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  • 151.
    Nair, Anu G.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Gutierrez-Arenas, Omar
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Eriksson, Olivia
    Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm.
    Hällgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Can MSNs listen to the cholinergic pause via M4R?Manuscript (preprint) (Other academic)
  • 152.
    Nair, Anu G.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Gutierrez-Arenas, Omar
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Eriksson, Olivia
    Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm.
    Jauhiainen, Alexandra
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
    Blackwell, Kim T.
    Krasnow Institute for Advanced Study, George Mason University, Fairfax, VA, USA.
    Hällgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Modeling Intracellular Signaling Underlying Striatal Function in Health and Disease2014In: Computational Neuroscience / [ed] Blackwell, K.T., Elsevier, 2014, Vol. 123, p. 277-304Chapter in book (Refereed)
    Abstract [en]

    Striatum, which is the input nucleus of the basal ganglia, integrates cortical and thalamic glutamatergic inputs with dopaminergic afferents from the substantia nigra pars cornpacta. The combination of dopamine and glutamate strongly modulates molecular and cellular properties of striatal neurons and the strength of corticostriatal synapses. These actions are performed via intracellular signaling networks, containing several intertwined feedback loops. Understanding the role of dopamine and other neuromodulators requires the development of quantitative dynamical models for describing the intracellular signaling, in order to provide precise unambiguous descriptions and quantitative predictions. Building such models requires integration of data from multiple data sources containing information regarding the molecular interactions, the strength of these interactions, and the subcellular localization of the molecules. Due to the uncertainty, variability, and sparseness of these data, parameter estimation techniques are critical for inferring or constraining the unknown parameters, and sensitivity analysis evaluates which parameters are most critical for a given observed macroscopic behavior. Here, we briefly review the modeling approaches and tools that have been used to investigate biochemical signaling in the striatum, along with some of the models built around striatum. We also suggest a future direction for the development of such models from the, now becoming abundant, high-throughput data.

  • 153.
    Nair, Anu G.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Manipal Univ, India.
    Gutierrez-Arenas, Omar
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Eriksson, Olivia
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Vincent, Pierre
    Hellgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Univ, Sweden; Karolinska Inst, Sweden.
    Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 41, p. 14017-14030Article in journal (Refereed)
    Abstract [en]

    Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/o and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.

  • 154. Najac, Marion
    et al.
    Diez, Alvaro
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Benito, Nuria
    Charpak, Serge
    De Saint Jan, Didier
    Intraglomerular Lateral Inhibition Promotes Spike Timing Variability in Principal Neurons of the Olfactory Bulb2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 10, p. 4319-4331Article in journal (Refereed)
    Abstract [en]

    The activity of mitral and tufted cells, the principal neurons of the olfactory bulb, is modulated by several classes of interneurons. Among them, diverse periglomerular (PG) cell types interact with the apical dendrites of mitral and tufted cells inside glomeruli at the first stage of olfactory processing. We used paired recording in olfactory bulb slices and two-photon targeted patch-clamp recording in vivo to characterize the properties and connections of a genetically identified population of PG cells expressing enhanced yellow fluorescent protein (EYFP) under the control of the Kv3.1 potassium channel promoter. Kv3.1–EYFP+ PG cells are axonless and monoglomerular neurons that constitute ∼30% of all PG cells and include calbindin-expressing neurons. They respond to an olfactory nerve stimulation with a short barrage of excitatory inputs mediated by mitral, tufted, and external tufted cells, and, in turn, they indiscriminately release GABA onto principal neurons. They are activated by even the weakest olfactory nerve input or by the discharge of a single principal neuron in slices and at each respiration cycle in anesthetized mice. They participate in a fast-onset intraglomerular lateral inhibition between principal neurons from the same glomerulus, a circuit that reduces the firing rate and promotes spike timing variability in mitral cells. Recordings in other PG cell subtypes suggest that this pathway predominates in generating glomerular inhibition. Intraglomerular lateral inhibition may play a key role in olfactory processing by reducing the similarity of principal cells discharge in response to the same incoming input.

  • 155. Nilsson, Mats E.
    et al.
    Schenkman, Bo N.
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH. Université Catholique de Louvain, Belgium.
    Blind people are more sensitive than sighted people to binaural sound-location cues, particularly inter-aural level differences2016In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 332, p. 223-232Article in journal (Refereed)
    Abstract [en]

    Blind people use auditory information to locate sound sources and sound-reflecting objects (echolocation). Sound source localization benefits from the hearing system's ability to suppress distracting sound reflections, whereas echolocation would benefit from "unsuppressing" these reflections. To clarify how these potentially conflicting aspects of spatial hearing interact in blind versus sighted listeners, we measured discrimination thresholds for two binaural location cues: inter-aural level differences (ILDs) and inter-aural time differences (ITDs). The ILDs or ITDs were present in single clicks, in the leading component of click pairs, or in the lagging component of click pairs, exploiting processes related to both sound source localization and echolocation. We tested 23 blind (mean age = 54 y), 23 sighted-age matched (mean age = 54 y), and 42 sighted-young (mean age = 26 y) listeners. The results suggested greater ILD sensitivity for blind than for sighted listeners. The blind group's superiority was particularly evident for ILD-lag-click discrimination, suggesting not only enhanced ILD sensitivity in general but also increased ability to unsuppress lagging clicks. This may be related to the blind person's experience of localizing reflected sounds, for which ILDs may be more efficient than ITDs. On the ITD-discrimination tasks, the blind listeners performed better than the sighted age-matched listeners, but not better than the sighted young listeners. ITD sensitivity declines with age, and the equal performance of the blind listeners compared to a group of substantially younger listeners is consistent with the notion that blind people's experience may offset age-related decline in ITD sensitivity.

  • 156.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Affinity proteomics for array based profiling of autoantibody repertoires.2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 69-70Article in journal (Other academic)
  • 157. Nordblom, Jonathan
    et al.
    Persson, Jonas K. E.
    Åberg, Jonas
    Blom, Hans
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Engqvist, Håkan
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Sjödahl, Johan
    Josephson, Anna
    Frostell, Arvid
    Thams, Sebastian
    Brundin, Lou
    Svensson, Mikael
    Mattsson, Per
    FGF1 containing biodegradable device with peripheral nerve grafts induces corticospinal tract regeneration and motor evoked potentials after spinal cord resection2012In: Restorative Neurology and Neuroscience, ISSN 0922-6028, E-ISSN 1878-3627, Vol. 30, no 2, p. 91-102Article in journal (Refereed)
    Abstract [en]

    Purpose: Repairing the spinal cord with peripheral nerve grafts (PNG) and adjuvant acidic fibroblast growth factor (FGF1) has previously resulted in partial functional recovery. To aid microsurgical placement of PNGs, a graft holder device was previously developed by our group. In hope for a translational development we now investigate a new biodegradable graft holder device containing PNGs with or without FGF1. Methods: Rats were subjected to a T11 spinal cord resection with subsequent repair using twelve white-to-grey matter oriented PNGs prepositioned in a biodegradable device with or without slow release of FGF1. Animals were evaluated with BBB-score, electrophysiology and immunohistochemistry including anterograde BDA tracing. Results: Motor evoked potentials (MEP) in the lower limb reappeared at 20 weeks after grafting. MEP responses were further improved in the group treated with adjuvant FGF1. Reappearance of MEPs was paralleled by NF-positive fibers and anterogradely traced corticospinal fibers distal to the injury. BBB-scores improved in repaired animals. Conclusions: The results continue to support that the combination of PNGs and FGF1 may be a regeneration strategy to reinnervate the caudal spinal cord. The new device induced robust MEPs augmented by FGF1, and may be considered for translational research.

