muscle myosin-II (NMII) reduced INM measures. Our framework enables quantification of cytoarchitecture NSC dynamics and may have implications in functional molecular studies, drug screening, and iPS cell-based platforms for disease modeling.

  12. Migratory capabilities of human umbilical cord blood-derived neural stem cells (HUCB-NSC) in vitro.

    Science.gov (United States)

    Janowski, Miroslaw; Lukomska, Barbara; Domanska-Janik, Krystyna

    2011-01-01

    Many types of neural progenitors from various sources have been evaluated for therapy of CNS disorders. Prerequisite for success in cell therapy is the ability for transplanted cells to reach appropriate target such as stroke lesion. We have established neural stem cell line from human umbilical cord blood neural stem (HUCB-NSC). In the present study we evaluated migratory capabilities of cells (HUCB-NSC) and the presence of various migration-related receptors. Immunocytochemical analysis revealed abundant expression of CXCR4, PDGFR-alpha, PDGFR-beta, c-Met, VEGFR, IGF-1R and PSA-NCAM receptors in non-adherent population of HUCB-NSC cultured in serum free (SF) conditions (SF cells). Biological activity of selected receptors was confirmed by HUCB-NSC in vitro migration towards SDF-1 and IGF-1 ligands. Additionally, rat brain-derived homogenates have been assessed for their chemoattractive activity of HUCB-NSC. Our experiments unveiled that brain tissue was more attracted for HUCB-NSC than single ligands with higher potency of injured than intact brain. Moreover, adherent HUCB-NSC cultured in low serum (LS) conditions (LS cells) were employed to investigate an impact of different extracellular matrix (ECM) proteins on cell motility. It turned out that laminin provided most permissive microenvironment for cell migration, followed by fibronectin and gelatin. Unexpected nuclear localization of CXCR4 in SF cells prompted us to characterize intracellular pattern of this expression in relation to developmental stage of cells cultured in different conditions. Continuous culture of LS cells revealed cytoplasmatic pattern of CXCR4 expression while HUCB-NSC cultured in high serum conditions (HS cells) resulted in gradual translocation of CXCR4 from nucleus to cytoplasm and then to arising processes. Terminal differentiation of HUCB-NSC was followed by CXCR4 expression decline.

  13. Quantitative Live Imaging of Human Embryonic Stem Cell Derived Neural Rosettes Reveals Structure-Function Dynamics Coupled to Cortical Development.

    Directory of Open Access Journals (Sweden)

    Omer Ziv

    2015-10-01

    Full Text Available Neural stem cells (NSCs are progenitor cells for brain development, where cellular spatial composition (cytoarchitecture and dynamics are hypothesized to be linked to critical NSC capabilities. However, understanding cytoarchitectural dynamics of this process has been limited by the difficulty to quantitatively image brain development in vivo. Here, we study NSC dynamics within Neural Rosettes--highly organized multicellular structures derived from human pluripotent stem cells. Neural rosettes contain NSCs with strong epithelial polarity and are expected to perform apical-basal interkinetic nuclear migration (INM--a hallmark of cortical radial glial cell development. We developed a quantitative live imaging framework to characterize INM dynamics within rosettes. We first show that the tendency of cells to follow the INM orientation--a phenomenon we referred to as radial organization, is associated with rosette size, presumably via mechanical constraints of the confining structure. Second, early forming rosettes, which are abundant with founder NSCs and correspond to the early proliferative developing cortex, show fast motions and enhanced radial organization. In contrast, later derived rosettes, which are characterized by reduced NSC capacity and elevated numbers of differentiated neurons, and thus correspond to neurogenesis mode in the developing cortex, exhibit slower motions and decreased radial organization. Third, later derived rosettes are characterized by temporal instability in INM measures, in agreement with progressive loss in rosette integrity at later developmental stages. Finally, molecular perturbations of INM by inhibition of actin or non-muscle myosin-II (NMII reduced INM measures. Our framework enables quantification of cytoarchitecture NSC dynamics and may have implications in functional molecular studies, drug screening, and iPS cell-based platforms for disease modeling.

  14. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction.

    Science.gov (United States)

    Rilling, James K; Demarco, Ashley C; Hackett, Patrick D; Chen, Xu; Gautam, Pritam; Stair, Sabrina; Haroon, Ebrahim; Thompson, Richmond; Ditzen, Beate; Patel, Rajan; Pagnoni, Giuseppe

    2014-01-01

    Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses

  15. Asymmetric generalization in adaptation to target displacement errors in humans and in a neural network model.

    Science.gov (United States)

    Westendorff, Stephanie; Kuang, Shenbing; Taghizadeh, Bahareh; Donchin, Opher; Gail, Alexander

    2015-04-01

    Different error signals can induce sensorimotor adaptation during visually guided reaching, possibly evoking different neural adaptation mechanisms. Here we investigate reach adaptation induced by visual target errors without perturbing the actual or sensed hand position. We analyzed the spatial generalization of adaptation to target error to compare it with other known generalization patterns and simulated our results with a neural network model trained to minimize target error independent of prediction errors. Subjects reached to different peripheral visual targets and had to adapt to a sudden fixed-amplitude displacement ("jump") consistently occurring for only one of the reach targets. Subjects simultaneously had to perform contralateral unperturbed saccades, which rendered the reach target jump unnoticeable. As a result, subjects adapted by gradually decreasing reach errors and showed negative aftereffects for the perturbed reach target. Reach errors generalized to unperturbed targets according to a translational rather than rotational generalization pattern, but locally, not globally. More importantly, reach errors generalized asymmetrically with a skewed generalization function in the direction of the target jump. Our neural network model reproduced the skewed generalization after adaptation to target jump without having been explicitly trained to produce a specific generalization pattern. Our combined psychophysical and simulation results suggest that target jump adaptation in reaching can be explained by gradual updating of spatial motor goal representations in sensorimotor association networks, independent of learning induced by a prediction-error about the hand position. The simulations make testable predictions about the underlying changes in the tuning of sensorimotor neurons during target jump adaptation. Copyright © 2015 the American Physiological Society.

  16. Neural systems underlying aversive conditioning in humans with primary and secondary reinforcers

    Directory of Open Access Journals (Sweden)

    Mauricio R Delgado

    2011-05-01

    Full Text Available Money is a secondary reinforcer commonly used across a range of disciplines in experimental paradigms investigating reward learning and decision-making. The effectiveness of monetary reinforcers during aversive learning and its neural basis, however, remains a topic of debate. Specifically, it is unclear if the initial acquisition of aversive representations of monetary losses depends on similar neural systems as more traditional aversive conditioning that involves primary reinforcers. This study contrasts the efficacy of a biologically defined primary reinforcer (shock and a socially defined secondary reinforcer (money during aversive learning and its associated neural circuitry. During a two-part experiment, participants first played a gambling game where wins and losses were based on performance to gain an experimental bank. Participants were then exposed to two separate aversive conditioning sessions. In one session, a primary reinforcer (mild shock served as an unconditioned stimulus (US and was paired with one of two colored squares, the conditioned stimuli (CS+ and CS-, respectively. In another session, a secondary reinforcer (loss of money served as the US and was paired with one of two different CS. Skin conductance responses were greater for CS+ compared to CS- trials irrespective of type of reinforcer. Neuroimaging results revealed that the striatum, a region typically linked with reward-related processing, was found to be involved in the acquisition of aversive conditioned response irrespective of reinforcer type. In contrast, the amygdala was involved during aversive conditioning with primary reinforcers, as suggested by both an exploratory fMRI analysis and a follow-up case study with a patient with bilateral amygdala damage. Taken together, these results suggest that learning about potential monetary losses may depend on reinforcement learning related systems, rather than on typical structures involved in more biologically based

  17. Induction of apoptotic death and retardation of neuronal differentiation of human neural stem cells by sodium arsenite treatment

    International Nuclear Information System (INIS)

    Ivanov, Vladimir N.; Hei, Tom K.

    2013-01-01

    Chronic arsenic toxicity is a global health problem that affects more than 100 million people worldwide. Long-term health effects of inorganic sodium arsenite in drinking water may result in skin, lung and liver cancers and in severe neurological abnormalities. We investigated in the present study whether sodium arsenite affects signaling pathways that control cell survival, proliferation and neuronal differentiation of human neural stem cells (NSC). We demonstrated that the critical signaling pathway, which was suppressed by sodium arsenite in NSC, was the protective PI3K–AKT pathway. Sodium arsenite (2–4 μM) also caused down-regulation of Nanog, one of the key transcription factors that control pluripotency and self-renewal of stem cells. Mitochondrial damage and cytochrome-c release induced by sodium arsenite exposure was followed by initiation of the mitochondrial apoptotic pathway in NSC. Beside caspase-9 and caspase-3 inhibitors, suppression of JNK activity decreased levels of arsenite-induced apoptosis in NSC. Neuronal differentiation of NSC was substantially inhibited by sodium arsenite exposure. Overactivation of JNK1 and ERK1/2 and down-regulation of PI3K–AKT activity induced by sodium arsenite were critical factors that strongly affected neuronal differentiation. In conclusion, sodium arsenite exposure of human NSC induces the mitochondrial apoptotic pathway, which is substantially accelerated due to the simultaneous suppression of PI3K–AKT. Sodium arsenite also negatively affects neuronal differentiation of NSC through overactivation of MEK–ERK and suppression of PI3K–AKT. - Highlights: ► Arsenite induces the mitochondrial apoptotic pathway in human neural stem cells. ► Arsenite-induced apoptosis is strongly upregulated by suppression of PI3K–AKT. ► Arsenite-induced apoptosis is strongly down-regulated by inhibition of JNK–cJun. ► Arsenite negatively affects neuronal differentiation by inhibition of PI3K–AKT

  18. Induction of apoptotic death and retardation of neuronal differentiation of human neural stem cells by sodium arsenite treatment

    Energy Technology Data Exchange (ETDEWEB)

    Ivanov, Vladimir N., E-mail: vni3@columbia.edu [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, NY 10032 (United States); Hei, Tom K. [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, NY 10032 (United States)

    2013-04-01

    Chronic arsenic toxicity is a global health problem that affects more than 100 million people worldwide. Long-term health effects of inorganic sodium arsenite in drinking water may result in skin, lung and liver cancers and in severe neurological abnormalities. We investigated in the present study whether sodium arsenite affects signaling pathways that control cell survival, proliferation and neuronal differentiation of human neural stem cells (NSC). We demonstrated that the critical signaling pathway, which was suppressed by sodium arsenite in NSC, was the protective PI3K–AKT pathway. Sodium arsenite (2–4 μM) also caused down-regulation of Nanog, one of the key transcription factors that control pluripotency and self-renewal of stem cells. Mitochondrial damage and cytochrome-c release induced by sodium arsenite exposure was followed by initiation of the mitochondrial apoptotic pathway in NSC. Beside caspase-9 and caspase-3 inhibitors, suppression of JNK activity decreased levels of arsenite-induced apoptosis in NSC. Neuronal differentiation of NSC was substantially inhibited by sodium arsenite exposure. Overactivation of JNK1 and ERK1/2 and down-regulation of PI3K–AKT activity induced by sodium arsenite were critical factors that strongly affected neuronal differentiation. In conclusion, sodium arsenite exposure of human NSC induces the mitochondrial apoptotic pathway, which is substantially accelerated due to the simultaneous suppression of PI3K–AKT. Sodium arsenite also negatively affects neuronal differentiation of NSC through overactivation of MEK–ERK and suppression of PI3K–AKT. - Highlights: ► Arsenite induces the mitochondrial apoptotic pathway in human neural stem cells. ► Arsenite-induced apoptosis is strongly upregulated by suppression of PI3K–AKT. ► Arsenite-induced apoptosis is strongly down-regulated by inhibition of JNK–cJun. ► Arsenite negatively affects neuronal differentiation by inhibition of PI3K–AKT.

  19. Cross-Linguistic Differences in the Neural Representation of Human Language: Evidence from Users of Signed Languages

    Science.gov (United States)

    Corina, David P.; Lawyer, Laurel A.; Cates, Deborah

    2013-01-01

    Studies of deaf individuals who are users of signed languages have provided profound insight into the neural representation of human language. Case studies of deaf signers who have incurred left- and right-hemisphere damage have shown that left-hemisphere resources are a necessary component of sign language processing. These data suggest that, despite frank differences in the input and output modality of language, core left perisylvian regions universally serve linguistic function. Neuroimaging studies of deaf signers have generally provided support for this claim. However, more fine-tuned studies of linguistic processing in deaf signers are beginning to show evidence of important differences in the representation of signed and spoken languages. In this paper, we provide a critical review of this literature and present compelling evidence for language-specific cortical representations in deaf signers. These data lend support to the claim that the neural representation of language may show substantive cross-linguistic differences. We discuss the theoretical implications of these findings with respect to an emerging understanding of the neurobiology of language. PMID:23293624

  20. Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans.

    Science.gov (United States)

    Feng, Chunliang; Hackett, Patrick D; DeMarco, Ashley C; Chen, Xu; Stair, Sabrina; Haroon, Ebrahim; Ditzen, Beate; Pagnoni, Giuseppe; Rilling, James K

    2015-12-01

    Recent research has examined the effects of oxytocin (OT) and vasopressin (AVP) on human social behavior and brain function. However, most participants have been male, while previous research in our lab demonstrated sexually differentiated effects of OT and AVP on the neural response to reciprocated cooperation. Here we extend our previous work by significantly increasing the number of participants to enable the use of more stringent statistical thresholds that permit more precise localization of OT and AVP effects in the brain. In a double-blind, placebo-controlled study, 153 men and 151 women were randomized to receive 24 IU intranasal OT, 20 IU intranasal AVP or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner's Dilemma Game with same-sex partners. Sex differences were observed for effects of OT on the neural response to reciprocated cooperation, such that OT increased the caduate/putamen response among males, whereas it decreased this response among females. Thus, 24 IU OT may increase the reward or salience of positive social interactions among men, while decreasing their reward or salience among women. Similar sex differences were also observed for AVP effects within bilateral insula and right supramarginal gyrus when a more liberal statistical threshold was employed. While our findings support previous suggestions that exogenous nonapeptides may be effective treatments for disorders such as depression and autism spectrum disorder, they caution against uniformly extending such treatments to men and women alike.

  1. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans.

    Science.gov (United States)

    Feng, C; Lori, A; Waldman, I D; Binder, E B; Haroon, E; Rilling, J K

    2015-09-01

    Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with functional magnetic resonance imaging while playing an iterated Prisoner's Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  2. WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.

    Science.gov (United States)

    Cavallin, Mara; Rujano, Maria A; Bednarek, Nathalie; Medina-Cano, Daniel; Bernabe Gelot, Antoinette; Drunat, Severine; Maillard, Camille; Garfa-Traore, Meriem; Bole, Christine; Nitschké, Patrick; Beneteau, Claire; Besnard, Thomas; Cogné, Benjamin; Eveillard, Marion; Kuster, Alice; Poirier, Karine; Verloes, Alain; Martinovic, Jelena; Bidat, Laurent; Rio, Marlene; Lyonnet, Stanislas; Reilly, M Louise; Boddaert, Nathalie; Jenneson-Liver, Melanie; Motte, Jacques; Doco-Fenzy, Martine; Chelly, Jamel; Attie-Bitach, Tania; Simons, Matias; Cantagrel, Vincent; Passemard, Sandrine; Baffet, Alexandre; Thomas, Sophie; Bahi-Buisson, Nadia

    2017-10-01

    Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders.

    Science.gov (United States)

    Lorenz, Carmen; Lesimple, Pierre; Bukowiecki, Raul; Zink, Annika; Inak, Gizem; Mlody, Barbara; Singh, Manvendra; Semtner, Marcus; Mah, Nancy; Auré, Karine; Leong, Megan; Zabiegalov, Oleksandr; Lyras, Ekaterini-Maria; Pfiffer, Vanessa; Fauler, Beatrix; Eichhorst, Jenny; Wiesner, Burkhard; Huebner, Norbert; Priller, Josef; Mielke, Thorsten; Meierhofer, David; Izsvák, Zsuzsanna; Meier, Jochen C; Bouillaud, Frédéric; Adjaye, James; Schuelke, Markus; Wanker, Erich E; Lombès, Anne; Prigione, Alessandro

    2017-05-04

    Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Renal denervation and hypertension - The need to investigate unintended effects and neural control of the human kidney.

    Science.gov (United States)

    Grisk, Olaf

    2017-05-01

    Increased renal sympathetic nerve activity (RSNA) is present in human and experimental forms of arterial hypertension. Experimental denervation studies showed that renal nerves contribute to the development of hypertension. Clinical trials provided equivocal results on the antihypertensive efficacy of renal denervation in patients spurring discussions on technical aspects of renal denervation and further research on the role of renal nerves for the regulation of kidney function as well as the pathophysiology of hypertension. This review summarizes recent findings on adrenoceptor expression and function in the human kidney, adrenoceptor-dependent regulation of sodium chloride transport in the distal nephron, experimental data on chronic RSNA and the development of high arterial pressure and consequences of renal denervation that may limit its antihypertensive efficacy. Future research needs to reduce the gap between our knowledge on neural control of renal function in animals vs. humans to facilitate translation of experimental animal data to humans. More experimental studies on the temporal relationship between RSNA and arterial pressure in the chronic setting are needed to better define the pathogenetic role of heightened RSNA in different forms of arterial hypertension in order to improve the rational basis for renal denervation in antihypertensive therapy. Finally, research on unintended consequences of renal denervation including but not limited to reinnervation and denervation supersensitivity needs to be intensified to further assess the potential of renal denervation to slow the progression of renal disease and hypertension. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Specific neural traces for intonational discourse categories as revealed by human-evoked potentials.

    Science.gov (United States)

    Borràs-Comes, Joan; Costa-Faidella, Jordi; Prieto, Pilar; Escera, Carles

    2012-04-01

    The neural representation of segmental and tonal phonological distinctions has been shown by means of the MMN ERP, yet this is not the case for intonational discourse contrasts. In Catalan, a rising-falling intonational sequence can be perceived as a statement or as a counterexpectational question, depending exclusively on the size of the pitch range interval of the rising movement. We tested here, using the MMN, whether such categorical distinctions elicited distinct neurophysiological patterns of activity, supporting their specific neural representation. From a behavioral identification experiment, we set the boundary between the two categories and defined four stimuli across the continuum. Although the physical distance between each pair of stimuli was kept constant, the central pair represented an across-category contrast, whereas the other pairs represented within-category contrasts. These four auditory stimuli were contrasted by pairs in three different oddball blocks. The mean amplitude of the MMN was larger for the across-category contrast, suggesting that intonational contrasts in the target language can be encoded automatically in the auditory cortex. These results are in line with recent findings in other fields of linguistics, showing that, when a boundary between categories is crossed, the MMN response is not just larger but rather includes a separate subcomponent.

  6. The neural basis of human social values: evidence from functional MRI.

    Science.gov (United States)

    Zahn, Roland; Moll, Jorge; Paiva, Mirella; Garrido, Griselda; Krueger, Frank; Huey, Edward D; Grafman, Jordan

    2009-02-01

    Social values are composed of social concepts (e.g., "generosity") and context-dependent moral sentiments (e.g., "pride"). The neural basis of this intricate cognitive architecture has not been investigated thus far. Here, we used functional magnetic resonance imaging while subjects imagined their own actions toward another person (self-agency) which either conformed or were counter to a social value and were associated with pride or guilt, respectively. Imagined actions of another person toward the subjects (other-agency) in accordance with or counter to a value were associated with gratitude or indignation/anger. As hypothesized, superior anterior temporal lobe (aTL) activity increased with conceptual detail in all conditions. During self-agency, activity in the anterior ventromedial prefrontal cortex correlated with pride and guilt, whereas activity in the subgenual cingulate solely correlated with guilt. In contrast, indignation/anger activated lateral orbitofrontal-insular cortices. Pride and gratitude additionally evoked mesolimbic and basal forebrain activations. Our results demonstrate that social values emerge from coactivation of stable abstract social conceptual representations in the superior aTL and context-dependent moral sentiments encoded in fronto-mesolimbic regions. This neural architecture may provide the basis of our ability to communicate about the meaning of social values across cultural contexts without limiting our flexibility to adapt their emotional interpretation.

  7. Human cortical neural correlates of visual fatigue during binocular depth perception: An fNIRS study.

    Directory of Open Access Journals (Sweden)

    Tingting Cai

    Full Text Available Functional near-infrared spectroscopy (fNIRS was adopted to investigate the cortical neural correlates of visual fatigue during binocular depth perception for different disparities (from 0.1° to 1.5°. By using a slow event-related paradigm, the oxyhaemoglobin (HbO responses to fused binocular stimuli presented by the random-dot stereogram (RDS were recorded over the whole visual dorsal area. To extract from an HbO curve the characteristics that are correlated with subjective experiences of stereopsis and visual fatigue, we proposed a novel method to fit the time-course HbO curve with various response functions which could reflect various processes of binocular depth perception. Our results indicate that the parietal-occipital cortices are spatially correlated with binocular depth perception and that the process of depth perception includes two steps, associated with generating and sustaining stereovision. Visual fatigue is caused mainly by generating stereovision, while the amplitude of the haemodynamic response corresponding to sustaining stereovision is correlated with stereopsis. Combining statistical parameter analysis and the fitted time-course analysis, fNIRS could be a promising method to study visual fatigue and possibly other multi-process neural bases.

  8. A Pontine Region is a Neural Correlate of the Human Affective Processing Network

    Directory of Open Access Journals (Sweden)

    Tatia M.C. Lee

    2015-11-01

    Full Text Available The in vivo neural activity of the pons during the perception of affective stimuli has not been studied despite the strong implications of its role in affective processing. To examine the activity of the pons during the viewing of affective stimuli, and to verify its functional and structural connectivity with other affective neural correlates, a multimodal magnetic resonance imaging methodology was employed in this study. We observed the in vivo activity of the pons when viewing affective stimuli. Furthermore, small-world connectivity indicated that the functional connectivity (FC between the pons and the cortico-limbic affective regions was meaningful, with the coefficient λ being positively associated with self-reported emotional reactivity. The FC between the pons and the cortico-limbic-striatal areas was related to self-reported negative affect. Corroborating this finding was the observation that the tract passing through the pons and the left hippocampus was negatively related to self-reported positive affect and positively correlated with emotional reactivity. Our findings support the framework that the pons works conjunctively with the distributed cortico-limbic-striatal systems in shaping individuals' affective states and reactivity. Our work paves the path for future research on the contribution of the pons to the precipitation and maintenance of affective disorders.

  9. Nanoparticle-mediated transcriptional modification enhances neuronal differentiation of human neural stem cells following transplantation in rat brain.

    Science.gov (United States)

    Li, Xiaowei; Tzeng, Stephany Y; Liu, Xiaoyan; Tammia, Markus; Cheng, Yu-Hao; Rolfe, Andrew; Sun, Dong; Zhang, Ning; Green, Jordan J; Wen, Xuejun; Mao, Hai-Quan

    2016-04-01

    Strategies to enhance survival and direct the differentiation of stem cells in vivo following transplantation in tissue repair site are critical to realizing the potential of stem cell-based therapies. Here we demonstrated an effective approach to promote neuronal differentiation and maturation of human fetal tissue-derived neural stem cells (hNSCs) in a brain lesion site of a rat traumatic brain injury model using biodegradable nanoparticle-mediated transfection method to deliver key transcriptional factor neurogenin-2 to hNSCs when transplanted with a tailored hyaluronic acid (HA) hydrogel, generating larger number of more mature neurons engrafted to the host brain tissue than non-transfected cells. The nanoparticle-mediated transcription activation method together with an HA hydrogel delivery matrix provides a translatable approach for stem cell-based regenerative therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Neural networks engaged in short-term memory rehearsal are disrupted by irrelevant speech in human subjects.

    Science.gov (United States)

    Kopp, Franziska; Schröger, Erich; Lipka, Sigrid

    2004-01-02

    Rehearsal mechanisms in human short-term memory are increasingly understood in the light of both behavioural and neuroanatomical findings. However, little is known about the cooperation of participating brain structures and how such cooperations are affected when memory performance is disrupted. In this paper we use EEG coherence as a measure of synchronization to investigate rehearsal processes and their disruption by irrelevant speech in a delayed serial recall paradigm. Fronto-central and fronto-parietal theta (4-7.5 Hz), beta (13-20 Hz), and gamma (35-47 Hz) synchronizations are shown to be involved in our short-term memory task. Moreover, the impairment in serial recall due to irrelevant speech was preceded by a reduction of gamma band coherence. Results suggest that the irrelevant speech effect has its neural basis in the disruption of left-lateralized fronto-central networks. This stresses the importance of gamma band activity for short-term memory operations.

  11. Experience of a Neural Network Imitator Applied to Diagnosis of Pre-pathological Conditions in Humans

    International Nuclear Information System (INIS)

    Belyashov, D.N.; Emelyanova, I.V.; Tichshenko, A.V.; Makarenko, N.G.; Sultanova, B.G.

