Muscle-controlling Neurons Know When They Mess Up

Whether it is playing a piano sonata or acing a tennis serve, the brain needs to orchestrate precise, coordinated control over the body’s many muscles. Moreover, there needs to be some kind of feedback from the senses should any of those movements go wrong. Neurons that coordinate those movements, known as Purkinje cells, and ones that provide feedback when there is an error or unexpected sensation, known as climbing fibers, work in close concert to fine-tune motor control.   

A team of researchers from the University of Pennsylvania and Princeton University has now begun to unravel the decades-spanning paradox concerning how this feedback system works.

At the heart of this puzzle is the fact that while climbing fibers send signals to Purkinje cells when there is an error to report, they also fire spontaneously, about once a second. There did not seem to be any mechanism by which individual Purkinje cells could detect a legitimate error signal from within this deafening noise of random firing. 

Using a microscopy technique that allowed the researchers to directly visualize the chemical signaling occurring between the climbing fibers and Purkinje cells of live, active mice, the Penn team has for the first time shown that there is a measurable difference between “true” and “false” signals.

This knowledge will be fundamental to future studies of fine motor control, particularly with regards to how movements can be improved with practice. 

The research was conducted by Javier Medina, assistant professor in the Department of Psychology in Penn’s School of Arts and Sciences, and Farzaneh Najafi, a graduate student in the Department of Biology. They collaborated with postdoctoral fellow Andrea Giovannucci and associate professor Samuel S. H. Wang of Princeton University.

It was published in the journal Cell Reports.

The cerebellum is one of the brain’s motor control centers. It contains thousands of Purkinje cells, each of which collects information from elsewhere in the brain and funnels it down to the muscle-triggering motor neurons. Each Purkinje cell receives messages from a climbing fiber, a type of neuron that extends from the brain stem and sends feedback about the associated muscles. 

“Climbing fibers are not just sensory neurons, however,” Medina said. “What makes climbing fibers interesting is that they don’t just say, ‘Something touched my face’; They say, ‘Something touched my face when I wasn’t expecting it.’ This is something that our brains do all the time, which explains why you can’t tickle yourself. There’s part of your brain that’s already expecting the sensation that will come from moving your fingers. But if someone else does it, the brain can’t predict it in the same way and it is that unexpectedness that leads to the tickling sensation.”

Not only does the climbing fiber feedback system for unexpected sensations serve as an alert to potential danger — unstable footing, an unseen predator brushing by — it helps the brain improve when an intended action doesn’t go as planned.    

“The sensation of muscles that don’t move in the way the Purkinje cells direct them to also counts as unexpected, which is why some people call climbing fibers ‘error cells,’” Medina said. “When you mess up your tennis swing, they’re saying to the Purkinje cells, ‘Stop! Change! What you’re doing is not right!’ That’s where they help you learn how to correct your movements.

“When the Purkinje cells get these signals from climbing fibers, they change by adding or tweaking the strength of the connections coming in from the rest of the brain to their dendrites. And because the Purkinje cells are so closely connected to the motor neurons, the changes to those synapses are going to result in changes to the movements that Purkinje cell controls.”

This is a phenomenon known as neuroplasticity, and it is fundamental for learning new behaviors or improving on them. That new neural pathways form in response to error signals from the climbing fibers allows the cerebellum to send better instructions to motor neurons the next time the same action is attempted.

The paradox that faced neuroscientists was that these climbing fibers, like many other neurons, are spontaneously activated. About once every second, they send a signal to their corresponding Purkinje cell, whether or not there were any unexpected stimuli or errors to report.

“So if you’re the Purkinje cell,” Medina said, “how are you ever going to tell the difference between signals that are spontaneous, meaning you don’t need to change anything, and ones that really need to be paid attention to?”

Medina and his colleagues devised an experiment to test whether there was a measurable difference between legitimate and spontaneous signals from the climbing fibers. In their study, the researchers had mice walk on treadmills while their heads were kept stationary. This allowed the researchers to blow random puffs of air at their faces, causing them to blink, and to use a non-invasive microscopy technique to look at how the relevant Purkinje cells respond.

