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  • 201.
    Vazin, Tandis
    KTH, School of Biotechnology (BIO), Gene Technology.
    Generation of Dopaminergic Neurons from Human Embryonic Stem Cells2008Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Since the first successful derivation of human embryonic stem cells (hESC), rapid progress has been attained in the development of strategies in differentiation of these cells into various neural lineages, with the fundamental objective of using these cells for replacement and repair of damaged neuronal circuits in the central nervous system (CNS). Of particular interest are midbrain dopaminergic (mDA) neurons, which play a central role in regulation of voluntary movement. Degeneration or loss of function of mDA neurons in the nigrostriatal pathway is associated with Parkinson disease (PD).

    Stromal-Derived Inducing Activity (SDIA) is recognized as one of the most efficient methods in restricting ESC differentiation to a dopaminergic lineage, and refers to the property of mouse stromal cell lines such as PA6 or MS5 to cause ESC to differentiate to DA neurons. Although this strategy has been extensively used to generate mDA neurons from hESC, the biochemical nature of SDIA is yet unknown. 

    In the present study mDA neurons were generated from the BG01V2 hESC line by SDIA. To examine whether SDIA exerts its effect directly on hESC and is responsible for early dopaminergic induction, neural progenitor cells (NPC) were enyzmatically isolated from the co-cultures and allowed to differentiate in feeder-free conditions. The isolated cells were committed to a mesencephalic neural lineage, and were capable of maintaining their phenotype and developing into postmitotic mDA neurons in feeder-free conditions. The mDA neurons showed neuronal excitability and dopamine transporter function. The in vitro proliferation and differentiation of the NPC was also investigated by a BrDU incorporation assay.

    Next, the maintenance of cellular memory and capacity for proliferation of the mesencephalic NPC was assessed. The NPC could be expanded in vitro by five-fold as neurospheres for up to two weeks while retaining their DA differentiation potential, but did not retain a stable phenotype over extended periods of time. Preliminary transplantation experiments of neurospheres in striatal lesioned animals indicated, however, that these cells could survive and conserve their phenotype in vivo.

    To gain additional insight into the biochemical role of SDIA in early dopaminergic induction of hESC, the separate contributions of cell surface activity and secreted factors were examined. The data revealed that the PA6 cell surface activity promoted cell survival and was mainly responsible for enhanced neurogenesis of hESC, whereas secreted factors provided DA lineage-specific instructions.

    In order to identify the soluble factors responsible for the DA phenotype-inducing component of SDIA, the gene expression profile of PA6 cells was compared to that of cell lines lacking the DA-inducing property. A number of soluble factors known to be associated with CNS development that were highly expressed in PA6 cells were identified as potential DA differentiation-inducing candidates. These differentially-expressed genes included stromal cell-derived factor 1 (SDF-1/CXCL12), pleiotrophin (PTN), insulin-like growth factor 2 (IGF2), and ephrin B1 (EFNB1). When these factors, termed SPIE, were applied to the hESC, they induced dopaminergic neuronal differentiation of hESC line, BG01V2 and other karyotypically normal hESC lines in vitro. Thus, it appears that SPIE comprises the DA phenotype-inducing property of SDIA. This may provide a simple and direct means of differentiating hESC to form DA neurons in a single step, without a requirement for co-culture, animal cell lines, or animal products.

  • 202.
    Venkateshvaran, Ashwin
    et al.
    KTH, School of Technology and Health (STH).
    Sola, S.
    Govind, Satish Chandra
    KTH, School of Technology and Health (STH).
    Dash, P. K.
    Barooah, B.
    Shahgaldi, Kambiz
    KTH, School of Technology and Health (STH).
    Sahlén, Anders
    KTH, School of Technology and Health (STH).
    Lund, L.
    Winter, Reidar
    KTH, School of Technology and Health (STH).
    Nagy, A. I.
    Manouras, Aristomenis
    KTH, School of Technology and Health (STH).
    The impact of arterial load on left ventricular performance: An invasive haemodynamic study in severe mitral stenosis2015In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 593, no 8, p. 1901-1912Article in journal (Refereed)
    Abstract [en]