  • 158.
    Nyberg, Tobias
    et al.
    Nippon Telegraph and Telephone Corporation.
    Shimada, Akiyoshi
    Nippon Telegraph and Telephone Corporation.
    Torimitsu, Keiichi
    Nippon Telegraph and Telephone Corporation.
    Ion conducting polymer microelectrodes for interfacing with neural networks2007In: Journal of Neuroscience Methods, ISSN 0165-0270, E-ISSN 1872-678X, Vol. 160, no 1, p. 16-25Article in journal (Refereed)
    Abstract [en]

    We have examined the stimulation and recording properties of conjugated polymer microelectrode arrays as interfaces with neural networks of dissociated cortical cells. In particular the stimulation properties were investigated as a means of supplying a neural network with information. The stimulation efficiency at low stimulation voltages was evaluated and referenced to bare indium tin oxide (ITO) electrodes. The polymer electrodes were electrochemically polymerized from a blend of poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) and ethylenedioxythiophene (EDOT) onto ITO microelectrodes. Dissociated cortical cells were then plated on the electrodes and cultivated to form neural networks. Polymer electrode stimulation evoked a much greater response from the network than stimulation from ITO electrodes. Neural interfaces using polymer electrodes could be maintained for several months.

  • 159.
    Olsson, T.
    et al.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Huang, J.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Hellström, Cecilia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Tengvall, K.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Kammer, P.
    German Canc Res Ctr, Heidelberg, Germany..
    Bistrom, M.
    Umea Univ, Dept Pharmacol & Clin Neurosci, Umea, Sweden..
    Bomfim, I. Lima
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Stridh, P.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Butt, J.
    German Canc Res Ctr, Heidellberg, Germany..
    Nicole, B.
    German Canc Res Ctr, Heidelberg, Germany..
    Michel, A.
    German Canc Res Ctr, Heidelberg, Germany..
    Ayoglu, Burcu
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Lundberg, K.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Lundberg, I.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Olafsson, S.
    deCode Genet, Reykavik, Iceland..
    Jonsdottir, I.
    deCode Genet, Reykavik, Iceland..
    Stefansson, K.
    deCode Genet, Reykavik, Iceland..
    Dilthey, A.
    Welcome Trust Ctr Human Genet, Oxford, England..
    Hillert, J.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Alfredsson, L.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Sundstrom, P.
    Umea Univ, Pharmacol & Clin Neurosci, Umea, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Waterboer, T.
    German Canc Res Ctr, Heidelberg, Germany..
    Kockum, I.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Molecular mimicry between the autoantigen Anoctamin 2 and Epstein Barr virus nuclear antigen 1 associates with increased risk for multiple sclerosis2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 64-64Article in journal (Other academic)
  • 160. Paille, Vincent
    et al.
    Fino, Elodie
    Du, Kai
    Morera-Herreras, Teresa
    Perez, Sylvie
    Hällgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Venance, Laurent
    GABAergic Circuits Control Spike-Timing-Dependent Plasticity2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 22, p. 9353-9363Article in journal (Refereed)
    Abstract [en]

    The spike-timing-dependent plasticity (STDP), a synaptic learning rule for encoding learning and memory, relies on relative timing of neuronal activity on either side of the synapse. GABAergic signaling has been shown to control neuronal excitability and consequently the spike timing, but whether GABAergic circuits rule the STDP remained unknown. Here we show that GABAergic signaling governs the polarity of STDP, because blockade of GABA(A) receptors was able to completely reverse the temporal order of plasticity at corticostriatal synapses in rats and mice. GABA controls the polarity of STDP in both striatopallidal and striatonigral output neurons. Biophysical simulations and experimental investigations suggest that GABA controls STDP polarity through depolarizing effects at distal dendrites of striatal output neurons by modifying the balance of two calcium sources, NMDARs and voltage-sensitive calcium channels. These findings establish a central role for GABAergic circuits in shaping STDP and suggest that GABA could operate as a Hebbian/anti-Hebbian switch.

  • 161.
    Papiol, Sergi
    et al.
    Univ Munich, Inst Psychiat Phen & Genom, Med Ctr, Munich, Germany..
    Just, David
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kannaiyan, Nirmal
    Univ Munich, Inst Psychiat Phen & Genom, Med Ctr, Munich, Germany.;Univ Munich, Med Ctr, Mol & Behav Neurobiol, Munich, Germany..
    Anderson-Schmidt, Heike
    Univ Med Ctr Goettingen, Gottingen, Germany..
    Budde, Monika
    Univ Munich, Inst Psychiat Phen & Genom, Med Ctr, Munich, Germany..
    Gade, Katrin
    Univ Munich, Inst Psychiat Phen & Genom, Med Ctr, Munich, Germany..
    Heilbronner, Urs
    Univ Munich, Inst Psychiat Phen & Genom, Med Ctr, Munich, Germany..
    Rossner, Moritz
    Univ Munich, Med Ctr, Mol & Behav Neurobiol, Munich, Germany..
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Schulze, Thomas
    Univ Munich, Inst Psychiat Phen & Genom, Med Ctr, Munich, Germany..
    HIGH-THROUGHPUT ANTIBODY-BASED PROFILING OF SERUM IN SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS: AN INTEGRATIVE GENOMICS-PROTEOMICS PILOT STUDY2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, p. S993-S994Article in journal (Other academic)
  • 162.
    Petersson, Marcus E.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Role of TRP channels in dendritic integration and subthreshold membrane potential plateaus2011In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 12, no Suppl 1, p. P110-Article in journal (Other academic)
  • 163.
    Petersson, Marcus E.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Stable subthreshold dendritic membrane potential plateaus maintained by TRP currents2011Conference paper (Refereed)
  • 164.
    Petersson, Marcus E.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    TRPC channels activated by group 1 mG1uR in Entorhinal pyramidal neurons support integration of low frequency (<10 Hz) synaptic inputs2009In: BMC Neuroscience, ISSN 1471-2202, Vol. 10, no Suppl 1, p. P26-Article in journal (Refereed)
  • 165.
    Petersson, Marcus E.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Yoshida, Motoharu
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Low-frequency summation of synaptically activated transient receptor potential channel-mediated depolarizations2011In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 34, no 4, p. 578-593Article in journal (Refereed)
    Abstract [en]

    Neurons sum their input by spatial and temporal integration. Temporally, presynaptic firing rates are converted to dendritic membrane depolarizations by postsynaptic receptors and ion channels. In several regions of the brain, including higher association areas, the majority of firing rates are low. For rates below 20 Hz, the ionotropic receptors alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor will not produce effective temporal summation. We hypothesized that depolarization mediated by transient receptor potential (TRP) channels activated by metabotropic glutamate receptors would be more effective, owing to their slow kinetics. On the basis of voltage-clamp and current-clamp recordings from a rat slice preparation, we constructed a computational model of the TRP channel and its intracellular activation pathway, including the metabotropic glutamate receptor. We show that synaptic input frequencies down to 3-4 Hz and inputs consisting of as few as three to five pulses can be effectively summed. We further show that the time constant of integration increases with increasing stimulation frequency and duration. We suggest that the temporal summation characteristics of TRP channels may be important at distal dendritic arbors, where spatial summation is limited by the number of concurrently active synapses. It may be particularly important in regions characterized by low and irregular rates.

