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  • 101.
    Nair, Anu G.
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Bhalla, Upinder S
    Kotaleski, Jeanette Hellgren
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsvetenskap och beräkningsteknik (CST).
    Role of DARPP-32 and ARPP-21 in the Emergence of Temporal Constraints on Striatal Calcium and Dopamine Integration2016Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 12, nr 9, artikel-id e1005080Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In reward learning, the integration of NMDA-dependent calcium and dopamine by striatal projection neurons leads to potentiation of corticostriatal synapses through CaMKII/PP1 signaling. In order to elicit the CaMKII/PP1-dependent response, the calcium and dopamine inputs should arrive in temporal proximity and must follow a specific (dopamine after calcium) order. However, little is known about the cellular mechanism which enforces these temporal constraints on the signal integration. In this computational study, we propose that these temporal requirements emerge as a result of the coordinated signaling via two striatal phosphoproteins, DARPP-32 and ARPP-21. Specifically, DARPP-32-mediated signaling could implement an input-interval dependent gating function, via transient PP1 inhibition, thus enforcing the requirement for temporal proximity. Furthermore, ARPP-21 signaling could impose the additional input-order requirement of calcium and dopamine, due to its Ca2+/calmodulin sequestering property when dopamine arrives first. This highlights the possible role of phosphoproteins in the temporal aspects of striatal signal transduction.

  • 102.
    Nair, Anu G.
    et al.
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Castro, Liliana R. V.
    Sorbonne Univ, CNRS, Biol Adaptat & Ageing, F-75005 Paris, France.;Biopsy Labex, Paris, France..
    El Khoury, Marianne
    Biopsy Labex, Paris, France.;Sorbonne Univ, CNRS, Neurosci Paris Seine, F-75005 Paris, France..
    Gorgievski, Victor
    Biopsy Labex, Paris, France.;Sorbonne Univ, CNRS, Neurosci Paris Seine, F-75005 Paris, France..
    Giros, Bruno
    Biopsy Labex, Paris, France.;Sorbonne Univ, CNRS, Neurosci Paris Seine, F-75005 Paris, France.;McGill Univ, Fac Med, Douglas Mental Hlth Univ Inst, Dept Psychiat, Montreal, PQ, Canada..
    Tzavara, Eleni T.
    Biopsy Labex, Paris, France.;Sorbonne Univ, CNRS, Neurosci Paris Seine, F-75005 Paris, France..
    Hellgren Kotaleski, Jeanette
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Vincent, Pierre
    Sorbonne Univ, CNRS, Biol Adaptat & Ageing, F-75005 Paris, France.;Biopsy Labex, Paris, France..
    The high efficacy of muscarinic M4 receptor in D1 medium spiny neurons reverses striatal hyperdopaminergia2019Ingår i: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 146, s. 74-83Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The opposing action of dopamine and acetylcholine has long been known to play an important role in basal ganglia physiology. However, the quantitative analysis of dopamine and acetylcholine signal interaction has been difficult to perform in the native context because the striatum comprises mainly two subtypes of medium-sized spiny neurons (MSNs) on which these neuromodulators exert different actions. We used biosensor imaging in live brain slices of dorsomedial striatum to monitor changes in intracellular cAMP at the level of individual MSNs. We observed that the muscarinic agonist oxotremorine decreases cAMP selectively in the MSN sub population that also expresses D-1 dopamine receptors, an action mediated by the M-4 muscarinic receptor. This receptor has a high efficacy on cAMP signaling and can shut down the positive cAMP response induced by dopamine, at acetylcholine concentrations which are consistent with physiological levels. This supports our prediction based on theoretical modeling that acetylcholine could exert a tonic inhibition on striatal cAMP signaling, thus supporting the possibility that a pause in acetylcholine release is required for phasic dopamine to transduce a cAMP signal in D1 MSNs. In vivo experiments with acetylcholinesterase inhibitors donepezil and tacrine, as well as with the positive allosteric modulators of M-4 receptor VU0152100 and VU0010010 show that this effect is sufficient to reverse the increased locomotor activity of DAT-knockout mice. This suggests that M-4 receptors could be a novel therapeutic target to treat hyperactivity disorders.

  • 103.
    Nair, Anu G.
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Gutierrez-Arenas, Omar
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Eriksson, Olivia
    Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm.
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Can MSNs listen to the cholinergic pause via M4R?Manuskript (preprint) (Övrigt vetenskapligt)
  • 104.
    Nair, Anu G.
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Gutierrez-Arenas, Omar
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, 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, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Modeling Intracellular Signaling Underlying Striatal Function in Health and Disease2014Ingår i: Computational Neuroscience / [ed] Blackwell, K.T., Elsevier, 2014, Vol. 123, s. 277-304Kapitel i bok, del av antologi (Refereegranskat)
    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.

  • 105.
    Nair, Anu G.
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Manipal Univ, India.
    Gutierrez-Arenas, Omar
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Eriksson, Olivia
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Vincent, Pierre
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, 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 Neurons2015Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, nr 41, s. 14017-14030Artikel i tidskrift (Refereegranskat)
    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.