    Key points: A hallmark of mitral stenosis (MS) is the markedly altered left ventricular (LV) loading. As most of the methods used to determine LV performance in MS patients are influenced by loading conditions, previous studies have shown conflicting results. The present study calculated LV elastance, which is a robust method to quantify LV function. We demonstrate that LV loading in MS patients is elevated but normalizes after valve repair and might be a result of reflex pathways. Additionally, we show that the LV in MS is less compliant than normal due to a combination of right ventricular loading and the valvular disease itself. Immediately after valve dilatation the increase in blood inflow into the LV results in even greater LV stiffness. Our findings enrich our understanding of heart function in MS patients and provide a simple reproducible way of assessing LV performance in MS. Left ventricular (LV) function in rheumatic mitral stenosis (MS) remains an issue of controversy, due to load dependency of previously employed assessment methods. We investigated LV performance in MS employing relatively load-independent indices robust to the altered loading state. We studied 106 subjects (32 ± 8 years, 72% female) with severe MS (0.8 ± 0.2 cm2) and 40 age-matched controls. MS subjects underwent simultaneous bi-ventricular catheterization and transthoracic echocardiography (TTE) before and immediately after percutaneous transvenous mitral commisurotomy (PTMC). Sphygmomanometric brachial artery pressures and TTE recordings were simultaneously acquired in controls. Single-beat LV elastance (E<inf>es</inf>) was employed for LV contractility measurements. Effective arterial elastance (E<inf>a</inf>) and LV diastolic stiffness were measured. MS patients demonstrated significantly elevated afterload (E<inf>a</inf>: 3.0 ± 1.3 vs. 1.5 ± 0.3 mmHg ml-1; P < 0.001) and LV contractility (E<inf>es</inf>: 4.1 ± 1.6 vs. 2.4 ± 0.5 mmHg ml-1; P < 0.001) as compared to controls, with higher E<inf>a</inf> in subjects with smaller mitral valve area (≤ 0.8 cm2) and pronounced subvalvular fusion. Stroke volume (49 ± 16 to 57 ± 17 ml; P < 0.001) and indexed LV end-diastolic volume (LVEDV<inf>index</inf>: 57 ± 16 to 64 ± 16 ml m-2; P < 0.001) increased following PTMC while E<inf>es</inf> and E<inf>a</inf> returned to more normal levels. Elevated LV stiffness was demonstrated at baseline and increased further following PTMC. Our findings provide evidence of elevated LV contractility, increased arterial load and increased diastolic stiffness in severe MS. Following PTMC, both LV contractility and afterload tend to normalize.

  • 203.
    Vlachos, Ioannis
    et al.
    University of Freiburg, Freiburg, Germany .
    Aertsen, Ad
    University of Freiburg, Freiburg, Germany .
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. University of Freiburg, Freiburg, Germany .
    Beyond Statistical Significance: Implications of Network Structure on Neuronal Activity2012In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 8, no 1, p. e1002311-Article in journal (Refereed)
    Abstract [en]

    It is a common and good practice in experimental sciences to assess the statistical significance of measured outcomes. For this, the probability of obtaining the actual results is estimated under the assumption of an appropriately chosen null-hypothesis. If this probability is smaller than some threshold, the results are deemed statistically significant and the researchers are content in having revealed, within their own experimental domain, a "surprising" anomaly, possibly indicative of a hitherto hidden fragment of the underlying "ground-truth". What is often neglected, though, is the actual importance of these experimental outcomes for understanding the system under investigation. We illustrate this point by giving practical and intuitive examples from the field of systems neuroscience. Specifically, we use the notion of embeddedness to quantify the impact of a neuron's activity on its downstream neurons in the network. We show that the network response strongly depends on the embeddedness of stimulated neurons and that embeddedness is a key determinant of the importance of neuronal activity on local and downstream processing. We extrapolate these results to other fields in which networks are used as a theoretical framework.