  • 166.
    Petersson, Marcus
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Long-lasting small-amplitude TRP-mediated dendritic depolarizations in CA1 pyramidal neurons are intrinsically stable and originate from distal tuft regions2012In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 36, no 7, p. 2917-2925Article in journal (Refereed)
    Abstract [en]

    In several regions of the nervous system, neurons display bi- or multistable intrinsic properties. Such stable states may be subthreshold and long-lasting, and can appear as a sustained afterdepolarization. In hippocampal CA1 pyramidal neurons, small-amplitude (1 mV) long-lasting (seconds) afterdepolarizations have been reported and are thought to depend on calcium-activated nonselective (CAN) currents recently identified as transient receptor potential (TRP) channels. Continuing our previous experimental and computational work on synaptically metabotropic glutamate receptor (mGluR)-activated TRP currents, we here explore small-amplitude long-lasting depolarizations in a detailed multicompartmental model of a CA1 pyramidal neuron. We confirm a previous hypothesis suggesting that the depolarization results from an interplay of TRP and voltage-gated calcium channels, and contribute to the understanding of the depolarization in several ways. Specifically, we show that: (i) the long-lasting depolarization may be intrinsically stable to weak excitatory and inhibitory input, (ii) the phenomenon is essentially located in distal apical dendrites, (iii) induction is facilitated if simultaneous input arrives at several dendritic branches, and if calcium- and/or mGluR-evoked signals undergo summation, suggesting that both spatial and temporal synaptic summation might be required for the depolarization to occur and (iv) we also show that the integration of inputs to oblique dendrites is strongly modulated by the presence of small-amplitude long-lasting depolarizations in distal tuft dendrites. To conclude, we suggest that small-amplitude long-lasting dendritic depolarizations may contribute to sustaining neural information during behavioural tasks in cases where information is separated in time, as in trace conditioning and delay tasks.

  • 167.
    Petersson, Marcus
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Obreja, Otilia
    Lampert, Angelika
    Carr, Richard
    Schmelz, Martin
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    C-type peripheral nociceptors differ in axonal ion channel densitiesManuscript (preprint) (Other academic)
  • 168.
    Platten, M.
    et al.
    KTH. Karolinska Inst, Stockholm, Sweden.;Royal Inst Technol, Stockholm, Sweden..
    Martola, J.
    Karolinska Inst, Stockholm, Sweden..
    Fink, K.
    Karolinska Inst, Stockholm, Sweden..
    Granberg, T.
    Karolinska Inst, Stockholm, Sweden..
    Precision of manual vs. automated corpus callosum atrophy measurements in multiple sclerosis2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 209-209Article in journal (Other academic)
  • 169. Raikov, Ivan
    et al.
    Cannon, Robert
    Clewley, Robert
    Cornelis, Hugo
    Davison, Andrew
    De Schutter, Erik
    Djurfeldt, Mikael
    Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan.
    Gleeson, Padraig
    Gorchetnikov, Anatoli
    Plesser, Hans Ekkehard
    Hill, Sean
    Hines, Michael
    Kriener, Birgit
    Le Franc, Yann
    Lo, Chung-Chan
    Morrison, Abigail
    Muller, Eilif
    Ray, Subhasis
    Schwabe, Lars
    Szatmary, Botond
    NineML: the network interchange for neuroscience modeling language2011In: Twentieth Annual Computational Neuroscience Meeting: CNS*2011 / [ed] Jean-Marc Fellous and Astrid Prinz, Springer Science+Business Media B.V., 2011Conference paper (Refereed)
  • 170.
    Ramanujam, R.
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.). Karolinska Inst, Sweden.
    Hedstrm, A. K.
    Manouchehrinia, A.
    Alfredsson, L.
    Olsson, T.
    Bottai, M.
    Hillert, J.
    Beneficial effect of smoking cessation on multiple sclerosis prognosis2015In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 21, p. 164-164Article in journal (Other academic)
  • 171. Roland, P
    et al.
    Svensson, Gert
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Lindeberg, Tony
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Risch, T
    Baumann, P
    Dehmel, A
    Fredriksson, Jesper
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Halldorson, Hjörleifur
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Forsberg, Lars
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Young, J
    Zilles, Karl
    A database generator for human brain imaging2001In: TINS - Trends in Neurosciences, ISSN 0166-2236, E-ISSN 1878-108X, Vol. 24, no 10, p. 562-564Article in journal (Refereed)
    Abstract [en]

    Sharing scientific data containing complex information requires new concepts and new technology. NEUROGENERATOR is a database generator for the neuroimaging community. A database generator is a database that generates new databases. The scientists submit raw PET and fMRI data to NEUROGENERATOR, which then processes the data in a uniform way to create databases of homogenous data suitable for data sharing, met-analysis and modelling the human brain at the systems level. These databases are then distributed to the scientists.

  • 172. Rosbacke, M.
    et al.
    Lindeberg, Tony
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Björkman, E.
    Roland, P. E.
    Evaluation of using absolute versus relative base level when analyzing brain activation images using the scale-space primal sketch2001In: Medical Image Analysis, ISSN 1361-8415, E-ISSN 1361-8423, Vol. 5, no 2, p. 89-110Article in journal (Refereed)
    Abstract [en]

    A dominant approach to brain mapping is to define functional regions in the brain by analyzing images of brain activation obtained from positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). This paper presents an evaluation of using one such tool, called the scale-space primal sketch, for brain activation analysis. A comparison is made concerning two possible definitions of a significance measure of blob structures in scale-space, where local contrast is measured either relative to a local or global reference level. Experiments on real brain data show that (i) the global approach with absolute base level has a higher degree of correspondence to a traditional statistical method than a local approach with relative base level, and that (ii) the global approach with absolute base level gives a higher significance to small blobs that are superimposed on larger scale structures, whereas the significance of isolated blobs largely remains unaffected. Relative to previously reported works, the following two technical improvements are also presented. (i) A post-processing tool is introduced for merging blobs that are multiple responses to image structures. This simplifies automated analysis from the scale-space primal sketch. (ii) A new approach is introduced for scale-space normalization of the significance measure, by collecting reference statistics of residual noise images obtained from the general Linear model.