  • 106.
    Nair, Anu G.
    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).
    Detection of phasic dopamine by D1 and D2 striatal medium spiny neuronsIngår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793Artikel i tidskrift (Refereegranskat)
  • 107. Paille, V
    et al.
    Du, K
    Deniau, J-M
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Fino, E
    Venance, L
    GABAergic microcircuits govern the corticostriatal spike-timing dependent plasticity2010Konferensbidrag (Refereegranskat)
    Abstract [en]

    We investigated the corticostriatal spike timing-dependentplasticity (STDP) at medium-sized spiny neurons (MSNs) as aHebbian learning rule. Here, we show that GABAergic microcircuitsgovern the spike-timing dependence. Indeed, whenGABAergic transmission was blocked (by GABAA blockers)the spike-timing dependence was totally reversed when comparedto control conditions. Post-pre pairings induced t-LTDand pre-post pairings induced t-LTP. In both control andGABAA blockade conditions, the t-LTP was NMDA receptordependent and the t-LTD was endocannabinoid dependent.The GABAergic inhibition at MSNs arises mainly from fastspiking interneurons. Indeed, we observed, in paravalbumin-GFP mice, that during STDP pairings fast-spiking interneuronsdischarge and exert a strong synaptic inhibitory weight onMSNs. In addition, both tonic and phasic components of suchGABAergic inhibition were involved in the spike-timing dependence.We observed a developmental shift of the spiketimingdependence correlated with the maturation of theGABAergic microcircuits: at P8-10, post-pre pairings induced t-LTD and pre-post pairings induced t-LTP, while a reversedSTDP timing-dependence was found after P20. To further ourunderstanding on dendritic GABAergic signal integration inMSNs, we simulated the experimental STDP protocols using abiophysically detailed MSN model. The simulation results predicteda significant influence of GABAergic inputs in distaldendrites, although not visible in the soma. Moreover, oursimulations showed that the balance between NMDA calciumand L-type calcium voltage channels could be shifted by eithertonic or phasic GABAergic inputs, or by their combinations.This in turn could influence whether NMDA-dependent LTP orL-type calcium- (also endocannabinoid-) dependent LTD occurs.In conclusion, we demonstrated that GABAergic microcircuitstightly govern the corticostriatal plasticity and re-orientate STDP along development.

  • 108. Paille, Vincent
    et al.
    Fino, Elodie
    Du, Kai
    Morera-Herreras, Teresa
    Perez, Sylvie
    Hällgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Venance, Laurent
    GABAergic Circuits Control Spike-Timing-Dependent Plasticity2013Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, nr 22, s. 9353-9363Artikel i tidskrift (Refereegranskat)
    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.

  • 109. Ritz, R
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Strandberg, P
    Larsson, A
    Lillberg, Y
    Chatzopoulou, E
    Holm, P
    Naeslund, M
    Wang, H
    Bjaalie, J.G.
    A new software center for the neuroinformatics community2008Ingår i: / [ed] William R Holmes, 2008Konferensbidrag (Refereegranskat)
    Abstract [en]

    The mission of the International Neuroinformatics Coordinating Facility is to coordinate and foster international activities in neuroinformatics. In general, this includes combining neuroscience and informatics research to develop and apply advanced tools and approaches essential for a major advancement in understanding the structure and function of the brain. There are a significant number of resources available for neuroscientists today, yet they are not used as widely as they should because discovering their existence and evaluating their quality and relevance remain tedious tasks. Furthermore, the development of such resources often relies on isolated laboratories where collaboration across projects would be beneficial. INCF has therefore created a Neuroinformatics Portal, and released a Software Center as its first component.

  • 110. Robertson, B
    et al.
    Jones, M
    Samuelsson, E
    Hill, R
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S
    The lamprey basal ganglia - A vertebrate blue-print2009Konferensbidrag (Refereegranskat)
  • 111. Samuelsson, E.
    et al.
    Hill, R.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Exploration of the lamprey pallidal neurons: a combined computational and experimental study2009Konferensbidrag (Refereegranskat)
    Abstract [en]

    The cortex-basal ganglia-thalamic loops are critical for the selection and initiation of motor actions[1]. The output stage of the basal ganglia, Globus Pallidus interna (GPi) and Substantia Nigra reticulata (SNr) in primates, plays an important role by providing tonic inhibition to motor centers in the brain stem and thalamus. GPi/SNr are controlled by input from the striatum, the input stage of the basal ganglia and also by other basal ganglia nuclei, Globus Pallidus externa (GPe) and Subthalamic nucleus (STN). In the present combined experimental and computational study, we investigate the membrane properties and the synaptic control of the neurons in the lamprey basal ganglia output stages. We have combined electrophysiological and immunohistochemical studies to investigate morphology and physiology properties. Using patch clamp techniques, we have recorded spontaneous activity and membrane properties [unpublished data].

  • 112. Samuelsson, E.
    et al.
    Hill, R.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    The basal ganglia output stage in the lamprey: a combined experimental and modeling study2009Konferensbidrag (Refereegranskat)
    Abstract [en]

    Based on previous immunohistochemical study Robertson et al., (J Comp Neurol, 2006) believed that a lamprey homolog of the primate globus pallidus interna (GPi) exists. They found GABAergic neurons in medial pallidum projecting to optic tectum, an area homologous to the superior colliculus in mammals. Medial pallidum in lamprey also receives GABAergic projections from striatum. This study aims to investigate the electrophysiological characteristics of the putative pallidal neurons.We have used lamprey brain slices and patch recordings to characterise neurons in the medial pallidum. The glutamate blockers CNQX and AP-V have been used to test spontaneous activity dependency of excitatory synaptic input. Projecting neurons in the pallidal area are sparsely scattered and do not form an easily detectable anatomical area. To record from projecting neurons we retrogradely labelled cell somas by tracer injections. The tracer (dextran 488 coupled ) was injected in optic tectum in the anaesthetized animal 12-24 hours before the experiment. Preliminary results show both tonically active and non active neurons in the medial pallidum. A majority of the neurons in rat entopeduncular nucleus, homologous of primate GPi, are persistently spontaneously active (Nakanishi et al., Brain Res, 1991). We have found neurons with frequency adaptation and with persistent spiking when depolarising current is injected.Recordings from labelled neurons display a subpopulation of spontaneously active neurons. These neurons were found in a narrow area near the border between the diencephalon and the mesencephalon. Results from blocking glutamatergic synaptic input indicate that intrinsic neuron properties generate the spontaneous activity. We have used the experimental findings to investigate a computer model of a lamprey pallidal neuron. The model have been tuned to replicate experimental data and characteristics of lamprey pallidal neurons.We therefore conclude that neurons with pallidal properties exist in lamprey and are homologous to primate globus pallidus interna, a output stage of basal ganglia.

