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

PLoS Comput Biol. 2022 Jun 16;18(6):e1010190. doi: 10.1371/journal.pcbi.1010190. eCollection 2022 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement / physiology
  • Cerebral Cortex* / physiology
  • Electroporation / methods
  • Female
  • Ferrets*
  • Humans
  • Neurons / physiology
  • Pregnancy

Grants and funding

MAH and SW are supported by Notre Dame International’s Asia Research Collaboration Grant. HK and KS are supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Takeda Science Foundation, Kanazawa University SAKIGAKE Project 2018, and Kanazawa University CHOZEN Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.