  • 173.
    Roudi, Yasser
    et al.
    KTH, Centres, Nordic Institute for Theoretical Physics NORDITA.
    Dunn, B.
    Hertz, John A.
    KTH, Centres, Nordic Institute for Theoretical Physics NORDITA.
    Multi-neuronal activity and functional connectivity in cell assemblies2015In: Current Opinion in Neurobiology, ISSN 0959-4388, E-ISSN 1873-6882, Vol. 32, p. 38-44Article in journal (Refereed)
    Abstract [en]

    Our ability to collect large amounts of data from many cells has been paralleled by the development of powerful statistical models for extracting information from this data. Here we discuss how the activity of cell assemblies can be analyzed using these models, focusing on the generalized linear models and the maximum entropy models and describing a number of recent studies that employ these tools for analyzing multi-neuronal activity. We show results from simulations comparing inferred functional connectivity, pairwise correlations and the real synaptic connections in simulated networks demonstrating the power of statistical models in inferring functional connectivity. Further development of network reconstruction techniques based on statistical models should lead to more powerful methods of understanding functional anatomy of cell assemblies.

  • 174.
    Runnerstam, Magnus
    et al.
    Department of Neurosurgery, Sahlgrenska University Hospital.
    Bao, Feng
    Department of Anatomy and Cell Biology, Göteborg University.
    Huang, Yinglai
    Department of Anatomy and Cell Biology, Göteborg University.
    Shi, Jingshan
    Department of Anatomy and Cell Biology, Göteborg Universit.
    Gutierrez, Elena
    Chalmers University of Technology, Crash Safety Division.
    Hamberger, Anders
    Department of Anatomy and Cell Biology, Göteborg University.
    Hansson, Hans-Arne
    Department of Anatomy and Cell Biology, Göteborg University.
    Viano, David
    Crash Safety Division, Chalmers University of Technology.
    Haglid, Kenneth
    Department of Anatomy and Cell Biology, Göteborg University.
    A New Model for Diffuse Brain Injury by Rotational Acceleration: II. Effects on Extracellular Glutamate, Intracranial Pressure, and Neuronal Apoptosis2001In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 18, no 3, p. 259-273Article in journal (Refereed)
  • 175. Sahasranamam, Ajith
    et al.
    Vlachos, Ioannis
    Aertsen, Ad
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). Bernstein Center Freiburg, University of Freiburg, Freiburg, Germany.
    Dynamical state of the network determines the efficacy of single neuron properties in shaping the network activity2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 26029Article in journal (Refereed)
    Abstract [en]

    Spike patterns are among the most common electrophysiological descriptors of neuron types. Surprisingly, it is not clear how the diversity in firing patterns of the neurons in a network affects its activity dynamics. Here, we introduce the state-dependent stochastic bursting neuron model allowing for a change in its firing patterns independent of changes in its input-output firing rate relationship. Using this model, we show that the effect of single neuron spiking on the network dynamics is contingent on the network activity state. While spike bursting can both generate and disrupt oscillations, these patterns are ineffective in large regions of the network state space in changing the network activity qualitatively. Finally, we show that when single-neuron properties are made dependent on the population activity, a hysteresis like dynamics emerges. This novel phenomenon has important implications for determining the network response to time-varying inputs and for the network sensitivity at different operating points.

  • 176.
    Sandberg, Anders
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    An autocatalytic model of STDP timing from slow calcium-dependent signals2005In: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 65-66, p. 603-608Article in journal (Refereed)
    Abstract [en]

    Data of spike timing-dependent plasticity (STDP) show a sharp temporal transition between potentiation and depression despite a relatively slow time course of calcium concentration. We show how autocatalytic amplification of initial concentration differences can enable a high degree of temporal selectivity and produce the sharp STDP weight change curve despite having a relatively slow time constant. This simple model is robust to parameter changes, noise and details of the model. The model correctly predicts the location of the maximum and minimum for STDP at +/- 10ms from coincidence.

  • 177.
    Schnepel, Philipp
    et al.
    University of California Berkeley, USA.
    Kumar, Arvind
    Bernstein Center Freiburg, Germany and University of Freiburg, Germany.
    Zohar, Mihael
    University of Freiburg, Germany.
    Aertsen, Ad
    University of Freiburg, Germany.
    Boucsein, Clemens
    University of Freiburg, Germany.
    Physiology and impact of horizontal connections in rat neocortex2014In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199Article in journal (Refereed)
    Abstract [en]

    Cortical information processing at the cellular level has predominantly been studied in local networks, which are dominated by strong vertical connectivity between layers. However, recent studies suggest that the bulk of axons targeting pyramidal neurons most likely originate from outside this local range, emphasizing the importance of horizontal connections. We mapped a subset of these connections to L5B pyramidal neurons in rat somatosensory cortex with photostimulation, identifying intact projections up to a lateral distance of 2 mm. Our estimates of the spatial distribution of cells presynaptic to L5B pyramids support the idea that the majority is located outside the local volume. The synaptic physiology of horizontal connections does not differ markedly from that of local connections, whereas the layer and cell-type-dependent pattern of innervation does. Apart from L2/3, L6A provides a strong source of horizontal connections. Implementing our data into a spiking neuronal network model shows that more horizontal connections promote robust asynchronous ongoing activity states and reduce noise correlations in stimulus-induced activity.

  • 178.
    Sedzik, Jan
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology, Transport Phenomena.
    Jastrzebski, Jan Pawel
    High-Resolution Structural Model of Porcine P2 Myelin Membrane Protein With Associated Fatty Acid Ligand: Fact or Artifact?2011In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 89, no 6, p. 909-920Article in journal (Refereed)
    Abstract [en]

    Myelin membrane is a biological complex of glial cells origin; it is composed of 25% (w/w) proteins and 75% lipids, and more than 300 proteins are associated with central nervous system myelin (for peripheral nervous system myelin, such data are lacking). Myelin plays an important role in maintaining propagation of nerve signals. To uncover the nature of propagation phenomena, it is essential to study biochemistry of myelin proteins and lipids, myelin composition, and myelin structure. Nearly all myelin proteins are like antigens, causing clinically well-defined devastating diseases; multiple sclerosis and Guillain-Barre syndrome are two of them. In this article, a high-resolution study (1.8 angstrom) of porcine myelin P2 protein is presented. Myelin was purified from porcine intradural spinal roots, which were stored at -80 degrees C for 10 years before myelin and P2 protein were purified (spinal roots were a gift of Prof. Kunio Kitamura, Saitama Medical School). The three-dimensional structural analysis uncovered embedded 18-carbons-long fatty acid. Some speculative interpretation is presented, to uncover how this ligand of fatty acid may form cholesterol ester and stabilize the myelin structure or form simple raft microdomain. Protein crystallography indicates that the ligand may be 18-carbons-long fatty acid. This is unlike previous work with mass spectrometry, in which three ligands were determined. In other protein crystallography-based studies of P2 (bovine), an oleic fatty acid was suggested, but, for recombinant (human) protein, palmitic acid was found. There is no fatty acid ligand in equine P2 protein.