The technique, two-photon microscopy, uses an infrared laser and a reflective dye to look deep into living tissue, providing information on both structure and chemical composition. Neural signals are transmitted within neurons by changing calcium concentrations, so the researchers used this technique to measure the amount of calcium contained within the Purkinje cells in real time.

Because the random puffs of air were unexpected stimuli for the mice, the researchers could directly compare the differences between legitimate and spontaneous signals in the eyelid-related Purkinje cells that made the mice blink.

“What we have found is that the Purkinje cell fills with more calcium when its corresponding climbing fiber sends a signal associated with that kind of sensory input, rather than a spontaneous one,” Medina said. “This was a bit of a surprise for us because climbing fibers had been thought of as ‘all or nothing’ for more than 50 years now.”

The mechanism that allows individual Purkinje cells to differentiate between the two kinds of climbing fiber signals is an open question. These signals come in bursts, so the number and spacing of the electrical impulses from climbing fiber to Purkinje cell might be significant. Medina and his colleagues also suspect that another mechanism is at play: Purkinje cells might respond differently when a signal from a climbing fiber is synchronized with signals coming elsewhere from the brain.   

Whether either or both of these explanations are confirmed, the fact that individual Purkinje cells are able to distinguish when their corresponding muscle neurons encounter an error must be taken into account in future studies of fine motor control. This understanding could lead to new research into the fundamentals of neuroplasticity and learning.    

“Something that would be very useful for the brain is to have information not just about whether there was an error but how big the error was — whether the Purkinje cell needs to make a minor or major adjustment,” Medina said. “That sort of information would seem to be necessary for us to get very good at any kind of activity that requires precise control. Perhaps climbing fiber signals are not as ‘all-or-nothing’ as we all thought and can provide that sort of graded information”

Epilepsy drug turns out to help adults acquire perfect pitch and learn language like kids

A team of researchers from across the globe believe they have discovered a means of re-opening “critical periods” in brain development, allowing adults to acquire abilities — such as perfect pitch or fluency in language — that could previously only be acquired early in life.

According to the study in Frontiers in Systems Neuroscience, the mood-stabilizing drug valproate allows the adult brain to absorb new information as effortlessly as it did during critical windows in childhood.

A critical period is “a fixed window of time, usually early in an organism’s lifespan, during which experience has lasting effects on the development of brain function and behavior.” They are, for example, what allows children to enter into language without any formal training in grammar or vocabulary.

The researchers postulated that because such periods close when enzymes “impose ‘brakes’ on neuroplasticity,” a drug that blocks the productions of those enzymes might be able to “reopen critical-period neuroplasticity.”

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New Theory of Synapse Formation in the Brain

The human brain keeps changing throughout a person’s lifetime. New connections are continually created while synapses that are no longer in use degenerate. To date, little is known about the mechanisms behind these processes. Jülich neuroinformatician Dr. Markus Butz has now been able to ascribe the formation of new neural networks in the visual cortex to a simple homeostatic rule that is also the basis of many other self-regulating processes in nature. With this explanation, he and his colleague Dr. Arjen van Ooyen from Amsterdam also provide a new theory on the plasticity of the brain – and a novel approach to understanding learning processes and treating brain injuries and diseases.

The brains of adult humans are by no means hard wired. Scientists have repeatedly established this fact over the last few years using different imaging techniques. This so-called neuroplasticity not only plays a key role in learning processes, it also enables the brain to recover from injuries and compensate for the loss of functions. Researchers only recently found out that even in the adult brain, not only do existing synapses adapt to new circumstances, but new connections are constantly formed and reorganized. However, it was not yet known how these natural rearrangement processes are controlled in the brain. In the open-access journal PLOS Computational Biology, Butz and van Ooyen now present a simple rule that explains how these new networks of neurons are formed.

"It’s very likely that the structural plasticity of the brain is the basis for long-term memory formation," says Markus Butz, who has been working at the recently established Simulation Laboratory Neuroscience at the Jülich Supercomputing Centre for the past few months. "And it’s not just about learning. Following the amputation of extremities, brain injury, the onset of neurodegenerative diseases, and strokes, huge numbers of new synapses are formed in order to adapt the brain to the lasting changes in the patterns of incoming stimuli."

