Constructive connectomics: How neuronal axons get from here to there using gene-expression maps derived from their family trees

During brain development, billions of axons must navigate over multiple spatial scales to reach specific neuronal targets, and so build the processing circuits that generate the intelligent behavior of animals. However, the limited information capacity of the zygotic genome puts a strong constraint on how, and which, axonal routes can be encoded. We propose and validate a mechanism of development that can provide an efficient encoding of this global wiring task. The key principle, confirmed through simulation, is that basic constraints on mitoses of neural stem cells—that mitotic daughters have similar gene expression to their parent and do not stray far from one another—induce a global hierarchical map of nested regions, each marked by the expression profile of its common progenitor population. Thus, a traversal of the lineal hierarchy generates a systematic sequence of expression profiles that traces a staged route, which growth cones can follow to their remote targets. We have analyzed gene expression data of developing and adult mouse brains published by the Allen Institute for Brain Science, and found them consistent with our simulations: gene expression indeed partitions the brain into a global spatial hierarchy of nested contiguous regions that is stable at least from embryonic day 11.5 to postnatal day 56. We use this experimental data to demonstrate that our axonal guidance algorithm is able to robustly extend arbors over long distances to specific targets, and that these connections result in a qualitatively plausible connectome. We conclude that, paradoxically, cell division may be the key to uniting the neurons of the brain.Author summary: The embryological development of each brain installs an essentially identical communication network between its cells that is roughly as complex as that between the billions of people living on Earth. Although vast scientific resources are currently applied to identifying the final pattern of connections, the connectome, there has until now been relatively little effort to answer the fundamental question of how this complex network across billions of neurons is realized through the mitotic elaboration of the initial embryonic cell. The problem is sharpened by the constraints that construction of the network is limited by the information budget of the initial genome, and that it has no pre-existing address space for placing neurons and guiding axons. We explain how Biology can solve this problem by using the family tree of neurons to install a global space of molecular addresses, which axons can use to navigate from their source neuron to its relatives. We provide experimental evidence for this familial address space in gene expression patterns of the developing mouse brain, and demonstrate through simulation that the experimentally observed address space indeed supports global navigation to produce a qualitatively plausible default connectome.