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Born Again Brains

The human brain continues to regenerate even in adulthood, thanks to adult neurogenesis, or the birth of new neurons from parental neural stem cells.

by Levi Gadye
Jun 12 2015, 1:10pm

Close up of CT scan of adult brain. Image: Shutterstock

Scrape a knee. Pull a muscle. Hell, break an arm. You can expect your skin, muscle, or bone, in whichever scenario, to repair itself with proper care and rest. But the human brain, spinal cord, and nerve network are a different story. Stare at the sun too long and you'll slowly go blind, from damaging light-sensitive neurons in your retina. Break your neck, and you may never walk again. And wear a helmet when you bike, won't you? Serious knocks to the head, not to mention strokes, or diseases like Alzheimer's, can all permanently damage the brain.

It was long assumed that the fragile nature of the brain reflected a fundamental difference between brain tissue and other tissues, like skin, which constantly shed worn-out or damaged cells and replace them with new ones. Even bone is replaced at a rate of about 10 percent per year in adults. But for the most part, the neurons in our brains and spinal cords are the same neurons we've had since childhood. Stem cells are responsible for the upkeep and repair of tissues like skin and bone, so for most of the history of neuroscience, we also believed that there couldn't be stem cells in the brain, given how irreplaceable every last neuron seemed to be.

In just the past twenty years, however, this dogma has been overturned. There are neural stem cells in particular regions in the brain, just as there are skin, muscle, and bone stem cells throughout the body. Your brain does continue growing even in adulthood, thanks to adult neurogenesis, or the birth of new neurons from parental neural stem cells. These new neurons constantly wire in our freshest memories, learned experiences, and, strangely, our most recently-encountered smells.

But beyond revolutionizing how we think about memory and smell, adult neurogenesis has given us the opportunity to learn how to fix the damaged brain. Some neuroscience labs have even begun to explore how to transplant neural stem cells back into the brain to regrow lost neurons and circuits.

Just fifty years ago, however, one might've been met with ridicule for suggesting to a scientist that the brain continues to grow in adults. Like many scientific discoveries, the case for adult neurogenesis was built slowly, as trickles of evidence coalesced over the course of decades. And like many breakthroughs in the study of the brain, this one began in rodents.

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In 1913, Santiago Ramón y Cajal, the grandfather of modern neuroscience, defined our understanding of the brain for much of the 20th century.

"Once development was ended, the fonts of growth and regeneration of the axons and dendrites dried up irrevocably," wrote Ramón y Cajal, who won the Nobel Prize in Physiology or Medicine in 1906, in what's become a widely-cited passage in the field of brain studies. "In adult centers, the nerve paths are something fixed and immutable: everything may die, nothing may be regenerated. It is for the science of the future to change, if possible, this harsh decree."

His reasoning was understandable. Brain-damaged patients never fully recovered from their injuries, and it was thought that the brain couldn't tolerate the introduction of new neurons into tried-and-true, complex neural circuits. Existing theories in memory didn't mesh well with the possibility of new neurons disrupting the traces of old memories. And most tellingly, scientists lacked the ability to track newborn cells, let alone definitively identify them as neurons.

In the 1960s, a new tool emerged for identifying newborn cells: a type of thymidine (T), one of the four building blocks of DNA, made with radioactive hydrogen (3H). This "tritiated" thymidine, when administered to an animal or person, would be taken up by cells that had recently replicated their DNA and divided, marking currently-dividing stem cells and their daughter cells with a radioactive signal.

By the end of the 1970s, scientists had used tritiated thymidine to reveal potential neural stem cells in the adult hippocampus, a brain region responsible for forming memories, and in the subventricular zone (SVZ), which creates neurons that migrate to the olfactory bulb, responsible for processing smell. Perhaps Ramón y Cajal's half-century-old proclamation was up for revision.

The brain was not immutable. It could grow even late in life. And repairing, or even enhancing, the developed brain was becoming a real possibility.

Exciting as these early findings were, though, "A lot of people were skeptical, and that's a very generous way of describing it," Rusty Gage, a professor in the Laboratory of Genetics at the Salk Institute, told me. Tritiated thymidine did mark dividing stem cells, but it was hard to pinpoint in individual cells using the crude radiation-detecting techniques that were available at the time. Few labs bothered to follow up on this work.