Activity regulates synapse formation

Τhese results show that the formation of new synapses is driven by the tendency of neurons to maintain a ‘pre-set’ electrical activity level. If the average electric activity falls below a certain threshold, the neurons begin to actively build new contact points. These are the basis for new synapses that deliver additional input – the neuron firing rate increases. This also works the other way round: as soon as the activity level exceeds an upper limit, the number of synaptic connections is reduced to prevent any overexcitation – the neuron firing rate falls. Similar forms of homeostasis frequently occur in nature, for example in the regulation of body temperature and blood sugar levels.

However, Markus Butz stresses that this does not work without a certain minimal excitation of the neurons: “A neuron that no longer receives any stimuli loses even more synapses and will die off after some time. We must take this restriction into account if we want the results of our simulations to agree with observations.” Using the visual cortex as an example, the neuroscientists have studied the principles according to which neurons form new connections and abandon existing synapses. In this region of the brain, about 10% of the synapses are continuously regenerated. When the retina is damaged, this percentage increases even further. Using computer simulations, the authors succeeded in reconstructing the reorganization of the neurons in a way that conforms to experimental results from the visual cortex of mice and monkeys with damaged retinas.

The visual cortex is particularly suitable for demonstrating the new growth rule, because it has a property referred to as retinotopy: This means that points projected beside each other onto the retina are also arranged beside each other when they are projected onto the visual cortex, just like on a map. If areas of the retina are damaged, the cells onto which the associated images are projected receive different inputs. “In our simulations, you can see that areas which no longer receive any input from the retina start to build crosslinks, which allow them to receive more signals from their neighbouring cells,” says Markus Butz. These crosslinks are formed slowly from the edge of the damaged area towards the centre, in a process resembling the healing of a wound, until the original activity level is more or less restored.

Synaptic and structural plasticity

"The new growth rule provides structural plasticity with a principle that is almost as simple as that of synaptic plasticity," says co-author Arjen van Ooyen, who has been working on models for the development of neural networks for decades. As early as 1949, psychology professor Donald Olding Hebb discovered that connections between neurons that are frequently activated will become stronger. Those that exchange little information will become weaker. Today, many scientists believe that this Hebbian principle plays a central role in learning and memory processes. While synaptic plasticity in involved primarily in short-term processes that take from a few milliseconds to several hours, structural plasticity extends over longer time scales, from several days to months.

Structural plasticity therefore plays a particularly important part during the (early) rehabilitation phase of patients affected by neurological diseases, which also lasts for weeks and months. The vision driving the project is that valuable ideas for the treatment of stroke patients could result from accurate predictions of synapse formation. If doctors knew how the brain structure of a patient will change and reorganize during treatment, they could determine the ideal times for phases of stimulation and rest, thus improving treatment efficiency.

New approach for numerous applications

"It was previously assumed that structural plasticity also follows the principle of Hebbian plasticity. The findings suggest that structural plasticity is governed by the homeostatic principle instead, which was not taken into consideration before," says Prof. Abigail Morrison, head of the Simulation Laboratory Neuroscience at Jülich. Her team is already integrating the new rule into the freely accessible simulation software NEST, which is used by numerous scientists worldwide.

These findings are also of relevance for the Human Brain Project. Neuroscientists, medical scientists, computer scientists, physicists, and mathematicians in Europe are working hand in hand to simulate the entire human brain on high-performance computers of the next generation in order to better understand how it functions. “Due to the complex synaptic circuitry in the human brain, it’s not plausible that its fault tolerance and flexibility are achieved based on static connection rules. Models are therefore required for a self-organization process,” says Prof. Markus Diesmann from Jülich’s Institute of Neuroscience and Medicine, who is involved in the project. He heads Computational and Systems Neuroscience (INM-6), a subinstitute working at the interface between neuroscientific research and simulation technology.

