P256 Structural and evolutionary insights of the neuropeptide connectome of Caenorhabditis species
Lidia Ripoll-Sánchez*1,2,Itai A. Toker4,Oliver Hobert4,Isabel Beets3,Petra E. Vértes1,2,5,William R. Schafer1,3,5
1MRC Laboratory of Molecular Biology, Cambridge, UK 2Department of Psychiatry, Cambridge University, Cambridge, UK 3Department of Biology, KU Leuven, Leuven, Belgium 4Department of Biological Sciences, Howard Hughes Medical Institute, Columbia University, New York, NY, USA 5co-senior authors
*Email: lsanchez@mrc-lmb.cam.ac.uk
Introduction
Neuropeptides modulate synaptically wired neuronal circuits. This modulation is critical to nervous system function, yet little is known about the structure and function of extrasynaptic signalling networks at a whole-organism level and how that is maintained over evolution.
Methods
To this end, we used single neuron gene expression [1] and deorphanisation data for neuropeptide-activated G-protein coupled receptors [2] to generate a connectome of 92 neuropeptide signalling networks inC. elegans[3].This network defined a connection when the sending neuron expressed a neuropeptide, the receiving neuron expressed the cognate receptor, and both neurons extended overlapping processes.We then used graph theory and machine learning methods to characterise its structural features.
Results
Our analysis on the connectivity pattern revealed a mesoscale structure for the core of the network, splitting it in three groups of neurons that act as highly controlled functional hubs. Notably inside these hubs, we identified a group of neurons that seem to be morphologically and biochemically adapted for neuropeptidergic communication. Furthermore, the co-expression pattern identified autocrine neuropeptidergic connections that may modulate locomotion control and evolutionary conserved intracellular neuropeptide signalling networks that could act as homeostatic regulators of the neuropeptidergic network. This network has a higher connection density than the synaptic and gap junction ones, connecting non-synaptically connected neurons [3].
Discussion
These findings challenge the idea that neuronal communication is primarily synaptic, revealing a dense, decentralised neuropeptide network with functional and structural roles. Additionally, conserved signalling patterns acrossCaenorhabditisspecies highlight the evolutionary significance of neuropeptide connectivity[4].Weexpect that this newly mapped neuropeptide connectomes, their analysis and the interactive website we developed to explore them (nemamod.org) will serve as a prototype for other animals and provide new insight into the structure of neuromodulatory networks in larger brains.
Acknowledgements This work was funded by the Howard Hughes Medical Institute and the NIH grants RO1 NS039996 & NIH RO1 NS100547 (to OH); the Medical Research Council grant MC-A023-5PB91 (to WRS); a Medical Research Council PhD fellowship (to LRS); the MQ Transforming Mental Health grant MGF17_24 (to PEV); and a postdoctoral fellowship from the Evelyn Gruss Lipper charitable foundation (to IAT). References 1.https://doi.org/10.1016/j.cell.2021.06.023 2.https://doi.org/10.1016/j.celrep.2023.113058 3.https://doi.org/10.1016/j.neuron.2023.09.043
