Although the C. elegans connectome has been a boon for scientists who study this nematode's behavior, the past two decades of research have also underscored the staggering intricacy of even a relatively small nervous system. "When you move onto behaviors that are more complex than a quick reflex, you're dealing with especially complicated pathways that are not immediately interpretable because they are not simple circuits—they are networks," explains Scott Emmons of Albert Einstein College of Medicine.
This past summer, in an attempt to confront some of that complexity, Emmons and his colleagues published a connectome of the male nematode's tail, which contains most of the 81 extra neurons that distinguish it from the hermaphrodite (giving the male a total of 383 neurons). It took Emmons and his team about three years to complete and publish the partial connectome: he used more or less the same techniques that Brenner relied on in the 1970s, albeit with faster computers, more powerful microscopes and digital cameras. The male C. elegans connectome also features a crucial piece of information missing from the original draft of its counterpart: synaptic weights. The many connections between neurons are not equal in strength—the more two neurons communicate, the stronger their link becomes and the more likely one is to fire when the other fires. Neurons may also be genetically programmed to form stronger connections with certain partners as the nervous system develops.
Analyzing synaptic weights in the male nematode's connectome has already given Emmons some ideas about neural development. Some neuroscientists have proposed that genes tightly regulate the strongest connections between neurons in C. elegans, whereas weaker connections are more or less accidents—neurons hooking up with whomever they bump into. Emmons's preliminary analysis shows that homologous pairs of neurons on either side of the nematode's body form highly similar strong and weak connections, suggesting that even the weak connections are not entirely random.
Synaptic weights are just one of the many layers of information missing from typical connectomes. To understand how neural circuits work, one also needs to know whether the relevant neurons are excitatory—increasing the likelihood that linked cells fire—or inhibitory, muffling their partners instead. Further complicating things, neglected neurons shrivel in the developing brain and new neurons sprout to replace them; in the adult brain, neurons change the strength of their connections with one another daily—such flexibility is essential for learning and memory. Yet another level of complexity involves neuromodulators: certain kinds of neurotransmitters and other small molecules that linger in the fluid surrounding neurons, changing how neurons behave in ways we do not yet fully understand. A prediction about how information will flow through a particular circuit based on a wiring diagram and synaptic weights might be completely wrong if one does not know which neuromodulators are hanging around at any given time.
A good example of how a static connectome fails to capture the dynamics of living neural networks comes from research on the stomatogastric ganglion (STG), a pair of neural circuits in crustaceans—including crayfish, crabs, lobsters and shrimp—that generate rhythmic behavior in response to food. One subcircuit repeatedly constricts and dilates the pyloric region of the stomach, the foyer to the small intestines. Another subcircuit pulsates the gastric mill, a muscular pouch lined with chitinous teeth that help break down food. Mapping all the connections between the 30 neurons in the crustacean STG was an important first step toward understanding how the STG controlled the crustacean digestive system. But it was by no means sufficient. Eve Marder of Brandeis University and others have shown that the neurons in the stomatogastric ganglion do not always use the same unchanging set of connections to communicate with one another. In the presence of certain neuromodulators, a neuron that contributes to the pyloric subcircuit might switch teams, joining the gastric mill subcircuit instead by changing the tempo at which it fires.
Because any brain or nervous system is so much more complex than what a connectome by itself represents, Movshon is certainly not alone in thinking that researchers' limited resources are better devoted to other areas of neuroscience. "I'm all in favor of Seung and others," Bargmann says, "but I don't think we should have a Manhattan Project for the connectome with such a huge amount of resources. We are not quite good enough at reading them. It wasn't like the human genome project, where we knew how to sequence DNA and said, 'Yeah, let's go for it!' Scaling up connectomes is a different issue."
Oliver Hobert of Columbia, another longtime C. elegans researcher, agrees that connectomics only scratches the surface. "It's like a road map that tells you where cars can drive, but does not tell you when or where cars are actually driving," he says. "Still, connectomics of C. elegans has given us wonderful testable hypotheses in terms of how neural circuits work. What we have learned from C. elegans diagrams are not just specific worm behaviors—they are logical principles common to much of biology."
*Editor's Note: The author is a member of NeuWrite, a workshop of scientists and writers that organized the debate at Columbia.