Neuroscientists bickered over the existence of adult neurogenesis in mammals for over twenty years. In the 1990s, a number of technical advances coincided to finally settle the debate, according to Gage. Better, non-radioactive markers for dividing stem cells; antibodies that specifically labeled neurons; and microscopes that captured images of thin planes of thick tissues all helped convince even naysayers that stem cells were indeed dividing and producing neurons in the adult brains of primates and rodents.

But did the adult human brain have the capacity to produce new neurons?

The human hippocampus, seen in red. Image: Wikimedia Commons

In 1998, the Gage lab had the unique opportunity to test that very question. A handful of terminally-ill cancer patients had been injected with a new marker of stem-cell division, BrdU, to track dividing cells in their tumors. Gage and his colleagues were able to analyze those patients' brain tissue post-mortem. The scientists found dividing neural stem cells and newborn neurons in the adult human hippocampus for the first time, laying to rest any lingering skepticism about the existence of human adult neurogenesis.

This changed everything. The brain was not immutable. It could grow even late in life. And repairing, or even enhancing, the developed brain was becoming a real possibility. But to get there, scientists needed to figure out why discrete parts of the brain were still growing in the first place.

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The brunt of the brain's growth occurs during gestation. Of the roughly 90 billion neurons in each of our brains, most are already present at birth. During childhood, these neurons stretch, contract, and connect and disconnect, as various circuits figure out how to manage our increasingly-complex behaviors and thoughts.

However, there are three places that produce new neurons in adults: the hippocampus and the SVZ, both located in the brain, and the olfactory epithelium, which is found just outside the brain in our nasal passageways. By volume, and by numbers of neurons, these regions make up just a fraction of the entire nervous system (on the order of dozens of millions of neurons), but without them, we'd be unable to store new memories or learn new things.

The hippocampus is probably the most-famous neurogenic (neuron-producing) brain region. It's a small, curvy sliver of tissue found deep inside the brain, but its size is deceiving. The hippocampus creates and recalls many of our memories, and it helps us learn.

The function of the hippocampus was first recognized in the 1950s, thanks to the case of Patient H.M., or Henry Molaison, an epilepsy patient who underwent brain surgery that removed most of his hippocampus. The surgery cured him of epilepsy, but left him partially amnestic, and unable to make new memories. Clearly, we needed the hippocampus for memory.

By the time adult neurogenesis was discovered in the human hippocampus in 1998, scientists were already knee-deep in their first experiments with learning, memory, and neurogenesis in rodents. One corner of the hippocampus, called the dentate gyrus, was the primary source of newborn neurons, and it literally grows, by volume and number of neurons, as memories pile up over time.

Strangely, the dentate gyrus develops later than the rest of the brain—and then it never stops growing. "It's thought that the dentate in humans doesn't even fully come on board until you're four years old," Gage told me. Hundreds of neurons are born each day, and their survival—and integration into the existing hippocampal circuit—depends on how much they are stimulated during a critical period in their development.

In other words, if you—or a mouse—experience something noteworthy, the adolescent neurons sitting in the dentate gyrus at that time will be stimulated to wire into the rest of the brain, creating a lasting memory. On the other hand, if "you have very little stimulation, a greater percentage of the cells that are born will die," says Gage.

Mouse hippocampus, imaged with a modern confocal microscope. The dentate gyrus, which constantly grows new neurons that help wire up our newest memories, is the V-shaped structure in the center of the image. Image: ZEISS Microscopy

Indeed, housing adult mice in what is called an "enriched environment" (think running wheels and the occasional bite of cheese) can cause the hippocampus to grow an additional 15 percent in 45 days, compared to housing them in a standard cage. This works out to an additional 100,000 neurons across the left and right dentate gyri, according to Gage.

Environmental enrichment is just one of many stimuli that can influence how fast the hippocampus grows. Stress and sleep deprivation can stunt adult neurogenesis; sex, exercise, and even anti-depressants have the opposite effect, increasing the birth of new neurons. Interestingly, while stress generally dampens neurogenesis, acutely-stressful (or traumatic) events are remembered better than mundane events, thanks to more-robust neurogenesis.