    1998-01-01

    The Governmental Resolution of the RK 'Program of Medical Rehabilitation for People Influenced by Nuclear Tests at STS in 1949-1990' was published in March 1997. Implementation of the program requires first of all to create the effective methods of operative diagnostics of arid zones' population. To our mind, for this aims systems analysis with elements of neural network classification is more effective. We demonstrate such an approach using the example of the modem diagnostics system creating to detect the pre-pathological states among population by express analysis and personal particulars. The following considerations were used in the base of the training set: 1) any formalism must be based oneself upon wealth of phenomenology (experience, intuition, the presence of symptoms); 2) typical attributes of disease can be divided on 2 groups - subjective and objective. The common state of patient is characterised by the first group and it can have no intercommunication with disease. The second one is obtained by laboratory inspection and it is not connected with patient sensations. Each of the objective at-tributes can be the attribute of several illnesses at once. In this case both the subjective and objective features must be used together; 3) acceptability of any scheme can be substantiated only statistically. The question about justifiability and sufficiency of training set always demands separate discussion. Personal particulars are more available for creating training set. The set must be professionally oriented in order to reduce of selection effects. For our experiment the fully-connected neural network ( computer software, imitating the work of neural computer) 'Multi Neuron' was chosen. Feature space using for the net work was created from the 206 personal particulars. The research aimed to determine pre-pathological states of the urinary system organs among industrial, office and professional workers in the mining industry connected with phosphorus

  12. A chemically defined substrate for the expansion and neuronal differentiation of human pluripotent stem cell-derived neural progenitor cells.

    Science.gov (United States)

    Tsai, Yihuan; Cutts, Josh; Kimura, Azuma; Varun, Divya; Brafman, David A

    2015-07-01

    Due to the limitation of current pharmacological therapeutic strategies, stem cell therapies have emerged as a viable option for treating many incurable neurological disorders. Specifically, human pluripotent stem cell (hPSC)-derived neural progenitor cells (hNPCs), a multipotent cell population that is capable of near indefinite expansion and subsequent differentiation into the various cell types that comprise the central nervous system (CNS), could provide an unlimited source of cells for such cell-based therapies. However the clinical application of these cells will require (i) defined, xeno-free conditions for their expansion and neuronal differentiation and (ii) scalable culture systems that enable their expansion and neuronal differentiation in numbers sufficient for regenerative medicine and drug screening purposes. Current extracellular matrix protein (ECMP)-based substrates for the culture of hNPCs are expensive, difficult to isolate, subject to batch-to-batch variations, and, therefore, unsuitable for clinical application of hNPCs. Using a high-throughput array-based screening approach, we identified a synthetic polymer, poly(4-vinyl phenol) (P4VP), that supported the long-term proliferation and self-renewal of hNPCs. The hNPCs cultured on P4VP maintained their characteristic morphology, expressed high levels of markers of multipotency, and retained their ability to differentiate into neurons. Such chemically defined substrates will eliminate critical roadblocks for the utilization of hNPCs for human neural regenerative repair, disease modeling, and drug discovery. Copyright © 2015. Published by Elsevier B.V.

  13. Human neural progenitor cells decrease photoreceptor degeneration, normalize opsin distribution and support synapse structure in cultured porcine retina.

    Science.gov (United States)

    Mollick, Tanzina; Mohlin, Camilla; Johansson, Kjell

    2016-09-01

    Retinal neurodegenerative disorders like retinitis pigmentosa, age-related macular degeneration, diabetic retinopathy and retinal detachment decrease retinal functionality leading to visual impairment. The pathological events are characterized by photoreceptor degeneration, synaptic disassembly, remodeling of postsynaptic neurons and activation of glial cells. Despite intense research, no effective treatment has been found for these disorders. The current study explores the potential of human neural progenitor cell (hNPC) derived factors to slow the degenerative processes in adult porcine retinal explants. Retinas were cultured for 3 days with or without hNPCs as a feeder layer and investigated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunohistochemical, western blot and quantitative real time-polymerase chain reaction (qRT-PCR) techniques. TUNEL showed that hNPCs had the capacity to limit photoreceptor cell death. Among cone photoreceptors, hNPC coculture resulted in better maintenance of cone outer segments and reduced opsin mislocalization. Additionally, maintained synaptic structural integrity and preservation of second order calbindin positive horizontal cells was also observed. However, Müller cell gliosis only seemed to be alleviated in terms of reduced Müller cell density. Our observations indicate that at 3 days of coculture, hNPC derived factors had the capacity to protect photoreceptors, maintain synaptic integrity and support horizontal cell survival. Human neural progenitor cell applied treatment modalities may be an effective strategy to help maintain retinal functionality in neurodegenerative pathologies. Whether hNPCs can independently hinder Müller cell gliosis by utilizing higher concentrations or by combination with other pharmacological agents still needs to be determined. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Visual gravity cues in the interpretation of biological movements: neural correlates in humans.

    Science.gov (United States)

    Maffei, Vincenzo; Indovina, Iole; Macaluso, Emiliano; Ivanenko, Yuri P; A Orban, Guy; Lacquaniti, Francesco

    2015-01-01

    Our visual system takes into account the effects of Earth gravity to interpret biological motion (BM), but the neural substrates of this process remain unclear. Here we measured functional magnetic resonance (fMRI) signals while participants viewed intact or scrambled stick-figure animations of walking, running, hopping, and skipping recorded at normal or reduced gravity. We found that regions sensitive to BM configuration in the occipito-temporal cortex (OTC) were more active for reduced than normal gravity but with intact stimuli only. Effective connectivity analysis suggests that predictive coding of gravity effects underlies BM interpretation. This process might be implemented by a family of snapshot neurons involved in action monitoring. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Convolutional Neural Network Achieves Human-level Accuracy in Music Genre Classification

    OpenAIRE

    Dong, Mingwen

    2018-01-01

    Music genre classification is one example of content-based analysis of music signals. Traditionally, human-engineered features were used to automatize this task and 61% accuracy has been achieved in the 10-genre classification. However, it's still below the 70% accuracy that humans could achieve in the same task. Here, we propose a new method that combines knowledge of human perception study in music genre classification and the neurophysiology of the auditory system. The method works by trai...

  16. Modeling long-term human activeness using recurrent neural networks for biometric data.

    Science.gov (United States)

    Kim, Zae Myung; Oh, Hyungrai; Kim, Han-Gyu; Lim, Chae-Gyun; Oh, Kyo-Joong; Choi, Ho-Jin

    2017-05-18

    With the invention of fitness trackers, it has been possible to continuously monitor a user's biometric data such as heart rates, number of footsteps taken, and amount of calories burned. This paper names the time series of these three types of biometric data, the user's "activeness", and investigates the feasibility in modeling and predicting the long-term activeness of the user. The dataset used in this study consisted of several months of biometric time-series data gathered by seven users independently. Four recurrent neural network (RNN) architectures-as well as a deep neural network and a simple regression model-were proposed to investigate the performance on predicting the activeness of the user under various length-related hyper-parameter settings. In addition, the learned model was tested to predict the time period when the user's activeness falls below a certain threshold. A preliminary experimental result shows that each type of activeness data exhibited a short-term autocorrelation; and among the three types of data, the consumed calories and the number of footsteps were positively correlated, while the heart rate data showed almost no correlation with neither of them. It is probably due to this characteristic of the dataset that although the RNN models produced the best results on modeling the user's activeness, the difference was marginal; and other baseline models, especially the linear regression model, performed quite admirably as well. Further experimental results show that it is feasible to predict a user's future activeness with precision, for example, a trained RNN model could predict-with the precision of 84%-when the user would be less active within the next hour given the latest 15 min of his activeness data. This paper defines and investigates the notion of a user's "activeness", and shows that forecasting the long-term activeness of the user is indeed possible. Such information can be utilized by a health-related application to proactively

  17. Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation

    Czech Academy of Sciences Publication Activity Database

    van Gorp, S.; Leerink, M.; Kakinohana, O.; Platoshyn, O.; Santucci, C.; Galik, J.; Joosten, E. A.; Hruška-Plocháň, Marian; Goldberg, D.; Marsala, S.; Johe, K.; Ciacci, J. D.; Marsala, M.

    2013-01-01

    Roč. 4, č. 57 (2013) ISSN 1757-6512 Institutional support: RVO:67985904 Keywords : spinal cord injury * human neural stem cells * spinal grafting * functional recovery * rat Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.634, year: 2013

  18. INCREASED MATERNAL SERUM ALPHA-FETOPROTEIN AND HUMAN CHORIONIC-GONADOTROPIN IN COMPROMISED PREGNANCIES OTHER THAN FOR NEURAL-TUBE DEFECTS OR DOWN-SYNDROME

    NARCIS (Netherlands)

    BEEKHUIS, [No Value; VANLITH, JMM; DEWOLF, BTHM; MANTINGH, A

    Intrauterine fetal death occurred in four women who were 'screen-positive' in a screening programme for neural tube defects (NTDs) and Down syndrome (DS). These women had very high levels of maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG). Therefore,

  19. Pyrolysed 3D-Carbon Scaffolds Induce Spontaneous Differentiation of Human Neural Stem Cells and Facilitate Real-Time Dopamine Detection

    DEFF Research Database (Denmark)

    Amato, Letizia; Heiskanen, Arto; Caviglia, Claudia

    2014-01-01

    Structurally patterned pyrolysed three-dimensional carbon scaffolds (p3Dcarbon) are fabricated and applied for differentiation of human neural stem cells (hNSCs) developed for cell replacement therapy and sensing of released dopamine. In the absence of differentiation factors (DF) the pyrolysed c...

  20. Over-expression of hNGF in adult human olfactory bulb neural stem cells promotes cell growth and oligodendrocytic differentiation

    NARCIS (Netherlands)

    H.E.S. Marei (Hany); A. Althani (Asmaa); N. Afifi (Nahla); A. Abd-Elmaksoud (Ahmed); C. Bernardini (Camilla); F. Michetti (Fabrizio); M. Barba (Marta); M. Pescatori (Mario); G. Maira (Giulio); E. Paldino (Emanuela); L. Manni (Luigi); P. Casalbore (Patrizia); C. Cenciarelli (Carlo)

    2013-01-01

    textabstractThe adult human olfactory bulb neural stem/progenitor cells (OBNC/PC) are promising candidate for cell-based therapy for traumatic and neurodegenerative insults. Exogenous application of NGF was suggested as a promising therapeutic strategy for traumatic and neurodegenerative diseases,

  1. Differentiated human midbrain-derived neural progenitor cells express excitatory strychnine-sensitive glycine receptors containing α2β subunits.

    Directory of Open Access Journals (Sweden)

    Florian Wegner

    Full Text Available BACKGROUND: Human fetal midbrain-derived neural progenitor cells (NPCs may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+-K(+-Cl(- co-transporter 1 (NKCC1-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. CONCLUSIONS/SIGNIFICANCE: These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.

  2. Differentiation of Equine Mesenchymal Stromal Cells into Cells of Neural Lineage: Potential for Clinical Applications

    Directory of Open Access Journals (Sweden)

    Claudia Cruz Villagrán

    2014-01-01

    Full Text Available Mesenchymal stromal cells (MSCs are able to differentiate into extramesodermal lineages, including neurons. Positive outcomes were obtained after transplantation of neurally induced MSCs in laboratory animals after nerve injury, but this is unknown in horses. Our objectives were to test the ability of equine MSCs to differentiate into cells of neural lineage in vitro, to assess differences in morphology and lineage-specific protein expression, and to investigate if horse age and cell passage number affected the ability to achieve differentiation. Bone marrow-derived MSCs were obtained from young and adult horses. Following demonstration of stemness, MSCs were neurally induced and microscopically assessed at different time points. Results showed that commercially available nitrogen-coated tissue culture plates supported proliferation and differentiation. Morphological changes were immediate and all the cells displayed a neural crest-like cell phenotype. Expression of neural progenitor proteins, was assessed via western blot or immunofluorescence. In our study, MSCs generated from young and middle-aged horses did not show differences in their ability to undergo differentiation. The effect of cell passage number, however, is inconsistent and further experiments are needed. Ongoing work is aimed at transdifferentiating these cells into Schwann cells for transplantation into a peripheral nerve injury model in horses.

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

    DEFF Research Database (Denmark)

    Dreyer-Andersen, Nanna; Almeida, Ana Sofia; Jensen, Pia

    2018-01-01

    Exploratory studies using human fetal tissue have suggested that intrastriatal transplantation of dopaminergic neurons may become a future treatment for patients with Parkinson's disease. However, the use of human fetal tissue is compromised by ethical, regulatory and practical concerns. Human stem...... cells constitute an alternative source of cells for transplantation in Parkinson's disease, but efficient protocols for controlled dopaminergic differentiation need to be developed. Short-term, low-level carbon monoxide (CO) exposure has been shown to affect signaling in several tissues, resulting...... in Parkinson's disease....

  4. Left-right asymmetry of maturation rates in human embryonic neural development

    OpenAIRE

    De Kovel, C.; Lisgo, S.; Karlebach, G.; Ju, J.; Cheng, G.; Fisher, S.; Francks, C.

    2017-01-01

    Background Left-right asymmetry is a fundamental organizing feature of the human brain, and neuro-psychiatric disorders such as schizophrenia sometimes involve alterations of brain asymmetry. As early as 8 weeks post conception, the majority of human fetuses move their right arms more than their left arms, but because nerve fibre tracts are still descending from the forebrain at this stage, spinal-muscular asymmetries are likely to play an important developmental role. Methods We used RNA seq...

  5. A common neural code for social and monetary rewards in the human striatum.

    Science.gov (United States)

    Wake, Stephanie J; Izuma, Keise

    2017-10-01

    Although managing social information and decision making on the basis of reward is critical for survival, it remains uncertain whether differing reward type is processed in a uniform manner. Previously, we demonstrated that monetary reward and the social reward of good reputation activated the same striatal regions including the caudate nucleus and putamen. However, it remains unclear whether overlapping activations reflect activities of identical neuronal populations or two overlapping but functionally independent neuronal populations. Here, we re-analyzed the original data and addressed this question using multivariate-pattern-analysis and found evidence that in the left caudate nucleus and bilateral nucleus accumbens, social vs monetary reward were represented similarly. The findings suggest that social and monetary rewards are processed by the same population of neurons within these regions of the striatum. Additional findings demonstrated similar neural patterns when participants experience high social reward compared to viewing others receiving low social reward (potentially inducing schadenfreude). This is possibly an early indication that the same population of neurons may be responsible for processing two different types of social reward (good reputation and schadenfreude). These findings provide a supplementary perspective to previous research, helping to further elucidate the mechanisms behind social vs non-social reward processing. © The Author (2017). Published by Oxford University Press.

  6. Functional MRI studies of the neural mechanisms of human brain attentional networks

    International Nuclear Information System (INIS)

    Hao Jing; Li Kuncheng; Chen Qi; Wang Yan; Peng Xiaozhe; Zhou Xiaolin

    2005-01-01

    Objective: To identify the neural mechanisms of the anterior attention network (AAN) and posterior attention network (PAN) , investigate the possible interaction between them with event-related functional MRI(ER-fMRI). Methods: Eight right-handed healthy volunteers participated in the experiment designed with inhibition of return in visual orienting and Stroop color-word interference effect. The fMRI data were collected on Siemens 1.5 T Sonata MRI systems and analyzed by AFNI to generate the activation map. Results: The data sets from 6 of 8 subjects were used in the study. The functional localizations of the Stroop and IOR, which manifest the function of the AAN and PAN respectively, were consistent with previous imaging researches. On cued locations, left inferior parietal lobule (IPL), area MT/V5, right dorsolateral prefrontal cortex (DLPFC) and left anterior cingulated cortex (ACC) were significantly activated. On uncued locations, right superior parietal lobule (SPL) and bilateral area MT/V5 were significantly activated. Conclusion: The AAN exerts control over the PAN, while its function can be in turn modulated by the PAN. There are interaction between the AAN and PAN. In addition, it is also proved that ER-fMRI is a feasible method to revise preexisting cognitive model and theory. (authors)

  7. Influence of attention focus on neural activity in the human spinal cord during thermal sensory stimulation.

    Science.gov (United States)

    Stroman, Patrick W; Coe, Brian C; Munoz, Doug P

    2011-01-01

    Perceptions of sensation and pain in healthy people are believed to be the net result of sensory input and descending modulation from brainstem and cortical regions depending on emotional and cognitive factors. Here, the influence of attention on neural activity in the spinal cord during thermal sensory stimulation of the hand was investigated with functional magnetic resonance imaging by systematically varying the participants' attention focus across and within repeated studies. Attention states included (1) attention to the stimulus by rating the sensation and (2) attention away from the stimulus by performing various mental tasks of watching a movie and identifying characters, detecting the direction of coherently moving dots within a randomly moving visual field and answering mentally-challenging questions. Functional MRI results spanning the cervical spinal cord and brainstem consistently demonstrated that the attention state had a significant influence on the activity detected in the cervical spinal cord, as well as in brainstem regions involved with the descending analgesia system. These findings have important implications for the detection and study of pain, and improved characterization of the effects of injury or disease. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Generation of highly purified neural stem cells from human adipose-derived mesenchymal stem cells by Sox1 activation.

    Science.gov (United States)

    Feng, Nianhua; Han, Qin; Li, Jing; Wang, Shihua; Li, Hongling; Yao, Xinglei; Zhao, Robert Chunhua

    2014-03-01

    Neural stem cells (NSCs) are ideal candidates in stem cell-based therapy for neurodegenerative diseases. However, it is unfeasible to get enough quantity of NSCs for clinical application. Generation of NSCs from human adipose-derived mesenchymal stem cells (hAD-MSCs) will provide a solution to this problem. Currently, the differentiation of hAD-MSCs into highly purified NSCs with biological functions is rarely reported. In our study, we established a three-step NSC-inducing protocol, in which hAD-MSCs were induced to generate NSCs with high purity after sequentially cultured in the pre-inducing medium (Step1), the N2B27 medium (Step2), and the N2B27 medium supplement with basic fibroblast growth factor and epidermal growth factor (Step3). These hAD-MSC-derived NSCs (adNSCs) can form neurospheres and highly express Sox1, Pax6, Nestin, and Vimentin; the proportion was 96.1% ± 1.3%, 96.8% ± 1.7%, 96.2% ± 1.3%, and 97.2% ± 2.5%, respectively, as detected by flow cytometry. These adNSCs can further differentiate into astrocytes, oligodendrocytes, and functional neurons, which were able to generate tetrodotoxin-sensitive sodium current. Additionally, we found that the neural differentiation of hAD-MSCs were significantly suppressed by Sox1 interference, and what's more, Step1 was a key step for the following induction, probably because it was associated with the initiation and nuclear translocation of Sox1, an important transcriptional factor for neural development. Finally, we observed that bone morphogenetic protein signal was inhibited, and Wnt/β-catenin signal was activated during inducing process, and both signals were related with Sox1 expression. In conclusion, we successfully established a three-step inducing protocol to derive NSCs from hAD-MSCs with high purity by Sox1 activation. These findings might enable to acquire enough autologous transplantable NSCs for the therapy of neurodegenerative diseases in clinic.

  9. Functional mapping of the neural basis for the encoding and retrieval of human episodic memory using H215O PET

    International Nuclear Information System (INIS)

    Lee, Jae Sung; Nam, Hyun Woo; Lee, Dong Soo; Lee, Sang Kun; Jang, Myoung Jin; Ahn, Ji Young; Park, Kwang Suk; Chung, June Key; Lee, Myung Chul

    2000-01-01

    Episodic memory is described as an 'autobiographical' memory responsible for storing a record of the events in our lives. We performed functional brain activation study using H 2 1 5O PET to reveal the neural basis of the encoding and the retrieval of episodic memory in human normal volunteers. Four repeated H 2 1 5O PET scans with two reference and two activation tasks were performed on 6 normal volunteers to activate brain areas engaged in encoding and retrieval with verbal materials. Images from the same subject were spatially registered and normalized using linear and nonlinear transformation. Using the means and variances for every condition which were adjusted with analysis of covariance, t-statistic analysis were performed voxel-wise. Encoding of episodic memory activated the opercular and triangular parts of left inferior frontal gyrus, right prefrontal cortex, medial frontal area, cingulate gyrus, posterior middle and inferior temporal gyri, and cerebellum, and both primary visual and visual association areas. Retrieval of episodic memory activated the triangular part of left inferior frontal gyrus and inferior temporal gyrus, right prefrontal cortex and medial temporal ares, and both cerebellum and primary visual and visual association areas. The activations in the opercular part of left inferior frontal gyrus and the right prefrontal cortex meant the essential role of these areas in the encoding and retrieval of episodic memeory. We could localize the neural basis of the encoding and retrieval of episodic memory using H 2 1 5O PET, which was partly consistent with the hypothesis of hemispheric encoding/retrieval asymmetry.=20

  10. Dynamic dependence on ATR and ATM for double-strand break repair in human embryonic stem cells and neural descendants.

    Science.gov (United States)

    Adams, Bret R; Golding, Sarah E; Rao, Raj R; Valerie, Kristoffer

    2010-04-02

    The DNA double-strand break (DSB) is the most toxic form of DNA damage. Studies aimed at characterizing DNA repair during development suggest that homologous recombination repair (HRR) is more critical in pluripotent cells compared to differentiated somatic cells in which nonhomologous end joining (NHEJ) is dominant. We have characterized the DNA damage response (DDR) and quality of DNA double-strand break (DSB) repair in human embryonic stem cells (hESCs), and in vitro-derived neural cells. Resolution of ionizing radiation-induced foci (IRIF) was used as a surrogate for DSB repair. The resolution of gamma-H2AX foci occurred at a slower rate in hESCs compared to neural progenitors (NPs) and astrocytes perhaps reflective of more complex DSB repair in hESCs. In addition, the resolution of RAD51 foci, indicative of active homologous recombination repair (HRR), showed that hESCs as well as NPs have high capacity for HRR, whereas astrocytes do not. Importantly, the ATM kinase was shown to be critical for foci formation in astrocytes, but not in hESCs, suggesting that the DDR is different in these cells. Blocking the ATM kinase in astrocytes not only prevented the formation but also completely disassembled preformed repair foci. The ability of hESCs to form IRIF was abrogated with caffeine and siRNAs targeted against ATR, implicating that hESCs rely on ATR, rather than ATM for regulating DSB repair. This relationship dynamically changed as cells differentiated. Interestingly, while the inhibition of the DNA-PKcs kinase (and presumably non-homologous endjoining [NHEJ]) in astrocytes slowed IRIF resolution it did not in hESCs, suggesting that repair in hESCs does not utilize DNA-PKcs. Altogether, our results show that hESCs have efficient DSB repair that is largely ATR-dependent HRR, whereas astrocytes critically depend on ATM for NHEJ, which, in part, is DNA-PKcs-independent.

  11. The effect of exogenous cortisol during sleep on the behavioral and neural correlates of emotional memory consolidation in humans.

    Science.gov (United States)

    van Marle, Hein J F; Hermans, Erno J; Qin, Shaozheng; Overeem, Sebastiaan; Fernández, Guillén

    2013-09-01

    A host of animal work demonstrates that the retention benefit for emotionally aversive over neutral memories is regulated by glucocorticoid action during memory consolidation. Particularly, glucocorticoids may affect systems-level processes that promote the gradual reorganization of emotional memory traces. These effects remain largely uninvestigated in humans. Therefore, in this functional magnetic resonance imaging study we administered hydrocortisone during a polysomnographically monitored night of sleep directly after healthy volunteers studied negative and neutral pictures in a double-blind, placebo-controlled, between-subjects design. The following evening memory consolidation was probed during a recognition memory test in the MR scanner by assessing the difference in brain activity associated with memory for the consolidated items studied before sleep and new, unconsolidated items studied shortly before test (remote vs. recent memory paradigm). Hydrocortisone administration resulted in elevated cortisol levels throughout the experimental night with no group difference at recent encoding or test. Behaviorally, we showed that cortisol enhanced the difference between emotional and neutral consolidated memory, effectively prioritizing emotional memory consolidation. On a neural level, we found that cortisol reduced amygdala reactivity related to the retrieval of these same consolidated, negative items. These findings show that cortisol administration during first post-encoding sleep had a twofold effect on the first 24h of emotional memory consolidation. While cortisol prioritized recognition memory for emotional items, it reduced reactivation of the neural circuitry underlying emotional responsiveness during retrieval. These findings fit recent theories on emotional depotentiation following consolidation during sleep, although future research should establish the sleep-dependence of this effect. Moreover, our data may shed light on mechanisms underlying

  12. A Hybrid Neural Network Approach for Kinematic Modeling of a Novel 6-UPS Parallel Human-Like Mastication Robot

    Directory of Open Access Journals (Sweden)

    Hadi Kalani

    2016-04-01

    Full Text Available Introduction we aimed to introduce a 6-universal-prismatic-spherical (UPS parallel mechanism for the human jaw motion and theoretically evaluate its kinematic problem. We proposed a strategy to provide a fast and accurate solution to the kinematic problem. The proposed strategy could accelerate the process of solution-finding for the direct kinematic problem by reducing the number of required iterations in order to reach the desired accuracy level. Materials and Methods To overcome the direct kinematic problem, an artificial neural network and third-order Newton-Raphson algorithm were combined to provide an improved hybrid method. In this method, approximate solution was presented for the direct kinematic problem by the neural network. This solution could be considered as the initial guess for the third-order Newton-Raphson algorithm to provide an answer with the desired level of accuracy. Results The results showed that the proposed combination could help find a approximate solution and reduce the execution time for the direct kinematic problem, The results showed that muscular actuations showed periodic behaviors, and the maximum length variation of temporalis muscle was larger than that of masseter and pterygoid muscles. By reducing the processing time for solving the direct kinematic problem, more time could be devoted to control calculations.. In this method, for relatively high levels of accuracy, the number of iterations and computational time decreased by 90% and 34%, respectively, compared to the conventional Newton method. Conclusion The present analysis could allow researchers to characterize and study the mastication process by specifying different chewing patterns (e.g., muscle displacements.

