RE1-silencing transcription factor (REST) inhibits expression of neuronal genes in non-neural cells.  Huntingtin sequesters REST in the cytoplasm of neurons, precluding transcriptional repression and allowing neuronal specification.  Mutations in huntingtin disrupt its interactions with REST, enabling repression of neuronal genes and contributing to Huntington’s disease (HD).  Among the genes inhibited by REST are several miRNAs — small, noncoding RNAs that inhibit translation by binding to complementary sequences in regulatory regions of mRNA.  Packer et al.  Found that the levels of several miRNAs decreased as HD progressed.  Of these, miR-9 and miR-9* had upstream regulatory regions that enabled repression by REST.  Interestingly, regulatory regions of REST and its cofactor CoREST have complementary sequences targeted by miR-9 and miR-9*, and miR-9 reduced expression of REST, while miR-9* targeted CoREST.  These molecules apparently form a double negative feedback loop, which is likely important for precise regulation of cell fate commitment.

Each year, thousands of publications present functional magnetic resonance imaging (fMRI) data that suggest that a particular brain region is active during a particular cognitive task.  Casual readers of such papers might forget that this technique does not actually measure neural activity, but rather blood oxygenation level-dependent (BOLD) contrasts.  Synaptic transmission requires large energy expenditures, and increased energy metabolism has been hypothesized to act directly on blood vessels to increase blood flow and alter BOLD signals.  This week, however, Devor et al.  Report that this hypothesis is not always correct.  As expected, stimulating the forepaw of rats increased blood oxygenation, vessel diameter, glucose uptake, spiking, and synaptic release in the contralateral primary somatosensory cortex.  In the ipsilateral cortex, however, neural activity and glucose uptake increased, but blood oxygenation and blood flow did not.  These results indicate that blood flow is not directly tied to metabolism, and BOLD signals do not always reflect neural activity.

Amyloid-B  (AB)  Is generally considered a toxic agent in Alzheimer’s disease, but it is also released during synaptic transmission in healthy brains.  Whether AB  Has a positive function — or is simply an unwanted byproduct created when amyloid precursor protein is cleaved to produce more essential fragments — remains a matter of debate.  Evidence from transgenic mice suggests the former: knock-out of enzymes required for AB  Production impairs memory and long-term potentiation (LTP).  More evidence for a positive role of AB  Is presented by Puzzo et al.  They found that picomolar (near physiological) amounts of monomeric and oligomeric AB42 enhanced LTP in mouse hippocampal slices and strengthened reference and contextual fear memory in vivo.  In contrast, nanomolar concentrations reduced LTP.  The enhancement of LTP appeared to occur presynaptically, likely by increasing calcium accumulation, and it required activation of a7 nicotinic acetylcholine receptors.  Whether monomeric AB, oligomeric AB, or both was responsible for the enhancement is unknown.

An action potential’s threshold and shape are governed by the distribution and subunit composition of voltage-gated sodium and potassium channels in the axon.  To learn how differences in subunit expression might contribute to the exact site of action potential initiation, Lorincz and Nusser examined the distribution of four potassium and sodium channel subunits (Nav1.1, Nav1.6, Kv1.1, and Kv1.2) in the axon initial segment (AIS) of neurons in several regions of adult rat brain.  The expression pattern was surprisingly heterogeneous across cell types and brain regions.  For example, only inhibitory interneurons expressed Nav1.1, and in some neurons, it was expressed along the entire AIS, whereas in others it was restricted to the proximal AIS.  Likewise, expression of other subunits was uniform or graded depending on cell type.  In Purkinje cells — in which action potential generation occurs in the first node of Ranvier rather than the AIS — neither potassium channel subunit was expressed in the AIS.

Shredded extracellular matrix (ECM) is toxic to neurons. Chen et al. Reveal a new mechanism for how ECM demolition causes brain damage. The study will appear in the December 29, 2008 issue of The Journal of Cell Biology (www.jcb.org).

A stroke or head injury kills large numbers of neurons through a process called excitotoxicity. A surge of the neurotransmitter glutamate jolts receptors such as the kainate receptor and stimulates cell death. Enzymes add to the death toll by chopping up ECM near the injury site. How ECM breakdown takes out neurons was mysterious. The standard view was that neurons perished because they got separated from the ECM as it dissolved.