  • 113. Samuelsson, Ebba
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Exploring GABAergic and dopaminergic effects in a minimal model of a medium spiny projection neuron2007Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 70, nr 12-okt, s. 1615-1618Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Striatum is the input stage of the basal ganglia, a collection of nuclei in the midbrain. The basal ganglia are involved in cognitive and motor behaviour, including reward-dependent learning. The reward system in the brain is heavily linked to the dopaminergic system, and many striatal neurons react in a reward-dependent manner. This study explores a minimal model of a striatal medium spiny (MS) projection neuron displaying dopamine-induced bistability. MS neurons mostly fluctuate between two states, a hyperpolarised down-state and a depolarised up-state. MS neurons are only active in the up-state and therefore spiking requires the transition from the down-state. For high dopamine levels in the model, the appearance of a bifurcation results in more distinct state transitions. GABAergic input from local fast-spiking interneurons to MS neurons results in a small depolarisation, but far from causing a transition to the up-state by itself. We investigate if a GABAergic PSP could facilitate the transition to the up-state elicited by glutamatergic input. The model predicts that GABAergic input to MS neurons might facilitate and speed up the transition to the up-state. The prerequisite for this is that the GABAergic enhancement starts slightly before the glutamatergic increase which causes the up-state transition.

  • 114.
    Sandström, Malin
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Scaling effects in a model of the olfactory bulb2007Ingår i: Neurocomputing, ISSN 0925-2312, Vol. 70, nr 10-12, s. 1802-1807Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most computational models of the olfactory bulb are much smaller than any biological olfactory bulb-usually because the number of granule cells is much lower. The resulting subsampling of the inhibitory input may distort network dynamics and processing. We have constructed a large-scale model of the zebrafish olfactory bulb, as well as two smaller models, using the efficient parallellizing neural simulator SPLIT and data from a previously existing GENESIS model. We are studying several characteristics-among them overall behaviour, degree of synchrony of mitral cells and the timescale of appearance of synchrony-using cross-correlation plots and synthesized EEGs. Larger models with higher proportions of granule cells to mitral cells appear to give more synchronized output, especially for stimuli with shorter timescales.

  • 115.
    Sandström, Malin
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hjorth, Johannes
    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.
    The impact of the distribution of isoforms on CaMKII activation2006Ingår i: Neurocomputing, ISSN 0925-2312, Vol. 69, nr 10-12, s. 1010-1013Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have developed a computational model of the regulation of alpha- and beta-CaMKII activity, in order to examine (i) the importance of neighbour subunit interactions and (ii) the effect the higher CaMCa4 affinity of beta-CaMKII has on the holoenzyme activity in different configurations with the same alpha: beta ratio. The model consists of a deterministic biochemical network coupled to stochastic activation of CaMKII The results suggest that CaMKII holoenzyme activity is non-linear and dependent on the holoenzyme configuration of isoforms. This is especially pronounced in situations with a high-dephosphorylation rate of CaMKII.

  • 116.
    Sandström, Malin
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Källgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Varying Olfactory Receptor Numbers Give Rise to a Fuzzy Code for Stimulus Concentration.Manuskript (preprint) (Övrigt vetenskapligt)
  • 117.
    Sandström, Malin
    et al.
    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.
    Rospars, Jean-Pierre
    Modeling the response of a population of olfactory receptor neurons to an odorant2009Ingår i: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 27, s. 337-355Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We modeled the firing rate of populations of olfactory receptor neurons (ORNs) responding to an odorant at different concentrations. Two cases were considered: a population of ORNs that all express the same olfactory receptor (OR), and a population that expresses many different ORs. To take into account ORN variability, we replaced single parameter values in a biophysical ORN model with values drawn from statistical distributions, chosen to correspond to experimental data. For ORNs expressing the same OR, we found that the distributions of firing frequencies are Gaussian at all concentrations, with larger mean and standard deviation at higher concentrations. For a population expressing different ORs, the distribution of firing frequencies can be described as the superposition of a Gaussian distribution and a lognormal distribution. Distributions of maximum value and dynamic range of spiking frequencies in the simulated ORN population were similar to experimental results.

