- Email: [email protected]
Simulation of a vertebrate receptor cell of the olfactory epithelium for use in network models
Neurocomputing 44–46 (2002) 177 – 182
www.elsevier.com/locate/neucom
Simulation of a vertebrate receptor cell of the olfactory epithelium for use in network models F&abio M. Sim˜oes-de-Souzaa; ∗ , Antonio C. Roqueb a Departamento
de Psicologia e Educaca˜ o, FFCLRP, Universidade de S˜ao Paulo, Av. Bandeirantes 3900, 14040-901 Ribeir˜ao Preto, SP, Brazil b Departamento de F()sica e Matem( atica, FFCLRP, Universidade de S˜ao Paulo, Av. Bandeirantes 3900, 14040-901 Ribeir˜ao Preto, SP, Brazil
Abstract We developed a realistic model of a bipolar receptor cell of the olfactory epithelium. It has four compartments, namely cilia, dendritic knob, dendrite and soma. Cilia is a biochemical compartment including the molecular pathways of odor interpretation; dendrite is a passive compartment without channels; dendritic knob has Ca2+ -dependent chloride channels; and soma has all channels of Traub’s CA3 hippocampal pyramidal neuron model plus Moczydlowski–Latorre’s BK channel model. A pool of molecular odors, which increase Ca2+ intracellular concentration and conductance of chloride channels, provides the input. The model’s bursting behavior comc 2002 Elsevier Science B.V. All rights pares well with experimental data found in literature. reserved. Keywords: Olfactory system; Olfactory receptor cell; Biochemical pathways; Olfactory epithelium
1. Introduction An important issue in the construction of large-scale biologically realistic neural network models is to develop single-neuron models which capture most of the typical features of real cells without using a large number of compartments and ionic channel types, which would turn the network simulation very expensive.
This work was funded by FAPESP. Corresponding author. Tel.: +55-16-6023768; fax: +55-16-6029949. E-mail addresses: [email protected] (F.M. Sim˜oes-de-Souza), [email protected]. usp.br (A.C. Roque). ∗
c 2002 Elsevier Science B.V. All rights reserved. 0925-2312/02/$ - see front matter PII: S 0 9 2 5 - 2 3 1 2 ( 0 2 ) 0 0 3 8 7 - 9
178
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
Fig. 1. Scheme of the model receptor cell.
In this work we present a four-compartment realistic model of a bipolar receptor cell of the vertebrate olfactory epithelium. A simulation of the model when stimulated by an odor was implemented using the GENESIS 2.2 neural simulator. The simulated Fring behavior exhibits similarities to some real data for vertebrate olfactory receptor cells described in the literature. The results reported here encourage the use of this model cell for the construction of a receptor layer in a large-scale model of the vertebrate primary olfactory system. 2. The model The model cell has four compartments, namely cilia, dendritic knob, dendrite and soma (Fig. 1). Cilia is a biochemical compartment (Fig. 2) constructed using the GENESIS tool kinetikit. It was adapted from Bhalla and Iyengar’s [1] model to incorporate the molecular pathways of odor interpretation [5,11]. Dendrite is a passive compartment without channels. Dendritic knob has Ca2+ dependent chloride channels. Soma is an adaptation of Traub’s [9] model for a CA3 hippocampal cell, containing all the channels used in that model plus a BK channel model developed by Moczydlowski and Latorre [6]. Each channel used in the soma compartment has an equivalent channel found in real bipolar receptor cells described in the literature [8]. The cell’s input is provided by a pool of molecular odors, which increase Ca2+ intracellular concentration. This leads to an increase in the conductance of chloride channels, causing membrane depolarization and generating electric bursts at the soma. 3. Results The simulated time course of the intracellular calcium concentration in cilia during an odor stimulus is shown in Fig. 3. It is similar to the behavior found experimentally by Leinders-Zufall et al. [4].
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
179
Fig. 2. Biochemical pathways simulated in the cilia compartment. Odor binds to a membrane receptor linked to Golf, which activates adenylate cyclase III (ACIII) leading to adenosil monophosphate cyclic (cAMP) production. The cAMP activates the cAMP-gated Ca2+ channels, increasing ion calcium (Ca2+ ) concentrations at cilia. The restoration of the calcium concentration to basal levels occurs via Ca2+ exchangers and by adaptation mechanisms through negative feedbacks involving cAMP-activated protein kinase (PKA), Ca2+ =Calmodulin (CaM), Ca2+ =Calmodulin-dependent protein kinase II (CaMKII) and Phosphodiesterase (PDE), inhibiting both the membrane receptors and calcium channels.
Fig. 3. Time variation of the model’s Ca2+ intracellular concentration in cilia during an odor stimulation.This response is similar to the one shown in Fig. 6 of [4], including the observed stochastic behavior.
