A significant step forward in understanding how brains work has been taken by Cambridge researchers, who for the first time have mapped how every neuron in the nervous system of a tiny worm communicates wirelessly.
Explaining how neurons communicate through extremely short proteins called neuropeptides will help scientists figure out how our emotions and mental states are controlled and provide insight into widespread neuropsychiatric conditions like eating disorders, OCD and PTSD.
The map details 31,479 neuropeptide interactions between the worm’s 302 neurons and shows where each neuropeptide, as well as each receptor for those peptides, acts in its nervous system.
Neuropeptides enable communication between neurons that are not immediately next to each other, meaning their networks are described as a wireless connectome.
A connectome is a map of the neurons in an organism’s brain and its detailed circuitry of neural pathways.
While there has been rapid progress in building connectomes for simple organisms, this is the first time anyone has built a map of a neuropeptide network in any animal.
Dr William Schafer and PhD student Lidia Ripoll-Sánchez, from MRC Laboratory of Molecular Biology in Cambridge, led the work with Petra Vértes, from the University of Cambridge, and Isabel Beets, from the University of Leuven in Belgium.
The team studied the harmless 1mm worm C. elegans, which lives in soil and is a favourite with researchers as it has a very simple anatomy but shares many essential characteristics with human biology.
Dr Schafer said: “Neuropeptides and their receptors are among the hottest new targets for neuroactive drugs. For example, the diabetes and obesity drug Wegovy targets the receptor for the peptide GLP-1. But the way these drugs act in the brain at the network level is not well-understood.
“The structure of neuropeptide networks suggests that they may process information in a different way to synaptic networks. Understanding how this works will not only help us understand how drugs work but also how our emotions and mental states are controlled.
“The idea of mapping these wireless networks has been one of our goals for a long time, but only now have the right combination of people and resources come together to make this actually possible.”
Neuropeptides are a diverse group known to play a critical role in lasting biological responses affecting mood, sexual behaviour, learning and memory, sleep and addiction.
They function throughout the nervous system as well as acting on other types of tissue as hormones.
Oxytocin, for example, is a neuropeptide, acting on various circuits in the brain that affect bonding between parents and children, but also causing contraction of the muscles of the uterus during childbirth.
Even in the brain, neuropeptides enable communication between neurons that are not connected by the synapses – physical junctions – that area used by classical neurotransmitters.
It is thought most neurons make both neuropeptides and neuropeptide receptors. This means the communication pathways formed by neuropeptides are extensive, complex neural networks, which are critical to the functioning of the brain and therefore critical to understanding the neuronal basis of behaviour.
Lidia said: “Basic mechanisms of neuropeptide signalling are shared in all animals: neuropeptides are released from dense core vesicles in cells and diffuse to neurons unconnected to the releasing cell by wired synapses.
“The worm’s nervous system is anatomically small, but at the molecular level its neuropeptide systems are highly complex, showing significant parallels to larger animals, and its synaptic connectome shows many features that are conserved in bigger brains. We expect the neuropeptide connectome of C. elegans will serve as a prototype to understand wireless signalling in larger nervous systems.”
To build the map, the researchers combined biochemical, anatomical and gene expression datasets. They used these to determine which neurons were able to communicate with each other using specific neuropeptide signals.
Then, with the network built, they used graph theory to analyse its structure and identify key topological features, as well as neurons with important roles in linking different parts of the network.
They found the wireless neuropeptide network in C. elegans has a different structure from wired connectomes, as they are denser, more decentralised and feature different key neurons, or hubs.
And the network connects parts of the nervous system isolated from the wired synaptic connectome.
Jo Latimer, head of neurosciences and mental health at the Medical Research Council, said: “This is another exciting and significant body of work by colleagues at the MRC Laboratory of Molecular Biology and others, adding to the connectome work of LMB researchers earlier this year. Not only have they worked out which neuropeptides act where in the animal’s nervous system, they have discovered that the network is complex, but clearly organised, with an information processing circuit within it.
“This is a further important step forward in understanding how brains and nervous systems work, and this increased understanding may have the potential to lead to the future development of targeted therapies for a range of conditions.”
Following the publication of the study in Neuron on Monday (November 6), the researchers say the next step will be to see whether the principles by which neuropeptide networks in worms are organised also apply in bigger brains.
They are already working with other collaborators to map wireless neuropeptide networks in animals such as fish, octopuses, mice and even humans.
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