Biological inspired simulation of neuron-astrocyte networks
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1
Tampere University of Technology, BioMediTech, Finland
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2
National Research Council (CNR), Institute for Complex Systems (ISC), Italy
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3
Tampere University of Technology, BioMediTech, Finland
1 Motivation
Astrocytes are known to affect the synaptic neuronal transmission and blood flow. However, role and functions of astrocytes in the neuronal communication on network level in health and disease calls for new insights. Astrocytes support the supply of nutrients to the neurons, and are responsible for the liquor regulation in the brain [1], [2]. They are involved in the processing, transfer and storage of information by the nervous system by releasing gliotransmitters which influence neuronal function [3], [4]. Here, we show the change of the neuronal activity when astrocytes are added to the network.
2 Material and Methods
The basis of the model was the spiking neuronal network model INEX [5] which consists of inhibitory and excitatory neurons. The probability of each neuron to spike follows an inhomogeneous Poisson process. In order to model the effects of astrocytes on tripartite synapses, we used a modified version of presynapse astrocyte interface by De Pittá et al. for excitatory synapses [6] which is based on Tsodyks-Markram model of synaptic activity [7]. We made further modification to the presynaptic model that enables astrocytes to increase or decrease synaptic strength based on gliotransmission model introduced by De Pittá et al. [7]. This modification takes into account different time scales of different transmitters, and thus, in our model which we call INEXA the effect of gliotransmission depends on time scales and neuronal activity. Astrocyte’s IP3 and calcium were modeled using simple exponential equations. In order to combine in each astrocyte the effect of synaptic inputs from all the excitatory synapses, the local astrocytic responses to each synapse were summed into a global astrocyte calcium response. The propagation of calcium waves in the astrocyte network was then modeled according to the simplified UAR calcium signaling modeled introduced in Lallouette et al. [8]. Astrocytes, when activated, signal back locally to their connected synapses by releasing glutamate and globally by GABA.
We simulated 2D networks modelling neural cell cultures on in vitro multielectrode arrays [9] with 200 excitatory and 50 inhibitory neurons with 10 per cent connectivity. We compare then the neuronal activity when no astrocytes and when 107 astrocytes (30% of all cells) are present. The network topology was defined with rule based stochastic process resulting in a network where an astrocyte is connected to approximately 120 nearby excitatory synapses. The simulated spike trains had a length of 5 minutes. We did ten repetitions of the simulations for both scenarios, without and with astrocytes, using the same parameters for the neuronal network.
For each of the simulations, we calculated the medians and lower and upper quartiles of spike rate, burst rate, burst duration, and average number of spikes per bursts. Briefly, to examine the intrinsic bursting, we used a modified version of the burst analysis algorithm [10] that relies on the cumulative moving average (CMA) and the skewness (alpha) of the interspike interval (ISI) histogram.
3 Results
The Figure 1 shows the medians and lower and upper quartiles of spike rate in spikes per minute, burst rate in bursts per minute, burst duration in milliseconds, and average number of spikes per bursts for 10 simulations of networks without and with astrocytes respectively. The spike rate is lower in the networks with astrocytes while the burst rate and the burst duration are similar. The average number of spikes per burst is increased when astrocytes are present.
4 Discussions
Our INEXA model is the first biologically inspired neuron-astrocyte network model with astrocyte network effects on neuronal behavior. We simulated neuronal networks without and with astrocytes. As expected, the overall neuronal network activity is reduced when astrocytes are presented since the release of astrocytic GABA in response to high activity reduces the overall activity [11], [12]. This prevents the system from excitotoxicity which is in dysfunction in astrocytes related diseases like epilepsy and Huntington’s disease [13]–[16]. While the spike rate is decreased the burst rate remains the same and we see less interburst spiking which implies a more synchronous bursting than in pure neuronal populations [11], [12], [17], [18].
5 Conclusions
We showed using our neural model INEXA that including astrocytes to the neuronal networks leads to burst and less interburst spiking.
Figure 1. Boxplots for the spike rate, burst rate, burst duration, and average number of spikes per bursts for neuronal networks without and with astrocytes respectively.
References:
[1] M. Amiri and N. Hosseinmardi, “Astrocyte-neuron interaction as a mechanism responsible for generation of neural synchrony: a study based on modeling and experiments,” J. Comput. Neurosci., vol. 34, pp. 489–504, Jun. 2013.