  • 179.
    Sedzik, Jan
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemical Engineering and Technology.
    Jastrzebski, Jan Pawel
    Grandis, Marina
    Glycans of Myelin Proteins2015In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 93, no 1, p. 1-18Article, review/survey (Refereed)
    Abstract [en]

    Human P0 is the main myelin glycoprotein of the peripheral nervous system. It can bind six different glycans, all linked to Asn(93), the unique glycosylation site. Other myelin glycoproteins, also with a single glycosylation site (PMP22 at Asn(36), MOG at Asn(31)), bind only one glycan. The MAG has 10 glycosylation sites; the glycoprotein OMgp has 11 glycosylation sites. Aside from P0, no comprehensive data are available on other myelin glycoproteins. Here we review and analyze all published data on the physicochemical structure of the glycans linked to P0, PMP22, MOG, and MAG. Most data concern bovine P0, whose glycan moieties have an MW ranging from 1,294.56 Da (GP3) to 2,279.94 Da (GP5). The pI of glycosylated P0 protein varies from pH 9.32 to 9.46. The most charged glycan is MS2 containing three sulfate groups and one glucuronic acid; whereas the least charged one is the BA2 residue. All glycans contain one fucose and one galactose. The most mannose rich are the glycans MS2 and GP4, each of them has four mannoses; OPPE1 contains five N-acetylglucosamines and one sulfated glucuronic acid; GP4 contains one sialic acid. Furthermore, human P0 variants causing both gain and loss of glycosylation have been described and cause peripheral neuropathies with variable clinical severity. In particular, the substitution (TM)-M-95 is a very common in Europe and is associated with a late-onset axonal neuropathy. Although peripheral myelin is made up largely of glycoproteins, mutations altering glycosylation have been described only in P0. This attractive avenue of research requires further study.

  • 180. Shi, Tie-Jun Sten
    et al.
    Xiang, Qiong
    Zhang, Ming-Dong
    Tortoriello, Giuseppe
    Hammarberg, Henrik
    Mulder, Jan
    Fried, Kaj
    Wagner, Ludwig
    Josephson, Anna
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Harkany, Tibor
    Hökfelt, Tomas
    Secretagogin is expressed in sensory CGRP neurons and in spinal cord of mouse and complements other calcium-binding proteins, with a note on rat and human2012In: Molecular Pain, ISSN 1744-8069, E-ISSN 1744-8069, Vol. 8, p. 80-Article in journal (Refereed)
    Abstract [en]

    Background: Secretagogin (Scgn), a member of the EF-hand calcium-binding protein (CaBP) superfamily, has recently been found in subsets of developing and adult neurons. Here, we have analyzed the expression of Scgn in dorsal root ganglia (DRGs) and trigeminal ganglia (TGs), and in spinal cord of mouse at the mRNA and protein levels, and in comparison to the well-known CaBPs, calbindin D-28k, parvalbumin and calretinin. Rat DRGs, TGs and spinal cord, as well as human DRGs and spinal cord were used to reveal phylogenetic variations. Results: We found Scgn mRNA expressed in mouse and human DRGs and in mouse ventral spinal cord. Our immunohistochemical data showed a complementary distribution of Scgn and the three CaBPs in mouse DRG neurons and spinal cord. Scgn was expressed in similar to 7% of all mouse DRG neuron profiles, mainly small ones and almost exclusively co-localized with calcitonin gene-related peptide (CGRP). This co-localization was also seen in human, but not in rat DRGs. Scgn could be detected in the mouse sciatic nerve and accumulated proximal to its constriction. In mouse spinal cord, Scgn-positive neuronal cell bodies and fibers were found in gray matter, especially in the dorsal horn, with particularly high concentrations of fibers in the superficial laminae, as well as in cell bodies in inner lamina II and in some other laminae. A dense Scgn-positive fiber network and some small cell bodies were also found in the superficial dorsal horn of humans. In the ventral horn, a small number of neurons were Scgn-positive in mouse but not rat, confirming mRNA distribution. Both in mouse and rat, a subset of TG neurons contained Scgn. Dorsal rhizotomy strongly reduced Scgn fiber staining in the dorsal horn. Peripheral axotomy did not clearly affect Scgn expression in DRGs, dorsal horn or ventral horn neurons in mouse. Conclusions: Scgn is a CaBP expressed in a subpopulation of nociceptive DRG neurons and their processes in the dorsal horn of mouse, human and rat, the former two co-expressing CGRP, as well as in dorsal horn neurons in all three species. Functional implications of these findings include the cellular refinement of sensory information, in particular during the processing of pain.

  • 181.
    Silverstein, David N.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST).
    Investigations of neural attractor dynamics in human visual awareness2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    What we see, how we see it and what emotions may arise from stimuli has long been studied by philosophers, psychologists, medical doctors and neuroscientists. This thesis work investigates a particular view on the possible dynamics, utilizing computational models of spiking neural attractor networks. From neurological studies on humans and other primates, we know visual perception and recognition of objects occur partly along the visual ventral stream, from V1 to V2, V4, IT and downstream to other areas. This visual awareness can be both conscious and unconscious and may also trigger an emotional response. As seen from many psychophysical experiments in backward masking (BM) and attentional blink (AB), some spatial and temporal dynamics can determine what becomes visually conscious and what does not. To explore this computationally, biophysical models of BM and AB were implemented and simulated to mimic human experiments, with the assumption that neural assemblies as attractor networks activate and propagate along the ventral stream and beyond. It was observed that attractor interference between percepts in sensory and associative cortex can occur during this activity. During typical human AB experimental trials in which two expected target symbols amongst distractors are presented less than 500 ms apart, the second target is often not reported as seen. When simulating this paradigm as two expected target neural attractors amongst distractors, it was observed in the present work that an initial attractor in associative cortex can impede the activation and propagation of a following attractor, which mimics missing conscious perception of the second target. It was also observed that simulating the presence of benzodiazepines (GABA agonists) will slow cortical dynamics and increase the AB, as previously shown in human experiments.

    During typical human BM experimental trials in which a brief target stimulus is followed by a masking stimulus after a short interval of less than 100 ms, recognition of the target can be impaired when in close spatial proximity. When simulating this paradigm using a biophysical model of V1 and V2 with feedforward and feedback connections, attractor targets were activated in V1 before imposition of a proximal metacontrast mask. If an activating target attractor in V1 is quiesced enough with lateral inhibition from a mask, or not reinforced by recurrent feedback from feedforward activation in V2, it is more likely to burn out before becoming fully active and progressing through V2 and beyond. BM was also simulated with an increasing stimulus interval and with the presence and absence of feedback activity. This showed that recurrent feedback diminishes BM effects and can make conscious perception more likely.