New Insight Into How Brain ‘Learns’ Cocaine Addiction

A team of researchers says it has solved the longstanding puzzle of why a key protein linked to learning is also needed to become addicted to cocaine. Results of the study, published in the Aug. 1 issue of the journal Cell, describe how the learning-related protein works with other proteins to forge new pathways in the brain in response to a drug-induced rush of the “pleasure” molecule dopamine. By adding important detail to the process of addiction, the researchers, led by a group at Johns Hopkins, say the work may point the way to new treatments.

“The broad question was why and how cocaine strengthened certain circuits in the brain long term, effectively re-wiring the brain for addiction,” says Paul Worley, M.D., a professor in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine. “What we found in this study was how two very different types of systems in the brain work together to make that happen.” Cocaine addiction, experts say, is among the strongest of addictions.

Worley did not come to the problem as an addiction researcher, but as an expert in a group of genes known as immediate early genes, which rapidly ramp up production in neurons when the brain is exposed to new information. In 2001, he said, a European group led by François Conquet of GlaxoSmithKline reported that deleting mGluR5, a protein complex that responds to the common brain-signaling molecule glutamate, made mice unresponsive to cocaine. “That finding came out of the blue,” says Worley, who knew mGluR proteins for their interactions with immediate early genes. “I never would have thought this type of protein was linked to dopamine and addiction, because the functions for it that we knew about up to that point were completely unrelated. That’s what scientists love: when you’re pretty sure something is right, but you don’t have a clue why.”

The finding set Worley’s research group on a long search for an explanation. Eventually, in addition to studying the effects of altering genes for the relevant proteins in mice, they partnered with experts in measuring the brain’s electrical signals and in a biophysical technique that detects when chemical bonds are rotated within protein molecules. Using different types of experiments, they pieced together a complex story of how dopamine released in response to cocaine works together with mGluR5 and immediate early genes to switch cells into synapse-strengthening mode.

“The process we identified explains how cocaine exposure can co-opt normal mechanisms of learning to induce addiction,” Worley says. Knowing the details of the mechanism may help researchers identify targets for potential drugs to treat addiction, he adds.

(Image: Milos Jokic)

Neuroscientists plant false memories in the brain

The phenomenon of false memory has been well-documented: In many court cases, defendants have been found guilty based on testimony from witnesses and victims who were sure of their recollections, but DNA evidence later overturned the conviction.

In a step toward understanding how these faulty memories arise, MIT neuroscientists have shown that they can plant false memories in the brains of mice. They also found that many of the neurological traces of these memories are identical in nature to those of authentic memories.

“Whether it’s a false or genuine memory, the brain’s neural mechanism underlying the recall of the memory is the same,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and senior author of a paper describing the findings in the July 25 edition of Science.

The study also provides further evidence that memories are stored in networks of neurons that form memory traces for each experience we have — a phenomenon that Tonegawa’s lab first demonstrated last year.

Neuroscientists have long sought the location of these memory traces, also called engrams. In the pair of studies, Tonegawa and colleagues at MIT’s Picower Institute for Learning and Memory showed that they could identify the cells that make up part of an engram for a specific memory and reactivate it using a technology called optogenetics.

Lead authors of the paper are graduate student Steve Ramirez and research scientist Xu Liu. Other authors are technical assistant Pei-Ann Lin, research scientist Junghyup Suh, and postdocs Michele Pignatelli, Roger Redondo and Tomas Ryan.

Seeking the engram

Episodic memories — memories of experiences — are made of associations of several elements, including objects, space and time. These associations are encoded by chemical and physical changes in neurons, as well as by modifications to the connections between the neurons.

Where these engrams reside in the brain has been a longstanding question in neuroscience. “Is the information spread out in various parts of the brain, or is there a particular area of the brain in which this type of memory is stored? This has been a very fundamental question,” Tonegawa says.

In the 1940s, Canadian neurosurgeon Wilder Penfield suggested that episodic memories are located in the brain’s temporal lobe. When Penfield electrically stimulated cells in the temporal lobes of patients who were about to undergo surgery to treat epileptic seizures, the patients reported that specific memories popped into mind. Later studies of the amnesiac patient known as “H.M.” confirmed that the temporal lobe, including the area known as the hippocampus, is critical for forming episodic memories.