  • 204. Vlachos, Ioannis
    et al.
    Deniz, Taskin
    Aertsen, Ad
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). University of Freiburg, Germany.
    Recovery of dynamics and function in spiking neural networks with closed-loop control2016In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, no 2, p. e1004720-Article in journal (Refereed)
    Abstract [en]

    There is a growing interest in developing novel brain stimulation methods to control disease-related aberrant neural activity and to address basic neuroscience questions. Conventional methods for manipulating brain activity rely on open-loop approaches that usually lead to excessive stimulation and, crucially, do not restore the original computations performed by the network. Thus, they are often accompanied by undesired side-effects. Here, we introduce delayed feedback control (DFC), a conceptually simple but effective method, to control pathological oscillations in spiking neural networks (SNNs). Using mathematical analysis and numerical simulations we show that DFC can restore a wide range of aberrant network dynamics either by suppressing or enhancing synchronous irregular activity. Importantly, DFC, besides steering the system back to a healthy state, also recovers the computations performed by the underlying network. Finally, using our theory we identify the role of single neuron and synapse properties in determining the stability of the closed-loop system.

  • 205. Vlachos, Ioannis
    et al.
    Herry, Cyril
    Lüthi, Andreas
    Aertsen, Ad
    University of Freiburg, Germany.
    Kumar, Arvind
    University of Freiburg, Germany.
    Context-Dependent Encoding of Fear and Extinction Memories in a Large-Scale Network Model of the Basal Amygdala2011In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 7, no 3, article id e1001104Article in journal (Refereed)
    Abstract [en]

    The basal nucleus of the amygdala (BA) is involved in the formation of context-dependent conditioned fear and extinction memories. To understand the underlying neural mechanisms we developed a large-scale neuron network model of the BA, composed of excitatory and inhibitory leaky-integrate-and-fire neurons. Excitatory BA neurons received conditioned stimulus (CS)-related input from the adjacent lateral nucleus (LA) and contextual input from the hippocampus or medial prefrontal cortex (mPFC). We implemented a plasticity mechanism according to which CS and contextual synapses were potentiated if CS and contextual inputs temporally coincided on the afferents of the excitatory neurons. Our simulations revealed a differential recruitment of two distinct subpopulations of BA neurons during conditioning and extinction, mimicking the activation of experimentally observed cell populations. We propose that these two subgroups encode contextual specificity of fear and extinction memories, respectively. Mutual competition between them, mediated by feedback inhibition and driven by contextual inputs, regulates the activity in the central amygdala (CEA) thereby controlling amygdala output and fear behavior. The model makes multiple testable predictions that may advance our understanding of fear and extinction memories.

  • 206. Vlachos, Ioannis
    et al.
    Zaytsev, Yury V
    Spreizer, Sebastian
    Aertsen, Ad
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Neural system prediction and identification challenge2013In: Frontiers in Neuroinformatics, ISSN 1662-5196, E-ISSN 1662-5196, Vol. 7, no DEC, p. 43-Article in journal (Refereed)
    Abstract [en]

    Can we infer the function of a biological neural network (BNN) if we know the connectivity and activity of all its constituent neurons? This question is at the core of neuroscience and, accordingly, various methods have been developed to record the activity and connectivity of as many neurons as possible. Surprisingly, there is no theoretical or computational demonstration that neuronal activity and connectivity are indeed sufficient to infer the function of a BNN. Therefore, we pose the Neural Systems Identification and Prediction Challenge (nuSPIC). We provide the connectivity and activity of all neurons and invite participants (1) to infer the functions implemented (hard-wired) in spiking neural networks (SNNs) by stimulating and recording the activity of neurons and, (2) to implement predefined mathematical/biological functions using SNNs. The nuSPICs can be accessed via a web-interface to the NEST simulator and the user is not required to know any specific programming language. Furthermore, the nuSPICs can be used as a teaching tool. Finally, nuSPICs use the crowd-sourcing model to address scientific issues. With this computational approach we aim to identify which functions can be inferred by systematic recordings of neuronal activity and connectivity. In addition, nuSPICs will help the design and application of new experimental paradigms based on the structure of the SNN and the presumed function which is to be discovered.

