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  • 51.
    Hellgren Kotaleski, Jeanette
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Wadden, A
    Lansner, A
    Grillner, S
    A continuous network model of the lamprey swimming rhythm generator - intersegmental coordination1994Konferensbidrag (Refereegranskat)
  • 52. Hill, R
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S
    Whole cell voltage clamp techniques in intact lamprey spinal cord and brainstem1994Konferensbidrag (Refereegranskat)
  • 53. Hjorth, J
    et al.
    Blackwell, K.T.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    FS networks as population detectors of correlated input activity2010Konferensbidrag (Refereegranskat)
  • 54.
    Hjorth, Johannes
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Blackwell, Kim T
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Gap Junctions between Striatal Fast-Spiking Interneurons Regulate Spiking Activity and Synchronization as a Function of Cortical Activity2009Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 29, nr 16, s. 5276-5286Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Striatal fast-spiking (FS) interneurons are interconnected by gap junctions into sparsely connected networks. As demonstrated for cortical FS interneurons, these gap junctions in the striatum may cause synchronized spiking, which would increase the influence that FS neurons have on spiking by the striatal medium spiny (MS) neurons. Dysfunction of the basal ganglia is characterized by changes in synchrony or periodicity, thus gap junctions between FS interneurons may modulate synchrony and thereby influence behavior such as reward learning and motor control. To explore the roles of gap junctions on activity and spike synchronization in a striatal FS population, we built a network model of FS interneurons. Each FS connects to 30-40% of its neighbors, as found experimentally, and each FS interneuron in the network is activated by simulated corticostriatal synaptic inputs. Our simulations show that the proportion of synchronous spikes in FS networks with gap junctions increases with increased conductance of the electrical synapse; however, the synchronization effects are moderate for experimentally estimated conductances. Instead, the main tendency is that the presence of gap junctions reduces the total number of spikes generated in response to synaptic inputs in the network. The reduction in spike firing is due to shunting through the gap junctions; which is minimized or absent when the neurons receive coincident inputs. Together these findings suggest that a population of electrically coupled FS interneurons may function collectively as input detectors that are especially sensitive to synchronized synaptic inputs received from the cortex.

  • 55.
    Hjorth, Johannes
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Blackwell, Kim T.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Gap junctions on striatal fast spiking interneurons reduce firing for non-correlated inputs2008Konferensbidrag (Refereegranskat)
  • 56.
    Hjorth, Johannes
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Elias, Alex Hanna
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    The significance of gap junction location in striatal fast spiking interneurons2007Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 70, nr 10-12, s. 1887-1891Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fast spiking (FS) interneurons in the striatunt are hypothesised to control spike timing in the numerous medium spiny (MS) projection neurons by inhibiting or delaying firing in the MS neurons. The FS neurons are connected to each other through electrical gap junctions. This might synchronise the FS neurons, leading to increased influence on target neurons. Here, we explore the possible difference between proximal and distal gap junction locations. Somatic and distal dendritic gap junctions with equal effective coupling coefficient, as defined for steady-state somatic inputs, showed significantly different effective coupling coefficient with transient inputs. However, the ability to synchronise spiking in pairwise coupled FS neurons, which received synaptic inputs as during striatal up-state periods, was as effective with distal gap junctions as with proximal ones. Proximal gap junctions, however, caused synchronisation within a more precise time window.

  • 57.
    Hjorth, Johannes
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hedlund, Lennart
    KTH, Skolan för datavetenskap och kommunikation (CSC).
    Blackwell, Kim T
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Synchronization Effects in Networks of Striatal Fast Spiking Interneurons - Role of Gap Junctions2008Ingår i: ADVANCES IN COGNITIVE NEURODYNAMICS, PROCEEDINGS / [ed] Wang R, Gu F, Shen E, TOTOWA: HUMANA PRESS INC , 2008, s. 63-66Konferensbidrag (Refereegranskat)
    Abstract [en]

    Recent studies have found gap junctions between striatal fast spiking interneurons (FSN). Gap junctions between neocortical FSNs cause increased synchrony of firing in response to current injection, but the effect of gap junctions in response to synaptic input is unknown. To explore this issue, we built a network model of FSNs. Each FSN connects to 30-40% of its neighbours, as found experimentally, and each FSN in the network is activated by simulated up-state synaptic inputs. Simulation experiments show that the proportion of synchronous spikes in coupled FSNs increases with gap junction conductance. Proximal gap junctions increase the synchronization more than distal gap junctions. During up-states the synchronization effects in FSNs coupled pairwise with proximal gap junctions are small for experimentally estimated gap junction conductances; however, higher order correlations are significantly increased in larger FSN networks.

  • 58.
    Hjorth, Johannes
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Up-State signaling and Coincidence Detection in Striatal Fast Spiking Interneurons Coupled through Gap JunctionsManuskript (Övrigt vetenskapligt)
  • 59.
    Hjorth, Johannes
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Klaus, Andreas
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    The influence of stuttering properties for firing activity in pairs of electrically coupled striatal fast-spiking interneurons2009Ingår i: Neuroinformatics 2009. Pilsen, Czech Republic, September 06 - 08,  2009, 2009Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    The striatum is the main input stage of the basal ganglia system, which is involved in executive functions of the forebrain – such as the planning and the selection of motor behavior. Feedforward inhibition of medium-sized spiny projection neurons in the striatum by fast-spiking interneurons is supposed to be an important determinant of controlling striatal output to later stages of the basal ganglia [1]. Striatal fast-spiking interneurons, which constitute approximately 1-2 % of all striatal neurons, show many similarities to cortical fast-spiking cells. In response to somatic current injection, for example, some of these neurons exhibit spike bursts with a variable number of action potentials (so called stuttering) [2-4]. Interestingly, the membrane potential between such stuttering episodes oscillates in the range of 20-100 Hz [3,5]. The first spike of each stuttering episode invariably occurs at a peak of the underlying subthreshold oscillation. In both cortex and striatum, fast-spiking cells have been shown to be inter-connected by gap junctions [6,7]. In vitro measurements as well as theoretical studies indicate that electrical coupling via gap junctions might be able to promote synchronous activity among these neurons [6,8].Here we use computational modeling to investigate how the presence of subthreshold oscillations and stuttering properties influence the synchronization of activity in pairs of electrically coupled fast-spiking neurons. We use the model of Golomb et al. [3], which we have extended with a dendritic tree in order to be able to simulate distal synaptic input. We show that gap junctions are able to synchronize both subthreshold membrane potential fluctuations as well as the stuttering periods in response to somatic current injection. In response to synaptic input, however, our model neuron rarely shows subthreshold oscillations, and the stuttering behavior changes to a firing pattern with single spikes or spike doublets. We furthermore investigate the effect of GABAergic (i.e. inhibitory) input to the model of the fast-spiking neuron and predict that inhibitory input is able to induce overlapping stuttering episodes in these cells. We finally discuss our results in the context of the feedforward inhibitory network which is likely to play an important role in striatal and basal ganglia function.