Chen et al. Found otherwise when they engineered mice to lack the ECM component laminin in the hippocampus, a brain region often damaged by stroke or injury. If cells languished after parting from the ECM, the researchers reasoned that mice missing laminin would suffer more damage from excitotoxicity. But when excitotoxicity was spurred with an injection of kainate—a molecule that, like glutamate, activates the kainate receptor—the laminin-lacking mice showed less brain damage. After a dose of diced laminin, however, the mutant mice were vulnerable to kainate, indicating that the fragments are the culprit in cell death.

The researchers discovered that chopped-up ECM kills cells by ramping up production of one subunit of the kainate receptor, known as KA1. They speculate that hiking the amount of KA1 subunits might make the receptor more sensitive and thus more likely to trigger an overreaction by the cell.

Although drugs that obstruct the glutamate receptor slow brain cell death, they can lead to serious cognitive impairment and even coma. The study suggests that drugs that block KA1 might provide an alternative way to save brain cells after stroke or head trauma.

A new study in the October 31st issue of Cell, a Cell Press journal, has revealed the molecular and cellular underpinnings of one of the most common, single gene causes for learning disability in humans.  The findings made in learning disabled mice offer new insight into what happens in the brain when we learn and remember.

While most previous studies have focused on the role of brain cells that excite other brain cells in the process of learning, the current results suggest that inhibitory neurons and a careful balance between excitatory and inhibitory signals may be just as essential, according to the researchers.  They liken the role of those inhibitory and excitatory signals in the brain to the role of red and green stoplights in directing traffic.

” The significance of these findings is two-fold,” said Alcino Silva of the University of California, Los Angeles.  “First, we have in great detail the exact mechanism for one of the most common single gene causes for learning disability known.  It’s also a beachhead in our understanding of the balance between excitation and inhibition critical for learning.”

Learning disabilities are estimated to affect one in five people worldwide.  “It’s a huge problem and there is little known about their causes,” Silva said.

To begin to chip away at those underlying causes for conditions that often have complex causes, Silva’s team began a hunt several years ago to unravel the mechanisms responsible for a couple of single gene disorders that lead to learning disability.

In the new study, they examined mice with learning disabilities resulting from a condition called neurofibromatosis type 1.  The condition stems from a defect in the Nf1 gene encoding a protein called neurofibromin.  Earlier studies showed that neurofibromin controls a “Ras/Erk” signal that is involved in long-term potentiation (LTP) and learning in mice.  LTP is a process that strengthens the connections between neurons in the brain–the cellular basis for learning and memory.

Now, the researchers have found that the deficits in spatial learning experienced by mice with an abnormal version of the Nf1 gene stem from an increased release by inhibitory neurons of a chemical nerve messenger (or neurotransmitter) called GABA.  GABA is the chief inhibitory neurotransmitter in the central nervous systems of mammals.

That rise in GABA leads to deficits in the plasticity of neurons required for learning and memory.  Importantly, they also show that the learning deficits in the mice can be reversed with treatments that reign GABA levels back in.  They also show that GABA levels normally swell when mice learn, suggesting that a balance of GABA is the key.

Silva’s team notes another recent study implicating changes in GABA inhibition in the learning deficits exhibited by an animal model of Down’s syndrome.  Although learning disability—characterized by profound changes in one part of brain function—differs widely from mental retardation, that finding together with the new study suggest there may nevertheless be a common thread, Silva said.

Ultimately, these insights could lead to new ways to treat learning disabilities, although reaching that goal won’t be a simple proposition.

” It won’t be a single step from the mechanism to finding a drug,” Silva said.  As with other complex disorders like cancer, he said, it will likely take years of exploration to turn scientific advances into medical applications.  Nevertheless, “the more insight we have into the mechanisms responsible, the more likely it is that our treatment efforts will be effective.  ”

The new study is also representative of the exciting advances in the study of neuroscience more broadly.

” We are at the beginning of a wonderful journey into how the human mind works,” Silva said.  “We are developing a highly detailed view of what goes on in the brain when we learn and remember.  There is nothing more inspiring; it’s what makes us who we are.”

A major puzzle for neurobiologists is how the brain can modify one microscopic connection, or synapse, at a time in a brain cell and not affect the thousands of other connections nearby.  Plasticity, the ability of the brain to precisely rearrange the connections between its nerve cells, is the framework for learning and forming memories.

Duke University Medical Center researchers have identified a missing-link molecule that helps to explain the process of plasticity and could lead to targeted therapies.

