Stan Kerstjens

Constructive Connectomics

During brain development, billions of axons navigate over long distances to form functional circuits. The absence of an explicit blueprint with an external reference frame and global coordinate space raises the question of how such self-construction can be coordinated. The question is sharpened by the limited information capacity of the genome, which discounts strategies that rely on the explicit encoding of billions of axon trajectories. We propose and validate a mechanism of development that can provide an efficient solution to the global wiring task. The key principle is that constraints inherent to mitosis implicitly induce a global hierarchical patterning of nested brain regions, each marked by a unique gene expression profile: If mitotic daughters have, on average, similar gene expression to their parent, and do not stray too far from one another; then the progenies of successive progenitors occupy nested and contiguous brain regions, and have an average expression that approximates their common progenitor, effectively embedding the global lineage tree in physical and expression space. Axons could exploit this organization for navigation by using the epigenetic landscape, which encodes the global lineage tree of expression states in every neuron's genome, as a roadmap to generate guidepost profiles for each leg of their journey to their targets. We confirm the operation of this mechanism through simulation; and have analyzed gene expression data of developing and adult mouse brains (sourced from the Allen Institute for Brain Science), and of larval zebrafish, and found them consistent with our simulations: gene expression indeed partitions the brain into a global spatial hierarchy of nested regions that is stable over pre- and postnatal time. Simulation of axon growth on these experimental data demonstrate that axons can indeed navigate robustly over long distances to specific targets, and generate a qualitatively plausible connectome.