Beyond Molecular Codes: Simple Rules to Wire Complex Brains

Abstract

Molecular codes, like postal zip codes, are generally considered a robust way to ensure the specificity of neuronal target selection. However, a code capable of unambiguously generating complex neural circuits is difficult to conceive. Here, we re-examine the notion of molecular codes in the light of developmental algorithms. We explore how molecules and mechanisms that have been considered part of a code may alternatively implement simple pattern formation rules sufficient to ensure wiring specificity in neural circuits. This analysis delineates a pattern-based framework for circuit construction that may contribute to our understanding of brain wiring.

Figure 1. From deterministic blueprints to stochastically branched structures in biology

(A) Schematic of a hypothetical electrical blueprint with deterministic definition of all contacts. (B) Schematic drawing of a Purkinje cell after a well-known drawing from Ramon y Cajal. The precise branching pattern, number and placement of dendritic endings is variable. (C) A simple computer-generated branched structure. The deterministic definition of all branches is generated by a few lines of code (Lindenmayer system) using L-Studio 4.2.13 by Przemyslaw Prusinkiewicz and Radek Karwowski (D) The same branched structure as in (C), but with stochastic pattern changes.

Figure 2. A theoretical experiment: given promiscuous synaptogenesis at any contact site, two simple rules are sufficient to generate layer and/or column specific synaptic contacts

(A) The rule ‘stop on pre-pre (or same cell type) contact’ prevents overlap of neighboring, parallel presynaptic terminal, leading to tiling in columns. The rule ‘stop on pre-post (or other cell type) contact prevents overlap within the column; the area where pre- and postsynaptic terminals meet defines a layer. Synapses can subsequently form ‘unspecifically’ between any pre-post contact and are yet restricted to a specific column and layer. (B) The ‘pre-pre’ rule is sufficient to maintain columns, but without a ‘pre-post’ rule overlap between different cell types lead to loss of a restricted layer. (C) The ‘pre-post’ rule is sufficient to maintain layers, but without a ‘pre-pre’ rule overlap between the same presynaptic cell types leads to loss of columnar restriction.