Project

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Genetic Analysis of Temperature and Pain Sensation in Caenorhabditis elegans

Applicant Glauser Dominique
Number 131943
Funding scheme Ambizione
Research institution Département de Biologie Faculté des Sciences Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Genetics
Start/End 01.12.2010 - 30.11.2013
Approved amount 576'196.30
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All Disciplines (4)

Discipline
Genetics
Zoology
Cellular Biology, Cytology
Neurophysiology and Brain Research

Keywords (27)

Neurobiology; Neuroscience; Behavior; Thermosensation; Thermal Nociception; Thermonociception; C. elegans; Worm; neurosciences; genetics; worm; Caenorhabditis elegans; nociception; pain; temperature sensation; behavior; escape; avoidance; optogenetics; channelrhodopsin; archeorhodopsin; caspase; neuronal ablation; neural circuit; quantitative analyses of behavior; mutagenesis screen; whole genome sequencing

Lay Summary (French)

Lead
La douleur est un problème médical de premier plan. Les médicaments disponibles ont soit une efficacité limitée, soit ont des effets secondaires indésirables. Il est dès lors important de développer de nouvelles approches pour la gestion de la douleur. Dans ce projet un organisme modèle simple est utilisé pour identifier de nouvelles cibles pour le traitement de la douleur.
Lay summary

Le but général de cette recherche est d’amener un éclairage nouveau sur les mécanismes de sensation de la température et la douleur avec l’utilisation d’approches génétiques et cellulaires chez Caenorhabditis elegans (C. elegans). Cet organisme modèle présente de nombreux avantages, notamment la disponibilité d’une carte complète de connectivité de son système nerveux, des méthodes génétiques efficaces et des comportements stéréotypés d’évitement de la chaleur nocive (fournissant un moyen simple d’évaluer leur réponse nociceptive). Durant mon travail postdoctoral, j’ai développé de nouveaux essais comportementaux permettant (1) de quantifier l’évitement de la chaleur nocive et (2) un crible à haut débit pour isoler des animaux mutants avec une réponse altérée. J’ai découvert plusieurs nouveaux gènes impliqués dans la nociception.

Les buts spécifiques du projet sont :

A) Décrire le réseau génétique contrôlant l’évitement de la chaleur nocive. Dans ce but, je vais (1) définir les interactions génétiques entre les nouveaux gènes impliqués dans la nociception et (2) étendre le crible génétique pour découvrir des gènes supplémentaires.

B) Caractériser le circuit neuronal sous-jacent. Dans ce but, je vais (1) identifier les neurones qui sont requis pour l’évitement de la chaleur nocive par des expériences d’ablation neuronale et (2) déterminer si leur activation ou inhibition est suffisante pour déclencher une réponse comportementale avec l’utilisation de canaux et de transporteurs transmembranaires activés par la lumière et exprimés dans des animaux transgéniques.

Caractériser les voies génétiques et neuronales impliquées dans la nociception est un prérequis à une utilisation avantageuse du modèle C. elegans dans le domaine. Le projet fournira une base solide pour un projet de recherche plus large dans le future. Puisque les mécanismes de nociception pourraient bien être conservés avec des organismes supérieurs, l’approche proposée pourrait fournir des pistes pour de nouvelles approches thérapeutiques de traitement de la douleur.

Direct link to Lay Summary Last update: 07.01.2013

Lay Summary (English)

Lead
Pain is a major patient concern in disease. Because available drugs are either only moderately effective or have detrimental side effects, there is an essential need for novel therapeutic solutions in pain management. In this project, a simple model organism is used to identify new potential drug targets.
Lay summary
Pain is a major patient concern in disease. Because available drugs are either only moderately effective or have detrimental side effects, there is an essential need for novel therapeutic solutions in pain management. In this project, a simple model organism is used to identify new potential drug targets.

Pain and temperature sensation are related processes. In mammals, heat-gated channels from the Transient Receptor Potential (TRP) family are well established thermoreceptors that also play a role in nociception (i.e. the perception of pain). Drugs targeting TRP channels, which have been developed in the last decade, are unfortunately only moderately efficient or associated with detrimental side effects. Apart from the TRP channels, we know very little on the molecular mechanisms underlying such complex physiological processes. There is notably a large lack of insights on potential TRP-independent thermosensory and nociceptive mechanisms that could represent novel drug targets.