    To better understand possible emotional components of visual perception and early regulation, visual signaling pathways to the amygdala were investigated and proposed for emotional salience and the possible onset of fear. While one subcortical and likely unconscious pathway (before amydala efferent signaling) was affirmed via the superior colliculus and pulvinar, four others traversed through the ventral stream. One traversed though IT on recognition, another via the OFC on conditioning, and two other possibly conscious pathways traversed though the parietal and then prefrontal cortex, one excitatory pathway via the ventral-medial area and one regulatory pathway via the ventral-lateral area. Predicted latencies were determined for these signaling pathways, which can be experimentally testable. The conscious feeling of fear itself may not occur until after interoceptive inspection.

    A pathology of attractor dynamics was also investigated, which can occur from the presence of a brain tumor in white matter. Due to degradation from tumor invasion of white matter projections between two simulated neocortical patches, information transfer between separate neural attractors degraded, leading first to recall errors and later to epileptic-like activity. Neural plasticity could partially compensate up to a point, before transmission failure. This suggests that once epileptic seizures start in glioma patients, compensatory plasticity may already be exhausted. Interestingly, the presence of additional noise could also partially compensate for white matter loss.

  • 182.
    Sjöstedt, Evelina
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bollerslev, Jens
    Mulder, Jan
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lindskog, Cecilia
    Ponten, Fredrik
    Casar-Borota, Olivera
    A specific antibody to detect transcription factor T-Pit: a reliable marker of corticotroph cell differentiation and a tool to improve the classification of pituitary neuroendocrine tumours2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 134, no 4, p. 675-677Article in journal (Refereed)
  • 183.
    Sjöstedt, Evelina
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Fagerberg, Linn
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Mitsios, Nicholas
    Karolinska Institutet.
    Adori, Csaba
    Karolinska Institutet.
    Oksvold, Per
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Limiszewka, Agnieszka
    Karolinska Insititutet.
    Kheder, Sania
    Karolinska Insitutiet.
    Norradin, Feria Hikmet
    Department of Immunology, Genetics and Pathology, Uppsala University.
    Lindskog, Cecilia
    Department of Immunology, Genetics and Pathology, Uppsala University.
    Pontén, Fredrik
    Department of immunology, genetics and pathology, Uppsala Univesity.
    Hökfelt, Tomas
    Karolinska Institutet.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Mulder, Jan
    Karolinska institutet.
    The transcriptomic landscape of mammalian brainManuscript (preprint) (Other academic)
  • 184.
    Smolinski, T.
    et al.
    Department of Psychology, Boston University, MA, USA.
    Patel, P.
    Department of Psychology, Boston University, MA, USA.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Hasselmo, M.
    Department of Psychology, Boston University, MA, USA.
    Schultheiss, N.
    Department of Psychology, Boston University, MA, USA.
    A computational intelligence approach to evaluation of membrane conductance interactions underlying persistent spiking, the f-I curve, and adaptive properties of medial entorhinal cortex neurons2012Conference paper (Refereed)
  • 185. Spreizer, Sebastian
    et al.
    Angelhuber, Martin
    Bahuguna, Jyotika
    Aertsen, Ad
    Kumar, Arvind
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Activity Dynamics and Signal Representation in a Striatal Network Model with Distance-Dependent Connectivity2017In: eNeuro, ISSN 2373-2822Article in journal (Refereed)
    Abstract [en]

    The striatum is the main input nucleus of the basal ganglia. Characterizing striatal activity dynamics is crucial to understanding mechanisms underlying action-selection, -initiation and -execution. Here, we studied the effects of spatial network connectivity on the spatio-temporal structure of striatal activity. We show that a striatal network with non-monotonically changing distance-dependent connectivity (according to a Gamma distribution) can exhibit a wide repertoire of spatio-temporal dynamics, ranging from spatially homogeneous asynchronous-irregular (AI) activity to a state with stable, spatially localized activity bumps, as in ‘winner-take-all’ (WTA) dynamics. Among these regimes, the unstable activity bumps (Transition Activity, TA) regime closely resembles the experimentally observed spatio-temporal activity dynamics and neuronal assemblies in the striatum. By contrast, striatal networks with monotonically decreasing distance-dependent connectivity (in a Gaussian fashion) can only exhibit an AI state. Thus, given the observation of spatially compact neuronal clusters in the striatum, our model suggests that recurrent connectivity among striatal projection neurons should vary non-monotonically. In brain disorders such as Parkinson’s disease, increased cortical inputs and high striatal firing rates are associated with a reduction in stimulus sensitivity. Consistent with this, our model suggests that strong cortical inputs drive the striatum to a WTA state, leading to low stimulus sensitivity and high variability. By contrast, the AI and TA states show high stimulus sensitivity and reliability. Thus, based on these results, we propose that in a healthy state the striatum operates in a AI/TA state and that lack of dopamine pushes it into a WTA state.Significance Statement Recent findings suggest that striatal activity is organized in spatially compact neuron clusters. Here, we show that striatal projection neurons should have a non-monotonically changing distance-dependent connectivity to obtain spatially localized activity patterns in striatum. Among the different states a striatal network can show, asynchronous-irregular and transition activity states closely resemble striatal activity in the healthy state. By contrast, strong cortical inputs as observed in Parkinson’s disease (PD) drive the network into a winner-take-all state, in which the striatum looses its stimulus sensitivity. Thus, our model makes specific predictions about the spatial network connectivity in the striatum and provides new insights about how the striatum might make a transition from a healthy state to a PD state.

  • 186. Szalisznyó, K.
    et al.
    Silverstein, David
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST). Karolinska Institutet, Sweden.
    Teichmann, M.
    Duffau, H.
    Smits, A.
    Cortico-striatal language pathways dynamically adjust for syntactic complexity: A computational study2017In: Brain and Language, ISSN 0093-934X, E-ISSN 1090-2155, Vol. 164, p. 53-62Article in journal (Refereed)
    Abstract [en]

    A growing body of literature supports a key role of fronto-striatal circuits in language perception. It is now known that the striatum plays a role in engaging attentional resources and linguistic rule computation while also serving phonological short-term memory capabilities. The ventral semantic and the dorsal phonological stream dichotomy assumed for spoken language processing also seems to play a role in cortico-striatal perception. Based on recent studies that correlate deep Broca-striatal pathways with complex syntax performance, we used a previously developed computational model of frontal-striatal syntax circuits and hypothesized that different parallel language pathways may contribute to canonical and non-canonical sentence comprehension separately. We modified and further analyzed a thematic role assignment task and corresponding reservoir computing model of language circuits, as previously developed by Dominey and coworkers. We examined the models performance under various parameter regimes, by influencing how fast the presented language input decays and altering the temporal dynamics of activated word representations. This enabled us to quantify canonical and non-canonical sentence comprehension abilities. The modeling results suggest that separate cortico-cortical and cortico-striatal circuits may be recruited differently for processing syntactically more difficult and less complicated sentences. Alternatively, a single circuit would need to dynamically and adaptively adjust to syntactic complexity.

