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Xenopus laevis, also known as the American clawed frog.

Tuft University researchers demonstrated in embryonic frogs that the brain plays an essential role in muscle and nerve development long before movement and other behaviors occur. Surprisingly, the brain also protects the embryo from agents that can cause defects – all while the brain is still developing itself.

The findings, published this week in Nature Communications, marks the earliest known events of the brain-body interface, according to the Tuft University team.

Frogs share many of the same basic biological mechanisms and processes as humans, making them a good model for biomedical research.

For this particular study, Xenopus laevis frog embryos were used to acquire a better understanding of the brain’s role in early development.

The team removed the brains of the frog embryos a little more than 27 hours after fertilization – prior to embryonic activity. The researchers identified three main areas that showed the most significant issues as a result of the embryo being brainless. The first, and most obvious, was abnormal development of the muscles and peripheral nervous system. The team also reported observations of diminished collagen density, shorter muscle fibers, and lack of the characteristic chevron patterning commonly found in healthy embryos.

“Peripheral nerves also grew ectopically and chaotically throughout the trunk, revealing that even regions far away from the brain depend on its presence and activity for normal embryogenesis,” the researchers noted.

The study also showed that the developing brain offers crucial protection against chemicals that would otherwise cause significant deformities.

The team found that the group of brainless embryos responded drastically different to exposure to chemicals that do not cause birth defects in normal embryos. When exposed, the embryos without brains developed severe deformities, including bent spinal cords and tails – proving that a normal, healthy brain is effective at safeguarding the embryo from influences that would otherwise cause malformation.

“Our data suggest that the brain exercises these functions using electrical and chemical channels that communicate locally and at a distance. Such distributed communications means we may be able to repair damage in a difficult-to-reach site by providing therapies to more easily-accessible tissues. Being able to treat one part of the body and see results in another part is particularly valuable in specialties like neuroregeneration,” said the paper’s first author, neuroscientist Celia Herrera-Rincon, Ph.D., a postdoctoral researcher in the Levin laboratory.

The scientists were able to reverse many of the defects caused by an absent brain by using scopolamine, a drug approved to regulate human neural function.

The findings could prompt new and improved ways to address birth defects, treat injuries, or regenerate complex organs, according to the team.

“Everyone knows that the brain guides behavior, but these data suggest that we need to revise our view of the brain as quiescent prior to an animal’s independent activity. Our research shows that the brain is engaged long before that, before it’s even fully built,” said Michael Levin, corresponding author of the paper and director of the Tufts Center for Regenerative and Developmental Biology.

The team plan to progress these findings into future research that will focus on a variety of objectives, including decoding specific information being sent through the newly identified communication channels from the brain, identifying other body structures that require brain presence and exploring relevance in other species, among other things.

Brainless frog embryos exposed to a teratogen develop crooked tails but embryos with a brain develop normal tails (inset) when exposed to the same agent. Photo: Celia Herrera-Rincon
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