DURHAM, N.H. — Researchers from the University of New Hampshire looked at the developmental process of the cerebral cortex —the outermost layer of the brain — and examined how neurons, or nerve cells, refine their positions in the  brain after birth. Their study shed light on the evolutionary transition from the three-layered cortex, considered an ancient structure, to the six-layered cortex, which is characteristic of higher mammals, including humans. The postnatal transition process has remained poorly understood, but this study provides the first evidence of a slow reverse movement of neurons that shift backward to reposition themselves. This process reshapes the six-layered neocortex, which is necessary for higher biological intelligence like learning, reasoning and memory.

“Imagine the placement of neurons in the brain’s cortex similar to skiing at a resort. The forward migration is like taking a ski lift to the top of the mountain and once at the top skiers often pause and gather, creating a temporary congestion. However, the mountain peak is not the final destination, so they disperse moving backward and spreading out across the downhill slope. Brain neurons behave in a similar way,” says Xuanmao Chen, associate professor of neurobiology at UNH. 

Earlier studies mostly focused on neurogenesis — the generation of neurons in the brain — and fast neuron migration all moving in one direction early in the development of an embryo. But researchers found that neurons slowly moved backwards to adjust their final position after birth, and the postnatal reverse movement of the neurons contributed to the evolutionary transition from the three-layered cortex to six-layered neocortex. They believe that without reverse movement, only compact three-layered cortices can develop and the proper formation of the sparse six-layered neocortex would not be possible.

“The six-layer neocortex is crucial for higher cognitive functions, including reasoning, language processing and mathematical abilities,” says Chen. “Animals with three-layered cortices, such as turtles, alligators and other reptiles, have a simpler brain structure that doesn’t allow them to learn difficult tasks or process a lot of information and they must rely more on instinctual behaviors rather than complex reasoning.” 

In the study, recently published in the journal Development, researchers present their results using mouse models to study the repositioning of these neurons. They used immunostaining to identify the direction of the cilia, or cell antennae, on the neurons in the postnatal layers of the mouse brain, such as the hippocampus and neocortex. They focused on the orientation of cilia antennae which sense and respond to their environment on the excitatory neurons. Researchers looked for orientation changes during postnatal development, finding cilia on younger neurons pointed in opposite directions from those on older neurons. In contrast, cilia on neurons in looser layers, such as the six-layer neocortex, predominately point in the same direction. Using this clue, the authors collected evidence showing neurons moved backwards against the direction of radial migration — the movement of newly formed neurons — during postnatal growth and repositioning. The researchers show that this reverse movement of neurons can promote gyrification — the process that creates folds on the brain’s surface — and might offer insights into how human brain architecture evolves. 

Researchers said the study provides critical insights into the formation of neocortical layers in humans and could have important implications in understanding the evolution of biological intelligence and developmental disorders like autistic spectrum disorders (ASD), lissencephaly (smooth brain disorder) and ciliopathies (disorders affecting cilia). And potentially, in the long term, could lead to the development of new treatments.

Co-authors, all at UNH, include Juan Yang, Soheila Mirhosseiniardakani, Liyan Qiu, Kostandina Bicja, Abigail Del Greco, Kevin Jungkai Lin and Mark Lyon.

Funding for this research was provided by the National Institutes of Health.

About UNH:
The University of New Hampshire inspires innovation and transforms lives in our state, nation and world. More than 16,000 students from 50 states and 87 countries engage with an award-winning faculty in top-ranked programs in business, engineering, law, health and human services, liberal arts and the sciences across more than 200 programs of study. A Carnegie Classification R1 institution, UNH partners with NASA, NOAA, NSF, and NIH, and received over $250 million in competitive external funding in FY24 to further explore and define the frontiers of land, sea and space.