180
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
Fig. 4. Simulated time course response of the chloride channel conductance to calcium concentration changes in cilia during the same odor stimulus applied in Fig. 3.
Fig. 5. Simulated response of the electric bursts produced at the soma to increasing odor concentrations. The spike frequency increases along with the odor concentration (downward), but with amplitude attenuation in the middle of the burst. This result is similar to Fig. 3 at the work of Trotier and MacLeod [10].
The temporal behavior of the Ca2+ -dependent chloride channel is shown in Fig. 4. It also reproduces Fndings of biological experiments [3,7]. The increase in the conductance of the chloride channels causes membrane depolarization at the dendritic knob, leading to electric bursts at the soma. Some examples of these simulated electric bursts for diCerent odor concentrations are shown in Fig. 5. They compare well with experimental data for salamander olfactory receptor cells found in the literature [10], exhibiting the characteristic decrease in spike amplitude at the central region of the burst.
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
181
4. Discussion and conclusion In this work, we managed to construct a biologically realistic model of an olfactory receptor cell with a relatively small number of compartments and ionic channels, and yet being able to reproduce some behavior observed experimentally. This receptor cell can be used in the construction of a model of the olfactory epithelium in a large-scale simulation of the vertebrate primary olfactory system. An important aspect of this receptor cell model is that it contains a realistic biochemical compartment. Therefore, it could be used to test competing theories on the biochemical pathways of odor interpretation [2,3,5,7,8,11]. References [1] U. Bhalla, R. Iyengar, Emergent properties of network of biological signaling pathways, Science 283 (1999) 381–387. [2] G.H. Gold, Controversial issues in vertebrate olfactory transduction, Ann. Rev. Physiol. 61 (1999) 857–871. [3] M. Hallani, J.W. Lynch, P.H. Barry, Characterization of calcium-activated chloride channels in patches excised from the dendritic knob of mammalian olfactory receptor neurons, J. Membrane Biol. 161 (1998) 163–171. [4] T. Leinders-Zufall, C.A.Greer, G.M Shepherd, F. Zufall, Imaging odor-induced calcium transients in single olfactory cilia: speciFcity of activation and role in transduction J. Neurosci. 18 (1998) 5630–5639. [5] A. Menini, Calcium signaling and regulation in olfactory neurons, Curr. Opin. Neurobiol. 9 (1999) 419–426. [6] E. Moczydlowski, R. Latorre, Gating kinetics of Ca2+ -activated K + channels from rat muscle incorporated into planar lipib bilayer: evidence for two voltage-dependent Ca2+ binding reactions J. Gen. Physiol. 82 (1983) 511–542. [7] D. Reuter, K. Zierold, W.H. SchrNoder, S. Frings, A depolarizing chloride current contributes to chemoelectrical transduction in olfactory sensory neurons in situ, J. Neurosci. 18 (1998) 6623–6630. [8] D. Schild, D. Restrepo, Transduction mechanisms in vertebrate olfactory receptor cells, Physiol. Rev. 78 (1998) 429–466. [9] R.D. Traub, R.K. Wong, R. Miles, H. Michelson, A model of a CA3 hippocampal pyramidal neuron incorporating voltage-clamp data on intrinsic conductances, J. Neurophysiol. 66 (1991) 635–650. [10] D. Trotier, P. MacLeod, Intracellular recordings from salamander olfactory receptor cells, Brain Res. 268 (1983) 225–237. [11] F. Zufall, T. Leinders-Zufall, The cellular and molecular basis of odor adaptation, Chem. Senses 25 (2000) 473–481.
F abio Marques Sim˜oes-de-Souza was born in Presidente Prudente, SP, Brazil. He received a Technical Degree in Industry Informatics from the ETEP, S˜ao Jos&e dos Campos, SP, Brazil, in 1994 and a B.Sc. in Biology from the University of S˜ao Paulo at Ribeir˜ao Preto, SP, Brazil, in 1999. He is presently enrolled in a MSc in Psychobiology at the University of S˜ao Paulo at Ribeir˜ao Preto, SP, Brazil. His scientiFc research is focused on modeling the vertebrate olfactory system, in particular the olfactory epithelium and bulb. Antonio Carlos Roque was born in S˜ao Paulo, SP, Brazil. He received his B.Sc. and M.Sc. in Physics from the State University of Campinas, Brazil, in 1985 and 1987, respectively. He received his Ph.D. in Computer Science and ArtiFcial Intelligence from the University of Sussex, UK, in 1992. In 1993 he joined
182
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
the faculty of the Department of Physics and Mathematics of the University of S˜ao Paulo at Ribeir˜ao Preto, SP, Brazil, where he founded and is the present coordinator of the Laboratory for Neural Networks and Computational Neuroscience. His research interests are computational neuroscience and medical applications of neural networks.