  • 207.
    Von Holst, Hans
    KTH, School of Technology and Health (STH), Neuronic Engineering (Closed 20130701). Karolinska University Hospital, Sweden.
    Traumatic brain injury: Evidence-based management and epidemiology updates2009In: Neuroepidemiology, ISSN 0251-5350, E-ISSN 1423-0208, Vol. 33, no 4, p. 314-315Article in journal (Refereed)
  • 208. Westin, Linda
    et al.
    Reuss, Matthias
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindskog, Maria
    Aperia, Anita
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Nanoscopic spine localization of Norbin, an mGluR5 accessory protein2014In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 15, p. 45-Article in journal (Refereed)
    Abstract [en]

    Background: Norbin is a neuron-specific, cytosolic protein that interacts with the metabotropic glutamate receptor 5 (mGluR5) and has a profound impact on mGluR5 signaling. Yet, little is known about its synaptic distribution. Results: Here we have analyzed the spatial relationship between Norbin, postsynaptic density protein 95 (PSD-95), actin and mGluR5 in spines using super-resolution microscopy. Norbin was found to have a high degree of colocalization with actin and a lower degree of colocalization with PSD-95. Co-immunoprecipitation studies confirmed that interaction occurs between Norbin and actin, but not between Norbin and PSD-95. Norbin was also found to have a high degree of colocalization with the perisynaptically located mGluR5. Findings based on structured illumination microscopy (3D-SIM) of exogenous expressed Norbin-GFP were confirmed by stimulated emission depletion microscopy (STED) of immunolabeled endogenous Norbin. Conclusions: Norbin associates with actin rather than with PSD-95 in dendritic spines. Results regarding protein localization and colocalization performed with conventional confocal microscopy must be interpreted with great caution. The now available super-resolution microscopy techniques provide more accurate information about sub-cellular protein localization than previously was possible.

  • 209.
    Wärnberg, Emil
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST). Dept.of Neuroscience,Karolinska Institutet, Sweden.
    Kumar, Arvind
    KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST).
    Perturbing low dimensional activity manifolds in spiking neuronal networks2019In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, no 5, article id e1007074Article in journal (Refereed)
    Abstract [en]

    Several recent studies have shown that neural activity in vivo tends to be constrained to a low-dimensional manifold. Such activity does not arise in simulated neural networks with homogeneous connectivity and it has been suggested that it is indicative of some other connectivity pattern in neuronal networks. In particular, this connectivity pattern appears to be constraining learning so that only neural activity patterns falling within the intrinsic manifold can be learned and elicited. Here, we use three different models of spiking neural networks (echo-state networks, the Neural Engineering Framework and Efficient Coding) to demonstrate how the intrinsic manifold can be made a direct consequence of the circuit connectivity. Using this relationship between the circuit connectivity and the intrinsic manifold, we show that learning of patterns outside the intrinsic manifold corresponds to much larger changes in synaptic weights than learning of patterns within the intrinsic manifold. Assuming larger changes to synaptic weights requires extensive learning, this observation provides an explanation of why learning is easier when it does not require the neural activity to leave its intrinsic manifold.

  • 210. Xiu, L.
    et al.
    Svensson, V.
    Johansson, E.
    Ek, A.
    Marcus, C.
    Ekstedt, M.
    KTH, School of Technology and Health (STH).
    Bedtime eating and sleep disturbances among 2 years old children2016In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 25, p. 326-327Article in journal (Other academic)
  • 211. Yim, Man Yi
    et al.
    Aertsen, Ad
    Kumar, Arvind
    Bernstein Center Freiburg and Neurobiology & Biophysics, Faculty of Biology, University of Freiburg, Freiburg, Germany.
    Significance of Input Correlations in Striatal Function2011In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 7, no 11Article in journal (Refereed)
    Abstract [en]

    The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia.