  • 118.
    Sandström, Malin
    et al.
    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.
    Rospars, Jean-Pierre
    Modelling the population of olfactory receptor neurons2007Manuskript (preprint) (Övrigt vetenskapligt)
  • 119.
    Suryanarayana, Shreyas M.
    et al.
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Hellgren Kotaleski, Jeanette
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för elektroteknik och datavetenskap (EECS). Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Grillner, Sten
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Gurney, Kevin N.
    Univ Sheffield, Dept Psychol, Sheffield, S Yorkshire, England..
    Roles for globus pallidus externa revealed in a computational model of action selection in the basal ganglia2019Ingår i: Neural Networks, ISSN 0893-6080, E-ISSN 1879-2782, Vol. 109, s. 113-136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The basal ganglia are considered vital to action selection - a hypothesis supported by several biologically plausible computational models. Of the several subnuclei of the basal ganglia, the globus pallidus externa (GPe) has been thought of largely as a relay nucleus, and its intrinsic connectivity has not been incorporated in significant detail, in any model thus far. Here, we incorporate newly revealed subgroups of neurons within the GPe into an existing computational model of the basal ganglia, and investigate their role in action selection. Three main results ensued. First, using previously used metrics for selection, the new extended connectivity improved the action selection performance of the model. Second, low frequency theta oscillations were observed in the subpopulation of the GPe (the TA or 'arkypallidal' neurons) which project exclusively to the striatum. These oscillations were suppressed by increased dopamine activity - revealing a possible link with symptoms of Parkinson's disease. Third, a new phenomenon was observed in which the usual monotonic relationship between input to the basal ganglia and its output within an action 'channel' was, under some circumstances, reversed. Thus, at high levels of input, further increase of this input to the channel could cause an increase of the corresponding output rather than the more usually observed decrease. Moreover, this phenomenon was associated with the prevention of multiple channel selection, thereby assisting in optimal action selection. Examination of the mechanistic origin of our results showed the so-called 'prototypical' GPe neurons to be the principal subpopulation influencing action selection. They control the striatum via the arkypallidal neurons and are also able to regulate the output nuclei directly. Taken together, our results highlight the role of the GPe as a major control hub of the basal ganglia, and provide a mechanistic account for its control function.

  • 120.
    Svantesson, Anna
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Nordström, Tommy
    KTH, Skolan för bioteknologi (BIO).
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Nyrén, Pål
    KTH, Skolan för bioteknologi (BIO).
    An Investigation of the Apyrase Stepin the Pyrosequencing Model:Combining Experiments and Simulations.2005Rapport (Övrigt vetenskapligt)
  • 121.
    Svantesson, Anna
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Westermark, Pål. O.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Gharizadeh, Baback
    KTH, Tidigare Institutioner, Bioteknologi.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Nyrén, Pål
    KTH, Tidigare Institutioner, Bioteknologi.
    A mathematical model of the Pyrosequencing reaction system2004Ingår i: Biophysical Chemistry, ISSN 0301-4622, E-ISSN 1873-4200, Vol. 110, nr 02-jan, s. 129-145Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Pyrosequencing(TM) technology is a newly developed DNA sequencing method that monitors DNA nucleotide incorporation in real-time. A set of coupled enzymatic reactions, together with bioluminescence, detects incorporated nucleotides in the form of light pulses, yielding a characteristic light profile. In this study, a biochemical model of the Pyrosequencing reaction system is suggested and implemented. The model is constructed utilizing an assumption of irreversible Michaelis-Menten rate equations and a constant incorporation efficiency. The kinetic parameters are studied and values are chosen to obtain as reliable simulation results as possible. The results presented here show strong resemblance with real experiments. The model is able to capture the dynamics of a single light pulse with great accuracy, as well as the overall characteristics of a whole pyrogram(TM). The plus- and minus-shift effects observed in experiments are successfully reconstructed by two constant efficiency factors. Furthermore, pulse broadening can partly be explained by apyrase inhibition and successive dilution.

  • 122.
    Svantesson, Anna
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Westermark, Pål O.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Nyrén, Pål
    KTH, Skolan för bioteknologi (BIO).
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Towards an Improved Polymerase Descriptionin the Pyrosequencing Model.2005Rapport (Övrigt vetenskapligt)
  • 123.
    Sweeney, Yann
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. University of Edinburgh, United Kingdom.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hennig, Matthias H.
    A Diffusive Homeostatic Signal Maintains Neural Heterogeneity and Responsiveness in Cortical Networks2015Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 11, nr 7, artikel-id e1004389Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gaseous neurotransmitters such as nitric oxide (NO) provide a unique and often overlooked mechanism for neurons to communicate through diffusion within a network, independent of synaptic connectivity. NO provides homeostatic control of intrinsic excitability. Here we conduct a theoretical investigation of the distinguishing roles of NO-mediated diffusive homeo-stasis in comparison with canonical non-diffusive homeostasis in cortical networks. We find that both forms of homeostasis provide a robust mechanism for maintaining stable activity following perturbations. However, the resulting networks differ, with diffusive homeostasis maintaining substantial heterogeneity in activity levels of individual neurons, a feature disrupted in networks with non-diffusive homeostasis. This results in networks capable of representing input heterogeneity, and linearly responding over a broader range of inputs than those undergoing non-diffusive homeostasis. We further show that these properties are preserved when homeostatic and Hebbian plasticity are combined. These results suggest a mechanism for dynamically maintaining neural heterogeneity, and expose computational advantages of non-local homeostatic processes.

  • 124. Tegner, J
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, A
    Grillner, S
     A computational and experimental study of rebound firing and modulatory effects on the lamprey spinal network1997Konferensbidrag (Refereegranskat)
  • 125. Tegner, J
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, A
    Grillner, S
    Computer simulations of low voltage activated calcium channels in the lamprey spinal network1996Konferensbidrag (Refereegranskat)
    Abstract [en]

