Your neurons are outnumbered. Many of the cells in your brain - in your whole nervous system, in fact - are not neurons, but glia. These busy little cells shape and insulate neural connections, provide vital nutrients for your neurons, regulate many of the automatic processes that keep you alive, and even enable your brain to learn and form memories. The latest research is revealing that glia are far more active and mysterious than we'd ever suspected. But their journey into the spotlight hasn't been an easy one. From set dressing to stardom Unlike neurons, which earned their starring roles in neuroscience as soon as researchers demonstrated what they did, neuroglia didn't get much respect until more than a century after their discovery. [caption id="attachment_347" align="alignleft" width="299" caption="Dwight Bergles and his team set out to understand the dynamic behavior of oligodendrocyte progenitor cells in the brain."][/caption] The man who first noted the existence of glia - a French physician named Rene Dutrochet - didn't even bother to give them a name when he noticed them in 1824; he just described them as "globules" that adhered between nerve fibers. In 1856, when the German anatomist Rudolf Virchow examined these "globules" in more detail, he figured they must be some sort of neural adhesive, which he named neuroglia - "nerve glue" in Greek. As publicity campaigns go, it wasn't the most promising start. Even worse, as other biologists investigated neuroglia over the next few decades, they started jumping to a variety of conclusions - not all of them accurate. For example, since glia appeared not to have axons - the long connective fibers that carry signals from one neuron to the next - most researchers assumed these cells must act as structural support; essentially serving as a stage on which neurons, the real stars of the show, could play their roles. Some even wondered if glia might not be nerve cells at all, but specially adapted skin cells instead. Though a few scientists did argue that glia also seemed to be crucial for neuron nutrition and healing, it was rare for anyone even to speculate that these cells might actually be involved in neural communication. That all began to change in the 1960s, when new teams of researchers - armed with new tools like RNA sequencing and protein analysis - discovered that glia not only respond to chemical signals from neurons, but can also send out signals of their own, and can even sculpt neural communication by coordinating their efforts. Glia suddenly looked less like set dressing and more like supporting actors. But glia have really only burst into the neuroscience spotlight in the past five years or so. Recent studies have found that a certain type of glial cell, known as an astrocyte, sends out some of the chemical signals that build up our sense of sleepiness throughout the day - and that inhibiting these signals can counteract some symptoms of depression. Other studies have found that glia can spark seizures, regulate blood flow in the brain, and gather protectively around damaged neurons. And in 2013, researchers who transplanted human astrocytes into mouse brains found that their modified mice learned more quickly and formed more memories than ordinary mice. Glia, it seems, may be starring players in their own right. In fact, new discoveries like these have led some scientists to label glia the "Other Brain" - and there's no denying that many of our brains' abilities, from self-repair to intelligence, would be all but impossible without them. Even so, these latest astrocyte findings spark new questions: What parts do lesser-known types of glia - oligodendrocytes, microglia and so on - have to play in our brains' ongoing drama? Could they, too, take on more active roles than we've suspected? A secret cell society Most brain cells - glia included - don't reproduce by cell division, like, say, blood or skin cells do. Instead, they form from progenitor cells - certain stem cells that come pre-programmed to develop on queue into mature glia. Many of these progenitors cells are, if anything, even more mysterious than the cells into which they later mature. And nowhere is this clearer than in the case of oligodendrocyte progenitor cells, which seem hardly to resemble their adult forms at all. [caption id="attachment_351" align="alignright" width="336" caption=" In this time-lapse photo series, an oligodendrocyte precursor cell moves into position near a site of neural injury."][/caption] You could think of mature oligodendrocytes as your brain's electrical contractors: These glial cells sheath your neurons' connective cables in the insulator protein myelin, which keeps synaptic signaling fast and efficient. In their adult form, oligodendrocytes remain sedentary along nerve cables in your brain - but in their progenitor form, they exhibit a startling variety of behaviors. For one thing, says Dwight Bergles, professor of neuroscience at the Johns Hopkins University School of Medicine, "these progenitor cells continue to divide throughout life, making more progenitor cells. And this proliferation of cells seems to be exquisitely controlled - you don't have over-production or under-production of progenitor cells; their number stays fairly constant." Bergles was intrigued by the persistent cycling of these progenitors, so he and his team determined to study the behavior of individual oligodendrocyte progenitors in living brains. The researchers set to work engineering mice in which just these cells make a green fluorescent protein, aiming to track their behavior on shorter timescales than ever before. What they discovered surprised them as much as anyone. Oligodendrocyte progenitors, the team observed, never sit still - they move and jostle each other all over your brain in a ceaseless semi-random parade. So when a progenitor dies or matures into an oligodendrocyte, another one's instantly formed on the spot. "This is very unusual," Bergles says, "because with neurons, with astroglia or even with adult oligodendrocytes, those types of cells would be in the same positions from one week to the next; they're very static." Oligodendrocyte progenitor cells, on the other hand, are constantly on the move; reorienting their processes, traveling throughout the surrounding tissue, dividing, dying and differentiating. But. these cells aren't just jostling around at random; they're