What Causes Brain Wrinkles?

Why do our brains have wrinkles? The simple answer is to make them more efficient. Scientists think that as we evolved and our cortexes expanded, our brains created folds to optimize how much brain matter could fit into our skulls. In addition, the speed in which our brains can send signals contributes to our intelligence, and the brain’s intricate and strategic folding shortens the distance that fibers have to project to contact different brain regions.

While scientists have pretty good theories as to why our brains are wrinkled, we don’t know exactly what physical events cause our brain matter to crumple up in the first place. That’s what a recent study from NYSCF – Robertson Investigator Jacob Hanna, PhD, and his colleagues at the Weizmann Institute of Science in Rehovot, Israel, sought to find out.

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The researchers used brain organoids (small, 3D aggregates of brain cells) to look at how the human brain develops. Unlike typical organoids, which lack blood vessels, can’t always efficiently deliver nutrients, and are hard to image, the organoids from Dr. Hanna’s lab were grown on microchip that helps mimic the brain’s natural environment. This “organ-on-a-chip” grows to resemble the structure and function of the brain, delivers nutrients, and allows for live imaging over the course of several weeks.

What the researchers found was that when our brains develop, they show something called “differential swelling,” meaning that certain parts grow faster than others. Specifically, the organoid’s outer regions expanded while its inner surface contracted, and when the organoid reached its critical density, it began to wrinkle. This wrinkling pattern was very similar to MRI images of fetal brains.

Brain organoids are made of neural-progenitor cells (cells that give rise to neurons) rather than neurons themselves, so they model a very early stage of development. The researchers explain that while organoid wrinkling is due to differential growth of progenitors, cortical folding in an actual human brain likely results from when non-dividing neurons migrate and crowd up the surface of the brain.

The researchers were also interested in modeling how the brain develops in lissencephaly, a condition in which the brain doesn’t create folds, resulting in intellectual disability and decreased life expectancy. To explore this condition, the researchers once again generated organoids, but this time with cells genetically modified to express a mutation leading to the disease. They found that the organoids wrinkled significantly less due to changes in nuclear motion. They also accumulated mutations in genes relating to the extracellular matrix and cytoskeleton (which typically contribute to cortex expansion).

This study is important because it demonstrates the ability of the “organ-on-a-chip” to successfully model the early developing cortex and reveals the physics behind our brain construction. For more information, check out the paper in Nature Physics, or read more in Haaretz.