The discovery of a molecule that moves new receptors to the synapse so that the neuron (nerve cell) can respond more strongly helps to explain several observations about plasticity, said Michael Ehlers, M.D., Ph.D., a Duke professor of neurobiology and senior author of the study published in the Oct. 31 issue of Cell.  “This may be a general delivery system in the brain and in other types of cells, and could have significance for all cell signaling.”

Ehlers said this could be a general way for all cells to locally modify their membranes with receptors, a process critical for many activities -cell signaling, tumor formation and tissue development.

“Part of plasticity involves getting receptors to the synaptic connections of nerve cells,” Ehlers said.  “The movement of neurotransmitter (chemical) receptors occurs through little packages that deliver molecules to the synapse when new memories form.  What we have discovered is the molecular motor that moves these packages when synapses are active.”

When neurons fire at the same time, their connections strengthen and a person can associate certain features.  “Once you have heard someone’s name, seen his face, where he was standing, all these features can be bound into a unified packet of information – a percept – and at a very cellular level this occurs by strengthening synaptic connections between co-active neurons,” said Ehlers, who is also a Howard Hughes Medical Investigator.

To learn and make new associations, the brain alters the strengths of the synapses’ electrical inputs onto cells that compute these features.  Scientists studied the hippocampus, where memories form, but this machinery could operate in other brain areas.

“One of earliest changes in Alzheimer’s disease is synapse dysfunction, so this molecule might be a new target for that disease,” he said.  “Abnormal movement of receptors may be implicated in brain development, in autism.”  He said the molecule potentially is involved “in the abnormal electrical activity of epilepsy and the overactive brain pathways of addiction.”

In a series of biochemistry and microscopic imaging experiments, Ehlers and colleagues found that the myosin Vb (five-b) molecule in hippocampal neurons responded to a flow of calcium ions from the synaptic space by popping up and into action.  One end of the myosin is attached the meshlike actin filaments so it can “walk” to the end of the nerve cells where receptors are.  On its other end, it tows an endosome, a packet that contains new receptors.

“These endosomes are like little memories waiting to happen,” Ehlers said.  “They are reservoirs of neurotransmitter receptors that brain cells deploy to add more receptors to a particular synapse.  More receptors equals stronger synapses.”

Electrical impulses cause one nerve cell to dump its neurotransmitter, in this case, glutamate, into the small space between neurons (the synapse), which activates neurotransmitter receptors on the receiving side.  These are ion channels that open in response to neurotransmitter and generate the electrical impulse.

When the scientists blocked myosin in single cells, this stopped the addition of new receptors and prevented electrical impulses from getting stronger, showing that myosin is essential to enhancing nerve cell connections.

“This is a very basic cellular mechanism of brain plasticity.  It is likely fundamental to brain development and disease,” Ehlers said.  “The myosin Vb molecule gives us a new way to think about designing therapies for treating memory loss, psychiatric disease and brain development.”

Applying electrical stimulation to the scalp and the underlying motor regions of the brain could make you more skilled at delicate tasks. Research published today in the open access journal BMC Neuroscience shows that a non-invasive brain-stimulation technique, transcranial direct current stimulation (tDCS), is able to improve the use of a person’s non-dominant hand.

Drs. Gottfried Schlaug and Bradley Vines from Beth Israel Deaconess Medical Center and Harvard Medical School, tested the effects of using tDCS over one side or both sides of the brain on sixteen healthy, right-handed volunteers, as well as testing the effect of simply pretending to carry out the procedure. The volunteers were not aware of which of the three procedures they were receiving. The test involved using the fingers of the left hand to key in a series of numbers displayed on a computer screen.

The results were striking; stimulating the brain over both the right and left motor regions (’dual hemisphere’ tDCS) resulted in a 24% improvement in the subjects’ scores. This was significantly better than stimulating the brain only over one motor region or using the sham treatment (16% and 12% improvements, respectively).

tDCS involves attaching electrodes to the scalp and passing a weak direct current through the scalp and skull to alter the excitability of the underlying brain tissue. The treatment has two principal modes depending on the direction in which the current runs between the two electrodes. Brain tissue that underlies the positive electrode (anode) becomes more excitable and the reverse is true for brain tissue that underlies the negative electrode (cathode). No relevant negative side effects have been reported with this type of non-invasive brain stimulation. It is not to be confused with electroconvulsive therapy, which uses currents around a thousand times higher.

