The brains of the matter. Understanding the cerebral cortex

The brain is the most complicated organ of any animal, formed and sculpted over 500 million years of evolution. And the cerebral cortex is a critical component. This folded grey matter forms the outside of the brain, and is the seat of higher cognitive functions such as language, episodic memory and voluntary movement.

The cerebral cortex of mammals has a unique layered structure where different types of neuron reside. The thickness of the cortical layer is roughly the same across different species, while the cortical surface area shows a dramatic increase (1000 fold from mouse to human). This difference underlies a significant expansion in the number of cortical neurons produced in the course of embryonic development, resulting in the increased function and complexity of the adult brain. A human cortex accommodates 16 billion neurons as opposed to a mouse’s mere 14 million.

Key elements of this problem are being addressed by Oxford Mathematical Biologist Noemi Picco in a new collaboration involving an interdisciplinary team of mathematicians including Philip Maini in Oxford and Thomas Woolley in  Cardiff and biologists Zoltán Molnár from the Department of Physiology, Anatomy and Genetics in Oxford and Fernando García-Moreno at the Achucarro Basque Center for Neuroscience in Bilbao.

In particular the team are developing a mathematical model of cortical neurogenesis, the process by which neurons grow and develop in the cerebral cortex. Given that species diversity originates from the divergence of developmental programmes, understanding the cellular and molecular mechanisms regulating cell number and diversity is critical for shedding light on cortex evolution.

Many factors influence how neurogenesis in the cortex differs between species, including the types of neurons and neural progenitor cells, the different ways in which they proliferate and differentiate, and the length of the process (85 days in a human, 8 days in a mouse). This project combines mathematical modelling and experimental observations to incorporate these different factors. A key determinant of the neuronal production is the modulation of proliferative (self-amplifying) and differentiative (neurogenic) divisions. By modelling the temporal changes in the propensity of different cell division types, we are able to identify the developmental programme that can justify the observed number of neurons in the cortex.

The growing availability of species-specific experimental data will allow the researchers to map all the possible evolutionary pathways of the cortex, and create a mathematical framework that is general enough to encompass all cortex developmental programmes, while being specifiable enough to be descriptive of single species. This, in turn, has the potential to create a new way to identify developmental brain disorders as deviations from the normal developmental program, giving a mechanistic insight into their cause and clinically actionable suggestions to correct them.

As part of the project, Noemi has released a Neurogenesis Simulator, an app that allows experimentalists to ‘play’ with the mathematical model, choosing the species and the model and calibrating the parameters, to observe how the model outcome changes without having to worry about the mathematical formulation and thereby generating even further cross-disciplinary collaboration.

Noemi’s work is supported by St John’s College Research Centre. This work has been accepted for publication and will soon appear in Cerebral Cortex. The article preprint is available.