  • 60. Hjorth, Johannes
    et al.
    Krieger, P
    Oliveira, R.F.
    Blackwell, Kim T
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    GABAergic control of dendritic calcium dynamics in striatal medium spiny neurons2008Konferensbidrag (Refereegranskat)
    Abstract [en]

    Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites [1, 2, 3]. Increased calcium levels trigger changes in plasticity [4, 5], which is important for learning and other functions [6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites [7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of GABAergic inputs on the dendritic calcium dynamics is investigated.

  • 61.
    Hjorth, Johannes
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Zilberter, M
    Oliveria, R.F.
    Blackwell, Kim T.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    GABAergic control of backpropagating action potentials in striatal medium spiny neurons2008Konferensbidrag (Refereegranskat)
    Abstract [en]

    Experiments have demonstrated the ability of action potentials to actively backpropagate in striatal medium spiny (MS) neurons, affecting the calcium levels in the dendrites[1-3]. Increased calcium levels trigger changes in plasticity[4,5], which is important for learning and other functions[6]. Studies in the hippocampus have shown that GABAergic input can modulate the backpropagation of action potentials from the soma to the distal dendrites[7]. The MS neurons receive both proximal feedforward GABAergic inhibition from fast spiking interneurons (FS), and distal feedback inhibition from other neighbouring MS neurons. In the present study the effect of these GABAergic inputs on the dendritic calcium dynamics is investigated.

  • 62.
    Huss, Mikael
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hess, Dietmar
    d'Incamps, Boris Lamotte
    El Manira, Abdeljabbar
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Role of A-current in lamprey locomotor network neurons2003Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 52-54, s. 295-300Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A compartmental model of lamprey central pattern generator neurons was built in order to examine the effects of a fast, transient, high-voltage-activated potassium current (A-current) found experimentally. The model consisted of a soma, a compartment corresponding to the axon initial segment, and a dendritic tree. The simulation showed that the A-current was necessary for repetitive spiking in the single neuron following current injection. The functional role of adding an A-current was also examined in a network model. In this model, the A-current stabilizes the swimming rhythm by making the burst cycle duration and the number of spikes per burst less variable. All these effects are also seen experimentally.

  • 63.
    Huss, Mikael
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA. KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Wallén, Peter
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    El Manira, Abdeljabbar
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    Grillner, Sten
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Roles of ionic currents in lamprey CPG neurons: a modeling study2007Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 97, nr 4, s. 2696-2711Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The spinal network underlying locomotion in the lamprey consists of a core network of glutamatergic and glycinergic interneurons, previously studied experimentally and through mathematical modeling. We present a new and more detailed computational model of lamprey locomotor network neurons, based primarily on detailed electrophysiological measurements and incorporating new experimental findings. The model uses a Hodgkin Huxley-like formalism and consists of 86 membrane compartments containing 12 types of ion currents. One of the goals was to introduce a fast, transient potassium current (K-t) and two sodium-dependent potassium currents, one faster (K-NaF) and one slower (K-NaS), in the model. Not only has the model lent support to the interpretation of experimental results but it has also provided predictions for further experimental analysis of single-network neurons. For example, K-t was shown to be one critical factor for controlling action potential duration. In addition, the model has proved helpful in investigating the possible influence of the slow afterhyperpolarization on repetitive firing during ongoing activation. In particular, the balance between the simulated slow sodium-dependent and calcium-dependent potassium currents has been explored, as well as the possible involvement of dendritic conductances.

  • 64.
    Huss, Mikael
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA. KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Wallén, Peter
    El Manira, Abdeljabbar
    Grillner, Sten
    Kotaleski, Jeanette Hellgren
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Functional roles of ionic currents in lamprey CPG neurons: a model studyManuskript (preprint) (Övrigt vetenskapligt)
  • 65.
    Huss, Mikael
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Wang, Di
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    Trané, Camilla
    KTH, Skolan för elektro- och systemteknik (EES).
    Wikström, Martin
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för elektro- och systemteknik (EES). KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    An experimentally constrained computational model of NMDA oscillations in lamprey CPG neurons2008Ingår i: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 15, nr 1, s. 108-121Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Rhythmicity is a characteristic of neural networks responsible for locomotion. In many organisms, activation of N-methyl-D-aspartate (NMDA) receptors leads to generation of rhythmic locomotor patterns. In addition, single neurons can display intrinsic, NMDA-dependent membrane potential oscillations when pharmacologically isolated from each other by tetrodotoxin (TTX) application. Such NMDA-TTX oscillations have been characterized, for instance, in lamprey locomotor network neurons. Conceptual and computational models have been put forward to explain the appearance and characteristics of these oscillations. Here, we seek to refine the understanding of NMDA-TTX oscillations by combining new experimental evidence with computational modelling. We find that, in contrast to previous computational predictions, the oscillation frequency tends to increase when the NMDA concentration is increased. We develop a new, minimal computational model which can incorporate this new information. This model is further constrained by another new piece of experimental evidence: that regular-looking NMDA-TTX oscillations can be obtained even after voltage-dependent potassium and high-voltage-activated calcium channels have been pharmacologically blocked. Our model conforms to several experimentally derived criteria that we have set up and is robust to parameter changes, as evaluated through sensitivity analysis. We use the model to re-analyze an old NMDA-TTX oscillation model, and suggest an explanation of why it failed to reproduce the new experimental data that we present here.

