Despite its small size—it could sit in the palm of your hand—the zebra finch is a remarkable learner. A songbird native to Australia, it’s renowned for its ability to pick up new songs. That talent has made it a favorite of scientists studying how animal brains imprint new skills, particularly vocal learning, or the capacity to perfect new sounds.
Researchers at Boston University, working with scientists at the Max Planck Institute for Biological Intelligence and the MRC Laboratory of Molecular Biology, have now discovered another quirk to the zebra finch brain—one that could also have implications for understanding our own. In a study that looked at the bird’s brain in unprecedented detail, the scientists uncovered new insights into neurogenesis—the birth, migration, and maturation of neurons—that may help the brain learn, add new skills, and restore and repair itself.
Observing the finch brain using a high-powered microscope, the researchers watched as new neurons made their way through the brain en route to bolstering existing circuits and connections. The expectation was that these neurons would step around established brain structures, including more mature brain cells, to better preserve them. Instead, the investigators saw the neurons tunnel right through. According to the BU-led team, the findings could help explain human vulnerability to a range of brain disorders. The researchers also noted that cell tunneling is used by some metastatic cancer cells.
“We found that in songbirds, new neurons in the adult brain behave like explorers forging a path through a dense jungle,” said Benjamin Scott, PhD, a BU College of Arts & Sciences assistant professor of psychological and brain sciences and the study’s corresponding author. That may help them learn new things or repair damage, but it could come with a cost to existing cells and memories—and that might be why neurogenesis is, in humans, something that doesn’t seem to extend beyond the womb. “This potentially disruptive behavior may help explain why humans and other mammals have limited capacity to regenerate brain tissue in adulthood,” commented Scott, “leaving us more vulnerable to neurodegenerative disorders such as Alzheimer’s disease.”
Scott is senior and corresponding author of the team’s published paper in Current Biology, titled “Songbird connectome reveals tunneling of migratory neurons in the adult striatum,” in which the researchers commented that their collective findings “… suggest that migrating neurons may physically reshape the mature circuit to reach their targets, revealing an unexpected degree of structural and functional plasticity in the adult brain.”
At birth our brains have pretty much all the neurons they are ever going to have. Other organs—from your skin to your heart—might get frequent cell updates, but the brain is working on version 1.0. That’s true for most mammals, but not for fish, reptiles, and birds—their brains get a regular refresh.
“This raises two questions,” said Scott, who’s also affiliated with BU’s centers for neurophotonics, photonics, and systems neuroscience. “Why do other species have high rates of neurogenesis throughout life and why is it so restricted in humans? And is there something we can learn from their biology that we might be able to harness in future?”
Scott typically studies the neural circuits that control behavior in humans and other mammals, but chose the zebra finch to investigate neurogenesis because it has a reputation as a champion species—it’s really good at generating new neurons. “Songbirds are valuable model organisms for the study of neuron migration in the adult brain,” the authors wrote. “In these species, new neurons integrate into brain regions that control complex learned behaviors, where they establish synapses with mature neurons and respond to sensory stimuli.”
However, the team pointed out, a key question is how these new neurons interact with mature circuit structures in the brain. “It is not known whether neurons pursue migratory routes that flexibly avoid these structural obstacles or deform surrounding tissue to reach their targets,” they wrote. “While prior studies have examined the molecular mechanisms and functional consequences of adult neurogenesis, few have investigated the physical interactions between migrating neurons and their surrounding microenvironment.”
For their newly reported study the team used electron microscopy (EM)-based connectomics to examine how migrating neurons interact with mature circuit elements. “We applied a new tool to study this process [neurogenesis] called electron microscopy-based connectomics—basically a really high-powered microscope—to image these cells at a very high resolution,” Scott explained. “Our first hope was just to say, what does this look like at a detail we couldn’t see before?”
Their resulting data revealed intricate interactions between migratory neurons in the adult striatum and their environment, but also showed up the tunneling neurons. “Our findings support a model in which migrating neurons disperse throughout dense neural tissue in multiple directions, making various contacts with surrounding structures,” the team wrote in summary. “In addition, our data reveal a previously undescribed form of neuron migration in which new neurons cause deformities in nearby neurons and synapses.”
The authors say that, to their knowledge, tunneling migration by neurons hasn’t previously been reported in the vertebrate nervous system. It’s possible that this is due to the constraints of study methods used, but it’s also possible that tunneling is a specialization of neurogenesis in birds.
If these new neurons are deforming brain tissue, commented Scott, are they also disrupting memories along the way? And, if neurogenesis comes with a cost, how does that balance against the brain’s capacity for learning new things and repairing after injury? And as the authors pointed out, “Interestingly, tunneling-like behavior has been described in metastatic cancer cells, which navigate confined spaces by actively deforming their microenvironments. Tunneling may therefore reflect a conserved strategy adopted by specialized migratory cell types in dense tissues.”
Scott has two—as yet untested—hypotheses for what the findings might mean for the human brain. The first is that our brains evolved to limit neurogenesis after birth as a form of protection—a way of making sure determined neurons couldn’t barge through mature connections and damage memory storage. “There is an alternative framing that is more optimistic,” he also noted. “Our discovery of tunneling shows how cells can move without glia scaffolds.”
These are the structures that operate as highways for migrating neurons. “Most glia scaffolds are lost in humans after birth, and this loss was thought to be an obstacle for neurogenesis in the adult brain,” says Scott. “However, our work shows that new neurons in the bird do not need this glia scaffold. This is exciting because it means that brain repair may not require specialized glia scaffolds.” That opens the door for scientists to explore potential stem-cell therapies that would spark neurogenesis in humans.
In summary, the authors wrote, “These results reveal the value of applying EM connectomics to adult neurogenesis and suggest that migratory neurons may dramatically perturb the existing functional circuits as they migrate and integrate. Furthermore, they reveal the remarkable structural flexibility of mature neural circuits.”
In current studies, Scott and the team in his BU Laboratory of Comparative Cognition are digging into the biology driving neurogenesis to uncover which genes are regulating the process. Much of the work merges ideas and tools from biomedical engineering and neuroethology, the study of the mechanisms underpinning animal behavior.
“Right now, we’re using a technique called single-cell RNA sequencing to identify genes that are expressed by these new neurons as they migrate,” said Scott. “We want to know what other cells they’re talking to as they move and how they are speaking to these different cells.” That’ll help them figure out whether neurons warn other cells they’re traveling through and how they know where to stop and integrate with a current circuit.
“We share a lot with our animal relatives on this planet,” noted Scott. And, while the term “bird brain” might be an insult, by learning more about the biology of songbird brains, he says, we could learn some remarkable things about our own.
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