    Low-voltage-activated calcium channels in the lamprey locomotor network: simulation and experiment. J. Neurophysiol. 77: 1795–1812, 1997. To evaluate the role of low-voltage-activated (LVA) calcium channels in the lamprey spinal locomotor network, a previous computer simulation model has been extended to include LVA calcium channels. It is also of interest to explore the consequences of a LVA conductance for the electrical behavior of the single neuron. The LVA calcium channel was modeled with voltage-dependent activation and inactivation using the m 3 h form, following a Hodgkin-Huxley paradigm. Experimental data from lamprey neurons was used to provide parameter values of the single cell model. The presence of a LVA calcium conductance in the model could account for the occurrence of a rebound depolarization in the simulation model. The influence of holding potential on the occurrence of a rebound as well the latency at which it is elicited was investigated and compared with previous experiments. The probability of a rebound increased at a more depolarized holding potential and the latency was also reduced under these conditions. Furthermore, the effect of changing the holding potential and the reversal potential of the calcium dependent potassium conductance were tested to determine under which conditions several rebound spikes could be elicited after a single inhibitory pulse in the simulation model. A reduction of the slow afterhyperpolarization (sAHP) after the action potential reduced the tendency for a train of rebound spikes. The experimental effects of γ-aminobutyric acid-B(GABAB) receptor activation were simulated by reducing the maximal LVA calcium conductance. A reduced tendency for rebound firing and a slower rising phase with sinusoidal current stimulation was observed, in accordance with earlier experiments. The effect of reducing the slow afterhyperpolarization and reducing the LVA calcium current was tested experimentally in the lamprey spinal cord, during N-methyl-d-aspartate (NMDA)-induced fictive locomotion. The reduction of burst frequency was more pronounced with GABAB agonists than with apamin (inhibitor of K(Ca) current) when using high NMDA concentration (high burst frequency). The burst frequency increased after the addition of a LVA calcium current to the simulated segmental network, due to a faster recovery during the inhibitory phase as the activity switches between the sides. This result is consistent with earlier experimental findings because GABAB receptor agonists reduce the locomotor frequency. These results taken together suggest that the LVA calcium channels contribute to a larger degree with respect to the burst frequency regulation than the sAHP mechanism at higher burst frequencies. The range in which a regular burst pattern can be simulated is extended in the lower range by the addition of LVA calcium channels, which leads to more stable activity at low locomotor frequencies. We conclude that the present model can account for rebound firing and trains of rebound spikes in lamprey neurons. The effects of GABAB receptor activation on the network level is consistent with a reduction of the calcium current through LVA calcium channels even though GABAB receptor activation will affect the sAHP indirectly and also presynaptic inhibition.

  • 126. Tegner, J
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, A
    Grillner, S
    Low voltage activated calcium channels in the lamprey locomotor network - simulation and experiment1997Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 77, s. 1795-1812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To evaluate the role of low-voltage-activated (LVA) calcium channels in the lamprey spinal locomotor network, a previous computer simulation model has been extended to include LVA calcium channels. It is also of interest to explore the consequences of a LVA conductance for the electrical behavior of the single neuron. The LVA calcium channel was modeled with voltage-dependent activation and inactivation using the m3h form, following a Hodgkin-Huxley paradigm. Experimental data from lamprey neurons was used to provide parameter values of the single cell model. The presence of a LVA calcium conductance in the model could account for the occurrence of a rebound depolarization in the simulation model. The influence of holding potential on the occurrence of a rebound as well the latency at which it is elicited was investigated and compared with previous experiments. The probability of a rebound increased at a more depolarized holding potential and the latency was also reduced under these conditions. Furthermore, the effect of changing the holding potential and the reversal potential of the calcium dependent potassium conductance were tested to determine under which conditions several rebound spikes could be elicited after a single inhibitory pulse in the simulation model. A reduction of the slow afterhyperpolarization (sAHP) after the action potential reduced the tendency for a train of rebound spikes. The experimental effects of gamma-aminobutyric acid-B (GABA(B)) receptor activation were simulated by reducing the maximal LVA calcium conductance. A reduced tendency for rebound firing and a slower rising phase with sinusoidal current stimulation was observed, in accordance with earlier experiments. The effect of reducing the slow afterhyperpolarization and reducing the LVA calcium current was tested experimentally in the lamprey spinal cord, during N-methyl-D-aspartate (NMDA)-induced fictive locomotion. The reduction of burst frequency was more pronounced with GABA(B) agonists than with apamin (inhibitor of K(Ca) current) when using high NMDA concentration (high burst frequency). The burst frequency increased after the addition of a LVA calcium current to the simulated segmental network, due to a faster recovery during the inhibitory phase as the activity switches between the sides. This result is consistent with earlier experimental findings because GABA(B) receptor agonists reduce the locomotor frequency. These results taken together suggest that the LVA calcium channels contribute to a larger degree with respect to the burst frequency regulation than the sAHP mechanism at higher burst frequencies. The range in which a regular burst pattern can be simulated is extended in the lower range by the addition of LVA calcium channels, which leads to more stable activity at low locomotor frequencies. We conclude that the present model can account for rebound firing and trains of rebound spikes in lamprey neurons. The effects of GABA(B) receptor activation on the network level is consistent with a reduction of the calcium current through LVA calcium channels even though GABA(B) receptor activation will affect the sAHP indirectly and also presynaptic inhibition.