  • 187.
    Szigyarto, Cristina Al-Khalili
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spitali, Pietro
    Leiden Univ, Med Ctr, Dept Human Genet, Albinusdreef 2, NL-2333 AA Leiden, Netherlands..
    Biomarkers of Duchenne muscular dystrophy: current findings2018In: Degenerative Neurological and Neuromuscular Disease, ISSN 1179-9900, Vol. 8, p. 1-13Article, review/survey (Refereed)
    Abstract [en]

    Numerous biomarkers have been unveiled in the rapidly evolving biomarker discovery field, with an aim to improve the clinical management of disorders. In rare diseases, such as Duchenne muscular dystrophy, this endeavor has created a wealth of knowledge that, if effectively exploited, will benefit affected individuals, with respect to health care, therapy, improved quality of life and increased life expectancy. The most promising findings and molecular biomarkers are inspected in this review, with an aim to provide an overview of currently known biomarkers and the technological developments used. Biomarkers as cells, genetic variations, miRNAs, proteins, lipids and/or metabolites indicative of disease severity, progression and treatment response have the potential to improve development and approval of therapies, clinical management of DMD and patients' life quality. We highlight the complexity of translating research results to clinical use, emphasizing the need for biomarkers, fit for purpose and describe the challenges associated with qualifying biomarkers for clinical applications.

  • 188. Tahvildari, Babak
    et al.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Alonso, Angel A.
    Hasselmo, Michael E.
    Switching between on and off states of persistent activity in lateral entorhinal layer III neurons2007In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 17, no 4, p. 257-263Article in journal (Refereed)
    Abstract [en]

    Persistent neural spiking maintains information during a, working memory task when a stimulus is no longer present. During I retention, this activity needs to be stable to distractors. More importantly, when retention is no longer relevant, cessation of the activity is necessary to enable processing and retention of subsequent information. Here, by means of intracellular recording with sharp microelectrode in in vitro rat brain slices, we demonstrate that single principal layer III neurons of the lateral entorhinal cortex (EC) generate persistent spiking activity with a novel ability to reliably toggle between spiking activity and a silent state. Our data indicates that in the presence of muscarmic receptor activation, persistent activity following an excitatory input may be induced and that a subsequent excitatory input can terminate this activity and cause the neuron to return to a silent state. Moreover, application of inhibitory hyperpolarizing stimuli is neither able to decrease the frequency of the persistent activity nor terminate it. The persistent activity can also be initiated and terminated by synchronized synaptic stimuli of layer II/III of the perirhinal cortex. The neuronal ability to switch On and Off persistent activity may facilitate the concurrent representation of temporally segregated information arriving in the EC and being directed toward the hippocampus.

  • 189. Tellez, Helio Fernandez
    et al.
    Morrison, Shawnda A.
    Neyt, Xavier
    Mairesse, Olivier
    Piacentini, Maria Francesca
    Macdonald-Nethercott, Eoin
    Pangerc, Andrej
    Dolenc-Groselj, Leja
    Eiken, Ola
    KTH, School of Technology and Health (STH), Basic Science and Biomedicine, Environmental Physiology.
    Pattyn, Nathalie
    Mekjavic, Igor B.
    Meeusen, Romain
    Exercise during Short-Term and Long-Term Continuous Exposure to Hypoxia Exacerbates Sleep-Related Periodic Breathing2016In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 39, no 4, p. 773-783Article in journal (Refereed)
    Abstract [en]

    Study Objectives: Exposure to hypoxia elevates chemosensitivity, which can lead to periodic breathing. Exercise impacts gas exchange, altering chemosensitivity; however, interactions between sleep, exercise and chronic hypoxic exposure have not been examined. This study investigated whether exercise exacerbates sleep-related periodic breathing in hypoxia. Methods: Two experimental phases. Short-Term Phase: a laboratory controlled, group-design study in which 16 active, healthy men (age: 25 +/- 3 y, height: 1.79 +/- 0.06 m, mass: 74 +/- 8 kg) were confined to a normobaric hypoxic environment (FIO2 = 0.139 +/- 0.003, 4,000 m) for 10 days, after random assignment to a sedentary (control, CON) or cycle-exercise group (EX). Long-Term Phase: conducted at the Concordia Antarctic Research Station (3,800 m equivalent at the Equator) where 14 men (age: 36 +/- 9 y, height: 1.77 +/- 0.09 m, mass: 75 +/- 10 kg) lived for 12-14 months, continuously confined. Participants were stratified post hoc based on self-reported physical activity levels. We quantified apnea-hypopnea index (AHI) and physical activity variables. Results: Short-Term Phase: mean AHI scores were significantly elevated in the EX group compared to CON (Night1 = CON: 39 +/- 51, EX: 91 +/- 59; Night10 = CON: 32 +/- 32, EX: 92 +/- 48; P = 0.046). Long-Term Phase: AHI was correlated to mean exercise time (R-2 = 0.4857; P = 0.008) and the coefficient of variation in night oxyhemoglobin saturation (SpO(2); R-2 = 0.3062; P = 0.049). Conclusions: Data indicate that exercise (physical activity) per se affects night SpO(2) concentrations and AHI after a minimum of two bouts of moderateintensity hypoxic exercise, while habitual physical activity in hypobaric hypoxic confinement affects breathing during sleep, up to 13+ months' duration

  • 190.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Börjesson, Sara
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University.
    Lundberg, Linnea
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Elinder, Fredrik
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e44388-Article in journal (Refereed)
    Abstract [en]

    A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet. PUFAs modulate the properties of a range of ion channels, including K and Na channels, and it has been hypothesized that these changes may be part of a mechanistic explanation of the ketogenic diet. Using computational modelling, we here study how experimentally observed PUFA-induced changes of ion channel activity affect neuronal excitability in CA1, in particular responses to synaptic input of high synchronicity. The PUFA effects were studied in two pathological models of cellular hyperexcitability associated with epileptogenesis. We found that experimentally derived PUFA modulation of the A-type K (K-A) channel, but not the delayed-rectifier K channel, restored healthy excitability by selectively reducing the response to inputs of high synchronicity. We also found that PUFA modulation of the transient Na channel was effective in this respect if the channel's steady-state inactivation was selectively affected. Furthermore, PUFA-induced hyperpolarization of the resting membrane potential was an effective approach to prevent hyperexcitability. When the combined effect of PUFA on the K-A channel, the Na channel, and the resting membrane potential, was simulated, a lower concentration of PUFA was needed to restore healthy excitability. We therefore propose that one explanation of the beneficial effect of PUFAs lies in its simultaneous action on a range of ion-channel targets. Furthermore, this work suggests that a pharmacological cocktail acting on the voltage dependence of the Na-channel inactivation, the voltage dependences of K-A channels, and the resting potential can be an effective treatment of epilepsy.

