Probabilistic axon targeting dynamics lead to individualized brain wiring

Abstract

Developmental variation in brain-wiring contributes to behavioural individuality1,2. However, how and when individualized wiring diagrams emerge and become stable during development remains largely unknown. Here, we explored axon targeting dynamics in individual brains using live-imaging of a developing Drosophila visual circuit and discovered that targeting choice is an algorithmic multi-step growth process with variable outcomes. Using optogenetics, we found that temporally restricted Notch lateral-inhibition defines a subset of neurons with a probabilistic potential to innervate distal targets. Next, axons from NotchOFF neurons amplify into long actin-rich multi-fibre structures necessary for distal growth. A subset of these NotchOFF neurons create distal targeting axons by stabilizing microtubule growth in one of their actin fibres. Amplified axons without tubulin-stabilized fibres retract, resulting in the stochastic selection of a different number of distal targeting axons in each brain. Pharmacological microtubule destabilization suffices to inhibit this targeting. We observed a similar axonal amplification-stabilization process in the developing chick spinal cord, suggesting a conserved mechanism. Finally, early microtubule patterns predict the adult brain- wiring of an individual in a target-independent manner prior to synapse formation3,4. Thus, we show that a temporal succession of genetically encoded stochastic processes explains the emergence of individual wiring variation.

Whole-brain annotation and multi-connectome cell typing quantifies circuit stereotypy inDrosophila

“…Brain wiring develops through a complex and probabilistic developmental process 63,64 . To interpret the connectome it is vital to obtain a basic understanding of how variable that biological process is.…”

A new view of axon growth and guidance grounded in the stochastic dynamics of actin networks

“…It has come to be recognized in many systems that cytoskeletal cell biology and biophysics are in their essence inherently probabilistic in nature, not just noisy to measure, but noisy in their essence, and indeed have evolved to use ‘noise’—random fluctuation—as a central element in their mechanism, just as we see here [ 42 , 100 – 103 ]. In a similar way, noisy fluctuation of filopodial number has been shown to be an essential element in the directional response of growth cones to a netrin gradient in C. elegans [ 42 ], and stochastic stabilization of a subset of filopodia by microtubule invasion is central to target selection in the Drosophila optic system [ 104 ]. Single-cell biological mechanisms, including pathfinding of individual growth cones, often cannot readily be accounted for by deterministic models.…”