  • 66.
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Modelling of motor systems including the dynamics in intracellular signaling networks involved in learning and synaptic plasticity2009Konferensbidrag (Övrigt vetenskapligt)
  • 67.
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Subcellular temporal computation and its role for synaptic plasticity2007Konferensbidrag (Övrigt vetenskapligt)
  • 68.
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    The functions of the striatal microcircuitry: a modeling approach2010Konferensbidrag (Övrigt vetenskapligt)
  • 69.
    Hällgren Kotaleski, Jeanette
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Blackwell, Kim T.
    Modelling the molecular mechanisms of synaptic plasticity using systems biology approaches2010Ingår i: Nature Reviews Neuroscience, ISSN 1471-003X, E-ISSN 1471-0048, Vol. 11, nr 4, s. 239-251Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Synaptic plasticity is thought to underlie learning and memory, but the complexity of the interactions between the ion channels, enzymes and genes that are involved in synaptic plasticity impedes a deep understanding of this phenomenon. Computer modelling has been used to investigate the information processing that is performed by the signalling pathways involved in synaptic plasticity in principal neurons of the hippocampus, striatum and cerebellum. In the past few years, new software developments that combine computational neuroscience techniques with systems biology techniques have allowed large-scale, kinetic models of the molecular mechanisms underlying long-term potentiation and long-term depression. We highlight important advancements produced by these quantitative modelling efforts and introduce promising approaches that use advancements in live-cell imaging.

  • 70.
    Hällgren Kotaleski, Jeanette
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S
    Networks in motion: bridging between intrinsic mechanisms and systems level function2010Konferensbidrag (Övrigt vetenskapligt)
  • 71.
    Hällgren Kotaleski, Jeanette
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lindskog, M
    Blackwell, K.T
    DARPP-32 acts as a temporal integrator: Results from a computer model2004Konferensbidrag (Övrigt vetenskapligt)
  • 72.
    Hällgren Kotaleski, Jeanette
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lindskog, M
    Blackwell, K.T
    Effect of temporal pattern on dopamine activated second messenger pathways2005Konferensbidrag (Övrigt vetenskapligt)
  • 73.
    Hällgren Kotaleski, Jeanette
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Plenz, D
    Blackwell, K.T.
    Background inputs and KA current influence firing of striatal fast spiking interneurons2004Konferensbidrag (Övrigt vetenskapligt)
  • 74.
    Kamali Sarvestani, Iman
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lindahl, Mikael
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    Ekeberg, Örjan
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    The arbitration-extension hypothesis: A hierarchical interpretation of the functional organization of the basal ganglia2011Ingår i: Frontiers in Systems Neuroscience, ISSN 1662-5137, E-ISSN 1662-5137, Vol. 5, s. 13-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Based on known anatomy and physiology, we present a hypothesis where the basal ganglia motor loop is hierarchically organized in two main subsystems: the arbitration system and the extension system. The arbitration system, comprised of the subthalamic nucleus, globus pallidus, and pedunculopontine nucleus, serves the role of selecting one out of several candidate actions as they are ascending from various brain stem motor regions and aggregated in the centromedian thalamus or descending from the extension system or from the cerebral cortex. This system is an action-input/action-output system whose winner-take-all mechanism finds the strongest response among several candidates to execute. This decision is communicated back to the brain stem by facilitating the desired action via cholinergic/glutamatergic projections and suppressing conflicting alternatives via GABAergic connections. The extension system, comprised of the striatum and, again, globus pallidus, can extend the repertoire of responses by learning to associate novel complex states to certain actions. This system is a state-input/action-output system, whose organization enables it to encode arbitrarily complex Boolean logic rules using striatal neurons that only fire given specific constellations of inputs (Boolean AND) and pallidal neurons that are silenced by any striatal input (Boolean OR). We demonstrate the capabilities of this hierarchical system by a computational model where a simulated generic "animal" interacts with an environment by selecting direction of movement based on combinations of sensory stimuli, some being appetitive, others aversive or neutral. While the arbitration system can autonomously handle conflicting actions proposed by brain stem motor nuclei, the extension system is required to execute learned actions not suggested by external motor centers. Being precise in the functional role of each component of the system, this hypothesis generates several readily testable predictions.

  • 75. Klaus, A.
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Synchronization effects between striatal fast-spiking interneurons forming networks with different topologies2008Ingår i: Frontiers in Neuroinformatics, ISSN 1662-5196, E-ISSN 1662-5196Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The basal ganglia are involved in executive functions of the forebrain, such as the planning and selection of motor behavior. In the striatum, which is the input stage of the basal ganglia system, fast-spiking interneurons provide an effective feedforward inhibition to the medium-sized spiny projection neurons. Thus, these fast-spiking neurons are able to control the striatal output to later stages in the basal ganglia. Recently, in modeling studies it has been shown that pairs of cells as well as randomly connected networks of electrically coupled fast-spiking cells are able to synchronize their activity. Here we want to investigate the influence of network topology and network size on the synchronization in a simulated network of striatal fast-spiking interneurons. We use a biophysically detailed single-cell model of the fast-spiking interneuron with 127 compartments (Hellgren Kotaleski et al., J Neurophysiology, 95: 331-41, 2006; Hjorth et al., Neurocomputing 70: 1887–1891, 2007), and parallelize the network model of electrically coupled fast-spiking cells using PGENESIS running on a Blue Gene/L supercomputer. General network statistics and synaptic input is constrained by published data from the striatum. Network topology is varied from ’regular’ over ’small-world’ to ’random’ (Watts & Strogatz, Nature 393: 440–442, 1998). Using common statistical measures, we will determine the extent of local and global synchronization for each network topology. Furthermore, we investigate the interactions in the network by means of Ising models (Schneidman et al., Nature 440: 1007–1012, 2006). We are particularly interested in the relation between the ’interaction’ – as obtained by the Ising model – and the underlying network topology; e. g., do directly coupled fast-spiking interneuron pairs synchronize most?So far, the small amount of fast-spiking cells in the striatum (less than 2 %) makes experimental studies on the network level difficult or even impossible. With our study we hope to gain a better understanding of interaction effects in the feedforward inhibitory network of the striatum.

