How do developing brains assemble and organize themselves?

Babies are born with brains pre-organized into areas dedicated to movement, vision, hearing and other functions, a critical infrastructure that equips them to start learning about the world from the moment they take their first breaths. But little is known about how the brain’s architecture is built because of the challenges involved in studying brain development before birth.

Enter fat-tailed dunnarts, mouse-like marsupials that are born after just 13 days of gestation, with brains still largely unformed. By monitoring the brain development of dunnart joeys as they matured in their mothers’ pouches, researchers at Washington University School of Medicine in St. Louis gleaned insights into how the outer surface of the brain, known as the cortex, organizes and structures itself — a crucial process that has been all but impenetrable to scientific investigation up to now. Understanding how brain structure normally emerges could provide essential clues to why and how the process sometimes goes awry, leading to neurological disorders.

The study is available online in the journal Proceedings of the National Academy of Sciences.

“Even as the cortex is still forming, distinct patterns of activity emerge in different functional areas of the brain,” said senior author Linda J. Richards, PhD, the Edison Professor of Neurobiology and head of the Department of Neuroscience. “These patterns may be critical for establishing connections between different brain areas. We’d like to know how patterned activity develops across the brain and what happens when that goes wrong. How do alterations to patterned activity disrupt how brain circuits are set up, and what implications might that have for brain conditions such as epilepsy or autism?”

The development of the nervous system in mammals, including humans, starts with the emergence of a so-called neural tube in the first weeks after conception. One end of the neural tube buds into a brain; the other lengthens into the spinal cord. Over several weeks, cells in the outer surface of the nascent brain organize themselves into the cerebral cortex, the crumpled outer surface of the brain responsible for memory, thinking, learning, sensing and emotions. A dunnart is born just after the neural tube forms, so its cerebral cortex develops while it is in its mother’s pouch. In people, the cerebral cortex begins to form about five weeks after conception and continues developing into the second trimester of pregnancy.

Along with Richards, the research team included co-author Geoffrey J. Goodhill, PhD, a professor of developmental biology and of neuroscience at the School of Medicine; as well as co-first authors Rodrigo Suárez, PhD, Tobias Bluett and Michael H. McCullough, PhD, all of whom were at the University of Queensland in Australia when the initial research was conducted.

When neurons are active, calcium levels rise inside the cells. To monitor neuronal activity in the joeys’ brains, the researchers used a fluorescent indicator that glowed when calcium levels rose. They found that patterns of activity emerged very early, even as new neurons were still being generated and the six-layered structure of the cortex was still under construction.

“Right from very early on you start to get a little bit of activity, which is not in any kind of pattern, but as soon as you can see patterns, they’re different in the somatosensory and the visual areas of the brain,” Richards said.

Distinct patterns of activity emerge about the same time that connections are established between the cortex and the thalamus, an egg-shaped structure in the middle of the brain that relays motor and sensory signals to the cortex. The researchers are now conducting further studies investigating the role of the thalamus in the development of the cortex, Richards said.

“Dunnarts and mice are separated by around 120 million years of evolution, and yet they have very similar early activity patterns,” Richards said. “It’s remarkable. Anything that is evolutionarily conserved over such a long time is probably vital to normal function. It’s highly likely that these area-specific patterns play a role in establishing the brain circuitry, which underpins all aspects of brain function, and dunnarts have transformed the way we can study these processes.”

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