  • 127. Tegner, Jesper
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Lansner, Anders
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Grillner, Sten
    Low-voltage-activated calcium channels in the lamprey locomotor network: Simulation and experiment1997Ingår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 77, nr 4, s. 1795-1812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To evaluate the role of low-voltage-activated (LVA) calcium channels in the lamprey spinal locomotor network, a previous computer simulation model has been extended to include LVA calcium channels. It is also of interest to explore the consequences of a LVA conductance for the electrical behavior of the single neuron. The LVA calcium channel was modeled with voltage-dependent activation and inactivation using the m(3)h form, following a Hodgkin-Huxley paradigm. Experimental data from lamprey neurons was used to provide parameter values of the single cell model. The presence of a LVA calcium conductance in the model could account for the occurrence of a rebound depolarization in the simulation model. The influence of holding potential on the occurrence of a rebound as well the latency at which it is elicited was investigated and compared with previous experiments. The probability of a rebound increased at a more depolarized holding potential and the latency was also reduced under these conditions. Furthermore, the effect of changing the holding potential and the reversal potential of the calcium dependent potassium conductance were tested to determine under which conditions several rebound spikes could be elicited after a single inhibitory pulse in the simulation model. A reduction of the slow afterhyperpolarization (sAHP) after the action potential reduced the tendency for a train of rebound spikes. The experimental effects of gamma-aminobutyric acid-B (GABA(B)) receptor activation were simulated by reducing the maximal LVA calcium conductance. A reduced tendency for rebound firing and a slower rising phase with sinusoidal current stimulation was observed, in accordance with earlier experiments. The effect of reducing the slow afterhyperpolarization and reducing the LVA calcium current was tested experimentally in the lamprey spinal cord, during N-methyl-D-aspartate (NMDA)-induced fictive locomotion. The reduction of burst frequency was more pronounced with GABA(B) agonists than with apamin (inhibitor of K-(Ca) current) when using high NMDA concentration (high burst frequency). The burst frequency increased after the addition of a LVA calcium current to the simulated segmental network, due to a faster recovery during the inhibitory phase as the activity switches between the sides. This result is consistent with earlier experimental findings because GABA(B) receptor agonists reduce the locomotor frequency. These results taken together suggest that the LVA calcium chancels contribute to a larger degree with respect to the burst frequency regulation than the sAHP mechanism at higher burst frequencies. The range in which a regular burst pattern can be simulated is extended in the lower range by the addition of LVA calcium channels, which leads to more stable activity at low locomotor frequencies. We conclude that the present model can account for rebound firing and trains of rebound spikes in lamprey neurons. The effects of GABA(B) receptor activation on the network level is consistent with a reduction of the calcium current through LVA calcium channels even though GABA(B) receptor activation will affect the sAHP indirectly and also presynaptic inhibition.

  • 128. Tegnér, J
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    The synaptic NMDA component desynchronizes neural bursters1999Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 26-27, s. 557-563Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The influence of excitatory and inhibitory coupling on synchronization depends on the temporal dynamics of the synapse. Slow excitation is desynchronizing whereas fast excitation tends to synchronize neuronal firing. Excitation via glutamatergic synapses, however, activates both ionotropic AMPA/kainate and NMDA receptors. Here we analyze the role of the synaptic NMDA component. We show that slowly bursting neurons desynchronize when connected by symmetrical NMDA synapses whereas they tend to synchronize when coupled with symmetrical AMPA/kainate synapses. This suggests that the effect on synchronization of an excitatory synapse also depends on the relative proportion of NMDA and AMPA/kainate synapses.

  • 129. Ullström, M
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Tegnér, Jon
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Aurell, Erik
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Grillner, Sten
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Activity-dependent modulation of adaptation produces a constant burst proportion in a model of the lamprey spinal locomotor generator.1998Ingår i: Biological Cybernetics, ISSN 0340-1200, E-ISSN 1432-0770, Vol. 79, nr 1, s. 1-14Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The neuronal network underlying lamprey swimming has stimulated extensive modelling on different levels of abstraction. The lamprey swims with a burst frequency ranging from 0.3 to 8-10 Hz with a rostrocaudal lag between bursts in each segment along the spinal cord. The swimming motor pattern is characterized by a burst proportion that is independent of burst frequency and lasts around 30%-40% of the cycle duration. This also applies in preparations in which the reciprocal inhibition in the spinal cord between the left and right side is blocked. A network of coupled excitatory neurons producing hemisegmental oscillations may form the basis of the lamprey central pattern generator (CPG). Here we explored how such networks, in principle, could produce a large frequency range with a constant burst proportion. The computer simulations of the lamprey CPG use simplified, graded output units that could represent populations of neurons and that exhibit adaptation. We investigated the effect of an active modulation of the degree of adaptation of the CPG units to accomplish a constant burst proportion over the whole frequency range when, in addition, each hemisegment is assumed to be self-oscillatory. The degree of adaptation is increased with the degree of stimulation of the network. This will make the bursts terminate earlier at higher burst rates, allowing for a constant burst proportion. Without modulated adaptation the network operates in a limited range of swimming frequencies due to a progressive increase of burst duration with increasing background stimulation. By introducing a modulation of the adaptation, a broad burst frequency range can be produced. The reciprocal inhibition is thus not the primary burst terminating factor, as in many CPG models, and it is mainly responsible for producing alternation between the left and right sides. The results are compared with the Morris-Lecar oscillator model with parameters set to produce a type A and type B oscillator, in which the burst durations stay constant or increase, respectively, when the background stimulation is increased. Here as well, burst duration can be controlled by modulation of the slow variable in a similar way as above. When oscillatory hemisegmental networks are coupled together in a chain a phase lag is produced. The production of a phase lag in chains of such oscillators is compared with chains of Morris-Lecar relaxation oscillators. Models relating to the intact versus isolated spinal cord preparation are discussed, as well as the role of descending inhibition.

