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Computational modeling of the lamprey CPG: from subcellular to network level
KTH, School of Computer Science and Communication (CSC), Numerical Analysis and Computer Science, NADA.
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Due to the staggering complexity of the nervous system, computer modelling is becoming one of the standard tools in the neuroscientist's toolkit. In this thesis, I use computer models on different levels of abstraction to compare hypotheses and seek un- derstanding about pattern-generating circuits (central pattern generators, or CPGs) in the lamprey spinal cord. The lamprey, an ancient and primitive animal, has long been used as a model system for understanding vertebrate locomotion. By examining the lamprey spinal locomotor network, which is a comparatively simple prototype of pattern-generating networks used in higher animals, it is possible to obtain insights about the design principles behind the spinal generation of locomotion.

A detailed computational model of a generic spinal neuron within the lamprey locomotor CPG network is presented. This model is based, as far as possible, on published experimental data, and is used as a building block for simulations of the whole CPG network as well as subnetworks. The model construction process itself revealed a number of interesting questions and predictions which point toward new laboratory experiments. For example, a novel potential role for KNaF channels was proposed, and estimates of relative soma/dendritic conductance densities for KCaN and KNaS channels were given. Apparent inconsistencies in predicted spike widths for intact vs. dissociated neurons were also found. In this way, the new model can be of benefit by providing an easy way to check the current conceptual understanding of lamprey spinal neurons.

Network simulations using this new neuron model were then used to address aspects of the overall coordination of pattern generation in the whole lamprey spinal cord CPG as well as rhythm-generation in smaller hemisegmental networks. The large-scale simulations of the whole spinal CPG yielded several insights: (1) that the direction of swimming can be determined from only the very rostral part of the cord, (2) that reciprocal inhibition, in addition to its well-known role of producing alternating left-right activity, facilitates and stabilizes the dynamical control of the swimming pattern, and (3) that variability in single-neuron properties may be crucial for accurate motor coordination in local circuits.

We used results from simulations of smaller excitatory networks to propose plausible mechanisms for obtaining self-sustaining bursting activity as observed in lamprey hemicord preparations. A more abstract hemisegmental network model, based on Izhikevich neurons, was used to study the sufficient conditions for obtaining bistability between a slower, graded activity state and a faster, non-graded activity state in a recurrent excitatory network. We concluded that the inclusion of synaptic dynamics was a sufficient condition for the appearance of such bistability.

Questions about rhythmic activity intrinsic to single spinal neurons – NMDA-TTX oscillations – were addressed in a combined experimental and computational study. We showed that these oscillations have a frequency which grows with the concentration of bath-applied NMDA, and constructed a new simplified computational model that was able to reproduce this as well as other experimental results.

A combined biochemical and electrophysiological model was constructed to examine the generation of IP3-mediated calcium oscillations in the cytosol of lamprey spinal neurons. Important aspects of these oscillations were captured by the combined model, which also makes it possible to probe the interplay between intracellular biochemical pathways and the electrical activity of neurons.

To summarize, this thesis shows that computational modelling of neural circuits on different levels of abstraction can be used to identify fruitful areas for further experimental research, generate experimentally testable predictions, or to give insights into possible design principles of systems that are currently hard to perform experiments on.

Place, publisher, year, edition, pages
Stockholm: KTH , 2007. , xii, 83 p.
Series
Trita-CSC-A, ISSN 1653-5723 ; 2007:10
National Category
Computer Science
Identifiers
URN: urn:nbn:se:kth:diva-4418ISBN: 978-91-7178-717-0 (print)OAI: oai:DiVA.org:kth-4418DiVA: diva2:12226
Public defence
2007-06-14, FB42, AlbaNova, Roslagstullsbacken 21, Stockholm, 13:00
Opponent
Supervisors
Note
QC 20100714Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2010-07-15Bibliographically approved
List of papers
1. Roles of ionic currents in lamprey CPG neurons: a modeling study
Open this publication in new window or tab >>Roles of ionic currents in lamprey CPG neurons: a modeling study
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2007 (English)In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 97, no 4, 2696-2711 p.Article in journal (Refereed) Published
Abstract [en]

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

National Category
Computer Science
Identifiers
urn:nbn:se:kth:diva-7262 (URN)10.1152/jn.00528.2006 (DOI)000247929900013 ()17287443 (PubMedID)2-s2.0-34147182685 (Scopus ID)
Note
QC 20100714Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2012-01-08Bibliographically approved
2. Central and local control principles for vertebrate locomotion
Open this publication in new window or tab >>Central and local control principles for vertebrate locomotion
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(English)Manuscript (Other academic)
National Category
Computer Science
Identifiers
urn:nbn:se:kth:diva-7263 (URN)
Note
QS 2011Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2011-12-22Bibliographically approved
3. Modelling self-sustained rhythmic activity in lamprey hemisegmental networks
Open this publication in new window or tab >>Modelling self-sustained rhythmic activity in lamprey hemisegmental networks
2006 (English)In: Neurocomputing, ISSN 0925-2312, Vol. 69, no 10-12, 1097-1102 p.Article in journal (Refereed) Published
Abstract [en]