  • 212.
    Yim, Man Yi
    et al.
    University of Hong Kong, Hong Kong.
    Kumar, Arvind
    Bernstein Center Freiburg, University of Freiburg, Germany .
    Aertsen, Ad
    Rotter, Stefan
    Impact of correlated inputs to neurons: modeling observations from in vivo intracellular recordings2014In: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 37, no 2, p. 293-304Article in journal (Refereed)
    Abstract [en]

    In vivo recordings in rat somatosensory cortex suggest that excitatory and inhibitory inputs are often correlated during spontaneous and sensory-evoked activity. Using a computational approach, we study how the interplay of input correlations and timing observed in experiments controls the spiking probability of single neurons. Several correlation-based mechanisms are identified, which can effectively switch a neuron on and off. In addition, we investigate the transfer of input correlation to output correlation in pairs of neurons, at the spike train and the membrane potential levels, by considering spike-driving and non-spike-driving inputs separately. In particular, we propose a plausible explanation for the in vivo finding that membrane potentials in neighboring neurons are correlated, but the spike-triggered averages of membrane potentials preceding a spike are not: Neighboring neurons possibly receive an ongoing bombardment of correlated subthreshold background inputs, and occasionally uncorrelated spike-driving inputs.

  • 213. Yoshida, Motoharu
    et al.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Hasselmo, Michael E.
    mGluR-dependent persistent firing in entorhinal cortex layer III neurons2008In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 28, no 6, p. 1116-1126Article in journal (Refereed)
    Abstract [en]

    Persistent firing is believed to be a crucial mechanism for memory function including working memory. Recent in vivo and in vitro findings suggest an involvement of metabotropic glutamate receptors (mGluRs) in persistent firing. Using whole-cell patch-recording techniques in a rat entorhinal cortex (EC) slice preparation, we tested whether EC layer III neurons display persistent firing due to mGluR activation, independently of cholinergic activation. Stimulation of the angular bundle drove persistent firing in 90% of the cells in the absence of a cholinergic agonist. The persistent firing was typically stable for > 4.5 min at which point persistent firing was terminated by the experimenter. The average frequency of the persistent firing was 2.1 Hz, ranging from 0.4 to 5.5 Hz. This persistent firing was observed even in the presence of atropine (2 mu M), suggesting that the persistent firing can occur independent of cholinergic activation. Furthermore, ionotropic glutamate and GABAergic synaptic blockers (2 mm kynurenic acid, 100 mu M picrotoxin and 1 mu M CGP55845) did not block the persistent firing. On the other hand, blockers of group I mGluRs (100 mu M LY367385 and 20 mu M MPEP) completely blocked or suppressed the persistent firing. An agonist of group I mGluRs (20 mu M DHPG) greatly enhanced the persistent firing induced by current injection. These results indicate that persistent firing can be driven through group I mGluRs in entorhinal layer III neurons, suggesting that glutamatergic synaptic input alone could enable postsynaptic neurons to hold input signals in the form of persistent firing.

  • 214.
    Zagal, Juan Cristobal
    et al.
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Björkman, Eva
    Lindeberg, Tony
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Roland, P.
    Signficance determination for the scale-space primal sketch by comparison of statistics of scale-space blob volumes computed from PET signals vs. residual noise2000In: : HBM'00 published in Neuroimage, volume 11, number 5, 2000, 2000, Vol. 11, p. 493-493Conference paper (Refereed)
    Abstract [en]

    A dominant approach to brain mapping is to define functional regions in the brain by analyzing brain activation images obtained by PET or fMRI. In [1], it has been shown that the scale-space primal sketch provides a useful tool for such analysis. Some attractive properties of this method are that it only makes few assumptions about the data and the process for extracting activations is fully automatic.

    In the present version of the scale-space primal sketch, however, there is no method for determining p-values. The purpose here is to present a new methodology for addressing this question, by introducing a descriptor referred to as the -curve, which serves as a first step towards determining the probability of false positives, i.e. alpha.

