How Are Complex Brains Built? Cephalopods Could Shed Light On Core Principles

If you’ve ever tried to glue together a model, assemble a piece of furniture, or even cook a complicated recipe, you know that seamlessly fitting its parts can be a challenge.

Now imagine trying to develop a functioning brain: millions or even billions of neurons, different lobes working simultaneously, dozens of body functions to control and maintain.

Humans and other animals build this remarkable machinery with apparent ease. How is it done—and is it always done the same way?

Most of our scientific knowledge is based on “a very small sliver of organisms, and we really do not have a grasp on a vast majority of the diversity that exists out there,” said Michael Barresi, a biology professor at Smith College. “And so what we think is a core concept of, say, neural development—it's just based on a finite number of organisms.”

This summer, Barresi is a Whitman Fellow at the Marine Biological Laboratory (MBL), embedded in MBL Director Nipam Patel’s lab. With help from staff from the Marine Resources Center, and in collaboration with Assistant Scientist Caroline Albertin and MBL Postoctoral Scientists Jenny McCarthy-Taylor and Jess Stock, Barresi and his team are researching brain development in both zebrafish (Danio rerio) and hummingbird bobtail squid (Euprymna berryi). Eventually, Barresi hopes to expand his work to include pygmy zebra octopus (Octopus chierchiae).

Zebrafish are well-studied and have brains that develop similarly to other vertebrates, including humans. Cephalopods, the group of animals that includes octopus, squid and cuttlefish, are comparatively understudied, but nonetheless boast complex brains. They’re also only distantly related to vertebrates, which means their brains—and the mechanisms they use to build them—evolved separately.

By comparing the two, Barresi can see if cephalopods approach brain development in unique ways, or if they independently arrived at brain-building methods similar to those in vertebrates. A better understanding of brain development could also lead to medical breakthroughs. Historically, most clinical advances have stemmed from basic biological findings, Barresi said.

“We need to be open to—and really, probably, pay more attention to—just understanding new basic biology,” he said. “Because it’ll open up a thousand doors.”

Some Assembly Required

Brain development is complicated, but Barresi is starting his research by focusing on two foundational tasks. The first is cell division. Building a brain means you need a lot of cells, so Barresi wants to find out where cells are reproducing in cephalopods.

“In the developing embryonic nervous system of E. berryi and O. chierchiae, where are cells dividing? Are there localized domains and regions of that early brain where there is an increase in cell proliferation?” he said. “I'll be looking at markers that will label cells that are proliferating, and do sophisticated imaging to try to spatially see where those are in the embryo.”

The second task is cell communication. Much of embryonic development relies on external  signals a cell receives that influence its fate, Barresi said. Scientists have identified certain common developmental signals, and Barresi plans to investigate if and how two of them—known as Hedgehog and Slit—affect cephalopod brain development.

Barresi plans to use confocal microscopy—a type of imaging in which molecules of interest can be tagged with fluorescent markers—to look at the arrangement of genes, proteins, and cells relative to one another, both in embryos developing normally and those that have been genetically tweaked to test hypotheses.

“And then what sort of phenotypes do you have?” he said. “If you get rid of Gene X and the eye is gone, then you know Gene X is important for eye development. We will be keeping a keen eye on how the brain develops in these genetically perturbed contexts.”

‘What Makes Us Who We Are’

The MBL is an ideal place for Barresi’s research, and he expressed gratitude to MBL Director Nipam Patel for allowing him and his team to embed in Patel’s lab for the summer.

“Nipam has unbelievable sophistication and experience with doing the kind of labeling approaches for gene expression that I'm interested in doing,” Barresi said. “So he's been really vital in that.”

Barresi also expressed excitement about continuing to connect his students to the MBL. He highlighted the contributions of Tania Novosolova and Delia Parco, the two undergraduates with him this summer.

Eventually, Barresi plans to establish aquaculture systems for maintaining squid and octopus at Smith College. Getting his research fully up and running could be a five- to eight-year process, he said; in the meantime, he hopes to continue his connections with the MBL.

“I've been very focused on vertebrate brain development, which has been awesome and fun, and I'm leveraging that experience to expand into the diversity of other complex brains,” he said. “That is going to take time, but that's what the whole second half of my career will be.”

Enduring patience comes naturally to Barresi, along with the curiosity that he says drives his work.

“I'm mostly focused on the basic neuroscience, because I absolutely love developmental biology and understanding what is underlying our brain construction,” he said. “Because that, in the end, is what makes us who we are.”