  13. Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans.

    Science.gov (United States)

    Skosnik, Patrick D; Hajós, Mihály; Cortes-Briones, Jose A; Edwards, Chad R; Pittman, Brian P; Hoffmann, William E; Sewell, Andrew R; D'Souza, Deepak C; Ranganathan, Mohini

    2018-06-01

    Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively. Human subjects (n = 15) completed four test days during which they received intravenous delta-9-tetrahydrocannabinol (Δ 9 -THC), cannabidiol (CBD), Δ 9 -THC + CBD, or placebo. Subjects engaged in a dual-click paradigm, and outcome measures included P50 gating ratio (S2/S1) and evoked power to S1 and S2. In order to examine CB1R specificity, rats (n = 6) were administered the CB1R agonist CP-55940, CP-55940+AM-251 (a CB1R antagonist), or vehicle using the same paradigm. LFPs were recorded from CA3 and entorhinal cortex. Both Δ 9 -THC (p < 0.007) and Δ 9 -THC + CBD (p < 0.004) disrupted P50 gating ratio compared to placebo, while CBD alone had no effect. Δ 9 -THC (p < 0.048) and Δ 9 -THC + CBD (p < 0.035) decreased S1 evoked theta power, and in the Δ 9 -THC condition, S1 theta negatively correlated with gating ratios (r = -0.629, p < 0.012 (p < 0.048 adjusted)). In rats, CP-55940 disrupted gating in both brain regions (p < 0.0001), and this was reversed by AM-251. Further, CP-55940 decreased evoked theta (p < 0.0077) and gamma (p < 0.011) power to S1, which was partially blocked by AM-251. These convergent human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta-band. Moreover, this suggests that the endocannabinoid system mediates theta oscillations relevant to perception and cognition. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Critical Branching Neural Networks

    Science.gov (United States)

    Kello, Christopher T.

    2013-01-01

    It is now well-established that intrinsic variations in human neural and behavioral activity tend to exhibit scaling laws in their fluctuations and distributions. The meaning of these scaling laws is an ongoing matter of debate between isolable causes versus pervasive causes. A spiking neural network model is presented that self-tunes to critical…

  15. Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase.

    Directory of Open Access Journals (Sweden)

    Xi-Juan Liu

    2017-07-01

    Full Text Available Congenital human cytomegalovirus (HCMV infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs. As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1 is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1 is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase.

  16. Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice

    Directory of Open Access Journals (Sweden)

    Jack C. Reidling

    2018-01-01

    Full Text Available Huntington's disease (HD is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP-grade human embryonic stem cell-derived neural stem cell (hNSC line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF in both models. These findings hold promise for future development of stem cell-based therapies.

  17. Direct Conversion of Human Umbilical Cord Blood into Induced Neural Stem Cells with SOX2 and HMGA2.

    Science.gov (United States)

    Kim, Jae-Jun; Shin, Ji-Hee; Yu, Kyung-Rok; Lee, Byung-Chul; Kang, Insung; Lee, Jin Young; Kim, Da-Hyun; Seo, Yoojin; Kim, Hyung-Sik; Choi, Soon Won; Kang, Kyung-Sun

    2017-11-30

    Recent advances have shown the direct reprogramming of mouse and human fibroblasts into induced neural stem cells (iNSCs) without passing through an intermediate pluripotent state. Thus, direct reprogramming strategy possibly provides a safe and homogeneous cellular platform. However, the applications of iNSCs for regenerative medicine are limited by the restricted availability of cell sources. Human umbilical cord blood (hUCB) cells hold great potential in that immunotyped hUCB units can be immediately obtained from public banks. Moreover, hUCB samples do not require invasive procedures during collection or an extensive culture period prior to reprogramming. We recently reported that somatic cells can be directly converted into iNSCs with high efficiency and a short turnaround time. Here, we describe the detailed method for the generation of iNSCs derived from hUCB (hUCB iNSCs) using the lineage-specific transcription factors SOX2 and HMGA2. The protocol for deriving iNSC-like colonies takes 1∼2 weeks and establishment of homogenous hUCB iNSCs takes additional 2 weeks. Established hUCB iNSCs are clonally expandable and multipotent producing neurons and glia. Our study provides an accessible method for generating hUCB iNSCs, contributing development of in vitro neuropathological model systems.

  18. Development of Human-level Decision Making Algorithm for NPPs through Deep Neural Networks : Conceptual Approach

    International Nuclear Information System (INIS)

    Kim, Seung Geun; Seong, Poong Hyun

    2017-01-01

    Development of operation support systems and automation systems are closely related to machine learning field. However, since it is hard to achieve human-level delicacy and flexibility for complex tasks with conventional machine learning technologies, only operation support systems with simple purposes were developed and high-level automation related studies were not actively conducted. As one of the efforts for reducing human error in NPPs and technical advance toward automation, the ultimate goal of this research is to develop human-level decision making algorithm for NPPs during emergency situations. The concepts of SL, RL, policy network, value network, and MCTS, which were applied to decision making algorithm for other fields are introduced and combined with nuclear field specifications. Since the research is currently at the conceptual stage, more research is warranted.

  19. Neural sources of visual working memory maintenance in human parietal and ventral extrastriate visual cortex.

    Science.gov (United States)

    Becke, Andreas; Müller, Notger; Vellage, Anne; Schoenfeld, Mircea Ariel; Hopf, Jens-Max

    2015-04-15

    Maintaining information in visual working memory is reliably indexed by the contralateral delay activity (CDA) - a sustained modulation of the event-related potential (ERP) with a topographical maximum over posterior scalp regions contralateral to the memorized input. Based on scalp topography, it is hypothesized that the CDA reflects neural activity in the parietal cortex, but the precise cortical origin of underlying electric activity was never determined. Here we combine ERP recordings with magnetoencephalography based source localization to characterize the cortical current sources generating the CDA. Observers performed a cued delayed match to sample task where either the color or the relative position of colored dots had to be maintained in memory. A detailed source-localization analysis of the magnetic activity in the retention interval revealed that the magnetic analog of the CDA (mCDA) is generated by current sources in the parietal cortex. Importantly, we find that the mCDA also receives contribution from current sources in the ventral extrastriate cortex that display a time-course similar to the parietal sources. On the basis of the magnetic responses, forward modeling of ERP data reveals that the ventral sources have non-optimal projections and that these sources are therefore concealed in the ERP by overlapping fields with parietal projections. The present observations indicate that visual working memory maintenance, as indexed by the CDA, involves the parietal cortical regions as well as the ventral extrastriate regions, which code the sensory representation of the memorized content. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Distributed neural signatures of natural audiovisual speech and music in the human auditory cortex.

    Science.gov (United States)

    Salmi, Juha; Koistinen, Olli-Pekka; Glerean, Enrico; Jylänki, Pasi; Vehtari, Aki; Jääskeläinen, Iiro P; Mäkelä, Sasu; Nummenmaa, Lauri; Nummi-Kuisma, Katarina; Nummi, Ilari; Sams, Mikko

    2017-08-15

    During a conversation or when listening to music, auditory and visual information are combined automatically into audiovisual objects. However, it is still poorly understood how specific type of visual information shapes neural processing of sounds in lifelike stimulus environments. Here we applied multi-voxel pattern analysis to investigate how naturally matching visual input modulates supratemporal cortex activity during processing of naturalistic acoustic speech, singing and instrumental music. Bayesian logistic regression classifiers with sparsity-promoting priors were trained to predict whether the stimulus was audiovisual or auditory, and whether it contained piano playing, speech, or singing. The predictive performances of the classifiers were tested by leaving one participant at a time for testing and training the model using the remaining 15 participants. The signature patterns associated with unimodal auditory stimuli encompassed distributed locations mostly in the middle and superior temporal gyrus (STG/MTG). A pattern regression analysis, based on a continuous acoustic model, revealed that activity in some of these MTG and STG areas were associated with acoustic features present in speech and music stimuli. Concurrent visual stimulus modulated activity in bilateral MTG (speech), lateral aspect of right anterior STG (singing), and bilateral parietal opercular cortex (piano). Our results suggest that specific supratemporal brain areas are involved in processing complex natural speech, singing, and piano playing, and other brain areas located in anterior (facial speech) and posterior (music-related hand actions) supratemporal cortex are influenced by related visual information. Those anterior and posterior supratemporal areas have been linked to stimulus identification and sensory-motor integration, respectively. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. An overview of neural function and feedback control in human communication.

    Science.gov (United States)

    Hood, L J

    1998-01-01

    The speech and hearing mechanisms depend on accurate sensory information and intact feedback mechanisms to facilitate communication. This article provides a brief overview of some components of the nervous system important for human communication and some electrophysiological methods used to measure cortical function in humans. An overview of automatic control and feedback mechanisms in general and as they pertain to the speech motor system and control of the hearing periphery is also presented, along with a discussion of how the speech and auditory systems interact.

  2. Healthy human CSF promotes glial differentiation of hESC-derived neural cells while retaining spontaneous activity in existing neuronal networks

    Directory of Open Access Journals (Sweden)

    Heikki Kiiski

    2013-05-01

    The possibilities of human pluripotent stem cell-derived neural cells from the basic research tool to a treatment option in regenerative medicine have been well recognized. These cells also offer an interesting tool for in vitro models of neuronal networks to be used for drug screening and neurotoxicological studies and for patient/disease specific in vitro models. Here, as aiming to develop a reductionistic in vitro human neuronal network model, we tested whether human embryonic stem cell (hESC-derived neural cells could be cultured in human cerebrospinal fluid (CSF in order to better mimic the in vivo conditions. Our results showed that CSF altered the differentiation of hESC-derived neural cells towards glial cells at the expense of neuronal differentiation. The proliferation rate was reduced in CSF cultures. However, even though the use of CSF as the culture medium altered the glial vs. neuronal differentiation rate, the pre-existing spontaneous activity of the neuronal networks persisted throughout the study. These results suggest that it is possible to develop fully human cell and culture-based environments that can further be modified for various in vitro modeling purposes.

  3. Sensitive Tumorigenic Potential Evaluation of Adult Human Multipotent Neural Cells Immortalized by hTERT Gene Transduction.

    Directory of Open Access Journals (Sweden)

    Kee Hang Lee

    Full Text Available Stem cells and therapeutic genes are emerging as a new therapeutic approach to treat various neurodegenerative diseases with few effective treatment options. However, potential formation of tumors by stem cells has hampered their clinical application. Moreover, adequate preclinical platforms to precisely test tumorigenic potential of stem cells are controversial. In this study, we compared the sensitivity of various animal models for in vivo stem cell tumorigenicity testing to identify the most sensitive platform. Then, tumorigenic potential of adult human multipotent neural cells (ahMNCs immortalized by the human telomerase reverse transcriptase (hTERT gene was examined as a stem cell model with therapeutic genes. When human glioblastoma (GBM cells were injected into adult (4-6-week-old Balb/c-nu, adult NOD/SCID, adult NOG, or neonate (1-2-week-old NOG mice, the neonate NOG mice showed significantly faster tumorigenesis than that of the other groups regardless of intracranial or subcutaneous injection route. Two kinds of ahMNCs (682TL and 779TL were primary cultured from surgical samples of patients with temporal lobe epilepsy. Although the ahMNCs were immortalized by lentiviral hTERT gene delivery (hTERT-682TL and hTERT-779TL, they did not form any detectable masses, even in the most sensitive neonate NOG mouse platform. Moreover, the hTERT-ahMNCs had no gross chromosomal abnormalities on a karyotype analysis. Taken together, our data suggest that neonate NOG mice could be a sensitive animal platform to test tumorigenic potential of stem cell therapeutics and that ahMNCs could be a genetically stable stem cell source with little tumorigenic activity to develop regenerative treatments for neurodegenerative diseases.

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

    Science.gov (United States)

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

    2016-10-01

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

  5. The Metal Neurotoxins: An Important Role in Current Human Neural Epidemics?

    Directory of Open Access Journals (Sweden)

    Keith Schofield

    2017-12-01

    Full Text Available Many published studies have illustrated that several of the present day neurological epidemics (autism, attention deficit disorder, Alzheimer’s cannot be correlated to any single neurotoxicant. However, the present scientific examination of the numerous global blood monitoring databases for adults that include the concentrations of the neurotoxic elements, aluminum (Al, arsenic (As, lead (Pb, manganese (Mn, mercury (Hg, and selenium (Se clearly indicate that, when considered in combination, for some, the human body may become easily over-burdened. This can be explained by changes in modern lifestyles. Similar data, solely for pregnant women, have been examined confirming this. All these elements are seen to be present in the human body and at not insignificant magnitudes. Currently suggested minimum risk levels (MRL for humans are discussed and listed together with averages of the reported distributions, together with their spread and maximum values. One observation is that many distributions for pregnant women are not too dissimilar from those of general populations. Women obviously have their individual baseline of neurotoxin values before pregnancy and any efforts to modify this to any significant degree is not yet clearly apparent. For any element, distribution shapes are reasonably similar showing broad distributions with extended tails with numerous outlier values. There are a certain fraction of people that lie well above the MRL values and may be at risk, especially if genetically susceptible. Additionally, synergistic effects between neurotoxins and with other trace metals are now also being reported. It appears prudent for women of child-bearing age to establish their baseline values well before pregnancy. Those at risk then can be better identified. Adequate instrumental testing now is commercially available for this. In addition, directives are necessary for vaccination programs to use only non-neurotoxic adjuvants, especially for

  6. Plasticity of Calcium Signaling Cascades in Human Embryonic Stem Cell-Derived Neural Precursors

    Czech Academy of Sciences Publication Activity Database

    Forostyak, Oksana; Romanyuk, Nataliya; Verkhratsky, A.; Syková, Eva; Dayanithi, Govindan

    2013-01-01

    Roč. 22, č. 10 (2013), s. 1506-1521 ISSN 1547-3287 R&D Projects: GA ČR GAP304/11/2373; GA ČR(CZ) GBP304/12/G069 Grant - others:FP7(XE) PITN-GA-2008-214003 project AXREGEN; FP7(XE) PITN-GA-2009-237956 project EdU-GLIA Institutional support: RVO:68378041 Keywords : human embryonic stem cells * voltage-operated Ca2+ channels * spontaneous Ca2+ oscillations Subject RIV: FH - Neurology Impact factor: 4.202, year: 2013

  7. Physical and neural entrainment to rhythm: human sensorimotor coordination across tasks and effector systems

    Directory of Open Access Journals (Sweden)

    Jessica Marie Ross

    2014-08-01

    Full Text Available The human sensorimotor system can be readily entrained to environmental rhythms, through multiple sensory modalities. In this review, we provide an overview of theories of timekeeping that make this neuroentrainment possible. First, we present recent evidence that contests the assumptions made in classic timekeeper models. The role of state estimation, sensory feedback and movement parameters on the organization of sensorimotor timing are discussed in the context of recent experiments that examined simultaneous timing and force control. This discussion is extended to the study of coordinated multi-effector movements and how they may be entrained.

  8. A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury.

    Science.gov (United States)

    Curtis, Erik; Martin, Joel R; Gabel, Brandon; Sidhu, Nikki; Rzesiewicz, Teresa K; Mandeville, Ross; Van Gorp, Sebastiaan; Leerink, Marjolein; Tadokoro, Takahiro; Marsala, Silvia; Jamieson, Catriona; Marsala, Martin; Ciacci, Joseph D

    2018-06-01

    We tested the feasibility and safety of human-spinal-cord-derived neural stem cell (NSI-566) transplantation for the treatment of chronic spinal cord injury (SCI). In this clinical trial, four subjects with T2-T12 SCI received treatment consisting of removal of spinal instrumentation, laminectomy, and durotomy, followed by six midline bilateral stereotactic injections of NSI-566 cells. All subjects tolerated the procedure well and there have been no serious adverse events to date (18-27 months post-grafting). In two subjects, one to two levels of neurological improvement were detected using ISNCSCI motor and sensory scores. Our results support the safety of NSI-566 transplantation into the SCI site and early signs of potential efficacy in three of the subjects warrant further exploration of NSI-566 cells in dose escalation studies. Despite these encouraging secondary data, we emphasize that this safety trial lacks statistical power or a control group needed to evaluate functional changes resulting from cell grafting. Copyright © 2018. Published by Elsevier Inc.

  9. Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Michal Aharonowiz

    Full Text Available BACKGROUND: Multiple sclerosis (MS is an immune mediated demyelinating disease of the central nervous system (CNS. A potential new therapeutic approach for MS is cell transplantation which may promote remyelination and suppress the inflammatory process. METHODS: We transplanted human embryonic stem cells (hESC-derived early multipotent neural precursors (NPs into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE, the animal model of MS. We studied the effect of the transplanted NPs on the functional and pathological manifestations of the disease. RESULTS: Transplanted hESC-derived NPs significantly reduced the clinical signs of EAE. Histological examination showed migration of the transplanted NPs to the host white matter, however, differentiation to mature oligodendrocytes and remyelination were negligible. Time course analysis of the evolution and progression of CNS inflammation and tissue injury showed an attenuation of the inflammatory process in transplanted animals, which was correlated with the reduction of both axonal damage and demyelination. Co-culture experiments showed that hESC-derived NPs inhibited the activation and proliferation of lymph node-derived T cells in response to nonspecific polyclonal stimuli. CONCLUSIONS: The therapeutic effect of transplantation was not related to graft or host remyelination but was mediated by an immunosuppressive neuroprotective mechanism. The attenuation of EAE by hESC-derived NPs, demonstrated here, may serve as the first step towards further developments of hESC for cell therapy in MS.

  10. Comparative Effects of Human Neural Stem Cells and Oligodendrocyte Progenitor Cells on the Neurobehavioral Disorders of Experimental Autoimmune Encephalomyelitis Mice

    Directory of Open Access Journals (Sweden)

    Dae-Kwon Bae

    2016-01-01

    Full Text Available Since multiple sclerosis (MS is featured with widespread demyelination caused by autoimmune response, we investigated the recovery effects of F3.olig2 progenitors, established by transducing human neural stem cells (F3 NSCs with Olig2 transcription factor, in myelin oligodendrocyte glycoprotein- (MOG- induced experimental autoimmune encephalomyelitis (EAE model mice. Six days after EAE induction, F3 or F3.olig2 cells (1 × 106/mouse were intravenously transplanted. MOG-injected mice displayed severe neurobehavioral deficits which were remarkably attenuated and restored by cell transplantation, in which F3.olig2 cells were superior to its parental F3 cells. Transplanted cells migrated to the injured spinal cord, matured to oligodendrocytes, and produced myelin basic proteins (MBP. The F3.olig2 cells expressed growth and neurotrophic factors including brain-derived neurotrophic factor (BDNF, nerve growth factor (NGF, ciliary neurotrophic factor (CNTF, and leukemia inhibitory factor (LIF. In addition, the transplanted cells markedly attenuated inflammatory cell infiltration, reduced cytokine levels in the spinal cord and lymph nodes, and protected host myelins. The results indicate that F3.olig2 cells restore neurobehavioral symptoms of EAE mice by regulating autoimmune inflammatory responses as well as by stimulating remyelination and that F3.olig2 progenitors could be a candidate for the cell therapy of demyelinating diseases including MS.

  11. An Empirical Study of Neural Network-Based Audience Response Technology in a Human Anatomy Course for Pharmacy Students.

    Science.gov (United States)

    Fernández-Alemán, José Luis; López-González, Laura; González-Sequeros, Ofelia; Jayne, Chrisina; López-Jiménez, Juan José; Carrillo-de-Gea, Juan Manuel; Toval, Ambrosio

    2016-04-01

    This paper presents an empirical study of a formative neural network-based assessment approach by using mobile technology to provide pharmacy students with intelligent diagnostic feedback. An unsupervised learning algorithm was integrated with an audience response system called SIDRA in order to generate states that collect some commonality in responses to questions and add diagnostic feedback for guided learning. A total of 89 pharmacy students enrolled on a Human Anatomy course were taught using two different teaching methods. Forty-four students employed intelligent SIDRA (i-SIDRA), whereas 45 students received the same training but without using i-SIDRA. A statistically significant difference was found between the experimental group (i-SIDRA) and the control group (traditional learning methodology), with T (87) = 6.598, p < 0.001. In four MCQs tests, the difference between the number of correct answers in the first attempt and in the last attempt was also studied. A global effect size of 0.644 was achieved in the meta-analysis carried out. The students expressed satisfaction with the content provided by i-SIDRA and the methodology used during the process of learning anatomy (M = 4.59). The new empirical contribution presented in this paper allows instructors to perform post hoc analyses of each particular student's progress to ensure appropriate training.

  12. Spatiotemporal neural characterization of prediction error valence and surprise during reward learning in humans.

    Science.gov (United States)

    Fouragnan, Elsa; Queirazza, Filippo; Retzler, Chris; Mullinger, Karen J; Philiastides, Marios G

    2017-07-06

    Reward learning depends on accurate reward associations with potential choices. These associations can be attained with reinforcement learning mechanisms using a reward prediction error (RPE) signal (the difference between actual and expected rewards) for updating future reward expectations. Despite an extensive body of literature on the influence of RPE on learning, little has been done to investigate the potentially separate contributions of RPE valence (positive or negative) and surprise (absolute degree of deviation from expectations). Here, we coupled single-trial electroencephalography with simultaneously acquired fMRI, during a probabilistic reversal-learning task, to offer evidence of temporally overlapping but largely distinct spatial representations of RPE valence and surprise. Electrophysiological variability in RPE valence correlated with activity in regions of the human reward network promoting approach or avoidance learning. Electrophysiological variability in RPE surprise correlated primarily with activity in regions of the human attentional network controlling the speed of learning. Crucially, despite the largely separate spatial extend of these representations our EEG-informed fMRI approach uniquely revealed a linear superposition of the two RPE components in a smaller network encompassing visuo-mnemonic and reward areas. Activity in this network was further predictive of stimulus value updating indicating a comparable contribution of both signals to reward learning.

  13. Neural mechanisms of transient neocortical beta rhythms: Converging evidence from humans, computational modeling, monkeys, and mice

    Science.gov (United States)

    Sherman, Maxwell A.; Lee, Shane; Law, Robert; Haegens, Saskia; Thorn, Catherine A.; Hämäläinen, Matti S.; Moore, Christopher I.; Jones, Stephanie R.

    2016-01-01

    Human neocortical 15–29-Hz beta oscillations are strong predictors of perceptual and motor performance. However, the mechanistic origin of beta in vivo is unknown, hindering understanding of its functional role. Combining human magnetoencephalography (MEG), computational modeling, and laminar recordings in animals, we present a new theory that accounts for the origin of spontaneous neocortical beta. In our MEG data, spontaneous beta activity from somatosensory and frontal cortex emerged as noncontinuous beta events typically lasting drive targeting proximal and distal dendrites of pyramidal neurons, where the defining feature of a beta event was a strong distal drive that lasted one beta period (∼50 ms). This beta mechanism rigorously accounted for the beta event profiles; several other mechanisms did not. The spatial location of synaptic drive in the model to supragranular and infragranular layers was critical to the emergence of beta events and led to the prediction that beta events should be associated with a specific laminar current profile. Laminar recordings in somatosensory neocortex from anesthetized mice and awake monkeys supported these predictions, suggesting this beta mechanism is conserved across species and recording modalities. These findings make several predictions about optimal states for perceptual and motor performance and guide causal interventions to modulate beta for optimal function. PMID:27469163

  14. Stimulation of neural differentiation in human bone marrow mesenchymal stem cells by extremely low-frequency electromagnetic fields incorporated with MNPs.

    Science.gov (United States)

    Choi, Yun-Kyong; Lee, Dong Heon; Seo, Young-Kwon; Jung, Hyun; Park, Jung-Keug; Cho, Hyunjin

    2014-10-01

    Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) have been investigated as a new cell-therapeutic solution due to their capacity that could differentiate into neural-like cells. Extremely low-frequency electromagnetic fields (ELF-EMFs) therapy has emerged as a novel technique, using mechanical stimulus to differentiate hBM-MSCs and significantly enhance neuronal differentiation to affect cellular and molecular reactions. Magnetic iron oxide (Fe3O4) nanoparticles (MNPs) have recently achieved widespread use for biomedical applications and polyethylene glycol (PEG)-labeled nanoparticles are used to increase their circulation time, aqueous solubility, biocompatibility, and nonspecific cellular uptake as well as to decrease immunogenicity. Many studies have used MNP-labeled cells for differentiation, but there have been no reports of MNP-labeled neural differentiation combined with EMFs. In this study, synthesized PEG-phospholipid encapsulated magnetite (Fe3O4) nanoparticles are used on hBM-MSCs to improve their intracellular uptake. The PEGylated nanoparticles were exposed to the cells under 50 Hz of EMFs to improve neural differentiation. First, we measured cell viability and intracellular iron content in hBM-MSCs after treatment with MNPs. Analysis was conducted by RT-PCR, and immunohistological analysis using neural cell type-specific genes and antibodies after exposure to 50 Hz electromagnetic fields. These results suggest that electromagnetic fields enhance neural differentiation in hBM-MSCs incorporated with MNPs and would be an effective method for differentiating neural cells.