www.elsevier.com/locate/neucom
Simulation of a vertebrate receptor cell of the olfactory epithelium for use in network models F&abio M. Sim˜oes-de-Souzaa; ∗ , Antonio C. Roqueb a Departamento
de Psicologia e Educaca˜ o, FFCLRP, Universidade de S˜ao Paulo, Av. Bandeirantes 3900, 14040-901 Ribeir˜ao Preto, SP, Brazil b Departamento de F()sica e Matem( atica, FFCLRP, Universidade de S˜ao Paulo, Av. Bandeirantes 3900, 14040-901 Ribeir˜ao Preto, SP, Brazil
Abstract We developed a realistic model of a bipolar receptor cell of the olfactory epithelium. It has four compartments, namely cilia, dendritic knob, dendrite and soma. Cilia is a biochemical compartment including the molecular pathways of odor interpretation; dendrite is a passive compartment without channels; dendritic knob has Ca2+ -dependent chloride channels; and soma has all channels of Traub’s CA3 hippocampal pyramidal neuron model plus Moczydlowski–Latorre’s BK channel model. A pool of molecular odors, which increase Ca2+ intracellular concentration and conductance of chloride channels, provides the input. The model’s bursting behavior comc 2002 Elsevier Science B.V. All rights pares well with experimental data found in literature. reserved. Keywords: Olfactory system; Olfactory receptor cell; Biochemical pathways; Olfactory epithelium
1. Introduction An important issue in the construction of large-scale biologically realistic neural network models is to develop single-neuron models which capture most of the typical features of real cells without using a large number of compartments and ionic channel types, which would turn the network simulation very expensive.
This work was funded by FAPESP. Corresponding author. Tel.: +55-16-6023768; fax: +55-16-6029949. E-mail addresses: [email protected] (F.M. Sim˜oes-de-Souza), [email protected]. usp.br (A.C. Roque). ∗
c 2002 Elsevier Science B.V. All rights reserved. 0925-2312/02/$ - see front matter PII: S 0 9 2 5 - 2 3 1 2 ( 0 2 ) 0 0 3 8 7 - 9
178
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
Fig. 1. Scheme of the model receptor cell.
In this work we present a four-compartment realistic model of a bipolar receptor cell of the vertebrate olfactory epithelium. A simulation of the model when stimulated by an odor was implemented using the GENESIS 2.2 neural simulator. The simulated Fring behavior exhibits similarities to some real data for vertebrate olfactory receptor cells described in the literature. The results reported here encourage the use of this model cell for the construction of a receptor layer in a large-scale model of the vertebrate primary olfactory system. 2. The model The model cell has four compartments, namely cilia, dendritic knob, dendrite and soma (Fig. 1). Cilia is a biochemical compartment (Fig. 2) constructed using the GENESIS tool kinetikit. It was adapted from Bhalla and Iyengar’s [1] model to incorporate the molecular pathways of odor interpretation [5,11]. Dendrite is a passive compartment without channels. Dendritic knob has Ca2+ dependent chloride channels. Soma is an adaptation of Traub’s [9] model for a CA3 hippocampal cell, containing all the channels used in that model plus a BK channel model developed by Moczydlowski and Latorre [6]. Each channel used in the soma compartment has an equivalent channel found in real bipolar receptor cells described in the literature [8]. The cell’s input is provided by a pool of molecular odors, which increase Ca2+ intracellular concentration. This leads to an increase in the conductance of chloride channels, causing membrane depolarization and generating electric bursts at the soma. 3. Results The simulated time course of the intracellular calcium concentration in cilia during an odor stimulus is shown in Fig. 3. It is similar to the behavior found experimentally by Leinders-Zufall et al. [4].
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
179
Fig. 2. Biochemical pathways simulated in the cilia compartment. Odor binds to a membrane receptor linked to Golf, which activates adenylate cyclase III (ACIII) leading to adenosil monophosphate cyclic (cAMP) production. The cAMP activates the cAMP-gated Ca2+ channels, increasing ion calcium (Ca2+ ) concentrations at cilia. The restoration of the calcium concentration to basal levels occurs via Ca2+ exchangers and by adaptation mechanisms through negative feedbacks involving cAMP-activated protein kinase (PKA), Ca2+ =Calmodulin (CaM), Ca2+ =Calmodulin-dependent protein kinase II (CaMKII) and Phosphodiesterase (PDE), inhibiting both the membrane receptors and calcium channels.
Fig. 3. Time variation of the model’s Ca2+ intracellular concentration in cilia during an odor stimulation.This response is similar to the one shown in Fig. 6 of [4], including the observed stochastic behavior.
180
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
Fig. 4. Simulated time course response of the chloride channel conductance to calcium concentration changes in cilia during the same odor stimulus applied in Fig. 3.