  • 215.
    Zelenina, Marina
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Regulation of brain aquaporins2010In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 57, no 4, p. 468-488Article in journal (Refereed)
    Abstract [en]

    Three aquaporins are expressed in the brain. AQP4, the predominant brain water channel, is expressed in astrocyte endfeet facing brain capillaries, perisynaptic spaces, and nodes of Ranvier. It is implicated in brain edema formation and resolution. It is also believed to assist clearance of K+. released during neuronal activity. AQP1 is expressed in epithelial cells of choroid plexus and is implicated in cerebrospinal fluid formation. AQP9, which has been reported to be present in astrocytes and in subpopulations of neurons, is implicated in the brain energy metabolism. All three brain AQPs are strongly upregulated in brain tumors and in injured brain tissue. Water and solute transport via AQPs depends on concentration gradients across the membrane, but the magnitude of the transport is to a large extent determined by the single channel permeability of AQPs and by their abundance in the cell membrane. The future therapies will have to address not only the forces driving the water and solute transport (e.g. as mannitol infusion does in the treatment of brain edema), but also the regulation of AQPs, which provide the means for water entry to the brain, for water exit from the brain, and for redistribution of water and solutes within the brain compartments. This review summarizes the data concerning structure, permeability, role in the brain, short-term and long-term regulation of the three AQPs.

  • 216. Zhang, M. -D
    et al.
    Barde, S.
    Szodorai, E.
    Josephson, A.
    Mitsios, N.
    Watanabe, M.
    Attems, J.
    Lubec, G.
    Kovács, G. M.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Mulder, J.
    Harkany, T.
    Hökfelt, T.
    Comparative anatomical distribution of neuronal calcium-binding protein (NECAB) 1 and -2 in rodent and human spinal cord2016In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, p. 1-21Article in journal (Refereed)
    Abstract [en]

    Neuronal calcium-binding protein 1 and -2 (NECAB1/2) localize to multiple excitatory neuron populations in the mouse spinal cord. Here, we analyzed rat and human spinal cord, combining in situ hybridization and immunohistochemistry, complementing newly collated data on mouse spinal cord for direct comparisons. Necab1/2 mRNA transcripts showed complementary distribution in rodent’s spinal cord. Multiple-labeling fluorescence histochemistry with neuronal phenotypic markers localized NECAB1 to a dense fiber plexus in the dorsal horn, to neurons mainly in superficial layers and to commissural interneurons in both rodent species. NECAB1-positive (+) motor neurons were only found in mice. NECAB1 distribution in the human spinal cord was similar with the addition of NECAB1-like immunoreactivity surrounding myelinated axons. NECAB2 was mainly present in excitatory synaptic boutons in the dorsal horn of all three species, and often in calbindin-D28k+ neuronal somata. Rodent ependymal cells expressed calbindin-D28k. In humans, they instead were NECAB2+ and/or calretinin+. Our results reveal that the association of NECAB2 to excitatory neuronal circuits in the spinal cord is evolutionarily conserved across the mammalian species investigated so far. In contrast, NECAB1 expression is more heterogeneous. Thus, our study suggests that the phenotypic segregation of NECAB1 and -2 to respective excitatory and inhibitory spinal systems can underpin functional modalities in determining the fidelity of synaptic neurotransmission and neuronal responsiveness, and might bear translational relevance to humans.

  • 217. Zhang, Ming-Dong
    et al.
    Tortoriello, Giuseppe
    Hsueh, Brian
    Tomer, Raju
    Ye, Li
    Mitsios, Nicholas
    Borgius, Lotta
    Grant, Gunnar
    Kiehn, Ole
    Watanabe, Masahiko
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mulder, Jan
    Deisseroth, Karl
    Harkany, Tibor
    Hökfelt, Tomas G. M.
    Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury2014In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, no 12, p. E1149-E1158Article in journal (Refereed)
    Abstract [en]