  15. Activation of Group II Metabotropic Glutamate Receptors Increases Proliferation but does not Influence Neuronal Differentiation of a Human Neural Stem Cell Line

    DEFF Research Database (Denmark)

    Dindler, Anne; Blaabjerg, Morten; Kamand, Morad

    2018-01-01

    of pharmacological activation and inhibition of mGluR2/3 on proliferation, differentiation and viability of a human neural stem cell line. Immunofluorescence staining revealed the presence of mGluR2/3 receptors on both proliferating and differentiating stem cells, including cells differentiated into β-tubulin III....... Western blot analysis revealed that the active, dimeric form of mGluR2/3 was mainly present on the proliferating cells, which may explain our findings. The present study emphasises the importance of glutamate and mGluRs on regulation of human neural stem cells and suggests a significant role of mGluR2....../3 during cell proliferation. This article is protected by copyright. All rights reserved....

  16. Study of the efficiency of transplantation of human neural stem cells to rats with spinal trauma: the use of functional load tests and BBB test.

    Science.gov (United States)

    Lebedev, S V; Karasev, A V; Chekhonin, V P; Savchenko, E A; Viktorov, I V; Chelyshev, Yu A; Shaimardanova, G F

    2010-09-01

    Human ensheating neural stem cells of the olfactory epithelium were transplanted to adult male rats immediately after contusion trauma of the spinal cord at T9 level rostrally and caudally to the injury. Voluntary movements (by a 21-point BBB scale), rota-rod performance, and walking along a narrowing beam were monitored weekly over 60 days. In rats receiving cell transplantation, the mean BBB score significantly increased by 11% by the end of the experiment. The mean parameters of load tests also regularly surpassed the corresponding parameters in controls. The efficiency of transplantation (percent of animals with motor function recovery parameters surpassing the corresponding mean values in the control groups) was 62% by the state of voluntary motions, 37% by the rota-rod test, and 32% by the narrowing beam test. Morphometry revealed considerable shrinking of the zone of traumatic damage in the spinal cord and activation of posttraumatic remyelination in animals receiving transplantation of human neural stem cells.

  17. Attention to Color Sharpens Neural Population Tuning via Feedback Processing in the Human Visual Cortex Hierarchy.

    Science.gov (United States)

    Bartsch, Mandy V; Loewe, Kristian; Merkel, Christian; Heinze, Hans-Jochen; Schoenfeld, Mircea A; Tsotsos, John K; Hopf, Jens-Max

    2017-10-25

    Attention can facilitate the selection of elementary object features such as color, orientation, or motion. This is referred to as feature-based attention and it is commonly attributed to a modulation of the gain and tuning of feature-selective units in visual cortex. Although gain mechanisms are well characterized, little is known about the cortical processes underlying the sharpening of feature selectivity. Here, we show with high-resolution magnetoencephalography in human observers (men and women) that sharpened selectivity for a particular color arises from feedback processing in the human visual cortex hierarchy. To assess color selectivity, we analyze the response to a color probe that varies in color distance from an attended color target. We find that attention causes an initial gain enhancement in anterior ventral extrastriate cortex that is coarsely selective for the target color and transitions within ∼100 ms into a sharper tuned profile in more posterior ventral occipital cortex. We conclude that attention sharpens selectivity over time by attenuating the response at lower levels of the cortical hierarchy to color values neighboring the target in color space. These observations support computational models proposing that attention tunes feature selectivity in visual cortex through backward-propagating attenuation of units less tuned to the target. SIGNIFICANCE STATEMENT Whether searching for your car, a particular item of clothing, or just obeying traffic lights, in everyday life, we must select items based on color. But how does attention allow us to select a specific color? Here, we use high spatiotemporal resolution neuromagnetic recordings to examine how color selectivity emerges in the human brain. We find that color selectivity evolves as a coarse to fine process from higher to lower levels within the visual cortex hierarchy. Our observations support computational models proposing that feature selectivity increases over time by attenuating the

  18. Dynamic dependence on ATR and ATM for double-strand break repair in human embryonic stem cells and neural descendants.

    Directory of Open Access Journals (Sweden)

    Bret R Adams

    2010-04-01

    Full Text Available The DNA double-strand break (DSB is the most toxic form of DNA damage. Studies aimed at characterizing DNA repair during development suggest that homologous recombination repair (HRR is more critical in pluripotent cells compared to differentiated somatic cells in which nonhomologous end joining (NHEJ is dominant. We have characterized the DNA damage response (DDR and quality of DNA double-strand break (DSB repair in human embryonic stem cells (hESCs, and in vitro-derived neural cells. Resolution of ionizing radiation-induced foci (IRIF was used as a surrogate for DSB repair. The resolution of gamma-H2AX foci occurred at a slower rate in hESCs compared to neural progenitors (NPs and astrocytes perhaps reflective of more complex DSB repair in hESCs. In addition, the resolution of RAD51 foci, indicative of active homologous recombination repair (HRR, showed that hESCs as well as NPs have high capacity for HRR, whereas astrocytes do not. Importantly, the ATM kinase was shown to be critical for foci formation in astrocytes, but not in hESCs, suggesting that the DDR is different in these cells. Blocking the ATM kinase in astrocytes not only prevented the formation but also completely disassembled preformed repair foci. The ability of hESCs to form IRIF was abrogated with caffeine and siRNAs targeted against ATR, implicating that hESCs rely on ATR, rather than ATM for regulating DSB repair. This relationship dynamically changed as cells differentiated. Interestingly, while the inhibition of the DNA-PKcs kinase (and presumably non-homologous endjoining [NHEJ] in astrocytes slowed IRIF resolution it did not in hESCs, suggesting that repair in hESCs does not utilize DNA-PKcs. Altogether, our results show that hESCs have efficient DSB repair that is largely ATR-dependent HRR, whereas astrocytes critically depend on ATM for NHEJ, which, in part, is DNA-PKcs-independent.

  19. Neural protein gamma-synuclein interacting with androgen receptor promotes human prostate cancer progression

    International Nuclear Information System (INIS)

    Chen, Junyi; Jiao, Li; Xu, Chuanliang; Yu, Yongwei; Zhang, Zhensheng; Chang, Zheng; Deng, Zhen; Sun, Yinghao

    2012-01-01

    Gamma-synuclein (SNCG) has previously been demonstrated to be significantly correlated with metastatic malignancies; however, in-depth investigation of SNCG in prostate cancer is still lacking. In the present study, we evaluated the role of SNCG in prostate cancer progression and explored the underlying mechanisms. First, alteration of SNCG expression in LNCaP cell line to test the ability of SNCG on cellular properties in vitro and vivo whenever exposing with androgen or not. Subsequently, the Dual-luciferase reporter assays were performed to evaluate whether the role of SNCG in LNCaP is through AR signaling. Last, the association between SNCG and prostate cancer progression was assessed immunohistochemically using a series of human prostate tissues. Silencing SNCG by siRNA in LNCaP cells contributes to the inhibition of cellular proliferation, the induction of cell-cycle arrest at the G1 phase, the suppression of cellular migration and invasion in vitro, as well as the decrease of tumor growth in vivo with the notable exception of castrated mice. Subsequently, mechanistic studies indicated that SNCG is a novel androgen receptor (AR) coactivator. It interacts with AR and promotes prostate cancer cellular growth and proliferation by activating AR transcription in an androgen-dependent manner. Finally, immunohistochemical analysis revealed that SNCG was almost undetectable in benign or androgen-independent tissues prostate lesions. The high expression of SNCG is correlated with peripheral and lymph node invasion. Our data suggest that SNCG may serve as a biomarker for predicting human prostate cancer progression and metastasis. It also may become as a novel target for biomedical therapy in advanced prostate cancer

  20. Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival

    Czech Academy of Sciences Publication Activity Database

    Ševc, J.; Goldberg, D.; van Gorp, S.; Leerink, M.; Juhás, Štefan; Juhásová, Jana; Marsala, S.; Hruška-Plocháň, Marian; Hefferan, M. P.; Motlík, Jan; Rypáček, František; Machová, Luďka; Kakinohana, O.; Santucci, C.; Johe, K.; Lukáčová, N.; Yamada, K.; Bui, J. D.; Marsala, M.

    2013-01-01

    Roč. 248, October (2013), s. 85-99 ISSN 0014-4886 R&D Projects: GA TA ČR TA01011466; GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 ; RVO:61389013 Keywords : immunosuppression * xenograft * human neural precursors Subject RIV: FH - Neurology; CD - Macromolecular Chemistry (UMCH-V) Impact factor: 4.617, year: 2013

  1. Neural Computations Mediating One-Shot Learning in the Human Brain

    Science.gov (United States)

    Lee, Sang Wan; O’Doherty, John P.; Shimojo, Shinsuke

    2015-01-01

    Incremental learning, in which new knowledge is acquired gradually through trial and error, can be distinguished from one-shot learning, in which the brain learns rapidly from only a single pairing of a stimulus and a consequence. Very little is known about how the brain transitions between these two fundamentally different forms of learning. Here we test a computational hypothesis that uncertainty about the causal relationship between a stimulus and an outcome induces rapid changes in the rate of learning, which in turn mediates the transition between incremental and one-shot learning. By using a novel behavioral task in combination with functional magnetic resonance imaging (fMRI) data from human volunteers, we found evidence implicating the ventrolateral prefrontal cortex and hippocampus in this process. The hippocampus was selectively “switched” on when one-shot learning was predicted to occur, while the ventrolateral prefrontal cortex was found to encode uncertainty about the causal association, exhibiting increased coupling with the hippocampus for high-learning rates, suggesting this region may act as a “switch,” turning on and off one-shot learning as required. PMID:25919291

  2. Inducible alpha-synuclein expression affects human Neural Stem Cell behavior.

    Science.gov (United States)

    Zasso, Jacopo; Mastad, Ahmed; Cutarelli, Alessandro; Conti, Luciano

    2018-04-19

    Converging evidence suggest that levels of alpha-Synuclein (aSyn) expression play a critical role in Parkinson's disease (PD). Several mutations of the SNCA gene, encoding for aSyn have been associated to either the familial or the sporadic forms of PD. Nonetheless, the mechanism underlying wild type aSyn-mediated neurotoxicity in neuronal cells as well as its specific driving role in PD pathogenesis has yet to be fully clarified. In this view, the development of proper in vitro cellular systems is a crucial step. Here we present a novel human Tet-on hNSC cell line, in which aSyn timing and level of expression can be tightly experimentally tuned. Induction of aSyn in self-renewing hNSCs leads to progressive formation of aSyn aggregates and impairs their proliferation and cell survival. Furthermore, aSyn induction during the neuronal differentiation process results in reduced neuronal differentiation and increased number astrocytes and undifferentiated cells in culture. Finally, acute aSyn induction in hNSC-derived dopaminergic neuronal cultures results in cell toxicity. This novel conditional in vitro cell model system may be a valuable tool for dissecting of aSyn pathogenic effects in hNSCs and neurons and in developing new potential therapeutic strategies.

  3. Neural control of blood flow during exercise in human metabolic syndrome.

    Science.gov (United States)

    Limberg, Jacqueline K; Morgan, Barbara J; Sebranek, Joshua J; Proctor, Lester T; Eldridge, Marlowe W; Schrage, William G

    2014-09-01

    α-Adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In an attempt to translate such findings to humans, we hypothesized that adults with MetSyn (n = 14, 35 ± 3 years old) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy control subjects (n = 16, 31 ± 3 years old). We measured muscle sympathetic nerve activity (MSNA; microneurography) and forearm blood flow (Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction). α-Adrenergic agonists (phenylephrine and clonidine) and an antagonist (phentolamine) were infused intra-arterially to assess α-adrenergic receptor responsiveness and restraint, respectively. Resting MSNA was ∼35% higher in adults with MetSyn (P exercise. Clonidine-mediated vasoconstriction was greater in adults with MetSyn (P  0.05). Interestingly, exercise-mediated vasodilatation was greater in MetSyn (P exercise blood flow during low-intensity hand-grip exercise when compared with age-matched healthy control subjects. These results suggest that adults with MetSyn exhibit compensatory vascular control mechanisms capable of preserving blood flow responses to exercise in the face of augmented sympathetic adrenergic activity. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

  4. Neural computations mediating one-shot learning in the human brain.

    Directory of Open Access Journals (Sweden)

    Sang Wan Lee

    2015-04-01

    Full Text Available Incremental learning, in which new knowledge is acquired gradually through trial and error, can be distinguished from one-shot learning, in which the brain learns rapidly from only a single pairing of a stimulus and a consequence. Very little is known about how the brain transitions between these two fundamentally different forms of learning. Here we test a computational hypothesis that uncertainty about the causal relationship between a stimulus and an outcome induces rapid changes in the rate of learning, which in turn mediates the transition between incremental and one-shot learning. By using a novel behavioral task in combination with functional magnetic resonance imaging (fMRI data from human volunteers, we found evidence implicating the ventrolateral prefrontal cortex and hippocampus in this process. The hippocampus was selectively "switched" on when one-shot learning was predicted to occur, while the ventrolateral prefrontal cortex was found to encode uncertainty about the causal association, exhibiting increased coupling with the hippocampus for high-learning rates, suggesting this region may act as a "switch," turning on and off one-shot learning as required.

  5. Nanoengineered Polystyrene Surfaces with Nanopore Array Pattern Alters Cytoskeleton Organization and Enhances Induction of Neural Differentiation of Human Adipose-Derived Stem Cells.

    Science.gov (United States)

    Jung, Ae Ryang; Kim, Richard Y; Kim, Hyung Woo; Shrestha, Kshitiz Raj; Jeon, Seung Hwan; Cha, Kyoung Je; Park, Yong Hyun; Kim, Dong Sung; Lee, Ji Youl

    2015-07-01

    Human adipose-derived stem cells (hADSCs) can differentiate into various cell types depending on chemical and topographical cues. One topographical cue recently noted to be successful in inducing differentiation is the nanoengineered polystyrene surface containing nanopore array-patterned substrate (NP substrate), which is designed to mimic the nanoscale topographical features of the extracellular matrix. In this study, efficacies of NP and flat substrates in inducing neural differentiation of hADSCs were examined by comparing their substrate-cell adhesion rates, filopodia growth, nuclei elongation, and expression of neural-specific markers. The polystyrene nano Petri dishes containing NP substrates were fabricated by a nano injection molding process using a nickel electroformed nano-mold insert (Diameter: 200 nm. Depth of pore: 500 nm. Center-to-center distance: 500 nm). Cytoskeleton and filopodia structures were observed by scanning electron microscopy and F-actin staining, while cell adhesion was tested by vinculin staining after 24 and 48 h of seeding. Expression of neural specific markers was examined by real-time quantitative polymerase chain reaction and immunocytochemistry. Results showed that NP substrates lead to greater substrate-cell adhesion, filopodia growth, nuclei elongation, and expression of neural specific markers compared to flat substrates. These results not only show the advantages of NP substrates, but they also suggest that further study into cell-substrate interactions may yield great benefits for biomaterial engineering.

  6. Neurite extension and neuronal differentiation of human induced pluripotent stem cell derived neural stem cells on polyethylene glycol hydrogels containing a continuous Young's Modulus gradient.

    Science.gov (United States)

    Mosley, Matthew C; Lim, Hyun Ju; Chen, Jing; Yang, Yueh-Hsun; Li, Shenglan; Liu, Ying; Smith Callahan, Laura A

    2017-03-01

    Mechanotransduction in neural cells involves multiple signaling pathways that are not fully understood. Differences in lineage and maturation state are suggested causes for conflicting reports on neural cell mechanosensitivity. To optimize matrices for use in stem cell therapy treatments transplanting human induced pluripotent stem cell derived neural stem cells (hNSC) into lesions after spinal cord injury, the effects of Young's Modulus changes on hNSC behavior must be understood. The present study utilizes polyethylene glycol hydrogels containing a continuous gradient in Young's modulus to examine changes in the Young's Modulus of the culture substrate on hNSC neurite extension and neural differentiation. Changes in the Young's Modulus of the polyethylene glycol hydrogels was found to affect neurite extension and cellular organization on the matrices. hNSC cultured on 907 Pa hydrogels were found to extend longer neurites than hNSC cultured on other tested Young's Moduli hydrogels. The gene expression of β tubulin III and microtubule-associated protein 2 in hNSC was affected by changes in the Young's Modulus of the hydrogel. The combinatory method approach used in the present study demonstrates that hNSC are mechanosensitive and the matrix Young's Modulus should be a design consideration for hNSC transplant applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 824-833, 2017. © 2016 Wiley Periodicals, Inc.

  7. Cross-sensory facilitation reveals neural interactions between visual and tactile motion in humans

    Directory of Open Access Journals (Sweden)

    Monica eGori

    2011-04-01

    Full Text Available Many recent studies show that the human brain integrates information across the different senses and that stimuli of one sensory modality can enhance the perception of other modalities. Here we study the processes that mediate cross-modal facilitation and summation between visual and tactile motion. We find that while summation produced a generic, non-specific improvement of thresholds, probably reflecting higher-order interaction of decision signals, facilitation reveals a strong, direction-specific interaction, which we believe reflects sensory interactions. We measured visual and tactile velocity discrimination thresholds over a wide range of base velocities and conditions. Thresholds for both visual and tactile stimuli showed the characteristic dipper function, with the minimum thresholds occurring at a given pedestal speed. When visual and tactile coherent stimuli were combined (summation condition the thresholds for these multi-sensory stimuli also showed a dipper function with the minimum thresholds occurring in a similar range to that for unisensory signals. However, the improvement of multisensory thresholds was weak and not directionally specific, well predicted by the maximum likelihood estimation model (agreeing with previous research. A different technique (facilitation did, however, reveal direction-specific enhancement. Adding a non-informative pedestal motion stimulus in one sensory modality (vision or touch selectively lowered thresholds in the other, by the same amount as pedestals in the same modality. Facilitation did not occur for neutral stimuli like sounds (that would also have reduced temporal uncertainty, nor for motion in opposite direction, even in blocked trials where the subjects knew that the motion was in the opposite direction showing that the facilitation was not under subject control. Cross-sensory facilitation is strong evidence for functionally relevant cross-sensory integration at early levels of sensory

  8. Functional size of human visual area V1: a neural correlate of top-down attention.

    Science.gov (United States)

    Verghese, Ashika; Kolbe, Scott C; Anderson, Andrew J; Egan, Gary F; Vidyasagar, Trichur R

    2014-06-01

    Heavy demands are placed on the brain's attentional capacity when selecting a target item in a cluttered visual scene, or when reading. It is widely accepted that such attentional selection is mediated by top-down signals from higher cortical areas to early visual areas such as the primary visual cortex (V1). Further, it has also been reported that there is considerable variation in the surface area of V1. This variation may impact on either the number or specificity of attentional feedback signals and, thereby, the efficiency of attentional mechanisms. In this study, we investigated whether individual differences between humans performing attention-demanding tasks can be related to the functional area of V1. We found that those with a larger representation in V1 of the central 12° of the visual field as measured using BOLD signals from fMRI were able to perform a serial search task at a faster rate. In line with recent suggestions of the vital role of visuo-spatial attention in reading, the speed of reading showed a strong positive correlation with the speed of visual search, although it showed little correlation with the size of V1. The results support the idea that the functional size of the primary visual cortex is an important determinant of the efficiency of selective spatial attention for simple tasks, and that the attentional processing required for complex tasks like reading are to a large extent determined by other brain areas and inter-areal connections. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Comparative performance analysis of human iPSC-derived and primary neural progenitor cells (NPC grown as neurospheres in vitro

    Directory of Open Access Journals (Sweden)

    Maxi Hofrichter

    2017-12-01

    hiPSC-NPCs-derived neurospheres seem to be useful for DNT evaluation representing early neural development in vitro. More system characterization by compound testing is needed to gain higher confidence in this method.

  10. Aural localization of silent objects by active human biosonar: neural representations of virtual echo-acoustic space.

    Science.gov (United States)

    Wallmeier, Ludwig; Kish, Daniel; Wiegrebe, Lutz; Flanagin, Virginia L

    2015-03-01

    Some blind humans have developed the remarkable ability to detect and localize objects through the auditory analysis of self-generated tongue clicks. These echolocation experts show a corresponding increase in 'visual' cortex activity when listening to echo-acoustic sounds. Echolocation in real-life settings involves multiple reflections as well as active sound production, neither of which has been systematically addressed. We developed a virtualization technique that allows participants to actively perform such biosonar tasks in virtual echo-acoustic space during magnetic resonance imaging (MRI). Tongue clicks, emitted in the MRI scanner, are picked up by a microphone, convolved in real time with the binaural impulse responses of a virtual space, and presented via headphones as virtual echoes. In this manner, we investigated the brain activity during active echo-acoustic localization tasks. Our data show that, in blind echolocation experts, activations in the calcarine cortex are dramatically enhanced when a single reflector is introduced into otherwise anechoic virtual space. A pattern-classification analysis revealed that, in the blind, calcarine cortex activation patterns could discriminate left-side from right-side reflectors. This was found in both blind experts, but the effect was significant for only one of them. In sighted controls, 'visual' cortex activations were insignificant, but activation patterns in the planum temporale were sufficient to discriminate left-side from right-side reflectors. Our data suggest that blind and echolocation-trained, sighted subjects may recruit different neural substrates for the same active-echolocation task. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  11. Human neural progenitor cell engraftment increases neurogenesis and microglial recruitment in the brain of rats with stroke.

    Directory of Open Access Journals (Sweden)

    Zahra Hassani

    Full Text Available Stem cell transplantation is to date one of the most promising therapies for chronic ischemic stroke. The human conditionally immortalised neural stem cell line, CTX0E03, has demonstrable efficacy in a rodent model of stroke and is currently in clinical trials. Nonetheless, the mechanisms by which it promotes brain repair are not fully characterised. This study investigated the cellular events occurring after CTX0E03 transplantation in the brains of rats that underwent ischemic stroke.We focused on the endogenous proliferative activity of the host brain in response to cell transplantation and determined the identity of the proliferating cells using markers for young neurons (doublecortin, Dcx and microglia (CD11b. So as to determine the chronology of events occurring post-transplantation, we analysed the engrafted brains one week and four weeks post-transplantation.We observed a significantly greater endogenous proliferation in the striatum of ischemic brains receiving a CTX0E03 graft compared to vehicle-treated ischemic brains. A significant proportion of these proliferative cells were found to be Dcx+ striatal neuroblasts. Further, we describe an enhanced immune response after CTX0E03 engraftment, as shown by a significant increase of proliferating CD11b+ microglial cells.Our study demonstrates that few Dcx+ neuroblasts are proliferative in normal conditions, and that this population of proliferative neuroblasts is increased in response to stroke. We further show that CTX0E03 transplantation after stroke leads to the maintenance of this proliferative activity. Interestingly, the preservation of neuronal proliferative activity upon CTX0E03 transplantation is preceded and accompanied by a high rate of proliferating microglia. Our study suggests that microglia might mediate in part the effect of CTX0E03 transplantation on neuronal proliferation in ischemic stroke conditions.

  12. Engrafted human induced pluripotent stem cell-derived anterior specified neural progenitors protect the rat crushed optic nerve.

    Directory of Open Access Journals (Sweden)

    Leila Satarian

    Full Text Available BACKGROUND: Degeneration of retinal ganglion cells (RGCs is a common occurrence in several eye diseases. This study examined the functional improvement and protection of host RGCs in addition to the survival, integration and neuronal differentiation capabilities of anterior specified neural progenitors (NPs following intravitreal transplantation. METHODOLOGY/PRINCIPAL FINDINGS: NPs were produced under defined conditions from human induced pluripotent stem cells (hiPSCs and transplanted into rats whose optic nerves have been crushed (ONC. hiPSCs were induced to differentiate into anterior specified NPs by the use of Noggin and retinoic acid. The hiPSC-NPs were labeled by green fluorescent protein or a fluorescent tracer 1,1' -dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI and injected two days after induction of ONC in hooded rats. Functional analysis according to visual evoked potential recordings showed significant amplitude recovery in animals transplanted with hiPSC-NPs. Retrograde labeling by an intra-collicular DiI injection showed significantly higher numbers of RGCs and spared axons in ONC rats treated with hiPSC-NPs or their conditioned medium (CM. The analysis of CM of hiPSC-NPs showed the secretion of ciliary neurotrophic factor, basic fibroblast growth factor, and insulin-like growth factor. Optic nerve of cell transplanted groups also had increased GAP43 immunoreactivity and myelin staining by FluoroMyelin™ which imply for protection of axons and myelin. At 60 days post-transplantation hiPSC-NPs were integrated into the ganglion cell layer of the retina and expressed neuronal markers. CONCLUSIONS/SIGNIFICANCE: The transplantation of anterior specified NPs may improve optic nerve injury through neuroprotection and differentiation into neuronal lineages. These NPs possibly provide a promising new therapeutic approach for traumatic optic nerve injuries and loss of RGCs caused by other diseases.