According to Schlaug, “The results of our study are relevant to clinical research on motor recovery after stroke. They point to the possibility that stimulating both sides of the brain simultaneously, using the effects of the direct current to block unwanted effects of one motor region while using the opposite effects of the direct current treatment on the other motor region to enhance and facilitate the function of that motor region might catalyze motor recovery”.

By manipulating the brain noninvasively in a new way with magnetic stimulation, researchers have shown that they can restore some experience of color where before there was no visual awareness whatsoever. They report their findings in the October 28th issue of Current Biology, a Cell Press publication.

The researchers made their discovery while studying a patient known as GY, who lacks vision in half of his visual field as a result of damage in one hemisphere of the primary visual cortex (a brain region also known as V1). That part of the brain had been considered absolutely essential for visual awareness, a notion that is challenged by the current findings, according to Juha Silvanto of the University of Essex.

“The implication is that even though [lesions in this part of the brain] abolish visual awareness, it can be restored,” Silvanto said. “The neural processes that make V1 critical may be taken over by other brain regions—not automatically, but you can make it happen.”

In the portion of his visual field controlled by the damaged part of the brain, GY has a condition called blindsight. This phenomenon can occur when people do not consciously see as a consequence of a V1 lesion. However, when forced to guess which way a moving object they “observed” was traveling, for instance, they get it right most of the time. In other words, despite the fact that they do not experience vision, they nonetheless continue to detect things around them.

In the new study, the researchers applied a method called transcranial magnetic stimulation (TMS) to GY’s primary visual cortex. By stimulating both the normal and the damaged hemispheres of the brain, the method can induce visions of flashes of light (or phosphenes) in the blind fields of people like GY.

This method has previously been used in a general way to stimulate entire brain regions. In the new study, Silvanto’s team developed a more targeted method to activate particular neurons with TMS by taking advantage of a trend that had been seen before: TMS preferentially activates those neurons that were less active to begin with.

They asked GY to look at a screen in the color red for a time; this adapts the brain to the color red, leaving the neurons responsible for the experience of red to become less active. They then applied TMS to GY’s damaged and intact visual processing centers. The result: he saw the color red.

“This was the first time this patient [consciously] experienced a colored visual percept in his blind field,” Silvanto said.

“In summary,” the researchers wrote, “our results show that in the absence of V1, color perception may be possible via the intact hemisphere.”

The more targeted TMS method the team developed is also an important technical advance for cognitive neuroscience, Silvanto added. “Now we can target the stimulation at specific populations of neurons,” he said. “It makes the resolution of the technique much higher.”

A universal bias in the way people perceive moving objects means that tennis referees are more likely to make mistakes when they call balls “out” than when they call them “in,” according to a new report in the October 28th issue of Current Biology, a Cell Press publication. Because recent rule changes allow professional tennis players to challenge the refs’ calls, athletes could exploit the new findings to their advantage, according to researchers at the University of California, Davis.

Like all visual illusions, the new discovery provides visual neuroscientists with a window on how the brain processes information, explained David Whitney.

“The visual system faces a big challenge when trying to code the locations of objects so that we can perceive them,” Whitney said. “Consider one of the difficulties: every time we move our eyes, the image on our retina moves. Even if our coffee cup is actually stationary on our desk, we move our eyes and head while reaching to pick it up so the image of the cup will move on our retina. This is a problem because the visual system is sluggish—it takes a hundred or more milliseconds for us to become aware of an image that strikes our retina. So, by the time we perceive an object like the coffee cup in one location, it will have already changed location as we move toward it. Our perception lags behind reality. The visual system has mechanisms that help alleviate this problem of living in the past, but these mechanisms are not perfect and occasionally result in visual illusions—like the misperception of tennis ball location we discovered.”

Similar kinds of perceptual biases in the visual system had been documented before, but rarely in real-world situations. People consistently misperceive moving objects as shifted in the direction of their motion, so that at any moment they appear to be farther along their path than they are. Whitney said he realized it might be possible to study this in the context of tennis when he saw a referee call overturned by a player’s challenge during a Wimbledon match.

On a tennis court, a ball could physically bounce in the court but be called out, or a ball could physically bounce out of the court but be called in. If tennis referees were bias-free, they would be equally likely to make each of these two kinds of errors. But because objects generally appear to be shifted in the direction of their motion, referees should incorrectly judge balls as being out more often.