  • 130. Ullström, M
    et al.
    Lansner, A
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S
    Significance of modulated adaptation for rhythm generation and intersegmental co-ordination in lamprey1998Konferensbidrag (Refereegranskat)
  • 131. Wadden, T
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, A
    Grillner, S
    Intersegmental coordination in the lamprey: Simulations using a continuous network model1996Konferensbidrag (Refereegranskat)
  • 132. Wadden, T
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, A
    Grillner, S
    Simulations of the intersegmental coordination during swimming in the lamprey using a continuous network model1995Konferensbidrag (Refereegranskat)
  • 133.
    Wadden, Tom
    et al.
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Hellgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Lansner, Anders
    KTH, Tidigare Institutioner                               , Numerisk analys och datalogi, NADA.
    Grillner, Sten
    Intersegmental coordination in the lamprey: Simulations using a network model without segmental boundaries1997Ingår i: Biological Cybernetics, ISSN 0340-1200, E-ISSN 1432-0770, Vol. 76, nr 1, s. 1-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Swimming in vertebrates such as eel and lamprey involves the coordination of alternating left and right activity in each segment. Forward swimming is achieved by a lag between the onset of activity in consecutive segments rostrocaudally along the spinal cord. The intersegmental phase lag is approximately 1% of the cycle duration per segment and is independent of the swimming frequency. Since the lamprey has approximately 100 spinal segments, at any given time one wave of activity is propagated along the body. Most previous simulations of intersegmental coordination in the lamprey have treated the cord as a chain of coupled oscillators or well-defined segments. Here a network model without segmental boundaries is described which can produce coordinated activity with a phase lag. This 'continuous' pattern-generating network is composed of a column of 420 excitatory interneurons (E1 to E420) and 300 inhibitory interneurons (C1 to C300) on each half of the simulated spinal cord. The interneurons are distributed evenly along the simulated spinal cord, and their connectivity is chosen to reflect the behavior of the intact animal and what is known about the length and strength of the synaptic connections. For example, E100 connects to all interneurons between E51 and E149, but at varying synaptic strengths, while E101 connects to all interneurons between E52 and E150. This unsegmented E-C network generates a motor pattern that is sampled by output elements similar to motoneurons (M cells), which are arranged along the cell column so that they receive input from seven E and five C interneurons. The M cells thus represent the summed excitatory and inhibitory input at different points along the simulated spinal cord and can be regarded as representing the ventral root output to the myotomes along the spinal cord. E and C interneurons have five simulated compartments and Hodgkin-Huxley based dynamics. The simulated network produces rhythmic output over a wide range of frequencies (1-11 Hz) with a phase lag constant over most of the length, with the exception of the 'cut' ends due to reduced synaptic input. As the inhibitory C interneurons in the simulation have more extensive caudal than rostral projections, the output of the simulation has positive phase lags, as occurs in forward swimming. However, unlike the biological network, phase lags in the simulation increase significantly with burst frequency, from 0.5% to 2.3% over the range of frequencies of the simulation. Local rostral or caudal increases in excitatory drive in the simulated network are sufficient to produce motor patterns with increased or decreased phase lags, respectively.

  • 134.
    Westermark, Pål
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA. KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Björklund, Anneli
    Grill, Valdemar
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic beta-cell2007Ingår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 292, nr 2, s. E373-E393Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pancreatic beta-cells respond to an increased glycolytic flux by secreting insulin. The signal propagation goes via mitochondrial metabolism, which relays the signal to different routes. One route is an increased ATP production that, via ATP-sensitive K+ (K-ATP) channels, modulates the cell membrane potential to allow calcium influx, which triggers insulin secretion. There is also at least one other "amplifying" route whose nature is debated; possible candidates are cytosolic NADPH production or malonyl-CoA production. We have used mathematical modeling to analyze this relay system. The model comprises the mitochondrial NADH shuttles and the mitochondrial metabolism. We found robust signaling toward ATP, malonyl-CoA, and NADPH production. The signal toward NADPH production was particularly strong. Furthermore, the model reproduced the experimental findings that blocking the NADH shuttles attenuates the signaling to ATP production while retaining the rate of glucose oxidation (Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T. Science 283: 981 - 985, 1999) and provides an explanation for this apparent paradox. The model also predicts that the mitochondrial malate dehydrogenase reaction may proceed backward, toward malate production, if the activity of malic enzyme is sufficiently high. An increased fatty acid oxidation rate was found to attenuate the signaling strengths. This theoretical study has implications for our understanding of both the healthy and the diabetic beta-cell.

  • 135.
    Westermark, Pål
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hällgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Derivation of a reversible Hill equation with modifiers affecting catalytic properties2004Ingår i: WSEAS Transactions on Biology and Biomedicine, ISSN 1109-9518, E-ISSN 2224-2902, Vol. 1, s. 91-98Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An existing generic enzyme rate equation, the reversible Hill equation, was generalized to account for modifiers affecting the catalytical properties of the enzyme as well as for the case of several substrates and products. The resulting generalized reversible Hill (GRH) equation has relatively few but operationally well-defined parameters. Its usefulness is demonstrated by fitting it to experimental data on mammalian muscle phosphofructokinase. The fit is superior to that of previous models to the same data. The rate equation derived is suitable for replacing more complicated rate equations when exact mechanisms are unknown and data is scarce or contradictory.

  • 136.
    Westermark, Pål
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Hällgren Kotaleski, Jeanette
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Glucose-stimulated insulin secretion - insights from modelling2004Ingår i: Recent Research Developments in Biophysics, Vol. 3, s. 325-350Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Insulin is secreted by the pancreatic β-cells in response to a raised blood glucose concentration. Glucose-stimulated insulin secretion (GSIS) is pulsatile and correlated with bursting electrical activity. We review the current understanding of pancreatic p-cell GSIS from a mathematical modelling perspective. We discuss the glycolysis and the mitochondrial metabolism and metabolic modelling thereof. In particular, we describe the theoretical basis for the hypothesis of an oscillatory glycolysis, which may be the cause of the pulsatile secretion. We also discuss the electrophysiology of the P-cell and present insights gained from mathematical modelling in this context. There are important causal connections between β-cell metabolism and electrophysiology. This brings about an unusual challenge for theoretical and computational biologists.