  13. Isolation, characterization, and differentiation of multipotent neural progenitor cells from human cerebrospinal fluid in fetal cystic myelomeningocele

    Directory of Open Access Journals (Sweden)

    Mario Marotta

    2017-07-01

    Full Text Available Despite benefits of prenatal in utero repair of myelomeningocele, a severe type of spina bifida aperta, many of these patients will still suffer mild to severe impairment. One potential source of stem cells for new regenerative medicine-based therapeutic approaches for spinal cord injury repair is neural progenitor cells (NPCs in cerebrospinal fluid (CSF. To this aim, we extracted CSF from the cyst surrounding the exposed neural placode during the surgical repair of myelomeningocele in 6 fetuses (20 to 26 weeks of gestation. In primary cultured CSF-derived cells, neurogenic properties were confirmed by in vitro differentiation into various neural lineage cell types, and NPC markers expression (TBR2, CD15, SOX2 were detected by immunofluorescence and RT-PCR analysis. Differentiation into three neural lineages was corroborated by arbitrary differentiation (depletion of growths factors or explicit differentiation as neuronal, astrocyte, or oligodendrocyte cell types using specific induction mediums. Differentiated cells showed the specific expression of neural differentiation markers (βIII-tubulin, GFAP, CNPase, oligo-O1. In myelomeningocele patients, CSF-derived cells could become a potential source of NPCs with neurogenic capacity. Our findings support the development of innovative stem-cell-based therapeutics by autologous transplantation of CSF-derived NPCs in damaged spinal cords, such as myelomeningocele, thus promoting neural tissue regeneration in fetuses.

  14. Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling

    Directory of Open Access Journals (Sweden)

    Sujeong Jang

    2015-01-01

    Full Text Available Stem cells are a powerful resource for cell-based transplantation therapies, but understanding of stem cell differentiation at the molecular level is not clear yet. We hypothesized that the Wnt pathway controls stem cell maintenance and neural differentiation. We have characterized the transcriptional expression of Wnt during the neural differentiation of hADSCs. After neural induction, the expressions of Wnt2, Wnt4, and Wnt11 were decreased, but the expression of Wnt5a was increased compared with primary hADSCs in RT-PCR analysis. In addition, the expression levels of most Fzds and LRP5/6 ligand were decreased, but not Fzd3 and Fzd5. Furthermore, Dvl1 and RYK expression levels were downregulated in NI-hADSCs. There were no changes in the expression of ß-catenin and GSK3ß. Interestingly, Wnt5a expression was highly increased in NI-hADSCs by real time RT-PCR analysis and western blot. Wnt5a level was upregulated after neural differentiation and Wnt3, Dvl2, and Naked1 levels were downregulated. Finally, we found that the JNK expression was increased after neural induction and ERK level was decreased. Thus, this study shows for the first time how a single Wnt5a ligand can activate the neural differentiation pathway through the activation of Wnt5a/JNK pathway by binding Fzd3 and Fzd5 and directing Axin/GSK-3ß in hADSCs.

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

    Science.gov (United States)

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

    2018-03-15

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

  16. Interaction of adult human neural crest-derived stem cells with a nanoporous titanium surface is sufficient to induce their osteogenic differentiation

    Directory of Open Access Journals (Sweden)

    Matthias Schürmann

    2014-07-01

    Full Text Available Osteogenic differentiation of various adult stem cell populations such as neural crest-derived stem cells is of great interest in the context of bone regeneration. Ideally, exogenous differentiation should mimic an endogenous differentiation process, which is partly mediated by topological cues. To elucidate the osteoinductive potential of porous substrates with different pore diameters (30 nm, 100 nm, human neural crest-derived stem cells isolated from the inferior nasal turbinate were cultivated on the surface of nanoporous titanium covered membranes without additional chemical or biological osteoinductive cues. As controls, flat titanium without any topological features and osteogenic medium was used. Cultivation of human neural crest-derived stem cells on 30 nm pores resulted in osteogenic differentiation as demonstrated by alkaline phosphatase activity after seven days as well as by calcium deposition after 3 weeks of cultivation. In contrast, cultivation on flat titanium and on membranes equipped with 100 nm pores was not sufficient to induce osteogenic differentiation. Moreover, we demonstrate an increase of osteogenic transcripts including Osterix, Osteocalcin and up-regulation of Integrin β1 and α2 in the 30 nm pore approach only. Thus, transplantation of stem cells pre-cultivated on nanostructured implants might improve the clinical outcome by support of the graft adherence and acceleration of the regeneration process.

  17. Large-scale generation of human iPSC-derived neural stem cells/early neural progenitor cells and their neuronal differentiation.

    Science.gov (United States)

    D'Aiuto, Leonardo; Zhi, Yun; Kumar Das, Dhanjit; Wilcox, Madeleine R; Johnson, Jon W; McClain, Lora; MacDonald, Matthew L; Di Maio, Roberto; Schurdak, Mark E; Piazza, Paolo; Viggiano, Luigi; Sweet, Robert; Kinchington, Paul R; Bhattacharjee, Ayantika G; Yolken, Robert; Nimgaonka, Vishwajit L; Nimgaonkar, Vishwajit L

    2014-01-01

    Induced pluripotent stem cell (iPSC)-based technologies offer an unprecedented opportunity to perform high-throughput screening of novel drugs for neurological and neurodegenerative diseases. Such screenings require a robust and scalable method for generating large numbers of mature, differentiated neuronal cells. Currently available methods based on differentiation of embryoid bodies (EBs) or directed differentiation of adherent culture systems are either expensive or are not scalable. We developed a protocol for large-scale generation of neuronal stem cells (NSCs)/early neural progenitor cells (eNPCs) and their differentiation into neurons. Our scalable protocol allows robust and cost-effective generation of NSCs/eNPCs from iPSCs. Following culture in neurobasal medium supplemented with B27 and BDNF, NSCs/eNPCs differentiate predominantly into vesicular glutamate transporter 1 (VGLUT1) positive neurons. Targeted mass spectrometry analysis demonstrates that iPSC-derived neurons express ligand-gated channels and other synaptic proteins and whole-cell patch-clamp experiments indicate that these channels are functional. The robust and cost-effective differentiation protocol described here for large-scale generation of NSCs/eNPCs and their differentiation into neurons paves the way for automated high-throughput screening of drugs for neurological and neurodegenerative diseases.

  18. Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles

    International Nuclear Information System (INIS)

    Oh, Jung-Hwa; Son, Mi-Young; Choi, Mi-Sun; Kim, Soojin; Choi, A-young; Lee, Hyang-Ae; Kim, Ki-Suk; Kim, Janghwan; Song, Chang Woo; Yoon, Seokjoo

    2016-01-01

    Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10–200 μg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24 h. The results showed that Ag NPs evoked significant toxicity in hESC-derived NPCs at 24 h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans. - Highlights: • This system served as a suitable model for developmental neurotoxicity testing. • Ag NPs induce the apoptosis in human neural cells by ROS generation. • Genes for development of neurons were dysregulated in response to Ag NPs. • Molecular events during early developmental neurotoxicity were proposed.

  19. Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Jung-Hwa [Korea Institute of Toxicology (KIT), Daejeon 34114 (Korea, Republic of); Department of human and environmental toxicology, University of Science & Technology, Daejeon 34113 (Korea, Republic of); Son, Mi-Young [Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahangno, Yuseong-gu, Daejeon 34141 (Korea, Republic of); Department of functional genomics, University of Science & Technology, 217 Gajungro, Yuseong-gu, Daejeon 34113 (Korea, Republic of); Choi, Mi-Sun; Kim, Soojin; Choi, A-young [Korea Institute of Toxicology (KIT), Daejeon 34114 (Korea, Republic of); Lee, Hyang-Ae; Kim, Ki-Suk [Korea Institute of Toxicology (KIT), Daejeon 34114 (Korea, Republic of); Department of human and environmental toxicology, University of Science & Technology, Daejeon 34113 (Korea, Republic of); Kim, Janghwan [Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahangno, Yuseong-gu, Daejeon 34141 (Korea, Republic of); Department of functional genomics, University of Science & Technology, 217 Gajungro, Yuseong-gu, Daejeon 34113 (Korea, Republic of); Song, Chang Woo, E-mail: cwsong@kitox.re.kr [Korea Institute of Toxicology (KIT), Daejeon 34114 (Korea, Republic of); Department of human and environmental toxicology, University of Science & Technology, Daejeon 34113 (Korea, Republic of); Yoon, Seokjoo, E-mail: sjyoon@kitox.re.kr [Korea Institute of Toxicology (KIT), Daejeon 34114 (Korea, Republic of); Department of human and environmental toxicology, University of Science & Technology, Daejeon 34113 (Korea, Republic of)

    2016-05-15

    Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10–200 μg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24 h. The results showed that Ag NPs evoked significant toxicity in hESC-derived NPCs at 24 h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans. - Highlights: • This system served as a suitable model for developmental neurotoxicity testing. • Ag NPs induce the apoptosis in human neural cells by ROS generation. • Genes for development of neurons were dysregulated in response to Ag NPs. • Molecular events during early developmental neurotoxicity were proposed.

  20. Targeted disruption in mice of a neural stem cell-maintaining, KRAB-Zn finger-encoding gene that has rapidly evolved in the human lineage.

    Directory of Open Access Journals (Sweden)

    Huan-Chieh Chien

    Full Text Available Understanding the genetic basis of the physical and behavioral traits that separate humans from other primates is a challenging but intriguing topic. The adaptive functions of the expansion and/or reduction in human brain size have long been explored. From a brain transcriptome project we have identified a KRAB-Zn finger protein-encoding gene (M003-A06 that has rapidly evolved since the human-chimpanzee separation. Quantitative RT-PCR analysis of different human tissues indicates that M003-A06 expression is enriched in the human fetal brain in addition to the fetal heart. Furthermore, analysis with use of immunofluorescence staining, neurosphere culturing and Western blotting indicates that the mouse ortholog of M003-A06, Zfp568, is expressed mainly in the embryonic stem (ES cells and fetal as well as adult neural stem cells (NSCs. Conditional gene knockout experiments in mice demonstrates that Zfp568 is both an NSC maintaining- and a brain size-regulating gene. Significantly, molecular genetic analyses show that human M003-A06 consists of 2 equilibrated allelic types, H and C, one of which (H is human-specific. Combined contemporary genotyping and database mining have revealed interesting genetic associations between the different genotypes of M003-A06 and the human head sizes. We propose that M003-A06 is likely one of the genes contributing to the uniqueness of the human brain in comparison to other higher primates.

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

    Science.gov (United States)

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

    2011-01-01

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

  2. Using an Artificial Neural Bypass to Restore Cortical Control of Rhythmic Movements in a Human with Quadriplegia

    Science.gov (United States)

    Sharma, Gaurav; Friedenberg, David A.; Annetta, Nicholas; Glenn, Bradley; Bockbrader, Marcie; Majstorovic, Connor; Domas, Stephanie; Mysiw, W. Jerry; Rezai, Ali; Bouton, Chad

    2016-09-01

    Neuroprosthetic technology has been used to restore cortical control of discrete (non-rhythmic) hand movements in a paralyzed person. However, cortical control of rhythmic movements which originate in the brain but are coordinated by Central Pattern Generator (CPG) neural networks in the spinal cord has not been demonstrated previously. Here we show a demonstration of an artificial neural bypass technology that decodes cortical activity and emulates spinal cord CPG function allowing volitional rhythmic hand movement. The technology uses a combination of signals recorded from the brain, machine-learning algorithms to decode the signals, a numerical model of CPG network, and a neuromuscular electrical stimulation system to evoke rhythmic movements. Using the neural bypass, a quadriplegic participant was able to initiate, sustain, and switch between rhythmic and discrete finger movements, using his thoughts alone. These results have implications in advancing neuroprosthetic technology to restore complex movements in people living with paralysis.

  3. Using Expectancy Theory to quantitatively dissociate the neural representation of motivation from its influential factors in the human brain: An fMRI study.

    Science.gov (United States)

    Kohli, Akshay; Blitzer, David N; Lefco, Ray W; Barter, Joseph W; Haynes, M Ryan; Colalillo, Sam A; Ly, Martina; Zink, Caroline F

    2018-05-08

    Researchers have yet to apply a formal operationalized theory of motivation to neurobiology that would more accurately and precisely define neural activity underlying motivation. We overcome this challenge with the novel application of the Expectancy Theory of Motivation to human fMRI to identify brain activity that explicitly reflects motivation. Expectancy Theory quantitatively describes how individual constructs determine motivation by defining motivation force as the product of three variables: expectancy - belief that effort will better performance; instrumentality - belief that successful performance leads to particular outcome, and valence - outcome desirability. Here, we manipulated information conveyed by reward-predicting cues such that relative cue-evoked activity patterns could be statistically mapped to individual Expectancy Theory variables. The variable associated with activity in any voxel is only reported if it replicated between two groups of healthy participants. We found signals in midbrain, ventral striatum, sensorimotor cortex, and visual cortex that specifically map to motivation itself, rather than other factors. This is important because, for the first time, it empirically clarifies approach motivation neural signals during reward anticipation. It also highlights the effectiveness of the application of Expectancy Theory to neurobiology to more precisely and accurately probe motivation neural correlates than has been achievable previously. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. The visual development of hand-centered receptive fields in a neural network model of the primate visual system trained with experimentally recorded human gaze changes.

    Science.gov (United States)

    Galeazzi, Juan M; Navajas, Joaquín; Mender, Bedeho M W; Quian Quiroga, Rodrigo; Minini, Loredana; Stringer, Simon M

    2016-01-01

    Neurons have been found in the primate brain that respond to objects in specific locations in hand-centered coordinates. A key theoretical challenge is to explain how such hand-centered neuronal responses may develop through visual experience. In this paper we show how hand-centered visual receptive fields can develop using an artificial neural network model, VisNet, of the primate visual system when driven by gaze changes recorded from human test subjects as they completed a jigsaw. A camera mounted on the head captured images of the hand and jigsaw, while eye movements were recorded using an eye-tracking device. This combination of data allowed us to reconstruct the retinal images seen as humans undertook the jigsaw task. These retinal images were then fed into the neural network model during self-organization of its synaptic connectivity using a biologically plausible trace learning rule. A trace learning mechanism encourages neurons in the model to learn to respond to input images that tend to occur in close temporal proximity. In the data recorded from human subjects, we found that the participant's gaze often shifted through a sequence of locations around a fixed spatial configuration of the hand and one of the jigsaw pieces. In this case, trace learning should bind these retinal images together onto the same subset of output neurons. The simulation results consequently confirmed that some cells learned to respond selectively to the hand and a jigsaw piece in a fixed spatial configuration across different retinal views.

  5. Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles.

    Science.gov (United States)

    Oh, Jung-Hwa; Son, Mi-Young; Choi, Mi-Sun; Kim, Soojin; Choi, A-Young; Lee, Hyang-Ae; Kim, Ki-Suk; Kim, Janghwan; Song, Chang Woo; Yoon, Seokjoo

    2016-05-15

    Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10-200μg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24h. The results showed that Ag NPs evoked significant toxicity in hESC-derived NPCs at 24h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Histamine H3 receptor density is negatively correlated with neural activity related to working memory in humans.

    Science.gov (United States)

    Ito, Takehito; Kimura, Yasuyuki; Seki, Chie; Ichise, Masanori; Yokokawa, Keita; Kawamura, Kazunori; Takahashi, Hidehiko; Higuchi, Makoto; Zhang, Ming-Rong; Suhara, Tetsuya; Yamada, Makiko

    2018-06-14

    The histamine H 3 receptor is regarded as a drug target for cognitive impairments in psychiatric disorders. H 3 receptors are expressed in neocortical areas, including the prefrontal cortex, the key region of cognitive functions such as working memory. However, the role of prefrontal H 3 receptors in working memory has not yet been clarified. Therefore, using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) techniques, we aimed to investigate the association between the neural activity of working memory and the density of H 3 receptors in the prefrontal cortex. Ten healthy volunteers underwent both fMRI and PET scans. The N-back task was used to assess the neural activities related to working memory. H 3 receptor density was measured with the selective PET radioligand [ 11 C] TASP457. The neural activity of the right dorsolateral prefrontal cortex during the performance of the N-back task was negatively correlated with the density of H 3 receptors in this region. Higher neural activity of working memory was associated with lower H 3 receptor density in the right dorsolateral prefrontal cortex. This finding elucidates the role of H 3 receptors in working memory and indicates the potential of H 3 receptors as a therapeutic target for the cognitive impairments associated with neuropsychiatric disorders.

  7. Neural Priming in Human Frontal Cortex: Multiple Forms of Learning Reduce Demands on the Prefrontal Executive System

    Science.gov (United States)

    Race, Elizabeth A.; Shanker, Shanti; Wagner, Anthony D.

    2009-01-01

    Past experience is hypothesized to reduce computational demands in PFC by providing bottom-up predictive information that informs subsequent stimulus-action mapping. The present fMRI study measured cortical activity reductions ("neural priming"/"repetition suppression") during repeated stimulus classification to investigate the mechanisms through…

  8. Systemic treatment of focal brain injury in the rat by human umbilical cord blood cells being at different level of neural commitment.

    Science.gov (United States)

    Gornicka-Pawlak, El Bieta; Janowski, Miroslaw; Habich, Aleksandra; Jablonska, Anna; Drela, Katarzyna; Kozlowska, Hanna; Lukomska, Barbara; Sypecka, Joanna; Domanska-Janik, Krystyna

    2011-01-01

    The aim of the study was to evaluate therapeutic effectiveness of intra-arterial infusion of human umbilical cord blood (HUCB) derived cells at different stages of their neural conversion. Freshly isolated mononuclear cells (D-0), neurally directed progenitors (D-3) and neural-like stem cells derived from umbilical cord blood (NSC) were compared. Focal brain damage was induced in rats by stereotactic injection of ouabain into dorsolateral striatum Three days later 10(7) of different subsets of HUCB cells were infused into the right internal carotid artery. Following surgery rats were housed in enriched environment for 30 days. Behavioral assessment consisted of tests for sensorimotor deficits (walking beam, rotarod, vibrissae elicited forelimb placing, apomorphine induced rotations), cognitive impairments (habit learning and object recognition) and exploratory behavior (open field). Thirty days after surgery the lesion volume was measured and the presence of donor cells was detected in the brain at mRNA level. At the same time immunohistochemical analysis of brain tissue was performed to estimate the local tissue response of ouabain injured rats and its modulation after HUCB cells systemic treatment. Functional effects of different subsets of cord blood cells shared substantial diversity in various behavioral tests. An additional analysis showed that D-0 HUCB cells were the most effective in functional restoration and reduction of brain lesion volume. None of transplanted cord blood derived cell fractions were detected in rat's brains at 30(th) day after treatment. This may suggest that the mechanism(s) underlying positive effects of HUCB derived cell may concern the other than direct neural cell supplementation. In addition increased immunoreactivity of markers indicating local cells proliferation and migration suggests stimulation of endogenous reparative processes by HUCB D-0 cell interarterial infusion.

  9. Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity.

    Directory of Open Access Journals (Sweden)

    Yoshiomi Kobayashi

    Full Text Available Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs for the repair of spinal cord injury (SCI in a non-human primate model. This study used a pre-evaluated "safe" hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus model of contusive SCI. SCI was induced at the fifth cervical level (C5, followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs. Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic.

  10. Open Ephys electroencephalography (Open Ephys  +  EEG): a modular, low-cost, open-source solution to human neural recording.

    Science.gov (United States)

    Black, Christopher; Voigts, Jakob; Agrawal, Uday; Ladow, Max; Santoyo, Juan; Moore, Christopher; Jones, Stephanie

    2017-06-01

    Electroencephalography (EEG) offers a unique opportunity to study human neural activity non-invasively with millisecond resolution using minimal equipment in or outside of a lab setting. EEG can be combined with a number of techniques for closed-loop experiments, where external devices are driven by specific neural signals. However, reliable, commercially available EEG systems are expensive, often making them impractical for individual use and research development. Moreover, by design, a majority of these systems cannot be easily altered to the specification needed by the end user. We focused on mitigating these issues by implementing open-source tools to develop a new EEG platform to drive down research costs and promote collaboration and innovation. Here, we present methods to expand the open-source electrophysiology system, Open Ephys (www.openephys.org), to include human EEG recordings. We describe the equipment and protocol necessary to interface various EEG caps with the Open Ephys acquisition board, and detail methods for processing data. We present applications of Open Ephys  +  EEG as a research tool and discuss how this innovative EEG technology lays a framework for improved closed-loop paradigms and novel brain-computer interface experiments. The Open Ephys  +  EEG system can record reliable human EEG data, as well as human EMG data. A side-by-side comparison of eyes closed 8-14 Hz activity between the Open Ephys  +  EEG system and the Brainvision ActiCHamp EEG system showed similar average power and signal to noise. Open Ephys  +  EEG enables users to acquire high-quality human EEG data comparable to that of commercially available systems, while maintaining the price point and extensibility inherent to open-source systems.

  11. Open Ephys electroencephalography (Open Ephys  +  EEG): a modular, low-cost, open-source solution to human neural recording

    Science.gov (United States)

    Black, Christopher; Voigts, Jakob; Agrawal, Uday; Ladow, Max; Santoyo, Juan; Moore, Christopher; Jones, Stephanie

    2017-06-01

    Objective. Electroencephalography (EEG) offers a unique opportunity to study human neural activity non-invasively with millisecond resolution using minimal equipment in or outside of a lab setting. EEG can be combined with a number of techniques for closed-loop experiments, where external devices are driven by specific neural signals. However, reliable, commercially available EEG systems are expensive, often making them impractical for individual use and research development. Moreover, by design, a majority of these systems cannot be easily altered to the specification needed by the end user. We focused on mitigating these issues by implementing open-source tools to develop a new EEG platform to drive down research costs and promote collaboration and innovation. Approach. Here, we present methods to expand the open-source electrophysiology system, Open Ephys (www.openephys.org), to include human EEG recordings. We describe the equipment and protocol necessary to interface various EEG caps with the Open Ephys acquisition board, and detail methods for processing data. We present applications of Open Ephys  +  EEG as a research tool and discuss how this innovative EEG technology lays a framework for improved closed-loop paradigms and novel brain-computer interface experiments. Main results. The Open Ephys  +  EEG system can record reliable human EEG data, as well as human EMG data. A side-by-side comparison of eyes closed 8-14 Hz activity between the Open Ephys  +  EEG system and the Brainvision ActiCHamp EEG system showed similar average power and signal to noise. Significance. Open Ephys  +  EEG enables users to acquire high-quality human EEG data comparable to that of commercially available systems, while maintaining the price point and extensibility inherent to open-source systems.

  12. Collagen-coated polylactic-glycolic acid (PLGA) seeded with neural-differentiated human mesenchymal stem cells as a potential nerve conduit.

    Science.gov (United States)

    Sulong, Ahmad Fadzli; Hassan, Nur Hidayah; Hwei, Ng Min; Lokanathan, Yogeswaran; Naicker, Amaramalar Selvi; Abdullah, Shalimar; Yusof, Mohd Reusmaazran; Htwe, Ohnmar; Idrus, Ruszymah Bt Hj; Haflah, Nor Hazla Mohamed

    2014-01-01

    Autologous nerve grafts to bridge nerve gaps pose various drawbacks. Nerve tissue engineering to promote nerve regeneration using artificial neural conduits has emerged as a promising alternative. To develop an artificial nerve conduit using collagen-coated polylactic-glycolic acid (PLGA) and to analyse the survivability and propagating ability of the neuro-differentiated human mesenchymal stem cells in this conduit. The PLGA conduit was constructed by dip-molding method and coated with collagen by immersing the conduit in collagen bath. The ultra structure of the conduits were examined before they were seeded with neural-differentiated human mesenchymal stem cells (nMSC) and implanted sub-muscularly on nude mice thighs. The non-collagen-coated PLGA conduit seeded with nMSC and non-seeded non-collagen-coated PLGA conduit were also implanted for comparison purposes. The survivability and propagation ability of nMSC was studied by histological and immunohistochemical analysis. The collagen-coated conduits had a smooth inner wall and a highly porous outer wall. Conduits coated with collagen and seeded with nMSCs produced the most number of cells after 3 weeks. The best conduit based on the number of cells contained within it after 3 weeks was the collagen-coated PLGA conduit seeded with neuro-transdifferentiated cells. The collagen-coated PLGA conduit found to be suitable for attachment, survival and proliferation of the nMSC. Minimal cell infiltration was found in the implanted conduits where nearly all of the cells found in the cell seeded conduits are non-mouse origin and have neural cell markers, which exhibit the biocompatibility of the conduits. The collagen-coated PLGA conduit is biocompatible, non-cytotoxic and suitable for use as artificial nerve conduits.

