Understanding how brains fold and misfold

Australian and Swiss researchers say they have new clues to how a baby’s brain folds as it develops in the womb, a process critical to healthy brain function.

Misfolding is linked with neurological conditions such as autism, anorexia, epilepsy and schizophrenia, but scientists do not fully understand what drives the folding process and why it sometimes goes wrong.

There currently are no therapies for the prevention or treatment of misfolding and no early test to detect problems before folding begins.

In a pre-clinical study using animal models, a team led by Australia’s RMIT University identified the genes linked with the development of the two types of brain folds – inward and outward – in the brain’s grey matter.

Writing in the journal Cerebral Cortex, they report finding differences in both genetic expression and neuron shape during the folding process.

“The next step is to determine the precise role these genes play in the process, so we can work towards identifying potential therapeutic targets and develop interventions to prevent and fix misfolding in the brain,” says RMIT’s co-chief investigator Mary Tolcos.

The researchers say previous studies have focussed on white matter or looked at animals with smooth brains rather than folded ones, largely overlooking grey matter. Grey matter is made up of neuron bodies and their connecting arms; white matter comprises the neurons’ long nerve fibres and their protective layer of fat.

The latest evidence suggests grey matter in the developing brain expands faster than white matter, creating mechanical instability that leads to brain folding. The resulting “hill” and “valley” folds follow a similar pattern in all folded brains of the same species.

Tolcos and colleagues investigated the genetic and microstructural differences in future grey matter, the cortical plate, in the parts of the brain just beneath the “hills” and “valleys”. These areas were analysed at three points of development: when the brain was smooth, semi-folded and fully folded.

“We found some genes have higher expression in regions that fold outward and lower expression in regions that fold inwards. Other genes reverse this pattern,” says RMIT’s Sebastian Quezada Rojas.

“Together, these genetic expression patterns might explain why the cortical folding pattern is so consistent between individuals of the same species.”

These genetic differences are also correlated with changes in grey matter neurons, with the study finding variations in the number of arms – or dendrites – that neurons grow in these regions during the folding process.

“We believe the regions that fold outward and inward are programmed to behave differently, and the shape of the neurons affects the way these areas fold,” Quezada Rojas says.

The project was a collaboration between RMIT, Australia’s Monash University, and Switzerland’s Federal Institute of Technology of Lausanne and University of Geneva.

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