[2] H. Kimelberg and M. Nedergaard, “Functions of astrocytes and their potential as therapeutic targets,” Neurotherapeutics, vol. 7, no. 4, pp. 338–353, 2010.
[3] A. Araque and M. Navarrete, “Glial cells in neuronal network function,” Philos. Trans. R. Soc. Lond. B. Biol. Sci., vol. 365, pp. 2375–2381, Aug. 2010.
[4] S. R. McIver, M. Faideau, and P. G. Haydon, Neural-Immune Interactions in Brain Function and Alcohol Related Disorders. Boston, MA: Springer US, 2013.
[5] K. Lenk, “A simple phenomenological neuronal model with inhibitory and excitatory synapses,” in Proceedings of the 5th international conference on Advances in nonlinear speech processing, 2011, pp. 232–238.
[6] M. De Pittà, V. Volman, H. Berry, and E. Ben-Jacob, “A tale of two stories: astrocyte regulation of synaptic depression and facilitation,” Plos Comput. Biol., vol. 7, no. 12, p. e1002293, Dec. 2011.
[7] M. V. Tsodyks and H. Markram, “The neural code between neocortical pyramidal neurons depends on neurotransmitter release probability,” Proc. Natl. Acad. Sci., vol. 94, no. 2, pp. 719–723, Jan. 1997.
[8] J. Lallouette, M. De Pittà, E. Ben-Jacob, and H. Berry, “Sparse short-distance connections enhance calcium wave propagation in a 3D model of astrocyte networks,” Front. Comput. Neurosci., vol. 8, pp. 1–18, Jan. 2014.
[9] G. Wallach, J. Lallouette, N. Herzog, M. De Pittà, E. Ben Jacob, H. Berry, and Y. Hanein, “Glutamate mediated astrocytic filtering of neuronal activity,” PLoS Comput. Biol., vol. 10, no. 12, p. e1003964, 2014.
[10] F. Kapucu, J. Tanskanen, J. E. Mikkonen, L. Ylä-Outinen, S. Narkilahti, and J. A. K. Hyttinen, “Burst analysis tool for developing neuronal networks exhibiting highly varying action potential dynamics,” Front. Comput. Neurosci., vol. 6, pp. 1–14, Jan. 2012.
[11] Q. Liu, A. E. Schaffner, Y. H. Chang, D. Maric, and J. L. Barker, “Persistent Activation of GABA_A Receptor/ Cl^- Channels by Astrocyte-Derived GABA in Cultured Embryonic Rat Hippocampal Neurons,” J. Neurophysiol., vol. 84, pp. 1392–1403, 2000.
[12] A. S. Kozlov, M. Angulo, E. Audinat, and S. Charpak, “Target cell-specific modulation of neuronal activity by astrocytes,” Proc. Natl. Acad. Sci. U.S.A., vol. 103, no. 43, pp. 10058–10063, 2006.
[13] N. J. Maragakis and J. D. Rothstein, “Mechanisms of Disease: astrocytes in neurodegenerative disease,” Nat. Clin. Pract. Neurol., vol. 2, no. 12, pp. 679–689, Dec. 2006.
[14] G. Seifert and C. Steinhäuser, “Neuron-astrocyte signaling and epilepsy,” Exp. Neurol., vol. 244, pp. 4–10, Jun. 2013.
[15] G. Seifert, G. Carmignoto, and C. Steinhäuser, “Astrocyte dysfunction in epilepsy,” Brain Res. Rev., vol. 63, no. 1–2, pp. 212–21, May 2010.
[16] V. Volman, M. Bazhenov, and T. J. Sejnowski, “Computational models of neuron-astrocyte interaction in epilepsy,” Front. Comput. Neurosci., vol. 6, p. 58, Jan. 2012.
[17] M. C. Angulo, K. Le Meur, A. S. Kozlov, S. Charpak, and E. Audinat, “GABA, a forgotten gliotransmitter,” Prog. Neurobiol., vol. 86, pp. 297–303, 2008.
[18] B.-E. Yoon and C. J. Lee, “GABA as a rising gliotransmitter,” Front. Neural Circuits, vol. 8, no. December, p. 141, 2014.
Astrocytes are known to affect the synaptic neuronal transmission and blood flow. However, role and functions of astrocytes in the neuronal communication on network level in health and disease calls for new insights. Astrocytes support the supply of nutrients to the neurons, and are responsible for the liquor regulation in the brain [1], [2]. They are involved in the processing, transfer and storage of information by the nervous system by releasing gliotransmitters which influence neuronal function [3], [4]. Here, we show the change of the neuronal activity when astrocytes are added to the network.