  13. Genome-wide association mapping in dogs enables identification of the homeobox gene, NKX2-8, as a genetic component of neural tube defects in humans.

    Directory of Open Access Journals (Sweden)

    Noa Safra

    Full Text Available Neural tube defects (NTDs is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition is reported among the more common birth defects in humans, leading to significant infant morbidity and mortality. The etiology remains poorly understood but genetic, nutritional, environmental factors, or a combination of these, are known to play a role in the development of NTDs. The variable conditions associated with NTDs occur naturally in dogs, and have been previously reported in the Weimaraner breed. Taking advantage of the strong linkage-disequilibrium within dog breeds we performed genome-wide association analysis and mapped a genomic region for spinal dysraphism, a presumed NTD, using 4 affected and 96 unaffected Weimaraners. The associated region on canine chromosome 8 (pgenome  =3.0 × 10(-5, after 100,000 permutations, encodes 18 genes, including NKX2-8, a homeobox gene which is expressed in the developing neural tube. Sequencing NKX2-8 in affected Weimaraners revealed a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein. The exons of NKX2-8 were sequenced in human patients with spina bifida and rare variants (rs61755040 and rs10135525 were found to be significantly over-represented (p=0.036. This is the first documentation of a potential role for NKX2-8 in the etiology of NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs.

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

    Directory of Open Access Journals (Sweden)

    Daniel L. Haus

    2014-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Eun Seong Lee

    2015-01-01

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

  16. Enhanced dopaminergic differentiation of human neural stem cells by synergistic effect of Bcl-xL and reduced oxygen tension

    DEFF Research Database (Denmark)

    Krabbe, Christina; Courtois, Elise; Jensen, Pia

    2009-01-01

    Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic different......Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic...... days at 20% oxygen, hVMbcl-x(L) cultures contained proportionally more tyrosine hydroxylase(TH)-positive cells than hVM1 control cultures. This difference was significantly potentiated from 11 +/- 0.8% to 17.2 +/- 0.2% of total cells when the oxygen tension was lowered to 3%. Immunocytochemistry and Q...

  17. Neural networks

    International Nuclear Information System (INIS)

    Denby, Bruce; Lindsey, Clark; Lyons, Louis

    1992-01-01

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

  18. Fatty acid-induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans.

    Science.gov (United States)

    Van Oudenhove, Lukas; McKie, Shane; Lassman, Daniel; Uddin, Bilal; Paine, Peter; Coen, Steven; Gregory, Lloyd; Tack, Jan; Aziz, Qasim

    2011-08-01

    Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression.

  19. Using Neural Pattern Classifiers to Quantify the Modularity of Conflict–Control Mechanisms in the Human Brain

    Science.gov (United States)

    Jiang, Jiefeng; Egner, Tobias

    2014-01-01

    Resolving conflicting sensory and motor representations is a core function of cognitive control, but it remains uncertain to what degree control over different sources of conflict is implemented by shared (domain general) or distinct (domain specific) neural resources. Behavioral data suggest conflict–control to be domain specific, but results from neuroimaging studies have been ambivalent. Here, we employed multivoxel pattern analyses that can decode a brain region's informational content, allowing us to distinguish incidental activation overlap from actual shared information processing. We trained independent sets of “searchlight” classifiers on functional magnetic resonance imaging data to decode control processes associated with stimulus-conflict (Stroop task) and ideomotor-conflict (Simon task). Quantifying the proportion of domain-specific searchlights (capable of decoding only one type of conflict) and domain-general searchlights (capable of decoding both conflict types) in each subject, we found both domain-specific and domain-general searchlights, though the former were more common. When mapping anatomical loci of these searchlights across subjects, neural substrates of stimulus- and ideomotor-specific conflict–control were found to be anatomically consistent across subjects, whereas the substrates of domain-general conflict–control were not. Overall, these findings suggest a hybrid neural architecture of conflict–control that entails both modular (domain specific) and global (domain general) components. PMID:23402762

  20. Using neural pattern classifiers to quantify the modularity of conflict-control mechanisms in the human brain.

    Science.gov (United States)

    Jiang, Jiefeng; Egner, Tobias

    2014-07-01

    Resolving conflicting sensory and motor representations is a core function of cognitive control, but it remains uncertain to what degree control over different sources of conflict is implemented by shared (domain general) or distinct (domain specific) neural resources. Behavioral data suggest conflict-control to be domain specific, but results from neuroimaging studies have been ambivalent. Here, we employed multivoxel pattern analyses that can decode a brain region's informational content, allowing us to distinguish incidental activation overlap from actual shared information processing. We trained independent sets of "searchlight" classifiers on functional magnetic resonance imaging data to decode control processes associated with stimulus-conflict (Stroop task) and ideomotor-conflict (Simon task). Quantifying the proportion of domain-specific searchlights (capable of decoding only one type of conflict) and domain-general searchlights (capable of decoding both conflict types) in each subject, we found both domain-specific and domain-general searchlights, though the former were more common. When mapping anatomical loci of these searchlights across subjects, neural substrates of stimulus- and ideomotor-specific conflict-control were found to be anatomically consistent across subjects, whereas the substrates of domain-general conflict-control were not. Overall, these findings suggest a hybrid neural architecture of conflict-control that entails both modular (domain specific) and global (domain general) components. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Recycling signals in the neural crest

    OpenAIRE

    Taneyhill, Lisa A.; Bronner-Fraser, Marianne E.

    2006-01-01

    Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

  2. Recycling signals in the neural crest.

    Science.gov (United States)

    Taneyhill, Lisa A; Bronner-Fraser, Marianne

    2005-01-01

    Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

  3. Tumor tropism of intravenously injected human-induced pluripotent stem cell-derived neural stem cells and their gene therapy application in a metastatic breast cancer model.

    Science.gov (United States)

    Yang, Jing; Lam, Dang Hoang; Goh, Sally Sallee; Lee, Esther Xingwei; Zhao, Ying; Tay, Felix Chang; Chen, Can; Du, Shouhui; Balasundaram, Ghayathri; Shahbazi, Mohammad; Tham, Chee Kian; Ng, Wai Hoe; Toh, Han Chong; Wang, Shu

    2012-05-01

    Human pluripotent stem cells can serve as an accessible and reliable source for the generation of functional human cells for medical therapies. In this study, we used a conventional lentiviral transduction method to derive human-induced pluripotent stem (iPS) cells from primary human fibroblasts and then generated neural stem cells (NSCs) from the iPS cells. Using a dual-color whole-body imaging technology, we demonstrated that after tail vein injection, these human NSCs displayed a robust migratory capacity outside the central nervous system in both immunodeficient and immunocompetent mice and homed in on established orthotopic 4T1 mouse mammary tumors. To investigate whether the iPS cell-derived NSCs can be used as a cellular delivery vehicle for cancer gene therapy, the cells were transduced with a baculoviral vector containing the herpes simplex virus thymidine kinase suicide gene and injected through tail vein into 4T1 tumor-bearing mice. The transduced NSCs were effective in inhibiting the growth of the orthotopic 4T1 breast tumor and the metastatic spread of the cancer cells in the presence of ganciclovir, leading to prolonged survival of the tumor-bearing mice. The use of iPS cell-derived NSCs for cancer gene therapy bypasses the sensitive ethical issue surrounding the use of cells derived from human fetal tissues or human embryonic stem cells. This approach may also help to overcome problems associated with allogeneic transplantation of other types of human NSCs. Copyright © 2012 AlphaMed Press.

  4. Effects of the Post-Spinal Cord Injury Microenvironment on the Differentiation Capacity of Human Neural Stem Cells Derived from Induced Pluripotent Stem Cells.

    Science.gov (United States)

    López-Serrano, Clara; Torres-Espín, Abel; Hernández, Joaquim; Alvarez-Palomo, Ana B; Requena, Jordi; Gasull, Xavier; Edel, Michael J; Navarro, Xavier

    2016-10-01

    Spinal cord injury (SCI) causes loss of neural functions below the level of the lesion due to interruption of spinal pathways and secondary neurodegenerative processes. The transplant of neural stem cells (NSCs) is a promising approach for the repair of SCI. Reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) is expected to provide an autologous source of iPSC-derived NSCs, avoiding the immune response as well as ethical issues. However, there is still limited information on the behavior and differentiation pattern of transplanted iPSC-derived NSCs within the damaged spinal cord. We transplanted iPSC-derived NSCs, obtained from adult human somatic cells, into rats at 0 or 7 days after SCI, and evaluated motor-evoked potentials and locomotion of the animals. We histologically analyzed engraftment, proliferation, and differentiation of the iPSC-derived NSCs and the spared tissue in the spinal cords at 7, 21, and 63 days posttransplant. Both transplanted groups showed a late decline in functional recovery compared to vehicle-injected groups. Histological analysis showed proliferation of transplanted cells within the tissue and that cells formed a mass. At the final time point, most grafted cells differentiated to neural and astroglial lineages, but not into oligodendrocytes, while some grafted cells remained undifferentiated and proliferative. The proinflammatory tissue microenviroment of the injured spinal cord induced proliferation of the grafted cells and, therefore, there are possible risks associated with iPSC-derived NSC transplantation. New approaches are needed to promote and guide cell differentiation, as well as reduce their tumorigenicity once the cells are transplanted at the lesion site.

  5. Short-Lived Human Umbilical Cord-Blood-Derived Neural Stem Cells Influence the Endogenous Secretome and Increase the Number of Endogenous Neural Progenitors in a Rat Model of Lacunar Stroke.

    Science.gov (United States)

    Jablonska, Anna; Drela, Katarzyna; Wojcik-Stanaszek, Luiza; Janowski, Miroslaw; Zalewska, Teresa; Lukomska, Barbara

    2016-11-01

    Stroke is the leading cause of severe disability, and lacunar stroke is related to cognitive decline and hemiparesis. There is no effective treatment for the majority of patients with stroke. Thus, stem cell-based regenerative medicine has drawn a growing body of attention due to the capabilities for trophic factor expression and neurogenesis enhancement. Moreover, it was shown in an experimental autoimmune encephalomyelitis (EAE) model that even short-lived stem cells can be therapeutic, and we have previously observed that phenomenon indirectly. Here, in a rat model of lacunar stroke, we investigated the molecular mechanisms underlying the positive therapeutic effects of short-lived human umbilical cord-blood-derived neural stem cells (HUCB-NSCs) through the distinct measurement of exogenous human and endogenous rat trophic factors. We have also evaluated neurogenesis and metalloproteinase activity as cellular components of therapeutic activity. As expected, we observed an increased proliferation and migration of progenitors, as well as metalloproteinase activity up to 14 days post transplantation. These changes were most prominent at the 7-day time point when we observed 30 % increases in the number of bromodeoxyuridine (BrdU)-positive cells in HUCB-NSC transplanted animals. The expression of human trophic factors was present until 7 days post transplantation, which correlated well with the survival of the human graft. For these 7 days, the level of messenger RNA (mRNA) in the analyzed trophic factors was from 300-fold for CNTF to 10,000-fold for IGF, much higher compared to constitutive expression in HUCB-NSCs in vitro. What is interesting is that there was no increase in the expression of rat trophic factors during the human graft survival, compared to that in non-transplanted animals. However, there was a prolongation of a period of increased trophic expression until 14 days post transplantation, while, in non-transplanted animals, there was a

  6. Artificial intelligence: Deep neural reasoning

    Science.gov (United States)

    Jaeger, Herbert

    2016-10-01

    The human brain can solve highly abstract reasoning problems using a neural network that is entirely physical. The underlying mechanisms are only partially understood, but an artificial network provides valuable insight. See Article p.471

  7. Treating spinal cord injury in rats with a combination of human fetal neural stem cells and hydrogels modified with serotonin

    Czech Academy of Sciences Publication Activity Database

    Růžička, Jiří; Romanyuk, Nataliya; Hejčl, Aleš; Vetrík, Miroslav; Hrubý, Martin; Cocks, G.; Cihlář, J.; Přádný, Martin; Price, J.; Syková, Eva; Jendelová, Pavla

    2013-01-01

    Roč. 73, č. 1 (2013), s. 102-115 ISSN 0065-1400 R&D Projects: GA ČR GAP108/10/1560; GA ČR(CZ) GPP304/11/P633; GA ČR GA13-00939S; GA AV ČR IAA500390902 Grant - others:GA MŠk(CZ) GAUK521712 Institutional support: RVO:68378041 ; RVO:61389013 Keywords : spinal cord hemisection * SPC-01 neural stem cells * hydrogel Subject RIV: FH - Neurology; CD - Macromolecular Chemistry (UMCH-V) Impact factor: 2.244, year: 2013

  8. Improved Exercise Tolerance with Caffeine Is Associated with Modulation of both Peripheral and Central Neural Processes in Human Participants

    DEFF Research Database (Denmark)

    Bowtell, Joanna L; Mohr, Magni; Fulford, Jonathan

    2018-01-01

    calcium handling and extracellular potassium regulation. Our aims were to investigate how caffeine (i) affects knee extensor PCr kinetics and pH during repeated sets of single-leg knee extensor exercise to task failure and (ii) modulates the interplay between central and peripheral neural processes. We...... hypothesized that the caffeine-induced extension of exercise capacity during repeated sets of exercise would occur despite greater disturbance of the muscle milieu due to enhanced peripheral and corticospinal excitatory output, central motor drive, and muscle contractility. Methods: Nine healthy active young...

  9. MEMBRAIN NEURAL NETWORK FOR VISUAL PATTERN RECOGNITION

    Directory of Open Access Journals (Sweden)

    Artur Popko

    2013-06-01

    Full Text Available Recognition of visual patterns is one of significant applications of Artificial Neural Networks, which partially emulate human thinking in the domain of artificial intelligence. In the paper, a simplified neural approach to recognition of visual patterns is portrayed and discussed. This paper is dedicated for investigators in visual patterns recognition, Artificial Neural Networking and related disciplines. The document describes also MemBrain application environment as a powerful and easy to use neural networks’ editor and simulator supporting ANN.

  10. A simple, xeno-free method for oligodendrocyte generation from human neural stem cells derived from umbilical cord: engagement of gelatinases in cell commitment and differentiation.

    Science.gov (United States)

    Sypecka, Joanna; Ziemka-Nalecz, Małgorzata; Dragun-Szymczak, Patrycja; Zalewska, Teresa

    2017-05-01

    Oligodendrocyte progenitors (OPCs) are ranked among the most likely candidates for cell-based strategies aimed at treating neurodegenerative diseases accompanied by dys/demyelination of the central nervous system (CNS). In this regard, different sources of stem cells are being tested to elaborate xeno-free protocols for efficient generation of OPCs for clinical applications. In the present study, neural stem cells of human umbilical cord blood (HUCB-NSCs) have been used to derive OPCs and subsequently to differentiate them into mature, GalC-expressing oligodendrocytes. Applied components of the extracellular matrix (ECM) and the analogues of physiological substances known to increase glial commitment of neural stem cells have been shown to significantly increase the yield of the resulting OPC fraction. The efficiency of ECM components in promoting oligodendrocyte commitment and differentiation prompted us to investigate the potential role of gelatinases in those processes. Subsequently, endogenous and ECM metalloproteinases (MMPs) activity has been compared with that detected in primary cultures of rat oligodendrocytes in vitro, as well as in rat brains in vivo. The data indicate that gelatinases are engaged in gliogenesis both in vitro and in vivo, although differently, which presumably results from distinct extracellular conditions. In conclusion, the study presents an efficient xeno-free method of deriving oligodendrocyte from HUCB-NSCs and analyses the engagement of MMP-2/MMP-9 in the processes of cell commitment and maturation. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  11. Safe and efficient method for cryopreservation of human induced pluripotent stem cell-derived neural stem and progenitor cells by a programmed freezer with a magnetic field.

    Science.gov (United States)

    Nishiyama, Yuichiro; Iwanami, Akio; Kohyama, Jun; Itakura, Go; Kawabata, Soya; Sugai, Keiko; Nishimura, Soraya; Kashiwagi, Rei; Yasutake, Kaori; Isoda, Miho; Matsumoto, Morio; Nakamura, Masaya; Okano, Hideyuki

    2016-06-01

    Stem cells represent a potential cellular resource in the development of regenerative medicine approaches to the treatment of pathologies in which specific cells are degenerated or damaged by genetic abnormality, disease, or injury. Securing sufficient supplies of cells suited to the demands of cell transplantation, however, remains challenging, and the establishment of safe and efficient cell banking procedures is an important goal. Cryopreservation allows the storage of stem cells for prolonged time periods while maintaining them in adequate condition for use in clinical settings. Conventional cryopreservation systems include slow-freezing and vitrification both have advantages and disadvantages in terms of cell viability and/or scalability. In the present study, we developed an advanced slow-freezing technique using a programmed freezer with a magnetic field called Cells Alive System (CAS) and examined its effectiveness on human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs). This system significantly increased cell viability after thawing and had less impact on cellular proliferation and differentiation. We further found that frozen-thawed hiPSC-NS/PCs were comparable with non-frozen ones at the transcriptome level. Given these findings, we suggest that the CAS is useful for hiPSC-NS/PCs banking for clinical uses involving neural disorders and may open new avenues for future regenerative medicine. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  12. Human brain basis of musical rhythm perception: common and distinct neural substrates for meter, tempo, and pattern.

    Science.gov (United States)

    Thaut, Michael H; Trimarchi, Pietro Davide; Parsons, Lawrence M

    2014-06-17

    Rhythm as the time structure of music is composed of distinct temporal components such as pattern, meter, and tempo. Each feature requires different computational processes: meter involves representing repeating cycles of strong and weak beats; pattern involves representing intervals at each local time point which vary in length across segments and are linked hierarchically; and tempo requires representing frequency rates of underlying pulse structures. We explored whether distinct rhythmic elements engage different neural mechanisms by recording brain activity of adult musicians and non-musicians with positron emission tomography (PET) as they made covert same-different discriminations of (a) pairs of rhythmic, monotonic tone sequences representing changes in pattern, tempo, and meter, and (b) pairs of isochronous melodies. Common to pattern, meter, and tempo tasks were focal activities in right, or bilateral, areas of frontal, cingulate, parietal, prefrontal, temporal, and cerebellar cortices. Meter processing alone activated areas in right prefrontal and inferior frontal cortex associated with more cognitive and abstract representations. Pattern processing alone recruited right cortical areas involved in different kinds of auditory processing. Tempo processing alone engaged mechanisms subserving somatosensory and premotor information (e.g., posterior insula, postcentral gyrus). Melody produced activity different from the rhythm conditions (e.g., right anterior insula and various cerebellar areas). These exploratory findings suggest the outlines of some distinct neural components underlying the components of rhythmic structure.

  13. Neural Correlates of Auditory Perceptual Awareness and Release from Informational Masking Recorded Directly from Human Cortex: A Case Study

    Directory of Open Access Journals (Sweden)

    Andrew R Dykstra

    2016-10-01

    Full Text Available In complex acoustic environments, even salient supra-threshold sounds sometimes go unperceived, a phenomenon known as informational masking. The neural basis of informational masking (and its release has not been well characterized, particularly outside auditory cortex. We combined electrocorticography in a neurosurgical patient undergoing invasive epilepsy monitoring with trial-by-trial perceptual reports of isochronous target-tone streams embedded in random multi-tone maskers. Awareness of such masker-embedded target streams was associated with a focal negativity between 100 and 200 ms and high-gamma activity between 50 and 250 ms (both in auditory cortex on the posterolateral superior temporal gyrus as well as a broad P3b-like potential (between ~300 and 600 ms with generators in ventrolateral frontal and lateral temporal cortex. Unperceived target tones elicited drastically reduced versions of such responses, if at all. While it remains unclear whether these responses reflect conscious perception, itself, as opposed to pre- or post-perceptual processing, the results suggest that conscious perception of target sounds in complex listening environments may engage diverse neural mechanisms in distributed brain areas.

  14. Sacred or Neural?

    DEFF Research Database (Denmark)

    Runehov, Anne Leona Cesarine

    Are religious spiritual experiences merely the product of the human nervous system? Anne L.C. Runehov investigates the potential of contemporary neuroscience to explain religious experiences. Following the footsteps of Michael Persinger, Andrew Newberg and Eugene d'Aquili she defines...... the terminological bounderies of "religious experiences" and explores the relevant criteria for the proper evaluation of scientific research, with a particular focus on the validity of reductionist models. Runehov's theis is that the perspectives looked at do not necessarily exclude each other but can be merged....... The question "sacred or neural?" becomes a statement "sacred and neural". The synergies thus produced provide manifold opportunities for interdisciplinary dialogue and research....

  15. Pathological classification of human iPSC-derived neural stem/progenitor cells towards safety assessment of transplantation therapy for CNS diseases.

    Science.gov (United States)

    Sugai, Keiko; Fukuzawa, Ryuji; Shofuda, Tomoko; Fukusumi, Hayato; Kawabata, Soya; Nishiyama, Yuichiro; Higuchi, Yuichiro; Kawai, Kenji; Isoda, Miho; Kanematsu, Daisuke; Hashimoto-Tamaoki, Tomoko; Kohyama, Jun; Iwanami, Akio; Suemizu, Hiroshi; Ikeda, Eiji; Matsumoto, Morio; Kanemura, Yonehiro; Nakamura, Masaya; Okano, Hideyuki

    2016-09-19

    The risk of tumorigenicity is a hurdle for regenerative medicine using induced pluripotent stem cells (iPSCs). Although teratoma formation is readily distinguishable, the malignant transformation of iPSC derivatives has not been clearly defined due to insufficient analysis of histology and phenotype. In the present study, we evaluated the histology of neural stem/progenitor cells (NSPCs) generated from integration-free human peripheral blood mononuclear cell (PBMC)-derived iPSCs (iPSC-NSPCs) following transplantation into central nervous system (CNS) of immunodeficient mice. We found that transplanted iPSC-NSPCs produced differentiation patterns resembling those in embryonic CNS development, and that the microenvironment of the final site of migration affected their maturational stage. Genomic instability of iPSCs correlated with increased proliferation of transplants, although no carcinogenesis was evident. The histological classifications presented here may provide cues for addressing potential safety issues confronting regenerative medicine involving iPSCs.

  16. Gender Recognition from Human-Body Images Using Visible-Light and Thermal Camera Videos Based on a Convolutional Neural Network for Image Feature Extraction

    Science.gov (United States)

    Nguyen, Dat Tien; Kim, Ki Wan; Hong, Hyung Gil; Koo, Ja Hyung; Kim, Min Cheol; Park, Kang Ryoung

    2017-01-01

    Extracting powerful image features plays an important role in computer vision systems. Many methods have previously been proposed to extract image features for various computer vision applications, such as the scale-invariant feature transform (SIFT), speed-up robust feature (SURF), local binary patterns (LBP), histogram of oriented gradients (HOG), and weighted HOG. Recently, the convolutional neural network (CNN) method for image feature extraction and classification in computer vision has been used in various applications. In this research, we propose a new gender recognition method for recognizing males and females in observation scenes of surveillance systems based on feature extraction from visible-light and thermal camera videos through CNN. Experimental results confirm the superiority of our proposed method over state-of-the-art recognition methods for the gender recognition problem using human body images. PMID:28335510

  17. Gender Recognition from Human-Body Images Using Visible-Light and Thermal Camera Videos Based on a Convolutional Neural Network for Image Feature Extraction.

    Science.gov (United States)

    Nguyen, Dat Tien; Kim, Ki Wan; Hong, Hyung Gil; Koo, Ja Hyung; Kim, Min Cheol; Park, Kang Ryoung

    2017-03-20

    Extracting powerful image features plays an important role in computer vision systems. Many methods have previously been proposed to extract image features for various computer vision applications, such as the scale-invariant feature transform (SIFT), speed-up robust feature (SURF), local binary patterns (LBP), histogram of oriented gradients (HOG), and weighted HOG. Recently, the convolutional neural network (CNN) method for image feature extraction and classification in computer vision has been used in various applications. In this research, we propose a new gender recognition method for recognizing males and females in observation scenes of surveillance systems based on feature extraction from visible-light and thermal camera videos through CNN. Experimental results confirm the superiority of our proposed method over state-of-the-art recognition methods for the gender recognition problem using human body images.

  18. Gender Recognition from Human-Body Images Using Visible-Light and Thermal Camera Videos Based on a Convolutional Neural Network for Image Feature Extraction

    Directory of Open Access Journals (Sweden)

    Dat Tien Nguyen

    2017-03-01

    Full Text Available Extracting powerful image features plays an important role in computer vision systems. Many methods have previously been proposed to extract image features for various computer vision applications, such as the scale-invariant feature transform (SIFT, speed-up robust feature (SURF, local binary patterns (LBP, histogram of oriented gradients (HOG, and weighted HOG. Recently, the convolutional neural network (CNN method for image feature extraction and classification in computer vision has been used in various applications. In this research, we propose a new gender recognition method for recognizing males and females in observation scenes of surveillance systems based on feature extraction from visible-light and thermal camera videos through CNN. Experimental results confirm the superiority of our proposed method over state-of-the-art recognition methods for the gender recognition problem using human body images.

  19. In vitro differentiation of adipose-tissue-derived mesenchymal stem cells into neural retinal cells through expression of human PAX6 (5a) gene.