However, these studies did not prove that engrams are actually stored in the hippocampus, Tonegawa says. To make that case, scientists needed to show that activating specific groups of hippocampal cells is sufficient to produce and recall memories.

To achieve that, Tonegawa’s lab turned to optogenetics, a new technology that allows cells to be selectively turned on or off using light.

For this pair of studies, the researchers engineered mouse hippocampal cells to express the gene for channelrhodopsin, a protein that activates neurons when stimulated by light. They also modified the gene so that channelrhodopsin would be produced whenever the c-fos gene, necessary for memory formation, was turned on.

In last year’s study, the researchers conditioned these mice to fear a particular chamber by delivering a mild electric shock. As this memory was formed, the c-fos gene was turned on, along with the engineered channelrhodopsin gene. This way, cells encoding the memory trace were “labeled” with light-sensitive proteins.

The next day, when the mice were put in a different chamber they had never seen before, they behaved normally. However, when the researchers delivered a pulse of light to the hippocampus, stimulating the memory cells labeled with channelrhodopsin, the mice froze in fear as the previous day’s memory was reactivated.

“Compared to most studies that treat the brain as a black box while trying to access it from the outside in, this is like we are trying to study the brain from the inside out,” Liu says. “The technology we developed for this study allows us to fine-dissect and even potentially tinker with the memory process by directly controlling the brain cells.”

Incepting false memories

That is exactly what the researchers did in the new study — exploring whether they could use these reactivated engrams to plant false memories in the mice’s brains.

First, the researchers placed the mice in a novel chamber, A, but did not deliver any shocks. As the mice explored this chamber, their memory cells were labeled with channelrhodopsin. The next day, the mice were placed in a second, very different chamber, B. After a while, the mice were given a mild foot shock. At the same instant, the researchers used light to activate the cells encoding the memory of chamber A.

On the third day, the mice were placed back into chamber A, where they now froze in fear, even though they had never been shocked there. A false memory had been incepted: The mice feared the memory of chamber A because when the shock was given in chamber B, they were reliving the memory of being in chamber A.

Moreover, that false memory appeared to compete with a genuine memory of chamber B, the researchers found. These mice also froze when placed in chamber B, but not as much as mice that had received a shock in chamber B without having the chamber A memory activated.

The researchers then showed that immediately after recall of the false memory, levels of neural activity were also elevated in the amygdala, a fear center in the brain that receives memory information from the hippocampus, just as they are when the mice recall a genuine memory.

These two papers represent a major step forward in memory research, says Howard Eichenbaum, a professor of psychology and director of Boston University’s Center for Memory and Brain.

“They identified a neural network associated with experience in an environment, attached a fear association with it, then reactivated the network to show that it supports memory expression. That, to me, shows for the first time a true functional engram,” says Eichenbaum, who was not part of the research team.

The MIT team is now planning further studies of how memories can be distorted in the brain.

“Now that we can reactivate and change the contents of memories in the brain, we can begin asking questions that were once the realm of philosophy,” Ramirez says. “Are there multiple conditions that lead to the formation of false memories? Can false memories for both pleasurable and aversive events be artificially created? What about false memories for more than just contexts — false memories for objects, food or other mice? These are the once seemingly sci-fi questions that can now be experimentally tackled in the lab.”

Novel ‘top-down’ mechanism repatterns developing brain regions

Dennis O’Leary of the Salk Institute was the first scientist to show that the basic functional architecture of the cortex, the largest part of the human brain, was genetically determined during development. But as it so often does in science, answering one question opened up many others. O’Leary wondered what if the layout of the cortex wasn’t fixed? What would happen if it were changed?

In the August issue of Nature Neuroscience, O’Leary, holder of the Vincent J. Coates Chair of Molecular Neurobiology at Salk, and Andreas Zembrzycki, a postdoctoral researcher in his lab, demonstrate that altering the cortical layout is possible, and that this alteration produces significant changes in parts of the brain that connect with the cortex and define its functional properties. These mechanisms may lay at the heart of neural developmental problems, such as autism spectrum disorders (ASD).