  • 76. Klaus, A.
    et al.
    Hjorth, Johannes
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    The influence of subthreshold membrane potential oscillations and GABAergic input on firing activity in striatal fast-spiking neurons2009Ingår i: BMC Neuroscience, ISSN 1471-2202, Vol. 10, nr Suppl.1, s. P244-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The striatum is the main input stage of the basal ganglia system, which is involved in executive functions of the forebrain, such as the planning and the selection of motor behavior. Feedforward inhibition of medium-sized spiny projection neurons in the striatum by fast-spiking interneurons is supposed to be an important determinant of controlling striatal output to later stages of the basal ganglia[1]. Striatal fast-spiking interneurons, which constitute approximately 1–2% of all striatal neurons, show many similarities to cortical fast-spiking cells. In response to somatic current injection, for example, some of these neurons exhibit spike bursts with a variable number of action potentials (so called stuttering)[2-4]. Interestingly, the membrane potential between such stuttering episodes oscillates in the range of 20–100 Hz[3,5]. The first spike of each stuttering episode invariably occurs at a peak of the underlying subthreshold oscillation. In both cortex and striatum, fast-spiking cells are inter-connected by gap junctions[6,7]. In vitro measurements as well as theoretical studies indicate that electrical coupling via gap junctions might be able to promote synchronous activity among these neurons[6,8]. Here we investigate the possible role of subthreshold oscillations on the synchronization of sub- and suprathreshold activity in a model of electrically coupled fast-spiking neurons. We use the model of Golomb et al.[3], which we extended with a dendritic tree so as to be able to simulate distal synaptic input. We show that gap junctions are able to synchronize subthreshold membrane potential fluctuations in response to somatic current injection. However, the oscillations are only prevalent in the subthreshold range and therefore require enough membrane potential depolarization[5]. In response to synaptic input, our model neuron only enters the subthreshold oscillatory regime with AMPA and NMDA synapses located at distal dendrites. Proximal synaptic input leads to more random fluctuations of the membrane potential, reflecting a smaller extent of dendritic filtering of the Poisson-distributed postsynaptic potentials. We furthermore investigate the effect of GABAergic (i.e. inhibitory) input to the model of the fast-spiking neuron and predict that inhibitory input is able to induce a stuttering episode in these cells. We finally discuss our results in the context of the feedforward inhibitory network, which is likely to play an important role in striatal and basal ganglia function.

  • 77. Klaus, A.
    et al.
    Planert, H.
    Hjorth, Johannes
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Berke, J.D.
    Silberberg, G.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Striatal fast-spiking interneurons: from firing patterns to postsynaptic impact2011Ingår i: Frontiers in Systems Neuroscience, ISSN 1662-5137, E-ISSN 1662-5137, Vol. 5, nr July, s. 57-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the striatal microcircuit, fast-spiking (FS) interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS) projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

  • 78. Kozlov, A. K.
    et al.
    Aurell, Erik
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Orlovsky, G. N.
    Deliagina, T. G.
    Zelenin, P. V.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Grillner, S.
    Modeling control of roll-plane body orientation in lamprey2000Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 32, s. 871-877Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A phenomenological model of the mechanism of stabilization of the dorsal-side-up orientation in the lamprey is suggested. Mathematical modeling is based on the experimental results on investigation of postural control in lampreys using combined in vivo and robotics approaches. Dynamics of the model agrees qualitatively with the experiment. It is shown by computer simulations that postural correction commands from one or several reticulospinal neurons provide information which may be sufficient for stabilization of body orientation in the lamprey.

  • 79. Kozlov, A. K.
    et al.
    Aurell, Erik
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Orlovsky, G. N.
    Deliagina, T. G.
    Zelenin, P. V.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Grillner, S.
    Modeling postural control in the lamprey2001Ingår i: Biological Cybernetics, ISSN 0340-1200, E-ISSN 1432-0770, Vol. 84, nr 5, s. 323-330Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A phenomenological model of the mechanism of stabilization of the body orientation during locomotion (dorsal side up) in the lamprey is presented. The mathematical modeling is based on experimental results obtained during investigations of postural control in lampreys using a combined in vivo and robotics approach. The dynamics of the model agree qualitatively with the experimental data. It is shown by computer simulations that postural correction commands from reticulospinal neurons provide information sufficient to stabilize body orientation in the lamprey. The model is based on differences between the effects exerted by the vestibular apparatus on the left and the right side.

  • 80.
    Kozlov, Alexander K.
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    A hemicord locomotor network of excitatory interneurons: a simulation study2007Ingår i: Biological Cybernetics, ISSN 0340-1200, E-ISSN 1432-0770, Vol. 96, nr 2, s. 229-243Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Locomotor burst generation is simulated using a full-scale network model of the unilateral excitatory interneuronal population. Earlier small-scale models predicted that a population of excitatory neurons would be sufficient to produce burst activity, and this has recently been experimentally confirmed. Here we simulate the hemicord activity induced under various experimental conditions, including pharmacological activation by NMDA and AMPA as well as electrical stimulation. The model network comprises a realistic number of cells and synaptic connectivity patterns. Using similar distributions of cellular and synaptic parameters, as have been estimated experimentally, a large variation in dynamic characteristics like firing rates, burst, and cycle durations were seen in single cells. On the network level an overall rhythm was generated because the synaptic interactions cause partial synchronization within the population. This network rhythm not only emerged despite the distributed cellular parameters but relied on this variability, in particular, in reproducing variations of the activity during the cycle and showing recruitment in interneuronal populations. A slow rhythm (0.4-2 Hz) can be induced by tonic activation of NMDA-sensitive channels, which are voltage dependent and generate depolarizing plateaus. The rhythm emerges through a synchronization of bursts of the individual neurons. A fast rhythm (4-12 Hz), induced by AMPA, relies on spike synchronization within the population, and each burst is composed of single spikes produced by different neurons. The dynamic range of the fast rhythm is limited by the ability of the network to synchronize oscillations and depends on the strength of synaptic connections and the duration of the slow after hyperpolarization. The model network also produces prolonged bouts of rhythmic activity in response to brief electrical activations, as seen experimentally. The mutual excitation can sustain long-lasting activity for a realistic set of synaptic parameters. The bout duration depends on the strength of excitatory synaptic connections, the level of persistent depolarization, and the influx of Ca2+ ions and activation of Ca2+-dependent K+ current.

