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fewer subjects and cuts down on expen- " I'm confi dent we'll see rons. So far, the approach has been applied sive scanner time. But individual variations only to millimeter-size chunks of tissue in interesting individual in the brain aren't hard to find for those worms and mice, but some researchers see a microconnectome of the human brain as an Rees says his interest was piqued by —DAVID VAN ESSEN, ultimate if distant goal. studies fi nding that the size of the human WASHINGTON UNIVERSITY IN ST. LOUIS It's not clear what such a circuit diagram primary visual cortex can vary up to three- would reveal. Proponents think it would fold. He wondered whether that resulted explain a great deal about how the brain in differences in vision, an idea his lab Whether the differences in neural cir- works and about the nature of individual dif- has been investigating with a combination cuitry that make each person unique will ferences. Critics contend that deciphering of optical illusions and functional mag- be visible at the resolution of MRI scans brain function from a circuit diagram—no netic resonance imaging (fMRI). At the is an open question. "It's sobering for sure matter how detailed—is like trying to fi g- end of 2010, Rees's group reported online that the resolution is only at the level of a ure out what a computer does by studying its in Nature Neuroscience that people with a millimeter or two, which means that each wiring diagram. In both cases, the circuitry smaller visual cortex more strongly experi- voxel contains literally hundreds of thou- may say something about what the machine ence certain illusions in which the apparent sands of neurons or axons," Van Essen is capable of, but it's the precise pattern of size of an object depends on its visual con- says. (A voxel is the smallest volume of electricity coursing through it at a given time text. The fi ndings suggest to Rees that even brain tissue discernable in a brain scan.) that determines what it's actually doing.
something as basic as how we perceive the "But I'm confident we'll see interesting It seems far off, but there may yet come world around us varies from person to per- individual differences." a day when brain scans and genetic tests can son in subtle ways that can be traced to vari- Other researchers are working on far predict—with enough accuracy to matter ations in brain anatomy. more detailed maps of neural circuitry. in the real world—an individual's mental Richard Haier, a neuroscientist at the Sometimes called microconnectomics, strengths and weaknesses, predisposition University of California, Irvine, is one of these efforts employ recently developed to psychiatric problems, or maybe even his the few intrepid scientists who've waded methods in genetic engineering, automated favorite color. In the meantime, in the cafes on October 10, 2012 into the potentially touchy realm of individ- microscopy, and image analysis to map out and bars, there will be plenty to discuss. ual differences in the brain that infl uence the synaptic connections of individual neu- intelligence. His work, beginning in the late 1980s, has identifi ed a network of regions of parietal and frontal cortex whose anatomy and activity correlates with scores on tests Can We Make Our Brains of general intelligence. At the same time, Haier's work suggests that this network More Plastic? isn't identical in all individuals with similar intelligence scores. In other words, smart brains may be built in a variety of ways. Rewiring the brain is hard work, and as of Russian grammar. So, will we one day The largest study ever undertaken to look we age it gets even more diffi cult. A baby be able to turn on—and control—our brain at individual wiring variations in the human exposed to multiple languages can, with- plasticity at will? brain is the Human Connectome Project, a out apparent effort, become fl uently bilin- Neuroscientists have begun to under- 5-year, $38.5 million effort funded by the gual or even trilingual. Most adults have to stand a few of the factors that govern the U.S. National Institute of Mental Health. work much harder to master new languages, fl exibility of certain parts of the maturing Now in its third year, the project aims to and few are able to achieve the fl uency of brain. By studying the development of sen- enroll 1200 healthy adults for a battery of native speakers. sory systems such as sight and hearing, behavioral tests and brain scans, includ- There are good reasons that our brains they have uncovered a network of genes ing diffusion imaging scans that show con- become less flexible as they mature: A and proteins that infl uence so-called criti- nections between regions of the brain. The developing brain gives up some of its cal periods, windows of time in which the overall goal is to investigate individual vari- plasticity in favor of effi ciency and stability. brain is primed for certain types of input. It ations in brain structure and activity and "A fully plastic brain is not very helpful," is during these critical periods that the brain how they may correlate with differences in says Gerd Kempermann, a neuroscien- becomes wired for certain tasks, such as memory, emotion, and other functions, says tist at the Center for Regenerative Thera- turning the signals received from the eyes David Van Essen of Washington University pies Dresden and the German Center for into recognizable images, or distinguish- in St. Louis, Missouri, who is one of the Neurodegenerative Diseases. "It learns ing sounds present in spoken language. If a project's leaders. everything but remembers nothing." Too brain doesn't receive the right inputs during The project will also examine herita- much plasticity may also play a role in some a critical period, it is extremely diffi cult to bility