The human cortex is involved in higher functions such as sensory perception, spatial reasoning, conscious thought and language. All mammals have areas in the cortex that process the senses, but they have them in different proportions. Mice, the favorite laboratory animal, are nocturnal, so they have a large somatosensory area (S1) in the cortex, responsible for somatosensation, or feelings of the body that include touch, pain, temperature and proprioception.

"The area layout of the cortex directly relates to the lifestyle of an animal," says Zembrzycki. "Areas are bigger or smaller according to the functional needs of the animal, not the physical size of the body parts from which they receive input."

Even with relative sizes to other species set in place, areas in the cortex of humans may differ greatly across individuals. Such variations may underlie why some people appear to be naturally better at certain perceptual tasks, such as hitting a baseball or detecting the details of visual illusions. In patients with neurological disorders, there is an even wider range of differences.

The neurons in S1 are arranged in functional groups called body maps according to the density of nerve endings in the skin; thus, there’s a larger group of neurons dedicated to the skin on the face, than the skin on the legs. Neurosurgeon Wilder Penfield famously illustrated this idea as a “sensory homunculus,” a cartoon of disproportionately sized body parts arching over the cortex. Mice have a similar “mouseunculus” in their cortex in which the body map of the facial whiskers is highly enlarged.

These perceptual maps are not set for life. For example, if innervation of a body part is diminished early in life during a critical period, its map may shrink, while other parts of the body map may grow in compensation. This is a version of “bottom-up plasticity,” in which external experience affects body maps in the brain.

In order to study cortical layout, O’Leary’s team altered a regulatory gene, Pax6, in the cortex in mice. In response, S1 became much smaller, demonstrating that Pax6 regulates its development. They found that the shrinkage in S1 subsequently affected other regions of the brain that feed sensory information into the cortex, but more interestingly, it also altered the body maps in these subcortical brain regions, overturning the idea that once established, these brain regions could only be changed by external experience. They dubbed this previously unknown phenomenon “top down plasticity.”

"Top-down plasticity complements in a reverse fashion the well-known bottom-up plasticity induced by sensory deprivation," says O’Leary.

Normally, the body map in S1 cortex mirrors similar body maps in the thalamus, the main switching station for sensory information, which transmits somatosensation from the body periphery to the S1 cortex through outgoing neural “wires” known as axons. In the newly discovered top-down plasticity, when S1 was made smaller, the sensory thalamus that feeds into it is also subsequently reduced in size.

But the story has a more intriguing twist. “According to our present knowledge about the development of sensory circuits, we anticipated that all body representations in S1 would be equally affected when S1 was made smaller,” says O’Leary. “It was a surprise to us that not only was the body map smaller, but some parts of it were completely missing. The specific deletion of parts of the body map is controlled by exaggerated competition for cortical resources dictated by S1 size and played out between the connections from thalamic neurons that form these maps in the cortex.”

"To put it in lay terms, ‘If you snooze, you lose,’" adds Zembrzycki. "Axons that differentiate later are preferentially excluded from the smaller S1 leading to the specific deletion of the body parts that they represent."

"The essential point about top-down plasticity is that altering the size and patterning of sensory cortex results in matching alterations in sensory thalamus through the selective death of thalamic neurons that normally would represent body parts absent from S1," Zembrzycki adds. "Therefore, a downstream part of the brain is repatterned to match the architecture in S1, resulting in aberrant wiring of the brain that has important implications for sensory perception and function. For example, autistics have very robust abnormalities in touching and other features of somatosensation."

O’Leary and Zembrzycki believe that this process provides significant insights into the development of autism and other neural disorders. “One of the hallmarks of the autistic brain early in development is the area profile seems to be abnormal, with for example, the frontal cortex being enlarged, while the overall cortex keeps its normal size,” says O’Leary. “It is implicit then that other cortical areas positioned behind the frontal areas, such as S1, would be reduced in size, and thalamus would exhibit defects that match those in sensory cortex, as has been shown to be the case in autistic patients.”