"Let's imagine two lunches—a lunch that I ate yesterday, and a lunch that I ate years ago when I was attacked by a manic zombie," Vlad Senatorov and Aaron Friedman, both graduate students in the lab of Daniela Kaufer at UC Berkeley, explained to me over email. "The information is the same (what and where I ate), but by tomorrow I'll forget the lunch from yesterday, yet I'll remember the 'emotionally charged' lunch for the rest of my life."

Gage, Senatorov, and Friedman are just three of the hundreds, possibly thousands, of scientists worldwide who continue to probe the hippocampus to learn how it actually stores and retrieves our diverse and colorful memories. We now know that the hippocampus separates how it stores different kinds of memory, handling spatial memories (like a mental map of your house) in a different region than emotional memories (a manic-zombie lunch). Some scientists have even figured out how to "trick" newborn hippocampal neurons into "remembering" events that never happened in transgenic mice, using optogenetics to activate old memories in new contexts.

While the hippocampus remains the most popular neurogenic region of the brain for neuroscientists, as the memory center of the brain, the other neurogenic brain region, the SVZ/olfactory bulb, and its sensory counterpart outside the brain, the olfactory epithelium, pull off some wild feats of neurogenesis as well. In all likelihood, this may be a relic of the historical reliance of our mammalian ancestors on their sense of smell. But for us, olfactory neurogenesis may hold the key for repairing the damaged human brain.

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The olfactory bulb (OB) was the second brain region that was found to contain newborn neurons in adults. Unlike the hippocampus, however, neurons in the OB must first migrate along biological railroad tracks from their birthplace, the SVZ, before reaching the OB and wiring into the olfactory circuit.

The SVZ is a small part of the lining of the lateral ventricles, which are two cavernous holes found in the middle of the brain. Adult neural stem cells produce neuroblasts (cells destined to become neurons) in the SVZ, and these neuroblasts travel to the OB along a path made of glia (support cells), called the rostral migratory stream. Neurons in the OB are organized into clusters, called glomeruli, that help sort out the raw information produced by the olfactory sensory organ, the olfactory epithelium (OE).

Recently, scientists have shown that newborn neurons in the OB don't simply decode information coming from the OE. Dr. Gregory Lepousez, a research associate in the Perception and Memory group at the Institut Pasteur, told me that he and his colleagues discovered that "adult-born neurons participate in the long-term integration of local sensory information with high-order attributes coming from the cortex [outer layers of the brain]."

This was a surprise for Lepousez, as well as the field, because it was long thought that the hippocampus was the site of learning new associations for novel stimuli, like scents. Instead, the OB takes on this role, providing learned context for smells. Lepousez even speculates that these new neurons may directly represent the olfactory 'engram,' or memory trace.

"I'd like to have a tri-synaptic circuit of the hippocampus so that we can … look at neurogenesis in the context of human cells"

The OE, on the other hand, is a layered tissue found in the nose that constantly produces new neurons for sensing scents in the air, serving a function akin to the retina of the eye. These olfactory sensory neurons (OSNs) expose their sensory structures (dendrites) to the external environment of the nostrils, a risk that necessitates their programmed self-sacrifice after a few months.

Adult neural stem cells constantly replace these OSNs with newer OSNs to ensure that smells are never detected by worn-out neurons. More perplexingly, because OSNs connect to the OB via long neural wires (axons), newborn OSNs must retrace the wiring paths of deceased OSNs and then connect with the correct glomerulus in the OB. This means that newborn OSNs somehow "know" how to maintain your sensation of "grandma's house" or "first girlfriend," even though those smells were first sensed by OSNs of your childhood or adolescence.

The migration of neuroblasts to the OB, the constant rebirth of OSNs in the OE that know exactly how to rewire back to the OB, and the physical growth of the hippocampus are all intriguing in their own right for biologists, but their properties make them promising candidates for brain therapies. So how are scientists planning on converting their knowledge of adult neurogenesis into therapies that might one day mitigate traumatic brain injuries or Alzheimer's disease?