coordinating a delicate dance of complex interactions. "The cells are constantly extending and adjusting their own networks of little filopodia - feelers that enable them to sense their local environment," Bergles says. Whereas other types of brain cells - neurons, for example - use small clusters of filopodia to steer their growth and connectivity at certain times, progenitor cells are covered in them. "The whole cell is almost like a neuron's growth cone, sniffing around its environment and looking for changes," Bergles says. "It's constantly reaching out, essentially asking its neighbors, 'Are you there? What about you - are you there?'" Those are important questions to for a progenitor cell to ask, because Bergles and his team also found that every progenitor cell occupies and defends its own personal territory, even as it travels throughout the brain. "Each time a progenitor cell reaches out and touches a neighbor, both cells pull back their filopodia and try growing in other directions," Bergles explains. "But if one of these cells dies or develops into a mature oligodendrocyte, that creates a void in the tissue, which allows one of the neighboring cells to grow into that void and expand its territory." This "conquer and divide" system, Bergles realized, is the mechanism that enables oligodendrocyte precursors to maintain their constant numbers over time. In other words, he says, "It allows the loss of these cells to be directly coupled to their replacement." But progenitor cells do more than just maintain the boundaries of their own domains. They're also active trauma technicians that can leap into action in response to brain injuries. Previous research has found that certain types of glial cells migrate to sites of nerve trauma and form what's known as a glial "scar" - not quite the same as a skin scar, but similar in function. Thus, Bergles and his team caused some minor nerve damage in the brains of living (but sedated) mice, and tracked the behavior of individual precursor cells in response. "Not only did our progenitor cells reorient themselves and move toward a local injury," Bergles says; "they also surrounded the injury in the same way that other glial cells, like microglia and astrocytes, do. What's more, these progenitors matured into something quite distinct from oligodendrocytes - a special type of scar-forming cell. As of right now, no one's sure what chemical signals trigger this alternate maturation - but it does seem to call the name of "oligodendrocyte progenitor" into question: These cells may be progenitors, but not only for oligodendrocytes. As if these revelations weren't intriguing enough, though, Bergles and his team also discovered another secret about progenitor cells: They actively communicate with neurons through chemical synapses, the main mode of communication used for communication between neurons. So how much influence might this network of proactive glia have on our thoughts, memories and personalities? And does this "Other Brain" of ours really qualify as a brain all its own? Sculptors of thought "It doesn't matter where in the brain you look; you can find synapses onto oligodendrocyte progenitor cells," Bergles says. In fact, he was one of the first scientists to observe synaptic connections between neurons and oligodendrocyte precursors, way back in his postdoctoral research days. Many other labs have since replicated those early findings, and have also found that other glial cells - like astrocytes and microglia - can respond to neurotransmitters; although, among glial cells, direct synapses appear to be reserved for oligodendrocyte progenitors. "Almost all glial cells express receptors for the same neurotransmitters that are sensed by neurons," Bergles explains. "They have receptors for glutamate, for GABA, for neuromodulators like norepinephrine, and for a variety of other neurotransmitter molecules - so it's pretty clear that they're listening in on some of the same chemical signals that neurons use for signaling back and forth." But unlike neurons, glial cells use this information for purposes we're only beginning to understand. [caption id="attachment_349" align="alignleft" width="336" caption="As an oligodendrocyte progenitor cell divides, each new progenitor explores its environment with filopodia, orienting itself around its neighbors."][/caption] It's clear, for one thing, that neural communication exerts a profound influence on the behavior of many types of glial cells. "If you block synaptic connectivity between neurons and glia during the process of brain development," Bergles says, "you can really retard the ability of the glia to proliferate and differentiate." That raises an obvious question: How much does neural communication depend on the support of glia? Neurodegenerative diseases provide some glimpses of answers. "In disorders like amyotrophic lateral sclerosis (Lou Gehrig's disease) and multiple sclerosis, we're realizing that neurodegeneration happens as a consequence of damage to oligodendrocytes," Bergles says. "If there aren't any oligodendrocytes to provide essential support to neurons, the neurons will wither and die." Other recent studies have found that astrocytes regulate the supply of glucose and oxygen that's funneled to neurons, and even actively control the process of breathing. Physical necessities aside, though, how much might glia actually shape our minds? Again, the latest research offers some tantalizing hints. Astrocytes in particular appear to play central roles in memory formation - in fact, one team of researchers implanted human astrocytes into mice, creating mice with super-fast learning abilities and ultra-powerful memories. Discoveries like these seem to indicate that astrocytes are every bit as crucial for human intelligence - and possibly even consciousness itself - as neurons are. Meanwhile, other types of glia - oligodendrocyte progenitors included - are still awaiting their moment in the spotlight. "I think we'll begin to see more experiments on these cells' interactions with neurons being performed over the next few years," Bergles says. The truths those experiments reveal are likely to continue reshaping our understanding of glial cells' roles in sculpting our brains - just as the process of understanding itself resculpts our neural connections. Images: Dwight Bergles
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