Whitney’s team confirmed that prediction. In a review of more than 4,000 randomly selected Wimbledon tennis points, the researchers uncovered 83 incorrect calls. Of those, 70 of the errors were of the type predicted.

Further study of the phenomenon in the laboratory confirmed that the refs’ mistakes are not the result of poor refereeing. Rather, the errors are a general artifact of the way the human brain processes visual information about motion.

Indeed, the researchers said, tennis players and audience members surely make the same mistakes that refs do. The new findings suggest, however, that players could maximize their opportunity to challenge calls by focusing on balls that are called “out,” since they are more likely to be incorrect.

The report also suggests that every shot in professional tennis should perhaps be reviewed by instant replay. “If that proves prohibitively time-consuming, the rules allowing players to challenge referee judgments should be scrutinized at least, in light of the current findings,” they wrote. “If all else fails,” they added, “perhaps professional tennis venues should follow the French, and universalize the clay court,” where skid marks on the clay reduce reliance on the referees’ motion perception.

Construction of the brain’s border fence is supervised by Wnt/b-catenin signaling, report Liebner et al. in The Journal of Cell Biology.

Like many a modern nation, the brain requires tight border security to maintain levels of nutrients and keep out toxic substances. The blood–brain barrier (BBB) is a virtually impermeable network of tight junctions between endothelial cells that prevents paracellular flow of materials. Because Wnt/b-catenin signaling is a major pathway regulating other aspects of brain development, the authors examined its potential role in constructing the BBB.

In brain endothelial cells, Wnt signaling was active during the time of maximum vascular development, but not after the BBB matured. Activation of the Wnt signaling pathway in vivo and in vitro promoted BBB development, and inactivation prevented it. In vitro increasing Wnt signaling also strengthened junctions between non-brain endothelial cells.

This suggests that Wnt signaling might be tweaked to mend the BBBs in patients where it has failed—such as in stroke—or to temporarily open the BBB to deliver drugs that would normally be shut out.

Many animals live longer when raised on low calorie diets.  But now researchers at Washington University School of Medicine in St. Louis have shown that they can extend the life spans of roundworms even when the worms are well fed — it just takes a chemical that blocks their sense of smell.

Three years ago, the researchers, led by Kerry Kornfeld, M.D., Ph.D., reported they found that a class of anticonvulsant medications made the roundworm Caenorhabditis elegans live longer.  But until now, they didn’t quite know what the drugs did to give the worms their longevity.  They report their latest findings in the Oct. 24 issue of the Public Library of Science Genetics.

“We’ve learned that the drugs inhibit neurons in the worm’s head that sense chemicals in their surroundings — the neurons are like the worm’s nose,” says Kornfeld, professor of developmental biology.  “Like roundworms that are grown in a food-scarce environment, the worms exposed to the anticonvulsant ethosuximide lived longer.  But these worms ate plenty of food.  That suggests that the worms’ sensation of food is critical to controlling their metabolism and life span.”

If roundworms sense that food is abundant, their metabolism adjusts accordingly.  Their bodies respond to promote rapid ingestion, rapid growth and rapid aging, Kornfeld explains.  In contrast, when the worms sense a shortage of food, they make “metabolic decisions” to delay growth, delay energy use and extend lifespan.

In the long term, Kornfeld’s goal is to identify compounds that could potentially delay human aging.  The research group for this project also included James Collins, Ph.D., Kim Evason, M.D., Ph.D., Chris Pickett, Ph.D., and Daniel Schneider.

Kornfeld’s lab studies C. elegans because they live only about two to three weeks, so experimental results can be obtained quickly.  In addition, the worms’ genome has been sequenced and extensively studied.

The scientists’ strategy has been to expose the roundworms to libraries of chemicals to identify compounds that delay aging and extend their lives.  That approach led to the unexpected result that some human anticonvulsants slow aging in C. elegans.

Now, further investigating the effect of one of those compounds, ethosuximide, the researchers found that it had the same life-extending effect as some well-studied genetic mutations in C. elegans.  These mutations inhibit the activity of some sensory neurons in the worm, and that helped the researchers conclude that ethosuximide also directly affected these neurons.  Roundworms treated with ethosuximide lived up to 29 percent longer than normal.