Retrovirus labeled granule neurons in the dentate gyrus of Alzheimer disease mouse model. Image: Wikimedia Commons

Because adult neurogenesis literally produces new neurons even in old age, one major dream in the field is to somehow co-opt the process to replace damaged or dying neurons in non-neurogenic regions of the brain (read: most of it). Given that neuroblasts (dividing cells destined to become neurons) migrate relatively long distances from the SVZ to the OB, some scientists believe we might someday be able to redirect these mobile cells to repair damaged brain regions. Similarly, the olfactory epithelium, in the nose, may one day provide adult neural stem cells for direct transplantation back into a patient's brain.

In fact, after a stroke, neuroblasts from the SVZ that would normally travel to the OB instead reroute themselves toward the site of the stroke. These neuroblasts fail to turn into neurons that might repair the damage wrought by the stroke, but the fact that they home toward the injury suggests that we might be able to coax them into actually replacing lost neurons.

The OE is even more alluring as a source of stem cells for future brain therapies. The OE continues to churn out new neurons at a high rate even in old age, while the hippocampus and SVZ progressively slow their neurogenesis over time, albeit without coming to a full stop. Dr. Jessica Brann, assistant professor of biology at Loyola University, is intrigued by this quality of the OE, which can also fully regenerate after all its neurons are killed off. (Full disclosure: I study this regeneration in my own Ph.D work).

Perhaps, someday, a simple swab of the OE might provide enough neural stem cells for a successful transplant of neuroblasts into the brain of a stroke patient, a possibility that is still on the minds of many neuroscientists, including both Gage and Brann. In fact, "the types of neurons we might want to replace in neurodegenerative diseases like Parkinson's are those with a long projecting axon," Brann told me. "Olfactory sensory neurons are just that kind of neuron."

While the hippocampus will never be a direct source of adult neural stem cells for therapies (it's located too deep in the brain), its study is already proving worthwhile in the development of other types of therapy. For instance, Senatorov and Friedman are taking one of the basic findings of their lab—that head injuries spur on a harmful molecular pathway in the hippocampus, decreasing neurogenesis and eventually causing epilepsy—and spinning it into a handful of marketable therapies.

"We're starting a company [called EnVivo Therapeutics] and developing a drug that can block this injury-induced pathway," Senatorov and Friedman told me. They believe that their drug will prevent epilepsy before it starts, when given soon following a traumatic brain injury.

Others plan to use the hippocampus as a model in which to study diseases and possibly discover new treatments. Gage, from the Salk Institute, is determined to study the hippocampus in a petri dish, a feat that would improve on our weak mouse models of human disease. "I would like to make a human hippocampus in vitro," he says. "I'd like to have a tri-synaptic circuit [mimicking the normal circuitry] of the hippocampus so that we can … look at neurogenesis in the context of human cells."

His lab has already worked out how to generate one type of human hippocampal neuron, called the dentate granule neuron, using techniques that convert ordinary human fibroblasts (connective tissue cells) first into generic stem cells (iPSCs), and then into adult neural stem cells. By comparing such artificial, adult neural stem cells and neurons from patients with schizophrenia with control cells from healthy patients, scientists can observe differences in neurogenesis that might be driving the symptoms of schizophrenia, and even ethically screen the effects of drugs on these diseased cells in petri dishes. Gage's lab is currently working on producing the two other types of hippocampal neurons, called CA3 and CA1 neurons, and Gage hopes to build his "little artificial hippocampus" in the next few years.

We may never know exactly why our brains continue to grow in just a handful of regions. Sources I spoke with speculated on the need for the brain to overwrite old, irrelevant memories; the evolutionary advantage of being able to finely discriminate between similar, but subtly different stimuli; and the benefit of limiting plasticity, or change, to just a handful of brain regions, while ensuring stability in others. Our still-adolescent knowledge of adult neurogenesis has already provided many fruits for science and medicine and its promise, in the context of a century of neuroscience, remains immense.

So don't despair that it's all downhill from 25. You've got more space to grow up in your noggin than you were probably ever told.

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