Caenorhabditis elegans is a small free-living nematode, whose anatomical simplicity, reduced size and ease of genetic manipulation has made it a powerful model organism for different research studies, including neuroscience. The C. elegans nervous system, made up of only 302 neurons, was the first to be fully characterized in neurons number and connections. Unraveling the working principles of neuronal networks requires the knowledge of single neurons functioning, which is normally achieved through electrophysiology experiments. In the case of C. elegans neurons, these experiments are particularly challenging due to the small size of neurons and difficulties in preserving the worm life and cell functionality after dissection. However, in the last few years, many efforts have been made to increase the number of characterized neurons. The increased amount of available electrophysiology data for C. elegans neurons has paved the way for extensive biophysical modeling of the nematode nervous system. This work aims at developing a comprehensive biophysical description of C.elegans neuronal dynamics, starting from the models of the single ionic currents. A biophysically accurate description of the neuronal dynamics is particularly important in a context where experimental informations are incomplete or missing since it could help to elucidate the molecular mechanisms at the basis of signal generation, integration and transmission. The models of single neurons here presented rely on a classical Hodgkin-Huxley description, adapted to describe the single ionic currents recorded in C. elegans neurons. These models are combined, according to gene expression profiles and available experimental data, to reproduce voltage-clamp experiments on four representative C. elegans neurons: AWCON, AIY, RIM, and RMD neurons. Moreover, a detailed analysis of the contribution of each ionic current to the whole-neuron dynamics is conducted by simulating the responses of in silico knockout neurons, where the contribution of one channel is suppressed, leaving unchanged the others. The modelling work allows, among the other results, to establish the central role of T-type calcium channels in the bistable behaviour of RMD neurons. Moreover, the electrical model of AWCON neuron is merged with a detailed model of the olfactory response developed by Usuyama et al. (Usuyama et al. PloS ONE 2012, 7(8): e42907) to obtain a unified description of the electro-chemical processes at the basis of AWCON mediated olfaction. A further refinement through genetic algorithm optimization of the electrical model of AWCON highlighted a previously unreported putative bistable behaviour, that is investigated with in silico knockout simulations and calcium imaging experiments. Finally, single-neurons models are used to build a biophysical model of a minimal circuit. In conclusion, this work provides a useful platform for the biophysical study of C. elegans nervous system, which could help to elucidate the molecular mechanisms at the basis of neuronal signalling and sensory processing, and could be applied to the study of complex neuronal functions such as sensory processing and motor control.

Biophysical modelling of Caenorhabditis elegans nervous system: from single cells up to neuronal networks / Martina Nicoletti - : . , 2021 Apr 09. ((33. ciclo

Biophysical modelling of Caenorhabditis elegans nervous system: from single cells up to neuronal networks

2021-04-09

Abstract

Caenorhabditis elegans is a small free-living nematode, whose anatomical simplicity, reduced size and ease of genetic manipulation has made it a powerful model organism for different research studies, including neuroscience. The C. elegans nervous system, made up of only 302 neurons, was the first to be fully characterized in neurons number and connections. Unraveling the working principles of neuronal networks requires the knowledge of single neurons functioning, which is normally achieved through electrophysiology experiments. In the case of C. elegans neurons, these experiments are particularly challenging due to the small size of neurons and difficulties in preserving the worm life and cell functionality after dissection. However, in the last few years, many efforts have been made to increase the number of characterized neurons. The increased amount of available electrophysiology data for C. elegans neurons has paved the way for extensive biophysical modeling of the nematode nervous system. This work aims at developing a comprehensive biophysical description of C.elegans neuronal dynamics, starting from the models of the single ionic currents. A biophysically accurate description of the neuronal dynamics is particularly important in a context where experimental informations are incomplete or missing since it could help to elucidate the molecular mechanisms at the basis of signal generation, integration and transmission. The models of single neurons here presented rely on a classical Hodgkin-Huxley description, adapted to describe the single ionic currents recorded in C. elegans neurons. These models are combined, according to gene expression profiles and available experimental data, to reproduce voltage-clamp experiments on four representative C. elegans neurons: AWCON, AIY, RIM, and RMD neurons. Moreover, a detailed analysis of the contribution of each ionic current to the whole-neuron dynamics is conducted by simulating the responses of in silico knockout neurons, where the contribution of one channel is suppressed, leaving unchanged the others. The modelling work allows, among the other results, to establish the central role of T-type calcium channels in the bistable behaviour of RMD neurons. Moreover, the electrical model of AWCON neuron is merged with a detailed model of the olfactory response developed by Usuyama et al. (Usuyama et al. PloS ONE 2012, 7(8): e42907) to obtain a unified description of the electro-chemical processes at the basis of AWCON mediated olfaction. A further refinement through genetic algorithm optimization of the electrical model of AWCON highlighted a previously unreported putative bistable behaviour, that is investigated with in silico knockout simulations and calcium imaging experiments. Finally, single-neurons models are used to build a biophysical model of a minimal circuit. In conclusion, this work provides a useful platform for the biophysical study of C. elegans nervous system, which could help to elucidate the molecular mechanisms at the basis of neuronal signalling and sensory processing, and could be applied to the study of complex neuronal functions such as sensory processing and motor control.
C.elegans; ion channels; biophysical modelling
Biophysical modelling of Caenorhabditis elegans nervous system: from single cells up to neuronal networks / Martina Nicoletti - : . , 2021 Apr 09. ((33. ciclo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12610/68699
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