Fig. 5. Simulated response of the electric bursts produced at the soma to increasing odor concentrations. The spike frequency increases along with the odor concentration (downward), but with amplitude attenuation in the middle of the burst. This result is similar to Fig. 3 at the work of Trotier and MacLeod [10].
The temporal behavior of the Ca2+ -dependent chloride channel is shown in Fig. 4. It also reproduces Fndings of biological experiments [3,7]. The increase in the conductance of the chloride channels causes membrane depolarization at the dendritic knob, leading to electric bursts at the soma. Some examples of these simulated electric bursts for diCerent odor concentrations are shown in Fig. 5. They compare well with experimental data for salamander olfactory receptor cells found in the literature [10], exhibiting the characteristic decrease in spike amplitude at the central region of the burst.
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
181
4. Discussion and conclusion In this work, we managed to construct a biologically realistic model of an olfactory receptor cell with a relatively small number of compartments and ionic channels, and yet being able to reproduce some behavior observed experimentally. This receptor cell can be used in the construction of a model of the olfactory epithelium in a large-scale simulation of the vertebrate primary olfactory system. An important aspect of this receptor cell model is that it contains a realistic biochemical compartment. Therefore, it could be used to test competing theories on the biochemical pathways of odor interpretation [2,3,5,7,8,11]. References [1] U. Bhalla, R. Iyengar, Emergent properties of network of biological signaling pathways, Science 283 (1999) 381–387. [2] G.H. Gold, Controversial issues in vertebrate olfactory transduction, Ann. Rev. Physiol. 61 (1999) 857–871. [3] M. Hallani, J.W. Lynch, P.H. Barry, Characterization of calcium-activated chloride channels in patches excised from the dendritic knob of mammalian olfactory receptor neurons, J. Membrane Biol. 161 (1998) 163–171. [4] T. Leinders-Zufall, C.A.Greer, G.M Shepherd, F. Zufall, Imaging odor-induced calcium transients in single olfactory cilia: speciFcity of activation and role in transduction J. Neurosci. 18 (1998) 5630–5639. [5] A. Menini, Calcium signaling and regulation in olfactory neurons, Curr. Opin. Neurobiol. 9 (1999) 419–426. [6] E. Moczydlowski, R. Latorre, Gating kinetics of Ca2+ -activated K + channels from rat muscle incorporated into planar lipib bilayer: evidence for two voltage-dependent Ca2+ binding reactions J. Gen. Physiol. 82 (1983) 511–542. [7] D. Reuter, K. Zierold, W.H. SchrNoder, S. Frings, A depolarizing chloride current contributes to chemoelectrical transduction in olfactory sensory neurons in situ, J. Neurosci. 18 (1998) 6623–6630. [8] D. Schild, D. Restrepo, Transduction mechanisms in vertebrate olfactory receptor cells, Physiol. Rev. 78 (1998) 429–466. [9] R.D. Traub, R.K. Wong, R. Miles, H. Michelson, A model of a CA3 hippocampal pyramidal neuron incorporating voltage-clamp data on intrinsic conductances, J. Neurophysiol. 66 (1991) 635–650. [10] D. Trotier, P. MacLeod, Intracellular recordings from salamander olfactory receptor cells, Brain Res. 268 (1983) 225–237. [11] F. Zufall, T. Leinders-Zufall, The cellular and molecular basis of odor adaptation, Chem. Senses 25 (2000) 473–481.
F abio Marques Sim˜oes-de-Souza was born in Presidente Prudente, SP, Brazil. He received a Technical Degree in Industry Informatics from the ETEP, S˜ao Jos&e dos Campos, SP, Brazil, in 1994 and a B.Sc. in Biology from the University of S˜ao Paulo at Ribeir˜ao Preto, SP, Brazil, in 1999. He is presently enrolled in a MSc in Psychobiology at the University of S˜ao Paulo at Ribeir˜ao Preto, SP, Brazil. His scientiFc research is focused on modeling the vertebrate olfactory system, in particular the olfactory epithelium and bulb. Antonio Carlos Roque was born in S˜ao Paulo, SP, Brazil. He received his B.Sc. and M.Sc. in Physics from the State University of Campinas, Brazil, in 1985 and 1987, respectively. He received his Ph.D. in Computer Science and ArtiFcial Intelligence from the University of Sussex, UK, in 1992. In 1993 he joined
182
F.M. Sim˜oes-de-Souza, A.C. Roque / Neurocomputing 44–46 (2002) 177 – 182
the faculty of the Department of Physics and Mathematics of the University of S˜ao Paulo at Ribeir˜ao Preto, SP, Brazil, where he founded and is the present coordinator of the Laboratory for Neural Networks and Computational Neuroscience. His research interests are computational neuroscience and medical applications of neural networks.