Skip to main content

Genetic dissection of a tonically active neural circuit

Periodic Reporting for period 1 - GENETONE (Genetic dissection of a tonically active neural circuit)

Reporting period: 2017-09-01 to 2019-08-31

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.
Genetic variation affecting experience-dependent plasticity of behavioral decisions

Starting from a collection of C. elegans mutants with impaired avoidance of oxygen and carbon dioxide, I discovered by genetic mapping and genome sequencing a mutation in a conserved dendritic scaffold protein that disrupts the plasticity of behavioral responses to these ambient stimuli. The identified protein, homologous to the family of ankyrin proteins in mammalian nervous systems, modulates escape from aversive gas stimuli according to previous experience. In collaboration with scientists in France, we found that this gene underlies variation in the experience-dependent plasticity of C. elegans behavior.

Cellular compartmentalization in the control of sensory responsiveness

Expression and cell-specific rescue studies showed that the identified ankyrin-like protein regulates plasticity of the tonic gas-sensing circuit directly at the level of sensory neurons. In these neurons, the molecular scaffold localized to the sensory endings that detect gas stimuli from the environment. Using biochemical approaches, I looked for its interaction partners and found it localizes core-signaling components of the gas-sensing machinery to sensory cilia. This finding highlights the functional importance of cellular compartmentalization for the dynamics of neural and behavioral responses.
Together with researchers from the US, we also discovered a role for a conserved MAPK signaling pathway in regulating the growth and morphology of dendritic endings in adult C. elegans neurons. The kinase localizes at the sensory endings where it constrains growth of a dendritic compartment, indicating another role for cellular compartmentalization in shaping neurons.

Neuropeptide-mediated plasticity and cross-modulation of behaviors

To understand how the identified protein of the ankyrin family affects the activity and output of the tonic circuit, I used tools to monitor calcium activity and gene expression. Interestingly, the scaffold protein altered expression of neuropeptide messengers required for the experience-dependent plasticity of behavior, while calcium activity in the circuit was unaffected.
In collaboration with another C. elegans group at the LMB institute, we identified a neuropeptide pathway that drives cross-modal sensitization in arousal. Taken together, these works underscore an important role of neuropeptide pathways in the experience-dependent crossmodulation of sensory responses.
In general, the work performed during this action advances our knowledge on the neurobiology of tonically active brain circuits, neuromodulation and evolution of behavior. Several techniques that were optimized in the course of this action go beyond the current state of the art and allowed to gain new perspectives on transcriptional changes and functions of genetic regulators in tonic circuits. It has provided mechanistic insights into growing areas of research interest and on genes with poorly characterized functions. Results of this work have been communicated on several occasions to the scientific community and public, via contributions to conferences and outreach activities such as the European Researchers Night. In addition, by initiating several international collaborations with groups within and outside LMB, this action has contributed to maintain and strengthen scientific excellence in Europe.