First map of insect larva brain is a landmark achievement led by Cambridge scientists

The first map to show every neuron in the brain of the fruit fly larva and how they are wired together has been created by Cambridge scientists.

The extraordinary achievement represents a major advance, as until now only the brains of very simple organisms had been mapped.

It will aid our understanding of how a brain works and how signals travel through it at a neural level, leading to behaviour and learning.

The research, which could also lead to future therapies, was spearheaded by the groups of Prof Marta Zlatic and Prof Albert Cardona in the Neurobiology Division of the MRC Laboratory of Molecular Biology in Cambridge, along with members of their groups in the University of Cambridge’s Department of Zoology and Department of Physiology, Development and Neuroscience respectively, in collaboration with Joshua T Vogelstein at Johns Hopkins University.

Their map – or ‘connectome’ – features all 3,016 neurons found in the brain of the larva of Drosophila melanogaster, along with the detailed circuitry of neural pathways within it. They painstakingly mapped the brain and its 548,000 synapses – the contact points connecting neurons – using computer-assisted reconstruction from electron micrographs.

It is the largest complete brain connectome ever mapped.

Prof Zlatic said: “The way the brain circuit is structured influences the computations the brain can do. But, up until this point, we’ve not seen the structure of any brain except of the roundworm C. elegans, the tadpole of a low chordate and the larva of a marine annelid, all of which have several hundred neurons. This means neuroscience has been mostly operating without circuit maps.

“Without knowing the structure of a brain, we’re guessing on the way computations are implemented. But now, we can start gaining a mechanistic understanding of how the brain works.”

Advances in electron microscopy enabled the entire brain to be imaged relatively quickly, before the brain circuitry was reconstructed from the data.

The technology is not yet capable of tackling larger brains, such as those of mammals, but the researchers say the work will nonetheless be a lasting reference for future studies of brain function in other animals.

“All brains are similar – they are all networks of interconnected neurons – and all brains of all species have to perform many complex behaviours: they all need to process sensory information, learn, select actions, navigate their environments, choose food, recognise their conspecifics, escape from predators etc.

“In the same way that genes are conserved across the animal kingdom, I think that the basic circuit motifs that implement these fundamental behaviours will also be conserved,” said Prof Zlatic, whose colleague Dr Michael Winding at the Department of Zoology was among those involved.

The brain structures of the fruit fly larva are similar to those of the adult fruit fly and larger insects. It has a rich behavioural repertoire, including learning, calculating values and action-selection.

Until now, scientists have only been able to build a picture of synapse-resolution circuity for larger brains by mapping select regions in isolation.

The team built their picture of the fruit fly larva connectome using thousands of slices of the larva’s brain imaged with a high-resolution electron microscope and annotated the connections between neurons.

They developed computational tools to identify likely pathways of information flow and different types of circuit patterns in the insect’s brain, discovering that some of the structural features are similar to state-of-the-art deep learning architecture.

“The most challenging aspect of this work was understanding and interpreting what we saw. We were faced with a complex neural circuit with lots of structure.

“In collaboration with Prof Priebe and Prof Vogestein’s groups at Johns Hopkins University, we developed computational tools to predict the relevant behaviours from the structures. By comparing this biological system, we can potentially also inspire better artificial networks,” said Prof Zlatic.

The LMB described the work as a “landmark achievement” that opens the door to future studies of neural circuits and brain function.

Jo Latimer, head of neurosciences and mental health at the Medical Research Council, said: “This is an exciting and significant body of work by colleagues at the MRC Laboratory of Molecular Biology and others.

“Not only have they mapped every single neuron in the insect’s brain, but they’ve also worked out how each neuron is connected. This is a big step forward in addressing key questions about how the brain works, particularly how signals move through the neurons and synapses leading to behaviour, and this detailed understanding may lead to therapeutic interventions in the future.”

The researchers will now dive deeper into the findings to discover, for example, the brain circuitry required for specific behavioural functions, such as learning and decision making. They also want to explore activity in the whole connectome while the insect is active.

The study was published last Friday (March 10) in Science.

A deep dive into the brain of the Drosophila larva

After mapping the brain of the Drosophila larva at synaptic resolution, the researchers carried out detailed analyses of the architecture of the circuits, including connection and neuron types, network hubs and circuit motifs.

They explored what neurons sent a signal (presynaptic) and which received the messages (postsynaptic).

They found 73 per cent of the brain’s in-out connecting hubs were postsynaptic to the learning centre or presynaptic to the dopaminergic neurons, which drive learning.

They used graph spectral embedding to hierarchically cluster neurons by synaptic connectivity into 93 neuron types which were internally consistent with features such as morphology and function

And they developed a new algorithm to track the brain’s signal propagation across polysynaptic pathways - involving multiple synapses. The ‘feedforward’ (sensory to output) and ‘feedback’ pathways, multisensory integration and cross-hemisphere interactions were all analysed.

They identified extensive multisensory integration throughout the brain, with numerous interconnected pathways from sensory neurons to output neurons forming a distributed processing network.

And they found the Drosophila brain’s architecture was highly recurrent, with 41 per cent of neurons receiving long-range recurrent input.

Recurrence was particularly noted in regions involved in learning and action selection. Dopaminergic neurons that drive learning were found to be among the most recurrent neurons in the brain.

Extensive communication across hemispheres was achieved by in-out hubs comprising contralateral neurons synapsed onto each other.

The researchers also analysed interactions between the brain and nerve cord, finding that descending neurons targeted a minority of premotor elements, which could be important in switching between locomotor states.

A subset of descending neurons targeted low-order post-sensory interneurons, which they believe modulate sensory processing.