    Neuronal calcium (Ca2+)-binding proteins 1 and 2 (NECAB1/2) are members of the phylogenetically conserved EF-hand Ca2+-binding protein superfamily. To date, NECABs have been explored only to a limited extent and, so far, not at all at the spinal level. Here, we describe the distribution, phenotype, and nerve injury-induced regulation of NECAB1/NECAB2 in mouse dorsal root ganglia (DRGs) and spinal cord. In DRGs, NECAB1/2 are expressed in around 70% of mainly small-and medium-sized neurons. Many colocalize with calcitonin gene-related peptide and isolectin B4, and thus represent nociceptors. NECAB1/2 neurons are much more abundant in DRGs than the Ca2+-binding proteins (parvalbumin, calbindin, calretinin, and secretagogin) studied to date. In the spinal cord, the NECAB1/2 distribution is mainly complementary. NECAB1 labels interneurons and a plexus of processes in superficial layers of the dorsal horn, commissural neurons in the intermediate area, and motor neurons in the ventral horn. Using CLARITY, a novel, bilaterally connected neuronal system with dendrites that embrace the dorsal columns like palisades is observed. NECAB2 is present in cell bodies and presynaptic boutons across the spinal cord. In the dorsal horn, most NECAB1/2 neurons are glutamatergic. Both NECAB1/2 are transported into dorsal roots and peripheral nerves. Peripheral nerve injury reduces NECAB2, but not NECAB1, expression in DRG neurons. Our study identifies NECAB1/2 as abundant Ca2+-binding proteins in pain-related DRG neurons and a variety of spinal systems, providing molecular markers for known and unknown neuron populations of mechanosensory and pain circuits in the spinal cord.

  • 218.
    Zhu, Fei
    et al.
    Univ Edinburgh, Genes Cognit Program, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland.;UCL Inst Neurol, Queen Sq, London WC1N 3BG, England..
    Cizeron, Melissa
    Univ Edinburgh, Genes Cognit Program, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland.;Univ Claude Bernard Lyon 1, Univ Lyon, Inst NeuroMyoGene, CNRS,UMR 5310,INSERM,U1217, F-69008 Lyon, France..
    Qiu, Zhen
    Univ Edinburgh, Genes Cognit Program, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland..
    Benavides-Piccione, Ruth
    CSIC, Inst Cajal, E-28002 Madrid, Spain.;UPM, Ctr Tecnol Biomed, Madrid 28223, Spain.;ISCIII, CIBERNED, Madrid 28031, Spain..
    Kopanitsa, Maksym V.
    Synome Ltd, Babraham Res Campus, Cambridge CB22 3AT, England.;Imperial Coll London, UK Dementia Res Inst, London W12 0NN, England..
    Skene, Nathan G.
    Univ Edinburgh, Genes Cognit Program, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland.;UCL Inst Neurol, Queen Sq, London WC1N 3BG, England.;Karolinska Inst, Dept Med Biochem & Biophys, Lab Mol Neurobiol, S-17177 Stockholm, Sweden..
    Koniaris, Babis
    Univ Edinburgh, Genes Cognit Program, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland..
    DeFelipe, Javier
    CSIC, Inst Cajal, E-28002 Madrid, Spain.;UPM, Ctr Tecnol Biomed, Madrid 28223, Spain.;ISCIII, CIBERNED, Madrid 28031, Spain..
    Fransén, Erik
    KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST).
    Komiyama, Noboru H.
    Univ Edinburgh, Genes Cognit Program, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland..
    Grant, Seth G. N.
    Univ Edinburgh, Genes Cognit Program, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland..
    Architecture of the Mouse Brain Synaptome2018In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 99, no 4, p. 781-+Article in journal (Refereed)
    Abstract [en]

    Synapses are found in vast numbers in the brain and contain complex proteomes. We developed genetic labeling and imaging methods to examine synaptic proteins in individual excitatory synapses across all regions of the mouse brain. Synapse catalogs were generated from the molecular and morphological features of a billion synapses. Each synapse subtype showed a unique anatomical distribution, and each brain region showed a distinct signature of synapse subtypes. Whole-brain synaptome cartography revealed spatial architecture from dendritic to global systems levels and previously unknown anatomical features. Synaptome mapping of circuits showed correspondence between synapse diversity and structural and functional connectomes. Behaviorally relevant patterns of neuronal activity trigger spatio-temporal postsynaptic responses sensitive to the structure of synaptome maps. Areas controlling higher cognitive function contain the greatest synapse diversity, and mutations causing cognitive disorders reorganized synaptome maps. Synaptome technology and resources have wide-ranging application in studies of the normal and diseased brain.