  • 137. WIkström, M
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hill, R.H
    Grillner, S
     5-HT1A like receptors modulates network output pattern for locomotion1994Konferensbidrag (Refereegranskat)
  • 138. Wikström, M
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hill, R.H.
    Grillner, S
    A 5-HT1A like receptor modulates fictive locomotion and the slow AHP in the lamprey1994Konferensbidrag (Refereegranskat)
  • 139. Wikström, M
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hill, R.H.
    Grillner, S
    Classification of the receptor responsible for the 5-HT effect on Ca-dependent K-channels in the lamprey1993Konferensbidrag (Refereegranskat)
  • 140. Wikström, M
    et al.
    Hill, R.H.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Grillner, S
    The action of 5-HT on calcium-dependent potassium channels and on the spinal locomotor network in lamprey is mediated by 5-HT1A-like receptors.1995Ingår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 678, s. 191-199Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    5-HT has a powerful modulatory action on the firing properties of single neurons as well as on locomotor activity. In lamprey, 5-HT increases the neuronal firing frequency in spinal neurons by reducing the conductance in Ca(2+)-dependent K+ channels (KCa) underlying the slow afterhyperpolarization (sAHP), and it also lowers the burst frequency of the spinal locomotor network. To elucidate which type of 5-HT receptor mediates these effects, different specific receptor agonists and antagonists were applied during intracellular current clamp recordings and during NMDA-induced fictive locomotion in the lamprey spinal cord in vitro preparation. The 5-HT1A receptor agonist 8-OH-DPAT ((+/-)-8-hydroxy-dipropylaminotetralin hydrobromide), the 5-HT1 receptor agonist 5-CT (5-carboxyamidotryptamine maleate) and the 5-HT2 receptor agonist alpha-CH3-5-HT (alpha-methylserotonin maleate) all reproduced the actions of 5-HT at both the cellular and the network levels. The effects of all agonists were completely or partially blocked by the 5-HT1A and 5-HT2 receptor antagonist spiperone (spiroperidol hydrochloride) while selective 5-HT2 receptor antagonists were ineffective. The selective 5-HT1A receptor antagonist S(-)-UH301 (S(-)-5-fluoro-8-hydroxy-dipropylaminotetralin hydrochloride) also counteracted the effect of 5-HT on the sAHP. 5-HT3 and 5-HT4 receptor agonists and antagonists were without effects. The intracellular coupling mechanism was not sensitive to pertussis toxin nor to the cAMP dependent protein kinase blocker (Rp)-cAMPS.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 141. Yang, K. H.
    et al.
    Hellgren Kotaleski, Jeanette
    Blackwell, K. T.
    The role of protein kinase C in the biochemical pathways of classical conditioning2001Ingår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 38, s. 79-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Evidence suggests that protein kinase C (PKC) is required for long term memory storage such as classical conditioning. Stimulation of parallel fibers (PF) and climbing fibers (CF) of the cerebellum leads to production of the second messengers diacylglycerol, arachidonic acid, and calcium which are activators of PKC. A model is developed that describes the cascade of biochemical reactions in response to PF and CF stimulation and leading to PKC activation. Model simulations are used to evaluate the temporal specificity of PKC activation and the sensitivity of PKC activation to the interstimulus interval (ISI) of classical conditioning. Simulations at different ISI show that if PF stimulation precedes CF stimulation, PKC activation is elevated.

  • 142. Yang, K-H
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Blackwell, K.T.
    The role of protein kinase C in the temporal specificity of Purkinje cells2000Konferensbidrag (Refereegranskat)
  • 143.
    Yapo, Cedric
    et al.
    Sorbonne Univ, CNRS, Biol Adaptat & Ageing, F-75005 Paris, France..
    Nair, Anu G.
    KTH, Skolan för datavetenskap och kommunikation (CSC). KTH, Centra, Science for Life Laboratory, SciLifeLab. Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India.;Manipal Univ, Manipal 576104, Karnataka, India.;Univ Zurich, Inst Mol Life Sci, Winterthurerstr 190, CH-8057 Zurich, Switzerland..
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC). KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurosci, S-17177 Solna, Sweden..
    Vincent, Pierre
    Sorbonne Univ, CNRS, Biol Adaptat & Ageing, F-75005 Paris, France..
    Castro, Liliana R. V.
    Sorbonne Univ, CNRS, Biol Adaptat & Ageing, F-75005 Paris, France..
    Switch-like PKA responses in the nucleus of striatal neurons2018Ingår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, nr 14, artikel-id UNSP jcs216556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although it is known that protein kinase A (PKA) in the nucleus regulates gene expression, the specificities of nuclear PKA signaling remain poorly understood. Here, we combined computational modeling and live-cell imaging of PKA-dependent phosphorylation in mouse brain slices to investigate how transient dopamine signals are translated into nuclear PKA activity in cortical pyramidal neurons and striatal medium spiny neurons. We observed that the nuclear PKA signal in striatal neurons featured an ultrasensitive responsiveness, associated with fast all-or-none responses, which is not consistent with the commonly accepted theory of a slow and passive diffusion of catalytic PKA in the nucleus. Our numerical model suggests that a positive feed-forward mechanism inhibiting nuclear phosphatase activity - possibly mediated by DARPP-32 (also known as PPP1R1B) - could be responsible for this non-linear pattern of nuclear PKA response, allowing for a better detection of the transient dopamine signals that are often associated with reward-mediated learning.

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