GENETONE · Genetic dissection of a tonically active neural circuit
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-09-01 → 2019-08-31
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Genetic dissection of a tonically active neural circuit
Understanding how the brain works is one of the fundamental challenges for 21st century science. Brain function relies on the ability of neurons to communicate dynamically, which can vary between individuals. Insight into neural signaling is therefore essential to learn how the brain operates or dysfunctions. In many vertebrate sensory systems persistent stimuli are encoded by tonically signaling neural circuits. Defects in these circuits link to sensory dysfunctions such as visual impairments, hearing loss, and chronic pain. Despite their importance and prevalence, tonic circuits have not been studied extensively at a molecular level, and how they modulate behavior remains elusive. In this project I have addressed these research questions by exploiting forward genetics to dissect a tonically active circuit in the genetic model organism Caenorhabditis elegans. In C. elegans, tonic signaling drives escape from high oxygen and carbon dioxide. By mapping and sequencing the genomes of C. elegans strains defective in this escape behavior, I discovered a genetic pathway that affects the experience-dependent plasticity of behavioral responses. Results of this genetic approach implicate a conserved dendritic scaffold protein that localizes the machinery for gas sensing to the cilia of sensory neurons. The molecular scaffold alters expression of neuropeptide messengers in the tonic circuit. These findings highlight the importance of cellular compartmentalization and neuropeptide molecules for reprogramming behavioral priorities according to experience.
Data: CORDIS, © European Union
Project objective
Understanding how the brain works is a fundamental challenge in biology and a priority of EU research. A subset of brain circuits can signal tonically to encode persistent stimuli. Such circuits are involved in many sensory systems (e.g. vision, hearing) and in homeostatic responses (e.g. temperature, pH, and posture control). How tonic activity is molecularly achieved remains poorly understood. In C. elegans a tonic circuit promotes aggregation behavior and escape from 21% oxygen. At its core this circuit comprises URX oxygen sensors that tonically stimulate RMG interneurons as oxygen approaches 21%, evoking a switch in behavioral state. Each neuron in the circuit can be imaged and selectively modified in vivo - providing a special opportunity to dissect a tonically active circuit. Genetic screens have isolated 74 mutants with behavioral defects linked to URX-RMG tonic activity and that appear to disrupt hitherto unstudied loci. I am currently identifying the genes defective in these mutants, something I expect to achieve by May 2016 when the Fellowship would begin. I propose to combine genetics, neural imaging, optogenetics and biochemistry to characterize these genes’ function. I expect to define groups of gene products that act together. Some will be hitherto uncharacterized in any animal. I propose to collaborate with partners in the host institute and elsewhere to characterize the function of conserved genetic pathways I discover in depth. I will gain added value from learning new approaches (e.g. biochemistry, CLEM, cell-specific RNA Seq) and by extending some of my findings into a vertebrate model. I expect my research to provide general insights into molecular mechanisms by which tonic circuits work, with potential implications for human disease. This project is likely to pioneer new lines of research indispensible to establish an independent research career, will broaden and deepen my technical expertise, and will help me develop new scientific networks.
Original text from CORDIS.
Participants
- UNITED KINGDOM RESEARCH AND INNOVATION · SWINDONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union