Recent studies of the lamprey spinal cord have shown that hemisegmental preparations can display rhythmic activity in response to a constant input drive. This activity is believed to be generated by a network of recurrently connected excitatory interneurons. A recent study found and characterized self-sustaining rhythmic activity-locomotor bouts-after brief electrical stimulation of hemisegmental preparations. The mechanisms behind the bouts are still unclear. We have developed a computational model of the hemisegmental network. The model addresses the possible involvement of NMDA, AMPA, acetylcholine, and metabotropic glutamate receptors as well as axonal delays in locomotor bouts.

Keyword
CPG; Excitatory interneuron; Network simulations; Self-sustaining activity
National Category
Computer Science
Identifiers
urn:nbn:se:kth:diva-7264 (URN)10.1016/j.neucom.2005.12.053 (DOI)000237873900022 ()2-s2.0-33646096740 (Scopus ID)
Note
QC 20100715. Conference: 14th Annual Computational Neuroscience Meeting (CNS 05). Madison, WI. JUL 17-21, 2005Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2011-10-04Bibliographically approved
4. Tonically driven and self-sustaining activity in the lamprey hemicord: when can they co-exist?
Open this publication in new window or tab >>Tonically driven and self-sustaining activity in the lamprey hemicord: when can they co-exist?
2007 (English)In: Neurocomputing, ISSN 0925-2312, Neurocomputing, ISSN 0925-2312, Vol. 70, no 10-12, 1882-1886 p.Article in journal (Refereed) Published
Abstract [en]

In lamprey hernisegmental preparations, two types of rhythmic activity are found: slower tonically driven activity which varies according to the external drive, and faster, more stereotypic activity that arises after a transient electrical stimulus. We present a simple conceptual model where a bistable excitable system can exhibit the two states. We then show that a neuronal network model can display the desired characteristics, given that synaptic dynamics-facilitation and saturation-are included. The model behaviour and its dependence on key parameters are illustrated. We discuss the relevance of our model to the lamprey locomotor system.

Keyword
Dynamical systems; Lamprey; Locomotion; Recurrent excitation
National Category
Computer Science
Identifiers
urn:nbn:se:kth:diva-6306 (URN)10.1016/j.neucom.2006.10.055 (DOI)000247215300055 ()2-s2.0-34247515220 (Scopus ID)
Note
QC 20100715. Uppdaterad från In press till Published 20100715.Available from: 2006-11-01 Created: 2006-11-01 Last updated: 2012-03-21Bibliographically approved
5. An experimentally constrained computational model of NMDA oscillations in lamprey CPG neurons
Open this publication in new window or tab >>An experimentally constrained computational model of NMDA oscillations in lamprey CPG neurons
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2008 (English)In: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 15, no 1, 108-121 p.Article in journal (Other academic) Published
Abstract [en]

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

Keyword
CPG; Frequency dependence; Locomotion; NMDA; Single-neuron oscillations
National Category
Computer Science
Identifiers
urn:nbn:se:kth:diva-7266 (URN)10.1007/s10827-007-0067-1 (DOI)000256824500006 ()18080179 (PubMedID)2-s2.0-45649085311 (Scopus ID)
Note
QC 20100715. Uppdaterad från manuskript till artikel 20100715.Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2010-07-15Bibliographically approved
6. mGluR-mediated calcium oscillations in the lamprey: a computational model
Open this publication in new window or tab >>mGluR-mediated calcium oscillations in the lamprey: a computational model
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2004 (English)In: Neurocomputing, ISSN 0925-2312, Vol. 58-60, 431-435 p.Article in journal (Refereed) Published
Abstract [en]

Slow Ca2+ oscillations caused by release from intracellular stores have been observed in neurons in the lamprey spinal cord. These oscillations are triggered by activation of metabotropic glutamate receptors on the cell surface. The pathway leading from receptor activation to the inositol triphosphate-mediated release of Ca2+ from the endoplasmatic reticulum has been modelled in order to facilitate further understanding of the nature of these oscillations. The model generates Ca2+ oscillations with a frequency range of 0.01-0.09 Hz. A prediction of the model is that the frequency will increase with a stronger extracellular glutamate signal.

Keyword
Calcium oscillations; Lamprey; mGluR5; Spinal cord
National Category
Computer Science
Identifiers
urn:nbn:se:kth:diva-7267 (URN)10.1016/j.neucom.2004.01.077 (DOI)000222245900065 ()
Note
QC 20100715. Titel ändrad 20100715, tidigare titel: mGluR-dependent calcium oscillations in lamprey spinal cord neurons.Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2011-10-27Bibliographically approved

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