The long-term goal of this research project is to shed new light on the mechanism of temperature and pain sensation with the use of genetic and cellular approaches in the small soil nematode Caenorhabditis elegans. This model organism presents several advantages, including the availability of a complete nervous system wiring diagram, efficient genetic techniques, and a stereotyped avoidance behavior in response to noxious heat, providing a simple readout of thermal nociception. Recent work by the principal investigator has demonstrated the suitability of this model by developing new assays to quantify the heat avoidance behavior in the worm and isolating mutant worms that fail to respond properly to noxious heat. The specific goals pursued are to characterize the genes affected in these mutants and identify the sensory neurons involved. Characterizing the genetic and neuronal pathways involved in thermal nociception is a prerequisite for an advantageous use of C. elegans model in the field. The project will provide a solid foundation for significant advance in the field of nociception. Because thermal nociception mechanisms might well be conserved from worm to human, the approach will provide novel insights on potential therapeutic targets in pain management.
Direct link to Lay Summary Last update: 07.01.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Dual Color Neural Activation and Behavior Control with Chrimson and CoChR in Caenorhabditis elegans.
Glauser Dominique (2015), Dual Color Neural Activation and Behavior Control with Chrimson and CoChR in Caenorhabditis elegans., in Genetics, -.
A conserved role for p48 homologs in protecting dopaminergic neurons from oxidative stress.
Glauser Dominique (2014), A conserved role for p48 homologs in protecting dopaminergic neurons from oxidative stress., in PLOS Genetics, -.
CaMKI-dependent regulation of sensory gene expression mediates experience-dependent plasticity in the operating range of a thermosensory neuron.
Glauser Dominique (2014), CaMKI-dependent regulation of sensory gene expression mediates experience-dependent plasticity in the operating range of a thermosensory neuron., in Neuron, -.
The balance between cytoplasmic and nuclear CaM kinase-1 signaling controls the operating range of noxious heat avoidance.
Glauser Dominique (2014), The balance between cytoplasmic and nuclear CaM kinase-1 signaling controls the operating range of noxious heat avoidance., in Neuron, -.
acr-23 Encodes a Monepantel-Sensitive Channel in Caenorhabditis elegans
Rufener Lucien, Bedoni Nicola, Baur Roland, Rey Samantha, Glauser Dominique A., Bouvier Jacques, Beech Robin, Sigel Erwin, Puoti Alessandro (2013), acr-23 Encodes a Monepantel-Sensitive Channel in Caenorhabditis elegans, in PLOS PATHOGENS, 9(8), 1003524.
Dynamic switching between escape and avoidance regimes reduces Caenorhabditis elegans exposure to noxious heat
Schild Lisa C., Glauser Dominique A. (2013), Dynamic switching between escape and avoidance regimes reduces Caenorhabditis elegans exposure to noxious heat, in NATURE COMMUNICATIONS, 4, 3198.
How and why Caenorhabditis elegans uses distinct escape and avoidance regimes to minimize exposure to noxious heat
Glauser Dominique A. (2013), How and why Caenorhabditis elegans uses distinct escape and avoidance regimes to minimize exposure to noxious heat, in Worm, 2(4), e27285.
Heat avoidance is regulated by transient receptor potential (TRP) channels and a neuropeptide signaling pathway in Caenorhabditis elegans.
Glauser Dominique A, Chen Will C, Agin Rebecca, Macinnis Bronwyn L, Hellman Andrew B, Garrity Paul A, Tan Man-Wah, Goodman Miriam B (2011), Heat avoidance is regulated by transient receptor potential (TRP) channels and a neuropeptide signaling pathway in Caenorhabditis elegans., in Genetics, 188(1), 91-103.
Intragenic alternative splicing coordination is essential for Caenorhabditis elegans slo-1 gene function
Glauser DA, Johnson BE, Aldrich RW, Goodman MB (2011), Intragenic alternative splicing coordination is essential for Caenorhabditis elegans slo-1 gene function, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 108(51), 20790-20795.