“Now we know what cells ethosuximide targets in C. elegans,” Kornfeld says.  “It’s likely that the drug prevents the nerve cells from being electrically active, but precisely how it does that is something we need to study further.  We also want to find out how the effect on the neurons is translated into an effect on the worms’ bodies to delay aging.”

Ethosuximide is used to treat seizure disorders in people.  Interestingly, a common side effect of the drug is the loss of the sense of taste.  Does that mean the ability to taste or smell food affects aging in people?  It’s probably not that simple, but it does hint at some sort of connection, Kornfeld says.  He says it’s possible that sensory perception cues have important metabolic consequences independent of what we actually eat.

“Emerging evidence suggests that core metabolic pathways that modulate lifespan in worms also modulate lifespan in vertebrates such as mice and perhaps humans,” Kornfeld says.  “Sensory pathways might also be fairly universal.  In an ancient common ancestor, these pathways might have caused metabolic adjustments that affect lifespan.  That could be reflected in our own biology.”

When reaching for an object, the brain prepares neural commands sent to the target muscles to minimize energy expenditure, according to a study published in PLoS Computational Biology by neuroscientists and mathematicians from the INSERM and ENSTA.

How the human brain organizes and controls our actions is a crucial question in life sciences. In recent decades, an important theoretical advance has been the use of computational models and the assumption that the brain behaves like an optimal controller. In most studies, an optimality criterion is chosen a priori and assumed to produce smooth and harmonious movements, as those recorded experimentally. Most existing models, however, fail to explain how our interactions with the external environment are integrated into optimization processes.

In particular, gravity is one of the constraints that permanently act upon the movements of living organisms. The simple observation of vertical arm movements reveals that muscle activity when moving upwards differs from when moving downwards. This led the authors to surmise that the brain takes advantage of gravitational force during movement, trying to optimize energy consumption. The discovery of this biological rule has resulted from the use of a hypothetical-deductive mathematical method which predicted short periods of muscle inactivation and direction-dependent hand kinematics. These predictions have been verified experimentally using human volunteers. Moreover, they have demonstrated a necessary and sufficient condition of optimal control for arm movements which is a novelty in motor control studies.

The authors explain how the brain plans movements by integrating biological and environmental constraints and the method may be of potential value for understanding motor dysfunction and guiding subsequent rehabilitation programs. Moreover, it opens the prospect of studying brain functions by a cooperative interaction of mathematicians and neuroscientists. Interestingly, the paper is a clear demonstration that mathematical principles and theories, formerly used for understanding the non-living world, are now used for understanding how biological organisms integrate these laws.

Life exists at the edge of chaos, where small changes can have striking and unanticipated effects, and major stimuli may go unheard. But there is no space for ambiguity when the brain needs to transform head motion into precise eye, head, and body movements that rapidly stabilize our posture and gaze; otherwise, we would stumble helplessly through the world, and our vision would resemble an undecipherable blur.In their latest study, published in the current issue of the journal Neuron, researchers at the Salk Institute for Biological Studies explain how the vestibular-ocular reflex, which keeps us and the world around us stable, achieves the accuracy it is famous for. Unlike most signals in the brain, whose transmission is frequency-dependent, signals from the vestibular system of the inner ear, which detects motion, are relayed in a linear fashion no matter how fast the neurons are firing.

“Most of what we know about signal transmission between neurons comes from studying special cortical or hippocampal neurons, but many vital functions, such as balance and breathing, are controlled by neurons in the brain stem, which, as we discovered, work very differently,” says Howard Hughes Medical Institute investigator Sascha du Lac, Ph.D., an associate professor in the Systems Neurobiology Laboratory. “Pursuing the mechanisms that control neurons in the brain stem is important for developing new classes of biotherapeutic agents.”

Du Lac and her team focus on a simple type of learning: How does the brain learn to stabilize an image on the retina and use eye movement to compensate for a moving head? This so-called vestibular-ocular reflex, or VOR, needs to be fast; for clear vision, head movements must be compensated for almost immediately. To achieve the necessary speed, the VOR-circuit involves only three types of neurons: sensory neurons, which detect head movement; motor neurons, directing eye muscles to relax or contract; and so-called vestibular nucleus neurons in the brainstem that link the two.

While the brevity of this circuit keeps reflex times short, it was less clear what qualities of the circuit ensure that eye velocity is precisely matched to head velocity. Since the VOR operates accurately no matter how fast we move our head, scientists long expected that the signal transmission at the synapses—specialized points of contact between nerve cells—that connect the sensory onto the vestibular nucleus neurons would be linear.