2 Material and Methods
The basis of the model was the spiking neuronal network model INEX [5] which consists of inhibitory and excitatory neurons. The probability of each neuron to spike follows an inhomogeneous Poisson process. In order to model the effects of astrocytes on tripartite synapses, we used a modified version of presynapse astrocyte interface by De Pittá et al. for excitatory synapses [6] which is based on Tsodyks-Markram model of synaptic activity [7]. We made further modification to the presynaptic model that enables astrocytes to increase or decrease synaptic strength based on gliotransmission model introduced by De Pittá et al. [7]. This modification takes into account different time scales of different transmitters, and thus, in our model which we call INEXA the effect of gliotransmission depends on time scales and neuronal activity. Astrocyte’s IP3 and calcium were modeled using simple exponential equations. In order to combine in each astrocyte the effect of synaptic inputs from all the excitatory synapses, the local astrocytic responses to each synapse were summed into a global astrocyte calcium response. The propagation of calcium waves in the astrocyte network was then modeled according to the simplified UAR calcium signaling modeled introduced in Lallouette et al. [8]. Astrocytes, when activated, signal back locally to their connected synapses by releasing glutamate and globally by GABA.
We simulated 2D networks modelling neural cell cultures on in vitro multielectrode arrays [9] with 200 excitatory and 50 inhibitory neurons with 10 per cent connectivity. We compare then the neuronal activity when no astrocytes and when 107 astrocytes (30% of all cells) are present. The network topology was defined with rule based stochastic process resulting in a network where an astrocyte is connected to approximately 120 nearby excitatory synapses. The simulated spike trains had a length of 5 minutes. We did ten repetitions of the simulations for both scenarios, without and with astrocytes, using the same parameters for the neuronal network.
For each of the simulations, we calculated the medians and lower and upper quartiles of spike rate, burst rate, burst duration, and average number of spikes per bursts. Briefly, to examine the intrinsic bursting, we used a modified version of the burst analysis algorithm [10] that relies on the cumulative moving average (CMA) and the skewness (alpha) of the interspike interval (ISI) histogram.
3 Results
The Figure 1 shows the medians and lower and upper quartiles of spike rate in spikes per minute, burst rate in bursts per minute, burst duration in milliseconds, and average number of spikes per bursts for 10 simulations of networks without and with astrocytes respectively. The spike rate is lower in the networks with astrocytes while the burst rate and the burst duration are similar. The average number of spikes per burst is increased when astrocytes are present.
4 Discussions
Our INEXA model is the first biologically inspired neuron-astrocyte network model with astrocyte network effects on neuronal behavior. We simulated neuronal networks without and with astrocytes. As expected, the overall neuronal network activity is reduced when astrocytes are presented since the release of astrocytic GABA in response to high activity reduces the overall activity [11], [12]. This prevents the system from excitotoxicity which is in dysfunction in astrocytes related diseases like epilepsy and Huntington’s disease [13]–[16]. While the spike rate is decreased the burst rate remains the same and we see less interburst spiking which implies a more synchronous bursting than in pure neuronal populations [11], [12], [17], [18].
5 Conclusions
We showed using our neural model INEXA that including astrocytes to the neuronal networks leads to burst and less interburst spiking.
Figure 1. Boxplots for the spike rate, burst rate, burst duration, and average number of spikes per bursts for neuronal networks without and with astrocytes respectively.
Keywords:
network,
simulation,
Neuron,
astrocyte
Conference:
MEA Meeting 2016 |
10th International Meeting on Substrate-Integrated Electrode Arrays, Reutlingen, Germany, 28 Jun - 1 Jul, 2016.
Presentation Type:
oral
Topic:
MEA Meeting 2016
Citation:
Lenk
K,
Räisänen
E and
Hyttinen
J
(2016). Biological inspired simulation of neuron-astrocyte networks.
Front. Neurosci.
Conference Abstract:
MEA Meeting 2016 |
10th International Meeting on Substrate-Integrated Electrode Arrays.
doi: 10.3389/conf.fnins.2016.93.00034
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Received:
22 Jun 2016;
Published Online:
24 Jun 2016.
*
Correspondence:
Dr. Kerstin Lenk, Tampere University of Technology, BioMediTech, Tampere, Finland, lenk.kerstin@gmail.com