Collaboration

Group / person Country
Types of collaboration
Frankfurt University, Alexander Gottschalk Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Stanford University School of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
University de Fribourg, Laurent Mène-Safrané Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University of Fribourg, Simon Sprecher Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
University of Fribourg, Alessandro Puoti Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Laboratory for Bioinformatics and Molecular Genetics, Freiburg/Brisgau University Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
University of Edinburgh, Mark Blaxter Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Graduate School of Biomedical Science, Tokyo Medical and Dental University Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Systems Biology of the Brain Talk given at a conference Tackling Nociception with Bottom-Up Systems Biology in C. elegans 30.07.2013 Fribourg, Switzerland Glauser Dominique;
ABCD Meeting 2013 Individual talk Calcium/Calmodulin-dependent signaling controls noxious heat evoked-behaviors in C. elegans 26.03.2013 Bern, Switzerland Glauser Dominique;
Basel Worm Meeting 2013 Talk given at a conference Identifying new molecular and neuronal pathways of nociception 14.03.2013 FMI, Basel, Switzerland Glauser Dominique;
LS2 Annual Meeting Poster A pipeline to identify new molecular and neuronal pathways of nociception 31.01.2013 Zürich, Switzerland Glauser Dominique;
LS2 Annual meeting Talk given at a conference A pipeline to identify new molecular and neuronal pathways of nociception 31.01.2013 Zürich, Switzerland Glauser Dominique;
C. elegans Neurobiology Meeting Poster Run-away or stay-away: How multiple behavioral strategies ensure optimal avoidance of noxious heat 14.06.2012 Heidelberg, Germany Glauser Dominique;
Junior Debiopharm Award minisymposium Talk given at a conference Worms don't like it hot: the molecular and neural substrates of thermal nociception and avoidance behaviors in Caenorhabditis elegans 31.05.2012 EPFL, Lausanne, Switzerland Glauser Dominique;
University of Fribourg, Dept. of Biology Seminar Individual talk The molecular and neural substrates of heat avoidance behaviors in Caenorhabditis elegans 19.04.2012 Fribourg, Switzerland Glauser Dominique;
ABCD meeting Individual talk Worms don't like it hot: molecular and neural substrates of an escape behavior 28.02.2012 Bern, Ch, Switzerland Glauser Dominique;
BENEFRI Workshop in Neuroscience 2012, “ANIMAL MODELS and HUMAN BRAIN RESEARCH” Talk given at a conference Worms don’t like it hot: Genetic dissection of an escape behaviour 18.01.2012 Fribourg, CH, Switzerland Glauser Dominique;
Bachelor Student Evening of the Dept. of Biology Poster C. elegans temperature and pain sensation 06.12.2011 Fribourg, CH, Switzerland Glauser Dominique;
Master Student Evening of the Dept. of Biology Poster C. elegans temperature and pain sensation 03.03.2011 Fribourg, CH, Switzerland Glauser Dominique;
Bachelor Student Evening of the Dept. of Biology Poster C. elegans temperature and pain sensation 02.12.2010 Fribourg, CH, Switzerland Glauser Dominique;


Self-organised

Title Date Place
BENEFRI Workshop in Neuroscience 2012, “ANIMAL MODELS and HUMAN BRAIN RESEARCH” 18.01.2012 Fribourg, CH, Switzerland

Associated projects

Number Title Start Funding scheme
150681 Molecular and neural substrates of nociception and aversive behaviors in Caenorhabditis elegans 01.09.2014 SNSF Professorships
155764 Intracellular Signals Tuning Nociceptors in C. elegans (ItSTINGs) 01.11.2015 SNSF Starting Grants
197607 Molecular and cellular pathways controlling nociception and its plasticity 01.11.2020 Project funding (Div. I-III)
121191 Thermosensation: identification des thermosenseurs neuronaux et moleculaires chez C. elegans 01.07.2008 Fellowships for prospective researchers
150353 Genetic Analysis of Temperature and Pain Sensation in Caenorhabditis elegans (follow-up) 01.12.2013 Ambizione

Abstract

The project aims at developing the use of C. elegans model organism to study temperature and pain sensation. Most C. elegans genes involved in temperature/pain sensation that we discovered so far are conserved in human, suggesting that our studies may bring insights on novel drug targets in pain management. Significant progresses made so far include:1) Methodology : we developed (i) thermo-electrical apparatus to control heat stimuli in time and space, (ii) a computer-assisted analysis protocol providing a quantitative and objective assessment of behavior, (iii) light-stimulus system to control channelrhodopsin and other light activated-proteins, (iv) a recombinase-based approach to target transgene expression in single neurons.2) Findings: through the systematic and combinatorial study of mutations, we were able to draft a map of the gene interaction network regulating temperature/pain sensation. Furthermore, thanks to those mutations and neuron specific "genetic rescue" experiments, we also obtained key information on the neural circuit regulating temperature/pain sensation and on the execution of heat avoidance behaviors. Specifically, we are now able to link specific neurons class to specific behavioral components.
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