  • 81.
    Kozlov, Alexander
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Aurell, Erik
    KTH, Skolan för elektro- och systemteknik (EES), Centra, ACCESS Linnaeus Centre. KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S
    Lansner, A
    Modeling of plasticity of the synaptic connections in the lamprey spinal CPG - consequences for network behavior2000Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 32-33, s. 441-446Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed. This is motivated by the experimentally found effects substance P and 5-hydroxytryptamin (5-HT) have on the inhibitory and excitatory synaptic transmission. The effects can be a change of the amplitude of the postsynaptic potentials as well as induction of an activity-dependent facilitation or depression during repetitive activation. Simulations show that network level effects (i.e. swimming frequency) of substance P and 5-HT can to a substantial part be explained based on their effects on the plasticity of the synaptic transmission.

  • 82.
    Kozlov, Alexander
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Aurell, Erik
    KTH, Skolan för elektro- och systemteknik (EES), Centra, ACCESS Linnaeus Centre. KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S
    Lansner, A
    Modeling of substance P and 5-HT induced synaptic plasticity in the lamprey spinal CPG - consequences for network pattern generation2001Ingår i: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 11, nr 2, s. 183-200Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed by means of simulations. This is motivated by the effects substance P (a tachykinin) and serotonin (5-hydroxytryptamin; 5-HT) have on synaptic transmission in the locomotor network. Activity-dependent synaptic depression and potentiation have recently been shown experimentally using paired intracellular recordings. Although normally activity-dependent plasticity presumably does not contribute to the patterning of network activity, this changes in the presence of the neuromodulators substance P and 5-HT, which evoke significant plasticity. Substance P can induce a faster and larger depression of inhibitory connections but potentiation of excitatory inputs, whereas 5-HT induces facilitation of both inhibitory and excitatory inputs. Changes in the amplitude of the first postsynaptic potential are also seen. These changes could thus be a potential mechanism underlying the modulatory role these substances have on the rhythmic network activity. The aim of the present study has been to implement the activity dependent synaptic depression and facilitation induced by substance P and 5-HT into two alternative models of the lamprey spinal locomotor network, one relying on reciprocal inhibition for bursting and one in which each hemicord is capable of oscillations. The consequences of the plasticity of inhibitory and excitatory connections are then explored on the network level. In the intact spinal cord, tachykinins and 5-HT, which can be endogenously released, increase and decrease the frequency of the alternating left-right burst pattern, respectively. The frequency decreasing effect of 5-HT has previously been explained based on its conductance decreasing effect on K(Ca) underlying the postspike afterhyperpolarization (AHP). The present simulations show that short-term synaptic plasticity may have strong effects on frequency regulation in the lamprey spinal CPG. In the network model relying on reciprocal inhibition, the observed effects substance P and 5-HT have on network behavior (i.e., a frequency increase and decrease respectively) can to a substantial part be explained by their effects on the total extent and time dynamics of synaptic depression and facilitation. The cellular effects of these substances will in the 5-HT case further contribute to its network effect.

  • 83.
    Kozlov, Alexander
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Aurell, Erik
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Grillner, S.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Modeling of plasticity of the synaptic connections in the lamprey spinal CPG - consequences for network behavior2000Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 32, s. 441-446Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed. This is motivated by the experimentally found effects substance P and 5-hydroxytryptamin (5-HT) have on the inhibitory and excitatory synaptic transmission. The effects can be a change of the amplitude of the postsynaptic potentials as well as induction of an activity-dependent facilitation or depression during repetitive activation. Simulations show that network level effects (i.e. swimming frequency) of substance P and 5-HT can to a substantial part be explained based on their effects on the plasticity of the synaptic transmission.

  • 84.
    Kozlov, Alexander
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Aurell, Erik
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Grillner, S.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Modeling of substance P and 5-HT induced synaptic plasticity in the lamprey spinal CPG: Consequences for network pattern generation2001Ingår i: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 11, nr 2, s. 183-200Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed by means of simulations. This is motivated by the effects substance P (a tachykinin) and serotonin (5-hydroxytryptamin; 5-HT) have on synaptic transmission in the locomotor network. Activity-dependent synaptic depression and potentiation have recently been shown experimentally using paired intracellular recordings. Although normally activity-dependent plasticity presumably does not contribute to the patterning of network activity, this changes in the presence of the neuromodulators substance P and 5-HT, which evoke significant plasticity. Substance P can induce a faster and larger depression of inhibitory connections but potentiation of excitatory inputs, whereas 5-HT induces facilitation of both inhibitory and excitatory inputs. Changes in the amplitude of the first postsynaptic potential are also seen. These changes could thus be a potential mechanism underlying the modulatory role these substances have on the rhythmic network activity. The aim of the present study has been to implement the activity dependent synaptic depression and facilitation induced by substance P and 5-HT into two alternative models of the lamprey spinal locomotor network, one relying on reciprocal inhibition for bursting and one in which each hemicord is capable of oscillations. The consequences of the plasticity of inhibitory and excitatory connections are then explored on the network level. In the intact spinal cord, tachykinins and 5-HT, which can be endogenously released, increase and decrease the frequency of the alternating left-right burst pattern, respectively. The frequency decreasing effect of 5-HT has previously been explained based on its conductance decreasing effect on K underlying the postspike afterhyperpolarization (AHP). The present simulations show that short-term synaptic plasticity may have strong effects on frequency regulation in the lamprey spinal CPG. In the network model relying on reciprocal inhibition, the observed effects substance P and 5-HT have on network behavior (i.e., a frequency increase and decrease respectively) can to a substantial part be explained by their effects on the total extent and time dynamics of synaptic depression and facilitation. The cellular effects of these substances will in the 5-HT case further contribute to its network effect.