    Science.gov (United States)

    Rezanejad, Habib; Soheili, Zahra-Soheila; Haddad, Farhang; Matin, Maryam M; Samiei, Shahram; Manafi, Ali; Ahmadieh, Hamid

    2014-04-01

    The neural retina is subjected to various degenerative conditions. Regenerative stem-cell-based therapy holds great promise for treating severe retinal degeneration diseases, although many drawbacks remain to be overcome. One important problem is to gain authentically differentiated cells for replacement. Paired box 6 protein (5a) (PAX6 (5a)) is a highly conserved master control gene that has an essential role in the development of the vertebrate visual system. Human adipose-tissue-derived stem cell (hADSC) isolation was performed by using fat tissues and was confirmed by the differentiation potential of the cells into adipocytes and osteocytes and by their surface marker profile. The coding region of the human PAX6 (5a) gene isoform was cloned and lentiviral particles were propagated in HEK293T. The differentiation of hADSCs into retinal cells was characterized by morphological characteristics, quantitative real-time reverse transcription plus the polymerase chain reaction (qPCR) and immunocytochemistry (ICC) for some retinal cell-specific and retinal pigmented epithelial (RPE) cell-specific markers. hADSCs were successfully isolated. Flow cytometric analysis of surface markers indicated the high purity (~97 %) of isolated hADSCs. After 30 h of post-transduction, cells gradually showed the characteristic morphology of neuronal cells and small axon-like processes emerged. qPCR and ICC confirmed the differentiation of some neural retinal cells and RPE cells. Thus, PAX6 (5a) transcription factor expression, together with medium supplemented with fibronectin, is able to induce the differentiation of hADSCs into retinal progenitors, RPE cells and photoreceptors.

  20. Improved Exercise Tolerance with Caffeine Is Associated with Modulation of both Peripheral and Central Neural Processes in Human Participants

    DEFF Research Database (Denmark)

    Bowtell, Joanna L; Mohr, Magni; Fulford, Jonathan

    2018-01-01

    Background: Caffeine has been shown to enhance exercise performance and capacity. The mechanisms remain unclear but are suggested to relate to adenosine receptor antagonism, resulting in increased central motor drive, reduced perception of effort, and altered peripheral processes such as enhanced...... men performed five sets of intense single-leg knee extensor exercise to task failure on four separate occasions: for two visits (6 mg·kg-1 caffeine vs placebo), quadriceps 31P-magnetic resonance spectroscopy scans were performed to quantify phosphocreatine kinetics and pH, and for the remaining two...... calcium handling and extracellular potassium regulation. Our aims were to investigate how caffeine (i) affects knee extensor PCr kinetics and pH during repeated sets of single-leg knee extensor exercise to task failure and (ii) modulates the interplay between central and peripheral neural processes. We...

  1. FOXOs modulate proteasome activity in human-induced pluripotent stem cells of Huntington's disease and their derived neural cells.

    Science.gov (United States)

    Liu, Yanying; Qiao, Fangfang; Leiferman, Patricia C; Ross, Alan; Schlenker, Evelyn H; Wang, Hongmin

    2017-11-15

    Although it has been speculated that proteasome dysfunction may contribute to the pathogenesis of Huntington's disease (HD), a devastating neurodegenerative disorder, how proteasome activity is regulated in HD affected stem cells and somatic cells remains largely unclear. To better understand the pathogenesis of HD, we analyzed proteasome activity and the expression of FOXO transcription factors in three wild-type (WT) and three HD induced-pluripotent stem cell (iPSC) lines. HD iPSCs exhibited elevated proteasome activity and higher levels of FOXO1 and FOXO4 proteins. Knockdown of FOXO4 but not FOXO1 expression decreased proteasome activity. Following neural differentiation, the HD-iPSC-derived neural progenitor cells (NPCs) demonstrated lower levels of proteasome activity and FOXO expressions than their WT counterparts. More importantly, overexpression of FOXO4 but not FOXO1 in HD NPCs dramatically enhanced proteasome activity. When HD NPCs were further differentiated into DARPP32-positive neurons, these HD neurons were more susceptible to death than WT neurons and formed Htt aggregates under the condition of oxidative stress. Similar to HD NPCs, HD-iPSC-derived neurons showed reduced proteasome activity and diminished FOXO4 expression compared to WT-iPSC-derived neurons. Furthermore, HD iPSCs had lower AKT activities than WT iPSCs, whereas the neurons derived from HD iPSC had higher AKT activities than their WT counterparts. Inhibiting AKT activity increased both FOXO4 level and proteasome activity, indicating a potential role of AKT in regulating FOXO levels. These data suggest that FOXOs modulate proteasome activity, and thus represents a potentially valuable therapeutic target for HD. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. DNA topoisomerase IIβ stimulates neurite outgrowth in neural differentiated human mesenchymal stem cells through regulation of Rho-GTPases (RhoA/Rock2 pathway) and Nurr1 expression.

    Science.gov (United States)

    Zaim, Merve; Isik, Sevim

    2018-04-25

    DNA topoisomerase IIβ (topo IIβ) is known to regulate neural differentiation by inducing the neuronal genes responsible for critical neural differentiation events such as neurite outgrowth and axon guidance. However, the pathways of axon growth controlled by topo IIβ have not been clarified yet. Microarray results of our previous study have shown that topo IIβ silencing in neural differentiated primary human mesenchymal stem cells (hMSCs) significantly alters the expression pattern of genes involved in neural polarity, axonal growth, and guidance, including Rho-GTPases. This study aims to further analyze the regulatory role of topo IIβ on the process of axon growth via regulation of Rho-GTPases. For this purpose, topo IIβ was silenced in neurally differentiated hMSCs. Cells lost their morphology because of topo IIβ deficiency, becoming enlarged and flattened. Additionally, a reduction in both neural differentiation efficiency and neurite length, upregulation in RhoA and Rock2, downregulation in Cdc42 gene expression were detected. On the other hand, cells were transfected with topo IIβ gene to elucidate the possible neuroprotective effect of topo IIβ overexpression on neural-induced hMSCs. Topo IIβ overexpression prompted all the cells to exhibit neural cell morphology as characterized by longer neurites. RhoA and Rock2 expressions were downregulated, whereas Cdc42 expression was upregulated. Nurr1 expression level correlated with topo IIβ in both topo IIβ-overexpressed and -silenced cells. Furthermore, differential translocation of Rho-GTPases was detected by immunostaining in response to topo IIβ. Our results suggest that topo IIβ deficiency could give rise to neurodegeneration through dysregulation of Rho-GTPases. However, further in-vivo research is needed to demonstrate if re-regulation of Rho GTPases by topo IIβ overexpression could be a neuroprotective treatment in the case of neurodegenerative diseases.

  3. Evolvable synthetic neural system

    Science.gov (United States)

    Curtis, Steven A. (Inventor)

    2009-01-01

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

  4. Neural correlates of vocal learning in songbirds and humans: cross-species fMRI studies into individual differences

    OpenAIRE

    Kant, Anne Marie van der

    2015-01-01

    Animal models, songbirds particularly, are increasingly used to study the human capacity for speech and language. In the light of understanding both language evolution and individual language acquisition these models are highly valuable, provided that they are studied within a valid comparative framework. In the past few decades, non-invasive methods such as functional Magnetic Resonance Imaging (fMRI) and Near-InfraRed Spectroscopy (NIRS) have become available for human as well as animal bra...

  5. A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers

    Directory of Open Access Journals (Sweden)

    Shi-Yu Yang

    2017-03-01

    Full Text Available Numerically the most important risk factor for the development of Parkinson's disease (PD is the presence of mutations in the glucocerebrosidase GBA1 gene. In vitro and in vivo studies show that GBA1 mutations reduce glucocerebrosidase (GCase activity and are associated with increased α-synuclein levels, reflecting similar changes seen in idiopathic PD brain. We have developed a neural crest stem cell-derived dopaminergic neuronal model that recapitulates biochemical abnormalities in GBA1 mutation-associated PD. Cells showed reduced GCase protein and activity, impaired macroautophagy, and increased α-synuclein levels. Advantages of this approach include easy access to stem cells, no requirement to reprogram, and retention of the intact host genome. Treatment with a GCase chaperone increased GCase protein levels and activity, rescued the autophagic defects, and decreased α-synuclein levels. These results provide the basis for further investigation of GCase chaperones or similar drugs to slow the progression of PD.

  6. Role of the cerebellum in reaching movements in humans. II. A neural model of the intermediate cerebellum.

    Science.gov (United States)

    Schweighofer, N; Spoelstra, J; Arbib, M A; Kawato, M

    1998-01-01

    The cerebellum is essential for the control of multijoint movements; when the cerebellum is lesioned, the performance error is more than the summed errors produced by single joints. In the companion paper (Schweighofer et al., 1998), a functional anatomical model for visually guided arm movement was proposed. The model comprised a basic feedforward/feedback controller with realistic transmission delays and was connected to a two-link, six-muscle, planar arm. In the present study, we examined the role of the cerebellum in reaching movements by embedding a novel, detailed cerebellar neural network in this functional control model. We could derive realistic cerebellar inputs and the role of the cerebellum in learning to control the arm was assessed. This cerebellar network learned the part of the inverse dynamics of the arm not provided by the basic feedforward/feedback controller. Despite realistically low inferior olive firing rates and noisy mossy fibre inputs, the model could reduce the error between intended and planned movements. The responses of the different cell groups were comparable to those of biological cell groups. In particular, the modelled Purkinje cells exhibited directional tuning after learning and the parallel fibres, due to their length, provide Purkinje cells with the input required for this coordination task. The inferior olive responses contained two different components; the earlier response, locked to movement onset, was always present and the later response disappeared after learning. These results support the theory that the cerebellum is involved in motor learning.

  7. Neural correlates of the eye dominance effect in human face perception: the left-visual-field superiority for faces revisited.

    Science.gov (United States)

    Jung, Wookyoung; Kang, Joong-Gu; Jeon, Hyeonjin; Shim, Miseon; Sun Kim, Ji; Leem, Hyun-Sung; Lee, Seung-Hwan

    2017-08-01

    Faces are processed best when they are presented in the left visual field (LVF), a phenomenon known as LVF superiority. Although one eye contributes more when perceiving faces, it is unclear how the dominant eye (DE), the eye we unconsciously use when performing a monocular task, affects face processing. Here, we examined the influence of the DE on the LVF superiority for faces using event-related potentials. Twenty left-eye-dominant (LDE group) and 23 right-eye-dominant (RDE group) participants performed the experiments. Face stimuli were randomly presented in the LVF or right visual field (RVF). The RDE group exhibited significantly larger N170 amplitudes compared with the LDE group. Faces presented in the LVF elicited N170 amplitudes that were significantly more negative in the RDE group than they were in the LDE group, whereas the amplitudes elicited by stimuli presented in the RVF were equivalent between the groups. The LVF superiority was maintained in the RDE group but not in the LDE group. Our results provide the first neural evidence of the DE's effects on the LVF superiority for faces. We propose that the RDE may be more biologically specialized for face processing. © The Author (2017). Published by Oxford University Press.

  8. Spatio-temporal Model of Endogenous ROS and Raft-Dependent WNT/Beta-Catenin Signaling Driving Cell Fate Commitment in Human Neural Progenitor Cells

    Science.gov (United States)

    Haack, Fiete; Lemcke, Heiko; Ewald, Roland; Rharass, Tareck; Uhrmacher, Adelinde M.

    2015-01-01

    Canonical WNT/β-catenin signaling is a central pathway in embryonic development, but it is also connected to a number of cancers and developmental disorders. Here we apply a combined in-vitro and in-silico approach to investigate the spatio-temporal regulation of WNT/β-catenin signaling during the early neural differentiation process of human neural progenitors cells (hNPCs), which form a new prospect for replacement therapies in the context of neurodegenerative diseases. Experimental measurements indicate a second signal mechanism, in addition to canonical WNT signaling, being involved in the regulation of nuclear β-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of β-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/β-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream β-catenin signaling, followed by continuous auto/paracrine WNT signaling, which crucially depends on lipid rafts. Our simulation studies further illustrate the elaborate spatio-temporal regulation of DVL, which, depending on its concentration and localization, may either act as direct inducer of the transient ROS/β-catenin signal or as amplifier during continuous auto-/parcrine WNT/β-catenin signaling. In addition we provide the first stochastic computational model of WNT/β-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent β-catenin activation. The model’s predictive ability is demonstrated under a wide range of varying conditions for in-vitro and in-silico reference data sets. Our in-silico approach is realized in a multi-level rule-based language, that facilitates the extension and modification of the

  9. Functional mapping of the neural basis for the encoding and retrieval of human episodic memory using H{sub 2}{sup 15}O PET

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    Lee, Jae Sung; Nam, Hyun Woo; Lee, Dong Soo; Lee, Sang Kun; Jang, Myoung Jin; Ahn, Ji Young; Park, Kwang Suk; Chung, June Key; Lee, Myung Chul [Seoul National Univ., Seoul (Korea, Republic of)

    2000-02-01

    Episodic memory is described as an 'autobiographical' memory responsible for storing a record of the events in our lives. We performed functional brain activation study using H{sub 2}{sup 1}5O PET to reveal the neural basis of the encoding and the retrieval of episodic memory in human normal volunteers. Four repeated H{sub 2}{sup 1}5O PET scans with two reference and two activation tasks were performed on 6 normal volunteers to activate brain areas engaged in encoding and retrieval with verbal materials. Images from the same subject were spatially registered and normalized using linear and nonlinear transformation. Using the means and variances for every condition which were adjusted with analysis of covariance, t-statistic analysis were performed voxel-wise. Encoding of episodic memory activated the opercular and triangular parts of left inferior frontal gyrus, right prefrontal cortex, medial frontal area, cingulate gyrus, posterior middle and inferior temporal gyri, and cerebellum, and both primary visual and visual association areas. Retrieval of episodic memory activated the triangular part of left inferior frontal gyrus and inferior temporal gyrus, right prefrontal cortex and medial temporal ares, and both cerebellum and primary visual and visual association areas. The activations in the opercular part of left inferior frontal gyrus and the right prefrontal cortex meant the essential role of these areas in the encoding and retrieval of episodic memeory. We could localize the neural basis of the encoding and retrieval of episodic memory using H{sub 2}{sup 1}5O PET, which was partly consistent with the hypothesis of hemispheric encoding/retrieval asymmetry.

  10. The effect of pulsed electric fields on the electrotactic migration of human neural progenitor cells through the involvement of intracellular calcium signaling.

    Science.gov (United States)

    Hayashi, Hisamitsu; Edin, Fredrik; Li, Hao; Liu, Wei; Rask-Andersen, Helge

    2016-12-01

    Endogenous electric fields (EFs) are required for the physiological control of the central nervous system development. Application of the direct current EFs to neural stem cells has been studied for the possibility of stem cell transplantation as one of the therapies for brain injury. EFs generated within the nervous system are often associated with action potentials and synaptic activity, apparently resulting in a pulsed current in nature. The aim of this study is to investigate the effect of pulsed EF, which can reduce the cytotoxicity, on the migration of human neural progenitor cells (hNPCs). We applied the mono-directional pulsed EF with a strength of 250mV/mm to hNPCs for 6h. The migration distance of the hNPCs exposed to pulsed EF was significantly greater compared with the control not exposed to the EF. Pulsed EFs, however, had less of an effect on the migration of the differentiated hNPCs. There was no significant change in the survival of hNPCs after exposure to the pulsed EF. To investigate the role of Ca 2+ signaling in electrotactic migration of hNPCs, pharmacological inhibition of Ca 2+ channels in the EF-exposed cells revealed that the electrotactic migration of hNPCs exposed to Ca 2+ channel blockers was significantly lower compared to the control group. The findings suggest that the pulsed EF induced migration of hNPCs is partly influenced by intracellular Ca 2+ signaling. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Remyelination Is Correlated with Regulatory T Cell Induction Following Human Embryoid Body-Derived Neural Precursor Cell Transplantation in a Viral Model of Multiple Sclerosis.

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    Warren C Plaisted

    Full Text Available We have recently described sustained clinical recovery associated with dampened neuroinflammation and remyelination following transplantation of neural precursor cells (NPCs derived from human embryonic stem cells (hESCs in a viral model of the human demyelinating disease multiple sclerosis. The hNPCs used in that study were derived by a novel direct differentiation method (direct differentiation, DD-NPCs that resulted in a unique gene expression pattern when compared to hNPCs derived by conventional methods. Since the therapeutic potential of human NPCs may differ greatly depending on the method of derivation and culture, we wanted to determine whether NPCs differentiated using conventional methods would be similarly effective in improving clinical outcome under neuroinflammatory demyelinating conditions. For the current study, we utilized hNPCs differentiated from a human induced pluripotent cell line via an embryoid body intermediate stage (EB-NPCs. Intraspinal transplantation of EB-NPCs into mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV resulted in decreased accumulation of CD4+ T cells in the central nervous system that was concomitant with reduced demyelination at the site of injection. Dampened neuroinflammation and remyelination was correlated with a transient increase in CD4+FOXP3+ regulatory T cells (Tregs concentrated within the peripheral lymphatics. However, compared to our earlier study, pathological improvements were modest and did not result in significant clinical recovery. We conclude that the genetic signature of NPCs is critical to their effectiveness in this model of viral-induced neurologic disease. These comparisons will be useful for understanding what factors are critical for the sustained clinical improvement.

  12. Antibody fragments directed against different portions of the human neural cell adhesion molecule L1 act as inhibitors or activators of L1 function.

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    Yan Wang

    Full Text Available The neural cell adhesion molecule L1 plays important roles in neuronal migration and survival, neuritogenesis and synaptogenesis. L1 has also been found in tumors of different origins, with levels of L1 expression correlating positively with the metastatic potential of tumors. To select antibodies targeting the varied functions of L1, we screened the Tomlinson library of recombinant human antibody fragments to identify antibodies binding to recombinant human L1 protein comprising the entire extracellular domain of human L1. We obtained four L1 binding single-chain variable fragment antibodies (scFvs, named I4, I6, I13, and I27 and showed by enzyme-linked immunosorbent assay (ELISA that scFvs I4 and I6 have high affinity to the immunoglobulin-like (Ig domains 1-4 of L1, while scFvs I13 and I27 bind strongly to the fibronectin type III homologous (Fn domains 1-3 of L1. Application of scFvs I4 and I6 to human SK-N-SH neuroblastoma cells reduced proliferation and transmigration of these cells. Treatment of SK-N-SH cells with scFvs I13 and I27 enhanced cell proliferation and migration, neurite outgrowth, and protected against the toxic effects of H(2O(2 by increasing the ratio of Bcl-2/Bax. In addition, scFvs I4 and I6 inhibited and scFvs I13 and I27 promoted phosphorylation of src and Erk. Our findings indicate that scFvs reacting with the immunoglobulin-like domains 1-4 inhibit L1 functions, whereas scFvs interacting with the fibronectin type III domains 1-3 trigger L1 functions of cultured neuroblastoma cells.

  13. Triadic (ecological, neural, cognitive) niche construction: a scenario of human brain evolution extrapolating tool use and language from the control of reaching actions.

    Science.gov (United States)

    Iriki, Atsushi; Taoka, Miki

    2012-01-12

    Hominin evolution has involved a continuous process of addition of new kinds of cognitive capacity, including those relating to manufacture and use of tools and to the establishment of linguistic faculties. The dramatic expansion of the brain that accompanied additions of new functional areas would have supported such continuous evolution. Extended brain functions would have driven rapid and drastic changes in the hominin ecological niche, which in turn demanded further brain resources to adapt to it. In this way, humans have constructed a novel niche in each of the ecological, cognitive and neural domains, whose interactions accelerated their individual evolution through a process of triadic niche construction. Human higher cognitive activity can therefore be viewed holistically as one component in a terrestrial ecosystem. The brain's functional characteristics seem to play a key role in this triadic interaction. We advance a speculative argument about the origins of its neurobiological mechanisms, as an extension (with wider scope) of the evolutionary principles of adaptive function in the animal nervous system. The brain mechanisms that subserve tool use may bridge the gap between gesture and language--the site of such integration seems to be the parietal and extending opercular cortices.

  14. BDNF Increases Survival and Neuronal Differentiation of Human Neural Precursor Cells Cotransplanted with a Nanofiber Gel to the Auditory Nerve in a Rat Model of Neuronal Damage

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    Yu Jiao

    2014-01-01

    Full Text Available Objectives. To study possible nerve regeneration of a damaged auditory nerve by the use of stem cell transplantation. Methods. We transplanted HNPCs to the rat AN trunk by the internal auditory meatus (IAM. Furthermore, we studied if addition of BDNF affects survival and phenotypic differentiation of the grafted HNPCs. A bioactive nanofiber gel (PA gel, in selected groups mixed with BDNF, was applied close to the implanted cells. Before transplantation, all rats had been deafened by a round window niche application of β-bungarotoxin. This neurotoxin causes a selective toxic destruction of the AN while keeping the hair cells intact. Results. Overall, HNPCs survived well for up to six weeks in all groups. However, transplants receiving the BDNF-containing PA gel demonstrated significantly higher numbers of HNPCs and neuronal differentiation. At six weeks, a majority of the HNPCs had migrated into the brain stem and differentiated. Differentiated human cells as well as neurites were observed in the vicinity of the cochlear nucleus. Conclusion. Our results indicate that human neural precursor cells (HNPC integration with host tissue benefits from additional brain derived neurotrophic factor (BDNF treatment and that these cells appear to be good candidates for further regenerative studies on the auditory nerve (AN.

  15. Ascorbic acid alters cell fate commitment of human neural progenitors in a WNT/β-catenin/ROS signaling dependent manner.

    Science.gov (United States)

    Rharass, Tareck; Lantow, Margareta; Gbankoto, Adam; Weiss, Dieter G; Panáková, Daniela; Lucas, Stéphanie

    2017-10-16

    Improving the neuronal yield from in vitro cultivated neural progenitor cells (NPCs) is an essential challenge in transplantation therapy in neurological disorders. In this regard, Ascorbic acid (AA) is widely used to expand neurogenesis from NPCs in cultures although the mechanisms of its action remain unclear. Neurogenesis from NPCs is regulated by the redox-sensitive WNT/β-catenin signaling pathway. We therefore aimed to investigate how AA interacts with this pathway and potentiates neurogenesis. Effects of 200 μM AA were compared with the pro-neurogenic reagent and WNT/β-catenin signaling agonist lithium chloride (LiCl), and molecules with antioxidant activities i.e. N-acetyl-L-cysteine (NAC) and ruthenium red (RuR), in differentiating neural progenitor ReNcell VM cells. Cells were supplemented with reagents for two periods of treatment: a full period encompassing the whole differentiation process versus an early short period that is restricted to the cell fate commitment stage. Intracellular redox balance and reactive oxygen species (ROS) metabolism were examined by flow cytometry using redox and ROS sensors. Confocal microscopy was performed to assess cell viability, neuronal yield, and levels of two proteins: Nucleoredoxin (NXN) and the WNT/β-catenin signaling component Dishevelled 2 (DVL2). TUBB3 and MYC gene responses were evaluated by quantitative real-time PCR. DVL2-NXN complex dissociation was measured by fluorescence resonance energy transfer (FRET). In contrast to NAC which predictably exhibited an antioxidant effect, AA treatment enhanced ROS metabolism with no cytotoxic induction. Both drugs altered ROS levels only at the early stage of the differentiation as no changes were held beyond the neuronal fate commitment stage. FRET studies showed that AA treatment accelerated the redox-dependent release of the initial pool of DVL2 from its sequestration by NXN, while RuR treatment hampered the dissociation of the two proteins. Accordingly, AA

  16. Probing neural mechanisms underlying auditory stream segregation in humans by transcranial direct current stimulation (tDCS).

    Science.gov (United States)

    Deike, Susann; Deliano, Matthias; Brechmann, André

    2016-10-01

    One hypothesis concerning the neural underpinnings of auditory streaming states that frequency tuning of tonotopically organized neurons in primary auditory fields in combination with physiological forward suppression is necessary for the separation of representations of high-frequency A and low-frequency B tones. The extent of spatial overlap between the tonotopic activations of A and B tones is thought to underlie the perceptual organization of streaming sequences into one coherent or two separate streams. The present study attempts to interfere with these mechanisms by transcranial direct current stimulation (tDCS) and to probe behavioral outcomes reflecting the perception of ABAB streaming sequences. We hypothesized that tDCS by modulating cortical excitability causes a change in the separateness of the representations of A and B tones, which leads to a change in the proportions of one-stream and two-stream percepts. To test this, 22 subjects were presented with ambiguous ABAB sequences of three different frequency separations (∆F) and had to decide on their current percept after receiving sham, anodal, or cathodal tDCS over the left auditory cortex. We could confirm our hypothesis at the most ambiguous ∆F condition of 6 semitones. For anodal compared with sham and cathodal stimulation, we found a significant decrease in the proportion of two-stream perception and an increase in the proportion of one-stream perception. The results demonstrate the feasibility of using tDCS to probe mechanisms underlying auditory streaming through the use of various behavioral measures. Moreover, this approach allows one to probe the functions of auditory regions and their interactions with other processing stages. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Neural Mechanisms of Foraging

    OpenAIRE

    Kolling, Nils; Behrens, Timothy EJ; Mars, Rogier B; Rushworth, Matthew FS

    2012-01-01

    Behavioural economic studies, involving limited numbers of choices, have provided key insights into neural decision-making mechanisms. By contrast, animals’ foraging choices arise in the context of sequences of encounters with prey/food. On each encounter the animal chooses to engage or whether the environment is sufficiently rich that searching elsewhere is merited. The cost of foraging is also critical. We demonstrate humans can alternate between two modes of choice, comparative decision-ma...

