| 1. |
- Huss, Mikael, et al.
(författare)
-
An experimentally constrained computational model of NMDA oscillations in lamprey CPG neurons
- 2008
-
Ingår i: Journal of Computational Neuroscience. - : Springer Science and Business Media LLC. - 0929-5313 .- 1573-6873. ; 15:1, s. 108-121
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
| 2. |
- Huss, Mikael, 1974-
(författare)
-
Computational modeling of the lamprey CPG : from subcellular to network level
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
| 3. |
|
|
| 4. |
- Huss, Mikael, et al.
(författare)
-
Currency and commodity metabolites : their identification and relation to the modularity of metabolic networks
- 2007
-
Ingår i: IET Systems Biology. - : Institution of Engineering and Technology (IET). - 1751-8849 .- 1751-8857. ; 1:5, s. 280-285
-
Tidskriftsartikel (refereegranskat)abstract
- The large-scale shape and function of metabolic networks are intriguing topics of systems biology. Such networks are on one hand commonly regarded as modular (i.e. built by a number of relatively independent subsystems), but on the other hand they are robust in a way not necessarily expected of a purely modular system. To address this question, we carefully discuss the partition of metabolic networks into subnetworks. The practice of preprocessing such networks by removing the most abundant substances, 'currency metabolites', is formalized into a network-based algorithm. We study partitions for metabolic networks of many organisms and find cores of currency metabolites and modular peripheries of what we call 'commodity metabolites'. The networks are found to be more modular than random networks but far from perfectly divisible into modules. We argue that cross-modular edges are the key for the robustness of metabolism.
|
|
| 5. |
- Huss, Mikael, et al.
(författare)
-
Modelling self-sustained rhythmic activity in lamprey hemisegmental networks
- 2006
-
Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 69:10-12, s. 1097-1102
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 6. |
- Huss, Mikael, et al.
(författare)
-
Prediction of transcription factor binding to DNA using rule induction methods
- 2006
-
Ingår i: Journal of Integrative Bioinformatics - JIB. - 1613-4516. ; 3:2, s. 42-
-
Tidskriftsartikel (refereegranskat)abstract
- In this study, we seek to develop a predictive model for finding the strength of bindingbetween a particular transcription factor (TF) variant and a particular DNA target variant.The DNA binding paired domains of the Pax transcription factors, which are our mainfocus, show seemingly fuzzy and degenerate binding to various DNA targets, and paireddomain-DNA binding is not a problem well suited for previously proposed algorithms.Here, we introduce a simple way to use rule induction for predicting the strength of TFDNAbinding. We have created a dataset consisting of 597 example cases for paireddomain-DNA binding by collecting information about all published and quantifiedinteractions between TF and DNA sequence variants. Application of the rule inductionbased method on this dataset yields a high, although far from ideal accuracy of 69.7%(based on cross-validation), but perhaps more importantly, several useful rules forpredicting the binding strength have been found. Although the primary motivation forintroducing the rule induction based methods is the lack of efficient algorithms for paireddomain-DNA binding prediction, we also show that the method can be applied with somesuccess to a more well-studied TF-DNA binding prediction task involving the earlygrowth response (EGR) TF family.
|
|
| 7. |
- Huss, Mikael, et al.
(författare)
-
Roles of ionic currents in lamprey CPG neurons : a modeling study
- 2007
-
Ingår i: Journal of Neurophysiology. - : American Physiological Society. - 0022-3077 .- 1522-1598. ; 97:4, s. 2696-2711
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 8. |
- Huss, Mikael, et al.
(författare)
-
Tonically driven and self-sustaining activity in the lamprey hemicord : when can they co-exist?
- 2007
-
Ingår i: Neurocomputing. - : Elsevier BV. - 0925-2312 .- 1872-8286. ; 70:10-12, s. 1882-1886
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 9. |
- Kozlov, Alexander, et al.
(författare)
-
Simple cellular and network control principles govern complex patterns of motor behavior
- 2009
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:47, s. 20027-20032
-
Tidskriftsartikel (refereegranskat)abstract
- The vertebrate central nervous system is organized in modules that independently execute sophisticated tasks. Such modules are flexibly controlled and operate with a considerable degree of autonomy. One example is locomotion generated by spinal central pattern generator networks (CPGs) that shape the detailed motor output. The level of activity is controlled from brainstem locomotor command centers, which in turn, are under the control of the basal ganglia. By using a biophysically detailed, full-scale computational model of the lamprey CPG (10,000 neurons) and its brainstem/forebrain control, we demonstrate general control principles that can adapt the network to different demands. Forward or backward locomotion and steering can be flexibly controlled by local synaptic effects limited to only the very rostral part of the network. Variability in response properties within each neuronal population is an essential feature and assures a constant phase delay along the cord for different locomotor speeds.
|
|
