Project description
Sex, worms, and avoidance may teach us something about neurodegenerative diseases
Males and females of the same species often demonstrate differences in more than their reproductive systems such as size, colouration, and behaviours. Dimorphisms arising in response to environmental cues have also been linked to sexual differences in disease processes, particularly neurological diseases. Scientists working on the EU-funded DimorphicCircuits project are delving deeper into sex-related differences in the nervous system and in neurally-mediated avoidance behaviour using C. elegans as the model system. C. elegans is the only organism for which the entire nervous system has been mapped. The adult worm's 302 neurons and 56 glial cells and all their synapses are known. DimorphicCircuits plans to utilise high-tech methods in a simple system to elucidate how sex modulates neuronal circuits.
Objective
In sexually reproducing species, males and females respond to environmental sensory cues and transform the input into sexually dimorphic traits. These dimorphisms are the basis for sex-biased phenotypes in many neurological diseases. Yet, complete understanding of the underlying mechanism is still missing. How does the sexual identity impose molecular changes to individual neurons and circuits? What are the sex-specific synaptic changes that occur during development in these circuits? We recently demonstrated a sexually dimorphic dimension of neuronal connectivity: neurons belonging to a shared nervous system rewire in a sex-specific manner to generate sexually dimorphic behaviors. New findings from our lab further reveal a significant difference in the way the two sexes in the nematode C. elegans respond to aversive stimuli. These dimorphic responses are mediated via sex-shared circuits that receive similar environmental input, yet respond differently.
Building on our exciting preliminary results, we seek to elucidate how genetic sex modulates neuronal function, neural circuit dynamics and behavior during development. This proposal will pursue three complementary objectives: (i) Map the repertoire of sexually dimorphic avoidance behaviors; (ii) Study the synaptic basis for the development of sexually dimorphic circuits; and (iii) Elucidate the molecular basis of sexually dimorphic neuronal circuits. These mechanisms can only be currently resolved in C. elegans, where the entire connectome of the nervous system for both sexes has been mapped. Using cutting-edge optogenetics, calcium imaging, activity-dependent trans-synaptic labeling, genetic screens and single-cell transcriptome analysis we will shed light on the elusive connection between genes, circuits and behavior. Understanding how genetic sex modulates neuronal circuits will aid in the development of novel gender-specific therapies.
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Funding Scheme
ERC-STG - Starting GrantHost institution
7610001 Rehovot
Israel