Orchestrated neuronal migration and cortical folding: A computational and experimental study

Abstract

Brain development involves precisely orchestrated genetic, biochemical, and mechanical events. At the cellular level, neuronal proliferation in the innermost zone of the brain followed by migration towards the outermost layer results in a rapid increase in brain surface area, outpacing the volumetric growth of the brain, and forming the highly folded cortex. This work aims to provide mechanistic insights into the process of brain development and cortical folding using a biomechanical model that couples cell division and migration with volumetric growth. Unlike phenomenological growth models, our model tracks the spatio-temporal development of cohorts of neurons born at different times, with each cohort modeled separately as an advection-diffusion process and the total cell density determining the extent of volume growth. We numerically implement our model in Abaqus/Standard (2020) by writing user-defined element (UEL) subroutines. For model calibration, we apply in utero electroporation (IUE) to ferret brains to visualize and track cohorts of neurons born at different stages of embryonic development. Our calibrated simulations of cortical folding align qualitatively with the ferret experiments. We have made our experimental data and finite-element implementation available online to offer other researchers a modeling platform for future study of neurological disorders associated with atypical neurodevelopment and cortical malformations.

Investigation of the mechanisms underlying the development and evolution of folds of the cerebrum using gyrencephalic ferrets

“…This result strongly suggests that Cdk5 in pyramidal neurons is important for the folding of the cerebrum. Given that Cdk5 is essential for the radial migration of cortical neurons from the ventricular surface to the pial surface of the cerebrum, it has been proposed that the radial migration of cortical neurons is crucial for cortical folding (Wang et al., 2022). Similarly, a mutation in SCN3A/Nav1.3 sodium channels was found to impede both radial migration and cortical folding (Smith et al., 2018).…”

Axonal tension contributes to consistent fold placement

“…[34][35][36][37][38][39] Simulations can not only provide quantitative information about stress, for instance, which is difficult to measure experimentally, but when combined with experiments, they can help to identify and evaluate potential mechanisms of folding. 40,41 However, the complexity of brain tissue is a challenge for the accuracy of finite element models. In addition to multiple cell types, complex mechanical behavior, 42 and highly heterogeneous structure and properties, 43,44 there is also an issue of scale.…”

Exploring the role of the outer subventricular zone during cortical folding through a physics-based model

“…Many previous studies tried to explain normal and abnormal cortical folding either from a purely biological or mechanical perspective ( Tallinen et al, 2014 ; Razavi et al, 2015 ). However, it will not be possible to capture the folding mechanism without considering both perspectives at the same time ( de Rooij and Kuhl, 2018 ; Zarzor et al, 2021 ; Wang et al, 2022 ). In other words, to fully understand the physiological and pathological mechanisms underlying cortical folding in the developing human brain, we need to study the coupling between cellular processes and mechanical forces – to eventually assess how disruption of cellular processes affect the folding pattern and lead to malformations of cortical development ( Guerrini et al, 2008 ; Blumcke et al, 2021 ; Llinares-Benadero and Borrell, 2019 ).…”