  • 219.
    Zou, Rongfeng
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Guanglin, Kuang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China..
    Nordberg, Agneta
    Karolinska Univ Hosp, Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res,Clin Geriatr Neo & Theme Aging, S-14183 Huddinge, Sweden..
    Långström, Bengt
    Uppsala Univ, Phys Organ Chem, Dept Chem, BMC, S-75123 Uppsala, Sweden..
    Tu, Yaoquan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Free Energy Profile for Penetration of Pittsburgh Compound-B into the Amyloid beta Fibril2019In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 10, no 3, p. 1783-1790Article in journal (Refereed)
    Abstract [en]

    The amyloid beta (A beta) fibril is a hallmark of Alzheimer's disease (AD) and has therefore served as an important target for early diagnosis of AD. The Pittsburgh Compound-B (PiB) is one of the most famous positron emission tomography (PET) tracers commonly used for in vivo detection of A beta fibrils. Many theoretical studies have predicted the existence of various core binding sites with different microenvironments for probes binding to the A beta fibril. However, little attention has been devoted to how the probes actually penetrate into the different core binding sites. In this study, an integrated molecular modeling scheme is used to study the penetration of PiB into the core binding sites of the A beta(1-42) fibril structure recently obtained by cryogenic electron microscopy. We find that there are two core binding sites for PiB with dramatic differences in cavity size and microenvironment properties, and furthermore that the penetration of PiB into site-1 is energetically prohibitive, whereas the penetration into site 2 is much more favorable. Therefore, the binding capacity at site-2 may be larger than that at site-1 despite its lower binding affinity. Our results thus suggest that site-2 may be a major binding site for PiB binding to A beta fibril and emphasize the importance to adopt a full dynamical picture when studying tracer fibril binding problems in general, something that in turn can be used to guide the development of tracers with higher affinity and selectivity for the A beta fibril.

  • 220. Åkerman, S.
    et al.
    Lindeberg, Tony
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Roland, P.
    Surface Model Generation and Segmentation of the Human Celebral Cortex for the Construction of Unfolded Cortical Maps1996In: Proc. 2nd International Conference on Functional Mapping of the Human Brain: HBM'96, published in Neuroimage, volume 3, number 3, 1996, p. S126-S126Conference paper (Refereed)
    Abstract [en]

    Representing the shape of the human cerebral cortex arises as a basic subproblem in several areas of brain science, such as when describing the anatomy of the cortex and when relating functional measurements to cortical regions. 

    Most current methods for building such representions of the cortical surface are either based on contours from two-dimensional cross sections or landmarks that have been obtained manually.

    In this article, we outline a methodology for semi-automatic contruction of a solely surface based representation of the human cerebral cortex in vivo for subsequent generation of  (unfolded) two-dimensional brain maps.

    The method is based on input data in the form of three-dimensional NMR images, and comprises the following main steps:

    • suppression of disturbing fine-scale structures by linear and non-linear scale-space techniques,
    • generation of a triangulated surface representation based on either iso-surfaces or three-dimensional edge detection,
    • division of the surface model into smaller segments based on differential invariants computed from the image data.

    When constructing an unfolded (flattened) surface representation, the instrinsic curvature of the cortex means that such a unfolding cannot be done without introducing distortions. To reduce this problem, we propose to cut the surface into smaller parts, where a ridge detector acts as guideline, and then unfold each patch individually, so as to obtain low distortions.

    Having a solely surface based representation of the cortex and expressing the image operations using multi-scale differential invariants in terms of scale-space derivatives as done in this work is a natural choice both in terms of conceptual and algorithmic simplicity. Moreover, explicitly handling the multi-scale nature of the data is necessary to obtain robust results.

2345 201 - 220 of 220
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