  18. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq

    Science.gov (United States)

    Whitmore, S. Scott; Wagner, Alex H.; DeLuca, Adam P.; Drack, Arlene V.; Stone, Edwin M.; Tucker, Budd A.; Zeng, Shemin; Braun, Terry A.; Mullins, Robert F.; Scheetz, Todd E.

    2014-01-01

    Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell-types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with

  19. Transcriptomic analysis across nasal, temporal, and macular regions of human neural retina and RPE/choroid by RNA-Seq.

    Science.gov (United States)

    Whitmore, S Scott; Wagner, Alex H; DeLuca, Adam P; Drack, Arlene V; Stone, Edwin M; Tucker, Budd A; Zeng, Shemin; Braun, Terry A; Mullins, Robert F; Scheetz, Todd E

    2014-12-01

    Proper spatial differentiation of retinal cell types is necessary for normal human vision. Many retinal diseases, such as Best disease and male germ cell associated kinase (MAK)-associated retinitis pigmentosa, preferentially affect distinct topographic regions of the retina. While much is known about the distribution of cell types in the retina, the distribution of molecular components across the posterior pole of the eye has not been well-studied. To investigate regional difference in molecular composition of ocular tissues, we assessed differential gene expression across the temporal, macular, and nasal retina and retinal pigment epithelium (RPE)/choroid of human eyes using RNA-Seq. RNA from temporal, macular, and nasal retina and RPE/choroid from four human donor eyes was extracted, poly-A selected, fragmented, and sequenced as 100 bp read pairs. Digital read files were mapped to the human genome and analyzed for differential expression using the Tuxedo software suite. Retina and RPE/choroid samples were clearly distinguishable at the transcriptome level. Numerous transcription factors were differentially expressed between regions of the retina and RPE/choroid. Photoreceptor-specific genes were enriched in the peripheral samples, while ganglion cell and amacrine cell genes were enriched in the macula. Within the RPE/choroid, RPE-specific genes were upregulated at the periphery while endothelium associated genes were upregulated in the macula. Consistent with previous studies, BEST1 expression was lower in macular than extramacular regions. The MAK gene was expressed at lower levels in macula than in extramacular regions, but did not exhibit a significant difference between nasal and temporal retina. The regional molecular distinction is greatest between macula and periphery and decreases between different peripheral regions within a tissue. Datasets such as these can be used to prioritize candidate genes for possible involvement in retinal diseases with

  20. Statistically based splicing detection reveals neural enrichment and tissue-specific induction of circular RNA during human fetal development.

    Science.gov (United States)

    Szabo, Linda; Morey, Robert; Palpant, Nathan J; Wang, Peter L; Afari, Nastaran; Jiang, Chuan; Parast, Mana M; Murry, Charles E; Laurent, Louise C; Salzman, Julia

    2015-06-16

    The pervasive expression of circular RNA is a recently discovered feature of gene expression in highly diverged eukaryotes, but the functions of most circular RNAs are still unknown. Computational methods to discover and quantify circular RNA are essential. Moreover, discovering biological contexts where circular RNAs are regulated will shed light on potential functional roles they may play. We present a new algorithm that increases the sensitivity and specificity of circular RNA detection by discovering and quantifying circular and linear RNA splicing events at both annotated and un-annotated exon boundaries, including intergenic regions of the genome, with high statistical confidence. Unlike approaches that rely on read count and exon homology to determine confidence in prediction of circular RNA expression, our algorithm uses a statistical approach. Using our algorithm, we unveiled striking induction of general and tissue-specific circular RNAs, including in the heart and lung, during human fetal development. We discover regions of the human fetal brain, such as the frontal cortex, with marked enrichment for genes where circular RNA isoforms are dominant. The vast majority of circular RNA production occurs at major spliceosome splice sites; however, we find the first examples of developmentally induced circular RNAs processed by the minor spliceosome, and an enriched propensity of minor spliceosome donors to splice into circular RNA at un-annotated, rather than annotated, exons. Together, these results suggest a potentially significant role for circular RNA in human development.

  1. An Analysis of Audio Features to Develop a Human Activity Recognition Model Using Genetic Algorithms, Random Forests, and Neural Networks

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    Carlos E. Galván-Tejada

    2016-01-01

    Full Text Available This work presents a human activity recognition (HAR model based on audio features. The use of sound as an information source for HAR models represents a challenge because sound wave analyses generate very large amounts of data. However, feature selection techniques may reduce the amount of data required to represent an audio signal sample. Some of the audio features that were analyzed include Mel-frequency cepstral coefficients (MFCC. Although MFCC are commonly used in voice and instrument recognition, their utility within HAR models is yet to be confirmed, and this work validates their usefulness. Additionally, statistical features were extracted from the audio samples to generate the proposed HAR model. The size of the information is necessary to conform a HAR model impact directly on the accuracy of the model. This problem also was tackled in the present work; our results indicate that we are capable of recognizing a human activity with an accuracy of 85% using the HAR model proposed. This means that minimum computational costs are needed, thus allowing portable devices to identify human activities using audio as an information source.

  2. Improved Exercise Tolerance with Caffeine Is Associated with Modulation of both Peripheral and Central Neural Processes in Human Participants

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    Joanna L. Bowtell

    2018-02-01

    Full Text Available BackgroundCaffeine has been shown to enhance exercise performance and capacity. The mechanisms remain unclear but are suggested to relate to adenosine receptor antagonism, resulting in increased central motor drive, reduced perception of effort, and altered peripheral processes such as enhanced calcium handling and extracellular potassium regulation. Our aims were to investigate how caffeine (i affects knee extensor PCr kinetics and pH during repeated sets of single-leg knee extensor exercise to task failure and (ii modulates the interplay between central and peripheral neural processes. We hypothesized that the caffeine-induced extension of exercise capacity during repeated sets of exercise would occur despite greater disturbance of the muscle milieu due to enhanced peripheral and corticospinal excitatory output, central motor drive, and muscle contractility.MethodsNine healthy active young men performed five sets of intense single-leg knee extensor exercise to task failure on four separate occasions: for two visits (6 mg·kg−1 caffeine vs placebo, quadriceps 31P-magnetic resonance spectroscopy scans were performed to quantify phosphocreatine kinetics and pH, and for the remaining two visits (6 mg·kg−1 caffeine vs placebo, femoral nerve electrical and transcranial magnetic stimulation of the quadriceps cortical motor area were applied pre- and post exercise.ResultsThe total exercise time was 17.9 ± 6.0% longer in the caffeine (1,225 ± 86 s than in the placebo trial (1,049 ± 73 s, p = 0.016, and muscle phosphocreatine concentration and pH (p < 0.05 were significantly lower in the latter sets of exercise after caffeine ingestion. Voluntary activation (VA (peripheral, p = 0.007; but not supraspinal, p = 0.074, motor-evoked potential (MEP amplitude (p = 0.007, and contractility (contraction time, p = 0.009; and relaxation rate, p = 0.003 were significantly higher after caffeine consumption, but at

  3. "NeuroStem Chip": a novel highly specialized tool to study neural differentiation pathways in human stem cells

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    Li Jia-Yi

    2007-02-01

    Full Text Available Abstract Background Human stem cells are viewed as a possible source of neurons for a cell-based therapy of neurodegenerative disorders, such as Parkinson's disease. Several protocols that generate different types of neurons from human stem cells (hSCs have been developed. Nevertheless, the cellular mechanisms that underlie the development of neurons in vitro as they are subjected to the specific differentiation protocols are often poorly understood. Results We have designed a focused DNA (oligonucleotide-based large-scale microarray platform (named "NeuroStem Chip" and used it to study gene expression patterns in hSCs as they differentiate into neurons. We have selected genes that are relevant to cells (i being stem cells, (ii becoming neurons, and (iii being neurons. The NeuroStem Chip has over 1,300 pre-selected gene targets and multiple controls spotted in quadruplicates (~46,000 spots total. In this study, we present the NeuroStem Chip in detail and describe the special advantages it offers to the fields of experimental neurology and stem cell biology. To illustrate the utility of NeuroStem Chip platform, we have characterized an undifferentiated population of pluripotent human embryonic stem cells (hESCs, cell line SA02. In addition, we have performed a comparative gene expression analysis of those cells versus a heterogeneous population of hESC-derived cells committed towards neuronal/dopaminergic differentiation pathway by co-culturing with PA6 stromal cells for 16 days and containing a few tyrosine hydroxylase-positive dopaminergic neurons. Conclusion We characterized the gene expression profiles of undifferentiated and dopaminergic lineage-committed hESC-derived cells using a highly focused custom microarray platform (NeuroStem Chip that can become an important research tool in human stem cell biology. We propose that the areas of application for NeuroStem microarray platform could be the following: (i characterization of the

  4. The Use of Human-Induced Pluripotent Stem Cell-Derived Neural Precursors in the Treatment of Brain and Spinal Cord Injury

    Czech Academy of Sciences Publication Activity Database

    Jendelová, Pavla; Kozubenko, Nataliya; Amemori, Takashi; Turnovcová, Karolína; Seminatore, CH.; Jirák, D.; Onteniente, B.; Syková, Eva

    2011-01-01

    Roč. 20, č. 4 (2011), s. 564-564 ISSN 0963-6897. [International Neural Transplantatioin and Repair Meeting/18th Annual Meeting of the American-Society-for- Neural - Therapy - and -Repair /11./. 04.05.2011-08.05.2011, Clearwater] Institutional research plan: CEZ:AV0Z50390703 Keywords : spinal cord * stem cell Subject RIV: FH - Neurology

  5. Clinical Trial of Human Fetal Brain-Derived Neural Stem/Progenitor Cell Transplantation in Patients with Traumatic Cervical Spinal Cord Injury

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    Ji Cheol Shin

    2015-01-01

    Full Text Available In a phase I/IIa open-label and nonrandomized controlled clinical trial, we sought to assess the safety and neurological effects of human neural stem/progenitor cells (hNSPCs transplanted into the injured cord after traumatic cervical spinal cord injury (SCI. Of 19 treated subjects, 17 were sensorimotor complete and 2 were motor complete and sensory incomplete. hNSPCs derived from the fetal telencephalon were grown as neurospheres and transplanted into the cord. In the control group, who did not receive cell implantation but were otherwise closely matched with the transplantation group, 15 patients with traumatic cervical SCI were included. At 1 year after cell transplantation, there was no evidence of cord damage, syrinx or tumor formation, neurological deterioration, and exacerbating neuropathic pain or spasticity. The American Spinal Injury Association Impairment Scale (AIS grade improved in 5 of 19 transplanted patients, 2 (A → C, 1 (A → B, and 2 (B → D, whereas only one patient in the control group showed improvement (A → B. Improvements included increased motor scores, recovery of motor levels, and responses to electrophysiological studies in the transplantation group. Therefore, the transplantation of hNSPCs into cervical SCI is safe and well-tolerated and is of modest neurological benefit up to 1 year after transplants. This trial is registered with Clinical Research Information Service (CRIS, Registration Number: KCT0000879.

  6. Two-way regulation between cells and aligned collagen fibrils: local 3D matrix formation and accelerated neural differentiation of human decidua parietalis placental stem cells.

    Science.gov (United States)

    Li, Wen; Zhu, Bofan; Strakova, Zuzana; Wang, Rong

    2014-08-08

    It has been well established that an aligned matrix provides structural and signaling cues to guide cell polarization and cell fate decision. However, the modulation role of cells in matrix remodeling and the feedforward effect on stem cell differentiation have not been studied extensively. In this study, we report on the concerted changes of human decidua parietalis placental stem cells (hdpPSCs) and the highly ordered collagen fibril matrix in response to cell-matrix interaction. With high-resolution imaging, we found the hdpPSCs interacted with the matrix by deforming the cell shape, harvesting the nearby collagen fibrils, and reorganizing the fibrils around the cell body to transform a 2D matrix to a localized 3D matrix. Such a unique 3D matrix prompted high expression of β-1 integrin around the cell body that mediates and facilitates the stem cell differentiation toward neural cells. The study offers insights into the coordinated, dynamic changes at the cell-matrix interface and elucidates cell modulation of its matrix to establish structural and biochemical cues for effective cell growth and differentiation. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model.

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    Desirée L Salazar

    2010-08-01

    Full Text Available Traumatic spinal cord injury (SCI results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+ and CD24(-/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the "window of opportunity" for intervention.

  8. Kidins220/ARMS depletion is associated with the neural-to Schwann-like transition in a human neuroblastoma cell line model.

    Science.gov (United States)

    Rogers, Danny A; Schor, Nina F

    2013-03-10

    Peripheral neuroblastic tumors exist as a heterogeneous mixture of neuroblastic (N-type) cells and Schwannian stromal (S-type) cells. These stromal cells not only represent a differentiated and less aggressive fraction of the tumor, but also have properties that can influence the further differentiation of nearby malignant cells. In vitro neuroblastoma cultures exhibit similar heterogeneity with N-type and S-type cells representing the neuroblastic and stromal portions of the tumor, respectively, in behavior, morphology, and molecular expression patterns. In this study, we deplete kinase D-interacting substrate of 220kD (Kidins220) with an shRNA construct and thereby cause morphologic transition of the human SH-SY5Y neuroblastoma cell line from N-type to S-type. The resulting cells have similar morphology and expression profile to SH-EP1 cells, a native S-type cell line from the same parent cell line, and to SH-SY5Y cells treated with BrdU, a treatment that induces S-type morphology. Specifically, both Kidins220-deficient SH-SY5Y cells and native SH-EP1 cells demonstrate down-regulation of the genes DCX and STMN2, markers for the neuronal lineage. We further show that Kidins220, DCX and STMN2 are co-down-regulated in cells of S-type morphology generated by methods other than Kidins220 depletion. Finally, we report that the association of low Kidins220 expression with S-type morphology and low DCX and STMN2 expression is demonstrated in spontaneously occurring human peripheral neuroblastic tumors. We propose that Kidins220 is critical in N- to S-type transition of neural crest tumor cells. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Heat shock protein 70 modulates neural progenitor cells dynamics in human neuroblastoma SH-SY5Y cells exposed to high glucose content.

    Science.gov (United States)

    Salimi, Leila; Rahbarghazi, Reza; Jafarian, Vahab; Biray Avci, Çıgır; Goker Bagca, Bakiye; Pinar Ozates, Neslihan; Khaksar, Majid; Nourazarian, Alireza

    2018-01-18

    In the current experiment, detrimental effects of high glucose condition were investigated on human neuroblastoma cells. Human neuroblastoma cell line SH-SY5Y were exposed to 5, 40, and 70 mM glucose over a period of 72 h. Survival rate and the proliferation of cells were analyzed by MTT and BrdU incorporation assays. Apoptosis was studied by the assays of flow cytometry and PCR array. In order to investigate the trans-differentiation capacity of the cell into mature neurons, we used immunofluorescence imaging to follow NeuN protein level. The transcription level of HSP70 was shown by real-time PCR analysis. MMP-2 and -9 activities were shown by gelatin Zymography. According to data from MTT and BrdU incorporation assay, 70 mM glucose reduced cell viability and proliferation rate as compared to control (5 mM glucose) and cells treated with 40 mM glucose (P Cell exposure to 70 mM glucose had potential to induced apoptosis after 72 h (P SH-SY5Y cells to detrimental effects of high glucose condition during trans-differentiation into mature neuron-like cells. Real-time PCR analysis confirmed the expression of HSP70 in cells under high content glucose levels, demonstrating the possible cell compensatory response to an insulting condition (p control vs 70 mM group  cells being exposed to 70 mM glucose. High glucose condition could abrogate the dynamics of neural progenitor cells. The intracellular level of HSP70 was proportional to cell damage in high glucose condition. © 2018 Wiley Periodicals, Inc.

  10. OTX2 exhibits cell-context-dependent effects on cellular and molecular properties of human embryonic neural precursors and medulloblastoma cells

    Directory of Open Access Journals (Sweden)

    Ravinder Kaur

    2015-10-01

    Full Text Available Medulloblastoma (MB is the most common malignant primary pediatric brain tumor and is currently divided into four subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH, Group 3 and Group 4. This extensive heterogeneity has made it difficult to assess the functional relevance of genes to malignant progression. For example, expression of the transcription factor Orthodenticle homeobox2 (OTX2 is frequently dysregulated in multiple MB variants; however, its role may be subtype specific. We recently demonstrated that neural precursors derived from transformed human embryonic stem cells (trans-hENs, but not their normal counterparts (hENs, resemble Groups 3 and 4 MB in vitro and in vivo. Here, we tested the utility of this model system as a means of dissecting the role of OTX2 in MB using gain- and loss-of-function studies in hENs and trans-hENs, respectively. Parallel experiments with MB cells revealed that OTX2 exerts inhibitory effects on hEN and SHH MB cells by regulating growth, self-renewal and migration in vitro and tumor growth in vivo. This was accompanied by decreased expression of pluripotent genes, such as SOX2, and was supported by overexpression of SOX2 in OTX2+ SHH MB and hENs that resulted in significant rescue of self-renewal and cell migration. By contrast, OTX2 is oncogenic and promotes self-renewal of trans-hENs and Groups 3 and 4 MB independent of pluripotent gene expression. Our results demonstrate a novel role for OTX2 in self-renewal and migration of hENs and MB cells and reveal a cell-context-dependent link between OTX2 and pluripotent genes. Our study underscores the value of human embryonic stem cell derivatives as alternatives to cell lines and heterogeneous patient samples for investigating the contribution of key developmental regulators to MB progression.

  11. Gene expression changes in the retina following subretinal injection of human neural progenitor cells into a rodent model for retinal degeneration.

    Science.gov (United States)

    Jones, Melissa K; Lu, Bin; Saghizadeh, Mehrnoosh; Wang, Shaomei

    2016-01-01

    Retinal degenerative diseases (RDDs) affect millions of people and are the leading cause of vision loss. Although treatment options for RDDs are limited, stem and progenitor cell-based therapies have great potential to halt or slow the progression of vision loss. Our previous studies have shown that a single subretinal injection of human forebrain derived neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) retinal degenerate rat offers long-term preservation of photoreceptors and visual function. Furthermore, neural progenitor cells are currently in clinical trials for treating age-related macular degeneration; however, the molecular mechanisms of stem cell-based therapies are largely unknown. This is the first study to analyze gene expression changes in the retina of RCS rats following subretinal injection of hNPCs using high-throughput sequencing. RNA-seq data of retinas from RCS rats injected with hNPCs (RCS(hNPCs)) were compared to sham surgery in RCS (RCS(sham)) and wild-type Long Evans (LE(sham)) rats. Differential gene expression patterns were determined with in silico analysis and confirmed with qRT-PCR. Function, biologic, cellular component, and pathway analyses were performed on differentially expressed genes and investigated with immunofluorescent staining experiments. Analysis of the gene expression data sets identified 1,215 genes that were differentially expressed between RCS(sham) and LE(sham) samples. Additionally, 283 genes were differentially expressed between the RCS(hNPCs) and RCS(sham) samples. Comparison of these two gene sets identified 68 genes with inverse expression (termed rescue genes), including Pdc, Rp1, and Cdc42ep5. Functional, biologic, and cellular component analyses indicate that the immune response is enhanced in RCS(sham). Pathway analysis of the differential expression gene sets identified three affected pathways in RCS(hNPCs), which all play roles in phagocytosis signaling. Immunofluorescent staining

  12. Neural Networks

    Directory of Open Access Journals (Sweden)

    Schwindling Jerome

    2010-04-01

    Full Text Available This course presents an overview of the concepts of the neural networks and their aplication in the framework of High energy physics analyses. After a brief introduction on the concept of neural networks, the concept is explained in the frame of neuro-biology, introducing the concept of multi-layer perceptron, learning and their use as data classifer. The concept is then presented in a second part using in more details the mathematical approach focussing on typical use cases faced in particle physics. Finally, the last part presents the best way to use such statistical tools in view of event classifers, putting the emphasis on the setup of the multi-layer perceptron. The full article (15 p. corresponding to this lecture is written in french and is provided in the proceedings of the book SOS 2008.

  13. Complex-Valued Neural Networks

    CERN Document Server

    Hirose, Akira

    2012-01-01

    This book is the second enlarged and revised edition of the first successful monograph on complex-valued neural networks (CVNNs) published in 2006, which lends itself to graduate and undergraduate courses in electrical engineering, informatics, control engineering, mechanics, robotics, bioengineering, and other relevant fields. In the second edition the recent trends in CVNNs research are included, resulting in e.g. almost a doubled number of references. The parametron invented in 1954 is also referred to with discussion on analogy and disparity. Also various additional arguments on the advantages of the complex-valued neural networks enhancing the difference to real-valued neural networks are given in various sections. The book is useful for those beginning their studies, for instance, in adaptive signal processing for highly functional sensing and imaging, control in unknown and changing environment, robotics inspired by human neural systems, and brain-like information processing, as well as interdisciplina...

  14. Memristor-based neural networks

    International Nuclear Information System (INIS)

    Thomas, Andy

    2013-01-01

    The synapse is a crucial element in biological neural networks, but a simple electronic equivalent has been absent. This complicates the development of hardware that imitates biological architectures in the nervous system. Now, the recent progress in the experimental realization of memristive devices has renewed interest in artificial neural networks. The resistance of a memristive system depends on its past states and exactly this functionality can be used to mimic the synaptic connections in a (human) brain. After a short introduction to memristors, we present and explain the relevant mechanisms in a biological neural network, such as long-term potentiation and spike time-dependent plasticity, and determine the minimal requirements for an artificial neural network. We review the implementations of these processes using basic electric circuits and more complex mechanisms that either imitate biological systems or could act as a model system for them. (topical review)

  15. Responses to hyperthermia. Optimizing heat dissipation by convection and evaporation: Neural control of skin blood flow and sweating in humans.

    Science.gov (United States)

    Smith, Caroline J; Johnson, John M

    2016-04-01

    Under normothermic, resting conditions, humans dissipate heat from the body at a rate approximately equal to heat production. Small discrepancies between heat production and heat elimination would, over time, lead to significant changes in heat storage and body temperature. When heat production or environmental temperature is high the challenge of maintaining heat balance is much greater. This matching of heat elimination with heat production is a function of the skin circulation facilitating heat transport to the body surface and sweating, enabling evaporative heat loss. These processes are manifestations of the autonomic control of cutaneous vasomotor and sudomotor functions and form the basis of this review. We focus on these systems in the responses to hyperthermia. In particular, the cutaneous vascular responses to heat stress and the current understanding of the neurovascular mechanisms involved. The available research regarding cutaneous active vasodilation and vasoconstriction is highlighted, with emphasis on active vasodilation as a major responder to heat stress. Involvement of the vasoconstrictor and active vasodilator controls of the skin circulation in the context of heat stress and nonthermoregulatory reflexes (blood pressure, exercise) are also considered. Autonomic involvement in the cutaneous vascular responses to direct heating and cooling of the skin are also discussed. We examine the autonomic control of sweating, including cholinergic and noncholinergic mechanisms, the local control of sweating, thermoregulatory and nonthermoregulatory reflex control and the possible relationship between sudomotor and cutaneous vasodilator function. Finally, we comment on the clinical relevance of these control schemes in conditions of autonomic dysfunction. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Changes in expression of the long noncoding RNA FMR4 associate with altered gene expression during differentiation of human neural precursor cells

    Directory of Open Access Journals (Sweden)

    Veronica Julia Peschansky

    2015-08-01

    Full Text Available CGG repeat expansions in the Fragile X mental retardation 1 (FMR1 gene are responsible for a family of associated disorders characterized by either intellectual disability and autism (Fragile X Syndrome, FXS, or adult-onset neurodegeneration (Fragile X-associated Tremor/Ataxia Syndrome, FXTAS. However, the FMR1 locus is complex and encodes several long noncoding RNAs (lncRNAs, whose expression is altered by repeat expansion mutations.The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. Full-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, including the methyl-CpG-binding domain protein 4 (MBD4. Furthermore, we found that in differentiating human neural precursor cells (hNPCs, FMR4 expression is developmentally regulated in opposition to expression of both FMR1 (which is expected to share a bidirectional promoter with FMR4 and MBD4.We therefore propose that FMR4’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.

  17. Rapid generation of sub-type, region-specific neurons and neural networks from human pluripotent stem cell-derived neurospheres

    Directory of Open Access Journals (Sweden)

    Aynun N. Begum

    2015-11-01

    Full Text Available Stem cell-based neuronal differentiation has provided a unique opportunity for disease modeling and regenerative medicine. Neurospheres are the most commonly used neuroprogenitors for neuronal differentiation, but they often clump in culture, which has always represented a challenge for neurodifferent