  • 85.
    Kozlov, Alexander
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Wallén, Peter
    Karolinska institutet, Neuroscience.
    Grillner, Sten
    Karolinska institutet, Neuroscience.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Detailed reduced models excitatory hemi-cord locomotor network lamprey2003Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    Rhythmic locomotor-related activity can be induced in the isolated hemi-spinal cord of lamprey during bath application of D-glutamate or NMDA (Cangiano and Grillner, 2003). This bursting activity is not dependent on glycinergic inhibition but relies on mutual glutamatergic excitation among network interneurons. The possibility of such oscillatory activity was suggested by earlier simulations (Hellgren-Kotaleski et al. 1999). Here the underlying mechanisms are further examined using both detailed and reduced mathematical models. The detailed network model comprises a population of compartmental excitatory interneurones with Na+, K+, Ca2+, KCa channels as well as two Ca-pools. The synaptic interactions are mediated by AMPA receptors and voltage-dependent NMDA receptors, as established experimentally. This model reproduces the main experimental observations on both cell and network level, including the slow (NMDA/Mg2+ dependent) and the fast rhythm. Burst frequency can be modulated by changing the AMPA and/or NMDA drive, the latter providing only a narrow dynamic range. Further, the distributed network of the entire hemi-cord has been simulated. A weakly asymmetric rostro-caudal connectivity (stronger descending) could support a uniform intersegmental phase lag along most of the spinal cord, whereas a symmetric connectivity could not. The intersegmental phase lag is effectively controlled (forward and backward direction) by adding excitation or inhibition to the most rostral segments. The detailed model was progressively reduced until only the most important (slow) currents remained. The dynamics of the reduced model followed that of the detailed model. Ca influx and activation of KCa currents was shown to play a key role in the burst generation.

  • 86.
    Kozlov, Alexander
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Huss, Mikael
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Grillner, Sten
    Central and local control principles for vertebrate locomotionManuskript (Övrigt vetenskapligt)
  • 87.
    Kozlov, Alexander
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Huss, Mikael
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, Sten
    Simple cellular and network control principles govern complex patterns of motor behavior2009Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 47, s. 20027-20032Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The vertebrate central nervous system is organized in modules that independently execute sophisticated tasks. Such modules are flexibly controlled and operate with a considerable degree of autonomy. One example is locomotion generated by spinal central pattern generator networks (CPGs) that shape the detailed motor output. The level of activity is controlled from brainstem locomotor command centers, which in turn, are under the control of the basal ganglia. By using a biophysically detailed, full-scale computational model of the lamprey CPG (10,000 neurons) and its brainstem/forebrain control, we demonstrate general control principles that can adapt the network to different demands. Forward or backward locomotion and steering can be flexibly controlled by local synaptic effects limited to only the very rostral part of the network. Variability in response properties within each neuronal population is an essential feature and assures a constant phase delay along the cord for different locomotor speeds.

  • 88.
    Kozlov, Alexander K.
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Kardamakis, Andreas A.
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, Sten
    Gating of steering signals through phasic modulation of reticulospinal neurons during locomotion2014Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 9, s. 3591-3596Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The neural control of movements in vertebrates is based on a set of modules, like the central pattern generator networks (CPGs) in the spinal cord coordinating locomotion. Sensory feedback is not required for the CPGs to generate the appropriate motor pattern and neither a detailed control from higher brain centers. Reticulospinal neurons in the brainstem activate the locomotor network, and the same neurons also convey signals from higher brain regions, such as turning/steering commands from the optic tectum (superior colliculus). A tonic increase in the background excitatory drive of the reticulospinal neurons would be sufficient to produce coordinated locomotor activity. However, in both vertebrates and invertebrates, descending systems are in addition phasically modulated because of feedback from the ongoing CPG activity. We use the lamprey as a model for investigating the role of this phasic modulation of the reticulospinal activity, because the brainstem-spinal cord networks are known down to the cellular level in this phylogenetically oldest extant vertebrate. We describe how the phasic modulation of reticulospinal activity from the spinal CPG ensures reliable steering/turning commands without the need for a very precise timing of on-or offset, by using a biophysically detailed large-scale (19,600 model neurons and 646,800 synapses) computational model of the lamprey brainstem-spinal cord network. To verify that the simulated neural network can control body movements, including turning, the spinal activity is fed to a mechanical model of lamprey swimming. The simulations also predict that, in contrast to reticulospinal neurons, tectal steering/turning command neurons should have minimal frequency adaptive properties, which has been confirmed experimentally.

  • 89. Krieger, P.
    et al.
    Hellgren Kotaleski, Jeanette
    Kettunen, P.
    El Manira, A. J.
    Interaction between metabotropic and ionotropic glutamate receptors regulates neuronal network activity2000Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 20, nr 14, s. 5382-5391Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Experimental and computational techniques have been used to investigate the group I metabotropic glutamate receptor (mGluR)-mediated increase in the frequency of spinal cord network activity underlying locomotion in the lamprey. Group I mGluR activation potentiated the amplitude of NMDA-induced currents in identified motoneurons and crossed caudally projecting network interneurons. Group I mGluRs also potentiated NMDA-induced calcium responses. This effect was blocked by a group I mGluR-specific antagonist, but not by blockers of protein kinase A, C, or G. The effect of group I mGluRs activation was also tested on NMDA-induced oscillations known to occur during fictive locomotion. Activation of these receptors increased the duration of the plateau phase and decreased the duration of the hyperpolarizing phase. These effects were blocked by a group I mGluR antagonist. To determine its role in the modulation of NMDA-induced oscillations and the locomotor burst frequency, the potentiation of NMDA receptors by mGluRs was simulated using computational techniques. Simulating the interaction between these receptors reproduced the modulation of the plateau and hyperpolarized phases of NMDA-induced oscillations, and the increase in the frequency of the locomotor rhythm. Our results thus show a postsynaptic interaction between group I mGluRs and NMDA receptors in lamprey spinal cord neurons, which can account for the regulation of the locomotor network output by mGluRs.