of brain characteristics by enrolling neurological disorders, including epilepsy recover from the defi cits that result. Chil- 300 pairs of twins, plus one or more non- and schizophrenia. dren born with cataracts or a lazy eye will twin siblings for each pair. Researchers will In certain situations, however, more plas- never see clearly unless the condition is cor- collect DNA for genotyping and possibly ticity could be helpful, making it easier for rected in the fi rst years of life. Both mice whole genome sequencing if the cost drops patients to recover after a stroke or spinal and humans that lack adequate social con- enough by the fi nal year of the project, Van cord injury, for example. And it would be tact as babies and juveniles have permanent nice to effortlessly pick up the intricacies behavioral and cognitive defi cits. 5 OCTOBER 2012 VOL 338 SCIENCE Published by AAAS tests on their knockout mice. So far, "they're really good at everything." That's certainly not the whole story, she adds: "There has to be some downside." One likely disadvantage is that too much rewiring can lead to short circuits—in a brain, that could mean seizures. Indeed, those same knockout mice respond to a smaller dose of seizure-inducing drugs than typical mice. In humans, the result of unleashing brain plasticity might be epi-lepsy. Shatz notes that unexplained epilepsy is much more common in childhood—when the brain is more plastic in many areas—and some epilepsy patients eventually outgrow their disease. A newborn "has to learn things fast or it's not going to survive. It's worth the risk of instability. But it's kind of dan-gerous to learn that fast. Once the organism has acquired fundamental experiences, you slow it down a bit and put on these brakes," Shatz says. Closing critical periods may also provide a fi rm foundation for further brain development, says Brigitte Röder, a neuro-psychologist at the University of Hamburg on October 10, 2012 in Germany. "If you're always shaking the basement, you can't build a taller house," she says. Takao Hensch, a neuroscientist at Boston Children's Hospital, notes that miss- Plasticity potential. A newborn neuron in an adult mouse brain.
ing plasticity brakes are suspects not only in epilepsy but also in schizophrenia and The critical periods that arise earliest in she says, and the brain can perhaps recover development govern senses such as sight, its lost capabilities.
Some evidence suggests that the brain's hearing, and balance. Later ones govern In lab animals, at least, that's possi- plasticity can be augmented without the higher-order skills such as language acqui- ble: Researchers have bred mice that lack danger posed by completely removing the sition and social interactions. Most critical some of the various genes that act as plas- brakes. Michael Merzenich, a neuroscien- periods occur during infancy and childhood, ticity brakes. When these so-called knock- tist and professor emeritus at the Univer- when the brain is still growing and produc- out mice lose sight in one of their eyes for a sity of California, San Francisco, explores ing new neurons. But more important than few days—the researchers suture it shut— how certain kinds of sensory signals— the new cells are the connections the neu- their brains quickly compensate and reas- mainly sound and touch—can rewire adult rons make with each other. Connections that sign more area to the good eye, a process brains. He and his colleagues have shown receive reinforcement are strengthened and that resembles the plasticity seen in newborn that specially designed computer games protected, for example, by the growth of brains. The mutant mice also recover from can improve performance on memory and myelin sheaths around axons. Connections strokes better than control animals. And in other cognitive tasks in both children and that go unused are pruned back. several tests of neural function, they seem older adults, even months after the training In recent years, evidence has mounted like supermice. On a rotarod, a kind of motor stops. Research led by Daphne Bavelier, a that the critical periods close not only skills test for lab mice that resembles a log- neuroscientist at the University of Geneva because plasticity-driving signals decrease, rolling contest, the knockout animals "are in Switzerland, has shown that play- but also because the brain begins to produce like Olympians," Shatz says. She and her ing action video games, such as Medal of S signals that limit new connections between colleagues have done a range of behavioral Honor, can improve vision and several NESIE cells. When scientists use genetic tricks to kinds of cognitive skills.
remove these brakes on brain plasticity in The success of those games might be " A fully plastic brain is not experimental mice, the critical periods last linked to the brain's reward and attention sys- well into adulthood. That's encouraging to very helpful. It learns tems, Hensch says. Several of the molecules those who wish to improve plasticity in adult identifi ed as plasticity brakes involve these everything but remembers humans, says Carla Shatz, a neuroscientist at pathways. Two drugs that enhance atten- Stanford University in Palo Alto, California. tion, fluoxetine (better known as Prozac) Boosting the plasticity of an adult human and Aricept, can lengthen or even reopen —GERD KEMPERMANN, SON SNYDER/F brain may not require replacing a whole net- CENTER FOR REGENERATIVE critical periods in experimental mice. Both JA: work of signals that turn on that fl exibility, THERAPIES DRESDEN drugs are now in clinical trials for revers- EDITCR she suggests. "Just take away the brakes," ing the effects of lazy eye in childhood, and SCIENCE VOL 338 5 OCTOBER 2012 Published by AAAS in one clinical trial fl uoxetine helped stroke patients recover lost motor skills.