However, transmission at most synapses is non-linear. Brain cells signal by sending electrical impulses along axons, long, hair-like extensions that reach out to neighboring nerve cells. When an electrical signal reaches the end of an axon, the voltage change triggers release of neurotransmitters, the brain’s chemical messengers. These neurotransmitter molecules then travel across the space between neurons at a synapse and trigger an electrical signal in the adjacent cell—or not.

“Most known synapses act as information filters, and both the probability and the extent of neurotransmitter release as well as the efficacy of the postsynaptic response depend heavily on the recent history of the synapse,” says first author Martha W. Bagnall, Ph.D., a former graduate student in du Lac’s lab and now a postdoctoral researcher at the University of California, San Diego. “But no matter whether you go jogging or watch TV on your couch, the VOR needs to accurately match sensory input with motor output,” she adds.

When Bagnall and her colleagues took a closer look at the first synapse in the VOR circuit, they found that no matter how fast the sensory neuron was firing, the same amount of neurotransmitter was released. And instead of vacillating, the post-synaptic neuron took the information and transmitted it faithfully.

A brain isn’t born fully organized. It builds its abilities through experience, making physical connections between neurons and organizing circuits to store and retrieve information in milliseconds for years afterwards.Now that process has been caught in the act for the first time by a Duke University research team that watched a naïve brain organize itself to interpret images of motion.

“This is the first time that anyone has been able to watch as visual experience selectively shapes the functional properties of individual neurons,” said David Fitzpatrick, professor of neurobiology and director of the Duke Institute for Brain Sciences. “These results emphasize just how important experience is for the early development of brain circuits.” The group’s findings appear online Oct. 22 in the journal Nature.

Using an advanced imaging system that can see changes in calcium levels within individual neurons as an indication of electrical activity, the team has been able to see inside the brain of a one-month old ferret as it opened its eyes for the first time and learned how to interpret moving images.

They watched the brain learning how to see. As a ferret learned to discriminate one pattern of motion from another over the course of a few hours, the researchers could see large numbers of individual neurons in the visual cortex develop specific responses and become organized into functional assemblies called cortical columns. Additional experiments confirmed that the changes were dependent on the neurons being activated by the animal’s experience with moving visual images.

The measurements were made using something called “in vivo two-photon laser scanning microscopy,” which allows researchers to focus on a virtual slice of living tissue a few microns thick, and up to 300 microns below the surface of the brain. By scanning at multiple depths, the researchers were able to examine the properties of hundreds of neurons in a single animal. A fluorescent dye sensitive to calcium allowed the scientists to detect changes in the activity of individual neurons as the learning occurred.

Ferrets are born with their eyes closed and remain so for the first 30 days or so, Fitzpatrick explained. What the Duke team saw happening as the animals opened their eyes and watched moving images for the first time was the emergence of columns of neurons sensitive to a particular feature of the visual stimulus: its direction of motion.

In visual areas of the mature brain, individual neurons are programmed to be most responsive to a particular direction of motion. Some are most responsive to left-to-right motion, for example, and others will be most responsive to down-to-up or right-to-left and so on. As signals from a visual stimulus enter these brain centers for interpretation, the entire collection of neurons that has been programmed to detect motion will fire signals to cast their votes, in effect, on which direction the stimulus is moving. Those neurons which are programmed to be most responsive to the direction the stimulus is actually moving cast the loudest votes.

“Before experience with a moving stimulus, individual neurons respond almost equally to opposite directions of motion and there is little order in the way they are arranged,” Fitzpatrick said. “But as a result of experience with moving images, their response to a particular direction of motion strengthens and they begin to act like their neighbors, forming columns of neurons with similar preferences. We have been able to visualize the self-organizing process by which the brain uses experience to guide the construction of circuits that are critical for interpreting moving stimuli.”

The scientists next have to figure out how neurons end up preferring one motion direction over another, and what aspects of the circuit are altered to create the direction-selective responses.

Fitzpatrick is confident that the findings from these experiments can be generalized to other brain regions and will be of value in understanding neurological and psychiatric disorders.

“Many people don’t realize that the vast majority of cortical connections are being formed at a time when experience can influence neural activity,” he said. “Understanding how experience shapes the architecture of developing neural circuits, and identifying the underlying cellular and molecular mechanisms could provide the key to a number of developmental brain disorders.”