  • 90. Lansner, A
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ullström, M
    Grillner, S
    Local spinal modulation of the calcium dependent potassium channel underlying slow adaptation in a model of the lamprey CPG1998Konferensbidrag (Refereegranskat)
  • 91. Lansner, A
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ullström, M
    Grillner, S
    Modulating the calcium dependent potassium conductance in a model of the lamprey CPG1997Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
    Abstract [en]

    The lampery is a primitive water-living vertebrate that moves by means of undulatory swimming. It is of particular interest as an experimental model for the neural generation of locomotin [Grillner et al..,,, 1995] a major advantage of this system is that the motor pattern underlying swimming can be elicited in an isolated piece of spinal cord. Being one of the best characterized vertebrate neuronal systems, the lampery spinal CPG has been the subject of a number of modelling and simulation studies.

  • 92.
    Lindahl, Mikael
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Action selection in the basal ganglia - a computational investigation2010Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    The classical explanation for how basal ganglia could perform action selection relies on the direct and indirect pathway. In this computational study we instead build on earlier studies viewing the part performing selection as consisting of the direct and hyperdirect pathways, with the indirect pathway playing the role of controlling the balance between these two [1]. The present model is a further development of a previous spiking neuron model [2], reimplemented in the software NEST [3] using conductance based integrate and fire neurons. We explore the functional consequences of including additional connections known from experimental studies, such as the collaterals from the direct pathway striatal medium spiny neurons to globus pallidus externa (GPe) as well as a dual indirect pathway through GPe. Simulation experiments suggest that this new model can perform selection with an improved sensitivity and over a larger range of dopamine modulation.

  • 93.
    Lindahl, Mikael
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Short term plasticity within the basal ganglia - a systems level computational investigation2011Ingår i: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 12, nr Suppl 1, s. P145-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Striatal direct pathway medium spiny neurons (MSNs) converge, with inhibitory synapses onto output nuclei substantia nigra reticulata (SNr), which keep neurons in the thalamus, superior colliculus and pendunculopontine nuclei under tonic inhibition[1]. Recent experimental findings[2] have found short term facilitation in MSN synapses onto SNr neurons. We investigate the functional consequences of these findings using a basal ganglia system level model, with spiking MSNs modeled according to Izhikevich’s simple model[3] and with facilitating synapses[4] fitted to data in[2]. The model is implemented in the NEST[5] simulator. We quantify how striatal populations of MSNs can control activity in SNr neurons, and to what extent this depends on having weak static, strong static and facilitating synapses between MSNs and SNr neurons.

    Our simulation experiments predict that facilitating synapses allow baseline firing of presynaptic MSNs without suppressing target SNr neurons, while burst activation of only a few of these presynaptic striatal neurons can suppress the activity of one SNr neuron. This is in accordance with extracellular recordings in awake animals[6], where task dependent activity is transferred from a broad striatal population to a smaller subpopulation, responding increasingly stronger during learning of a task dependent behavior.

  • 94.
    Lindahl, Mikael
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsvetenskap och beräkningsteknik (CST).
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsvetenskap och beräkningsteknik (CST).
    Untangling basal ganglia network dynamics and function: role of dopamine depletion and inhibition investigated in a spiking network modelManuskript (preprint) (Övrigt vetenskapligt)
  • 95.
    Lindahl, Mikael
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Kotaleski, Jeanette Hellgren
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Untangling Basal Ganglia Network Dynamics and Function: Role of Dopamine Depletion and Inhibition Investigated in a Spiking Network Model2016Ingår i: ENEURO, ISSN 2373-2822, Vol. 3, nr 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The basal ganglia are a crucial brain system for behavioral selection, and their function is disturbed in Parkinson's disease (PD), where neurons exhibit inappropriate synchronization and oscillations. We present a spiking neural model of basal ganglia including plausible details on synaptic dynamics, connectivity patterns, neuron behavior, and dopamine effects. Recordings of neuronal activity in the subthalamic nucleus and Type A (TA; arkypallidal) and Type I (TI; prototypical) neurons in globus pallidus externa were used to validate the model. Simulation experiments predict that both local inhibition in striatum and the existence of an indirect pathway are important for basal ganglia to function properly over a large range of cortical drives. The dopamine depletion-induced increase of AMPA efficacy in corticostriatal synapses to medium spiny neurons (MSNs) with dopamine receptor D2 synapses (CTX-MSN D2) and the reduction of MSN lateral connectivity (MSN-MSN) were found to contribute significantly to the enhanced synchrony and oscillations seen in PD. Additionally, reversing the dopamine depletion-induced changes to CTX-MSN D1, CTX-MSN D2, TA-MSN, and MSN-MSN couplings could improve or restore basal ganglia action selection ability. In summary, we found multiple changes of parameters for synaptic efficacy and neural excitability that could improve action selection ability and at the same time reduce oscillations. Identification of such targets could potentially generate ideas for treatments of PD and increase our understanding of the relation between network dynamics and network function.