Fluoxetine also seems to influence another type of brain plasticity, the growth of new neurons throughout life in certain parts of the brain. Although most neuro- genesis stops in childhood, two areas of the brain keep producing new neurons: the subventricular zone, which connects to the The brain poses many more than just the fi ve quandaries we've highlighted olfactory bulb; and the subgranular zone of on these pages. Delve into any one of them and you'll soon run into another. the dentate gyrus, a part of the hippocam- Remembering the past (p. 30), for example, is a signifi cant part of human pus. There are several ways to boost the pro- experience, which raises one of the slipperiest questions in all of science: duction of new neurons in these regions; What is the biological basis of consciousness? (See Science, 1 July 2005, increased physical exercise and exposure to p. 79.) The elusive nature of that problem has convinced some researchers unfamiliar or complex environments are two to stick to memory. "It's as close to consciousness as I can get and still look clear neurogenesis enhancers. Fluoxetine myself in the mirror in the morning," quips Loren Frank, a neuroscientist at and other antidepressants that act through the University of California, San Francisco. Below are six more mysteries of the dopamine pathway also increase the neu- the brain that any neuroscientist should be proud to tackle. –GREG MILLER
ronal birthrate and may keep the newborn neurons fl exible longer. What this ongoing production of neu- rons means for the brain is unclear, how- Star power. Researchers now realize that star-shaped astrocytes do more ever. Although the rate of adult neurogenesis than just clean up after neurons. Recent studies fi nd that they help shape in an individual's brain is correlated with synaptic connections in the developing brain, infl uence synaptic function certain kinds of learning, the connection is throughout life, and may go haywire in a number of neuropsychiatric disor- on October 10, 2012 not straightforward. ders. Given that astrocytes make up nearly half the cells in the human brain, Some evidence points to the idea that in we know too little about them.
the dentate gyrus, the new neurons may aid the brain in adjusting to new environments, Uncharted territories. What the heck does the habenula do? Or how perhaps by helping the brain detect unfamil- about the retrosplenial cortex? Some brain regions get all the love from neu- iar aspects of an otherwise familiar setting.
roimagers (yes, we're talking about you, anterior cingulate), while others get Kempermann has proposed that adult neuro- ignored. There's still much to learn about these rarely studied regions, their genesis might be an adaptation that has anatomical connections, and their contributions to cognition and behavior.
helped certain animals—mice and humans, for example—to adapt to and thrive in a Snooze fest. Why we sleep isn't just a mystery of the brain, but consid- wide variety of unstable ecological niches.
ering that it's the brain that switches animals into slumber mode, the organ The new neurons "are an extreme form must be at the heart of it. Do animals sleep simply to conserve energy and of plasticity," says Fred Gage, a neurosci- stay out of trouble in the dangerous dark? Or is sleep necessary, as some entist at the Salk Institute for Biological newer research suggests, to reset the brain to meet the challenges of a Studies in San Diego, California. He and brand-new day? And what, if anything, does dreaming accomplish? his colleagues have found that the newborn cells seem to have their own critical period, What's the code? Asking how information is encoded in the nervous lasting roughly 4 weeks, during which they system may be one step shy of asking how the brain works. But getting are particularly excitable. (Recent stud- a better handle on how neural fi ring patterns—or is it which neurons are ies suggest that fl uoxetine might lengthen doing the fi ring?—represent information is crucial for understanding every- this period.) Gage speculates that the birth thing we do, including perception, memory, and decision-making. of neurons provides a continually fresh source of short-term critical periods for cer- Getting reconnected. The inability of the central nervous system of tain kinds of learning throughout life. The adult mammals to regenerate after injury is a vexing puzzle. Research with ISES newborn neurons "are young kids that rodents has led to a better understanding of the cellular signals that put the EN respond to everything," he says. By the time brakes on such repair. But translating that work to people with spinal inju- UROG one set of neurons has grown up and settled ries remains an elusive goal.
NE down, there's another set of cells ready to take their place. Feeling immune. Many immune system proteins take on different roles Determining how those new neurons in the brain, and immune responses are known or suspected contributors to FUNC interact with the circuits already in place a number of brain disorders. Yet scientists have only scratched the surface ER/D might help scientists better understand of how the immune system and nervous system interact. Recent fi ndings NY how the circuits are wired in the first that the gut microbiota may act through the immune system to infl uence SON SA place—and how to safely and effi ciently the brain and behavior add another intriguing twist. T: JDI rewire when needed. REC –GRETCHEN VOGEL SCIENCE VOL 338 5 OCTOBER 2012 Published by AAAS


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