  • 191.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    KA channels reduce dendritic depolarization from synchronized synaptic input: implication for neural processing and epilepsy2008In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 9, no Suppl 1, p. P45-Article in journal (Refereed)
  • 192.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    KA channels suppress cellular responses to fast ripple activity – implications for epilepsy2009In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 10, no Suppl 1, p. P226-Article in journal (Refereed)
  • 193.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Restoring ion channel pathology by parameter optimization2011In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 12, no Suppl 1, p. P334-Article in journal (Refereed)
  • 194.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Reversing Nerve Cell Pathology by Optimizing Modulatory Action on Target Ion Channels2011In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 101, no 8, p. 1871-1879Article in journal (Refereed)
    Abstract [en]

    In diseases of the brain, the distribution and properties of ion channels display deviations from healthy control subjects. We studied three cases of ion channel alteration related to epileptogenesis. The first case of ion channel alteration represents an enhanced sodium current, the second case addresses the downregulation of the transient potassium current K(A), and the third case relates to kinetic properties of K(A) in a patient with temporal lobe epilepsy. Using computational modeling and optimization, we aimed at reversing the pathological characteristics and restoring normal neural function by altering ion channel properties. We identified two key aspects of neural dysfunction in epileptogenesis: an enhanced response to synaptic input in general and to highly synchronized synaptic input in particular. In previous studies, we showed that the potassium channel K(A) played a major role in neural responses to highly synchronized input. It was therefore selected as the target upon which modulators would act. In biophysical simulations, five experimentally characterized endogenous modulations on the K(A) channel were included. Relative concentrations of these modulators were controlled by a numerical optimizer that compared model output to predefined neural output, which represented a normal physiological response. Several solutions that restored the neuron function were found. In particular, distinct subtype compositions of the auxiliary proteins Kv channel-interacting proteins 1 and dipeptidyl aminopeptidase-like protein 6 were able to restore changes imposed by the enhanced sodium conductance or suppressed K(A) conductance. Moreover, particular combinations of protein kinese C, calmodulin-dependent protein kinase II, and arachidonic acid were also able to restore these changes as well as the channel pathology found in a patient with temporal lobe epilepsy. The solutions were further analyzed for sensitivity and robustness. We suggest that the optimization procedure can be used not only for neurons, but also for other organs with excitable cells, such as the heart and pancreas where channelopathies are found.

  • 195.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Migliore, Michele
    Institute of Biophysics, National Research Council.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Integration of synchronous synaptic input in CA1 pyramidal neuron depends on spatial and temporal distributions of the input2013In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 23, no 1, p. 87-99Article in journal (Refereed)
    Abstract [en]

    Highly synchronized neural firing has been discussed in relation to learning and memory, for instance sharp-wave activity in hippocampus. We were interested to study how a postsynaptic CA1 pyramidal neuron would integrate input of different levels of synchronicity. In previous work using computational modeling we studied how the integration depends on dendritic conductances. We found that the transient A-type potassium channel KA was able to selectively suppress input of high synchronicity. In recent years, compartmentalization of dendritic integration has been shown. We were therefore interested to study the influence of localization and pattern of synaptic input over the dendritic tree of the CA1 pyramidal neuron. We find that the selective suppression increases when synaptic inputs are placed on oblique dendrites further out from the soma. The suppression also increases along the radial axis from the apical trunk out to the end of oblique dendrites. We also find that the KA channel suppresses the occurrence of dendritic spikes. Moreover, recent studies have shown interaction between synaptic inputs. We therefore studied the influence of apical tuft input on the integration studied above. We find that excitatory input provides a modulatory influence reducing the capacity of KA to suppress synchronized activity, thus facilitating the excitatory drive of oblique dendritic input. Conversely, inhibitory tuft input increases the suppression by KA providing a larger control of oblique depolarizing factors on the CA1 pyramidal neuron in terms of what constitutes the most effective level of synchronicity. Furthermore, we show that the selective suppression studied above depends on the conductance of the KA channel. KA, as several other potassium channels, is modulated by several neuromodulators, for instance acetylcholine and dopamine, both of which have been discussed in relation to learning and memory. We suggest that dendritic conductances and their modulatory systems may be part of the regulation of processing of information, in particular for how network synchronicity affects learning and memory.

  • 196.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Brain Institute, Stockholm, Sweden.
    Petersson, Marcus
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Brain Institute, Stockholm, Sweden.
    Obreja, Otilia
    Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg.
    Lampert, Angelika
    Inst. of Physiol. and Pathophysiology, Friedrich-Alexander-Uni versität Erlangen-Nürnberg.
    Carr, Richard
    Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg.
    Schmelz, Martin
    Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg,.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Brain Institute, Stockholm, Sweden.
    Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors2014In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 111, no 9, p. 1721-1735Article in journal (Refereed)
    Abstract [en]

    Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients.

  • 197.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Petersson, Marcus
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Obreja, Otilia
    Lampert, Angelika
    Carr, Richard
    Schmelz, Martin
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Modelling post spike excitability changes in peripheral C-fibres2012Manuscript (preprint) (Other academic)
  • 198. Uhlen, Per
    et al.
    Fritz, Nicolas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Smedler, Erik
    Malmersjoe, Seth
    Kanatani, Shigeaki
    Calcium Signaling in Neocortical Development2015In: Developmental Neurobiology, ISSN 1932-8451, E-ISSN 1932-846X, Vol. 75, no 4, p. 360-368Article in journal (Refereed)
    Abstract [en]

    The calcium ion (Ca2+) is an essential second messenger that plays a pivotal role in neurogenesis. In the ventricular zone (VZ) of the neocortex, neural stem cells linger to produce progenitor cells and subsequently neurons and glial cells, which together build up the entire adult brain. The radial glial cells, with their characteristic radial fibers that stretch from the inner ventricular wall to the outer cortex, are known to be the neural stem cells of the neocortex. Migrating neurons use these radial fibers to climb from the proliferative VZ in the inner part of the brain to the outer layers of the cortex, where differentiation processes continue. To establish the complex structures that constitute the adult cerebral cortex, proliferation, migration, and differentiation must be tightly controlled by various signaling events, including cytosolic Ca2+ signaling. During development, cells regularly exhibit spontaneous Ca2+ activity that stimulates downstream effectors, which can elicit these fundamental cell processes. Spontaneous Ca2+ activity during early neocortical development depends heavily on gap junctions and voltage dependent Ca2+ channels, whereas later in development neurotransmitters and synapses exert an influence. Here, we provide an overview of the literature on Ca2+ signaling and its impact on cell proliferation, migration, and differentiation in the neocortex. We point out important historical studies and review recent progress in determining the role of Ca2+ signaling in neocortical development. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 360-368, 2015

  • 199. van Leeuwen, W.
    et al.
    Kecklund, G.
    Dahlgren, Anna
    KTH, School of Technology and Health (STH), Patientsäkerhet.
    Kircher, A.
    Lutzhoft, M.
    Barnett, M.
    Åkerstedt, T.
    Fatigue, Sleepiness And Sleep In Maritime Watch Systems: A Series Of Simulator Studies2012In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 35, p. A203-A203Article in journal (Other academic)
  • 200. Van Leeuwen, W. M. A.
    et al.
    Kircher, A.
    Dahlgren, Anna
    KTH, School of Technology and Health (STH), Patientsäkerhet.
    Lutzhoft, M.
    Barnett, M.
    Kecklund, G.
    Akerstedt, T.
    Sleep and sleepiness while on watch in a simulated '4 h on/8 h off' maritime watch system2012In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 21, p. 331-331Article in journal (Other academic)
12345 151 - 200 of 220
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