  • 96.
    Lindahl, Mikael
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Sarvestani, Iman Kamali
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ekeberg, Örjan
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Signal enhancement in the output stage of the basal ganglia by synaptic short-term plasticity in the direct, indirect, and hyperdirect pathways2013Ingår i: Frontiers in Computational Neuroscience, ISSN 1662-5188, E-ISSN 1662-5188, Vol. 7, s. UNSP 76-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many of the synapses in the basal ganglia display short-term plasticity. Still, computational models have not yet been used to investigate how this affects signaling. Here we use a model of the basal ganglia network, constrained by available data, to quantitatively investigate how synaptic short-term plasticity affects the substantia nigra reticulata (SNr), the basal ganglia output nucleus. We find that SNr becomes particularly responsive to the characteristic burst-like activity seen in both direct and indirect pathway striatal medium spiny neurons (MSN). As expected by the standard model, direct pathway MSNs are responsible for decreasing the activity in SNr. In particular, our simulations indicate that bursting in only a few percent of the direct pathway MSNs is sufficient for completely inhibiting SNr neuron activity. The standard model also suggests that SNr activity in the indirect pathway is controlled by MSNs disinhibiting the subthalamic nucleus (STN) via the globus pallidus externa (GPe). Our model rather indicates that SNr activity is controlled by the direct GPe-SNr projections. This is partly because GPe strongly inhibits SNr but also due to depressing STN-SNr synapses. Furthermore, depressing GPe-SNr synapses allow the system to become sensitive to irregularly firing GPe subpopulations, as seen in dopamine depleted conditions, even when the GPe mean firing rate does not change. Similar to the direct pathway, simulations indicate that only a few percent of bursting indirect pathway MSNs can significantly increase the activity in SNr. Finally, the model predicts depressing STN-SNr synapses, since such an assumption explains experiments showing that a brief transient activation of the hyperdirect pathway generates a tri-phasic response in SNr, while a sustained STN activation has minor effects. This can be explained if STN-SNr synapses are depressing such that their effects are counteracted by the (known) depressing GPe-SNr inputs.

  • 97. Lindskog, M
    et al.
    Blackwell, K.T.
    Wikstrom, M
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    A kinetic model on DARPP-32 and the PKA/PP1 cascade2002Konferensbidrag (Refereegranskat)
  • 98. Lindskog, M.
    et al.
    Halnes, Geir
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Oliveira, R. F.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Blackwell, K. T.
    Biochemical Networks in Psychiatric Disease2010Ingår i: Systems Biology in Psychiatric Research: From High-Throughput Data to Mathematical Modeling, Wiley-VCH Verlagsgesellschaft, 2010, s. 301-320Kapitel i bok, del av antologi (Refereegranskat)
  • 99. Lindskog, Maria
    et al.
    Kim, MyungSook
    Wikstrom, Martin A.
    Blackwell, Kim T.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation2006Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, nr 9, s. 1045-1060Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Reinforcement learning theorizes that strengthening of synaptic connections in medium spiny neurons of the striatum occurs when glutamatergic input (from cortex) and dopaminergic input (from substantia nigra) are received simultaneously. Subsequent to learning, medium spiny neurons with strengthened synapses are more likely to fire in response to cortical input alone. This synaptic plasticity is produced by phosphorylation of AMPA receptors, caused by phosphorylation of various signalling molecules. A key signalling molecule is the phosphoprotein DARPP-32, highly expressed in striatal medium spiny neurons. DARPP-32 is regulated by several neurotransmitters through a complex network of intracellular signalling pathways involving cAMP (increased through dopamine stimulation) and calcium (increased through glutamate stimulation). Since DARPP-32 controls several kinases and phosphatases involved in striatal synaptic plasticity, understanding the interactions between cAMP and calcium, in particular the effect of transient stimuli on DARPP-32 phosphorylation, has major implications for understanding reinforcement learning. We developed a computer model of the biochemical reaction pathways involved in the phosphorylation of DARPP-32 on Thr34 and Thr75. Ordinary differential equations describing the biochemical reactions were implemented in a single compartment model using the software XPPAUT. Reaction rate constants were obtained from the biochemical literature. The first set of simulations using sustained elevations of dopamine and calcium produced phosphorylation levels of DARPP-32 similar to that measured experimentally, thereby validating the model. The second set of simulations, using the validated model, showed that transient dopamine elevations increased the phosphorylation of Thr34 as expected, but transient calcium elevations also increased the phosphorylation of Thr34, contrary to what is believed. When transient calcium and dopamine stimuli were paired, PKA activation and Thr34 phosphorylation increased compared with dopamine alone. This result, which is robust to variation in model parameters, supports reinforcement learning theories in which activity-dependent long-term synaptic plasticity requires paired glutamate and dopamine inputs.

  • 100. Manninen, Tiina
    et al.
    Hituri, Katri
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Blackwell, Kim T.
    Linne, Marja-Leena
    Postsynaptic signal transduction models for long-term potentiation and depression2010Ingår i: FRONTIERS IN COMPUTATIONAL NEUROSCIENCE, ISSN 1662-5188, Vol. 4, s. 152-Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    More than a hundred biochemical species, activated by neurotransmitters binding to transmembrane receptors, are important in long-term potentiation (LTP) and long-term depression (LTD). To investigate which species and interactions are critical for synaptic plasticity, many computational postsynaptic signal transduction models have been developed. The models range from simple models with a single reversible reaction to detailed models with several hundred kinetic reactions. In this study, more than a hundred models are reviewed, and their features are compared and contrasted so that similarities and differences are more readily apparent. The models are classified according to the type of synaptic plasticity that is modeled (LTP or LTD) and whether they include diffusion or electrophysiological phenomena. Other characteristics that discriminate the models include the phase of synaptic plasticity modeled (induction, expression, or maintenance) and the simulation method used (deterministic or stochastic). We find that models are becoming increasingly sophisticated, by including stochastic properties, integrating with electrophysiological properties of entire neurons, or incorporating diffusion of signaling molecules. Simpler models continue to be developed because they are computationally efficient and allow theoretical analysis. The more complex models permit investigation of mechanisms underlying specific properties and experimental verification of model predictions. Nonetheless, it is difficult to fully comprehend the evolution of these models because (1) several models are not described in detail in the publications, (2) only a few models are provided in existing model databases, and (3) comparison to previous models is lacking. We conclude that the value of these models for understanding molecular mechanisms of synaptic plasticity is increasing and will be enhanced further with more complete descriptions and sharing of the published models.

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