Across biology, function follows form. The structure of a wing provides insight into flight; the anatomy of the lung suggests mechanisms for gas exchange. When applied to the brain, however, this approach falters. The uniform, gelatinous consistency of the mammalian brain belies an almost inconceivable cellular complexity: billions of nerve cells (neurons), interacting through trillions of connections (synapses), form circuits that perceive stimuli, store memories and generate emotions. What if we had a complete map of these connections? Would this help us to understand how the brain works? This is the premise of ‘connectomics’, the systematic identification of all connections in a nervous system. Writing in Nature, Cook et al.1 report the complete connectomes of both sexes of a tiny roundworm — a major step towards understanding how a brain’s function emerges from its form.
Long before the word connectomics was first uttered, the ideas behind it were apparent to the late Sydney Brenner, who, in the 1960s, famously sought to ‘tame’ a creature whose nervous system might be completely mapped2. Brenner settled on the millimetre-long nematode Caenorhabditis elegans, affectionately known to those who study it as ‘the worm’. The worm’s nervous system comprises just a few hundred neurons, whose position and overall structure are identical between individuals. Yet it controls complex, instinctive behaviours, allows these to be modified according to a worm’s needs, and learns simple associations.
The worm is small enough to imagine slicing it up like a tiny salami, and, with tremendous patience, tracing the structure of each neuron and its connections across microscopy images of the slices (Fig. 1). Exactly this was heroically undertaken in the 1970s and 1980s. The resulting connectome — the first of its kind — was reported in a classic 1986 paper3 known colloquially as ‘The mind of the worm’. Important refinements have followed4–6, and neurobiologists have been working diligently to understand how behaviour emerges from the circuits described.
But this connectome was for only one sex, the hermaphrodite — a self-fertile individual that is considered the worm’s female equivalent. So the extent of sex differences in the wiring has been unclear. Moreover, because the original connectome was built manually, it remained possible that it contained some errors. To address these problems, workers from the same group as Cook et al. developed and used software7 to reconstruct the connectome of the adult male’s tail, a region that houses circuits present only in this sex. Now, Cook et al. report the rest of the male connectome, including the nerve ring — the region in the head in which the worm’s heavy computing takes place. Not satisfied with this, the authors also rebuilt the entire hermaphrodite connectome from scratch, using their software to reanalyse the original 1980s micrographs.
These new connectomes reveal rich, nuanced information that will advance the field in many ways. Whereas the original connectomes report each synapse as simply being present, Cook et al. provide each with a physical location and a weight — an indirect measure of strength based on physical size. This level of detail will enable much more sophisticated analysis and modelling of circuit function. Thanks to the software’s sensitivity, the researchers also identify thousands of previously overlooked connections in the hermaphrodite. Using the tools of network theory, they provide interesting new classifications of groups of neurons on the basis of their connectivity. By comparing their reconstructions of the worm’s left and right sides, which are largely symmetrical, the authors estimate the accuracy of their connectome data, which is reassuringly high.
The new connectomes also include the outputs of the nervous system — features that have never been catalogued rigorously in any organism. This reveals previously unknown connections to the intestine, epidermis and male gonad that will surely inspire new ideas about worm physiology and metabolism. The authors also find unexpected complexity in the control of body muscles; this might force neuroscientists to reconsider their understanding of how movement emerges from circuit function.
And what about sex differences? Remarkably, Cook et al. find that numerous connections — up to 30% — seem to differ in strength between hermaphrodites and males. Differences such as these have already been noted in the tail, where they optimize copulatory behaviour7,8. But their preponderance in the head, where the gross anatomy of the nervous system is nearly equivalent between the sexes, is surprising.
The authors confirmed some of these differences by directly visualizing particular synapses in live worms. This showed that the average size of certain connections does indeed differ by sex, but also that ranges of size can overlap substantially. Thus, as in other systems, biological sex can nudge developmental mechanisms, creating tendencies as well as absolute differences. The sex differences identified do not radically change the structure of the connectome, but they do raise fascinating questions about how these alterations modulate decision-making and behaviour.
The study does have some limitations. Because most regions were reconstructed just once, the amount of variation between individuals remains unknown. Some features of the new connectomes could arise from past experiences specific to the individuals that were sampled. Another issue regards the synaptic weights: it’s not clear how a connection’s strength might scale with its physical size. Finally, although the connectomes include many new connections, they also lack some that were present in the previous versions. So, can we consider the new connectomes ‘complete’? This is as much a philosophical issue as a technical one.
The new connectomes highlight a vexing point about neural circuits and the promise of connectomics itself: inferring function from structure alone is fraught with difficulty. Depicted graphically, the new connectomes don’t obviously resemble artificial neural networks or the wiring schematics of simple electronic devices; they look more like the cobwebs that lurk at the back of the broom cupboard. Most neurons are extensively interconnected with many others, such that any two are linked through a very short path. Although intriguing patterns can be identified, distinct circuits for specific behavioural responses are not readily apparent. As others have pointed out9, the connectome is only a map of possibilities. Functional circuits probably emerge spontaneously through the dynamic modulation of individual synapses. The connectome shows all these synapses simultaneously, offering few clues about which might be active at a given time.
Thus, the physical structure of the connectome provides essential insight into the nervous system, but is in itself insufficient for an understanding of the whole. Fortunately, groundbreaking imaging approaches could bridge the chasm between circuit structure and function. Using fluorescent indicators of neuronal activity, it is now feasible to ‘watch’ signals flow through the nervous system of a freely behaving worm in real time10,11. Superimposing these activity patterns onto the connectome should provide the information necessary to understand how the nervous system’s structure constrains its function. This, in turn, will bring us closer to building a detailed simulation of the nervous system, generating a virtual worm that ‘lives’ inside a computer12. This is still far off; but only if we can accurately simulate and rationally manipulate a nervous system can we begin to truly understand it. Once again, Brenner’s tiny worm, occupying its unique sweet spot between simplicity and complexity, finds itself on the front line of biology’s most challenging problems.
Nature 571, 40-42 (2019)