Researchers find new clue to cause of human narcolepsy

In 2000, researchers at the UCLA Center for Sleep Research published findings showing that people suffering from narcolepsy, a disorder characterized by uncontrollable periods of deep sleep, had 90 percent fewer neurons containing the neuropeptide hypocretin in their brains than healthy people. The study was the first to show a possible biological cause of the disorder.

Subsequent work by this group and others demonstrated that hypocretin is an arousing chemical that keeps us awake and elevates both mood and alertness; the death of hypocretin cells, the researchers said, helps explain the sleepiness of narcolepsy. But it has remained unclear what kills these cells.

Now the same UCLA team reports that an excess of another brain cell type — this one containing histamine — may be the cause of the loss of hypocretin cells in human narcoleptics.

UCLA professor of psychiatry Jerome Siegel and colleagues report in the current online edition of the journal Annals of Neurology that people with the disorder have nearly 65 percent more brain cells containing the chemical histamine. Their research suggests that this excess of histamine cells causes the loss of hypocretin cells in human narcoleptics.

Narcolepsy is a chronic disorder of the central nervous system characterized by the brain’s inability to control sleep–wake cycles. It causes sudden bouts of sleep and is often accompanied by cataplexy, an abrupt loss of voluntary muscle tone that can cause person to collapse. According to the National Institutes of Health, narcolepsy is thought to affect roughly one in every 3,000 Americans. Currently, there is no cure.

Histamine is a body chemical that works as part of the immune system to kill invading cells. When the immune system goes awry, histamine can act on a person’s eyes, nose, throat, lungs, skin or gastrointestinal tract, causing the symptoms of allergy that many people are familiar with. But histamine is also present in a type of brain cell.

For the study, researchers examined five narcoleptic brains and seven control brains from human cadavers. Prior to death, all the narcoleptics had been diagnosed by a sleep disorder center as having narcolepsy with cataplexy. These brains were also compared with the brains of three narcoleptic mouse models and to the brains of narcoleptic dogs.

The researchers found that the humans with narcolepsy had an average of 64 percent more histamine neurons. Interestingly, the team did not see an increased number of these cells in any of the animal models of narcolepsy.

"Humans and animals with narcolepsy share the same symptoms, but we did not see the histamine cell changes we saw in humans in the animal models we examined," said Siegel, who directs the Center for Sleep Research at the UCLA Semel Institute for Neuroscience and Human Behavior and is the senior author of the research. "We know that narcolepsy in the animal models is caused by engineered genetic changes that block hypocretin function. However, in humans, we did not know why the hypocretin cells die.

"Our current findings indicate that the increase of histamine cells that we see in human narcolepsy may cause the loss of hypocretin cells," he said.

The study results may also further our understanding of brain plasticity, Siegel noted. While scientists have known of the existence neurogenesis — the process by which the brain is populated with new neurons — it was thought to function mainly to replace existing cells that had died.

"This paper shows for the first time that neuronal numbers can increase greatly and not just serve as replacement cells," he said. "In the current example, this appears to be pathological with the destruction of hypocretin, but in other circumstances, it may underlie recovery and learning and open new routes to treatment of a number of neurological disorders."

Study Shows a Solitary Mutation Can Destroy Critical ‘Window’ of Early Brain Development

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown in animal models that brain damage caused by the loss of a single copy of a gene during very early childhood development can cause a lifetime of behavioral and intellectual problems.

The study, published this week in the Journal of Neuroscience, sheds new light on the early development of neural circuits in the cortex, the part of the brain responsible for functions such as sensory perception, planning and decision-making.

The research also pinpoints the mechanism responsible for the disruption of what are known as “windows of plasticity” that contribute to the refinement of the neural connections that broadly shape brain development and the maturing of perception, language, and cognitive abilities.

The key to normal development of these abilities is that the neural connections in the brain cortex—the synapses—mature at the right time.

In an earlier study, the team, led by TSRI Associate Professor Gavin Rumbaugh, found that in mice missing a single copy of the vital gene, certain synapses develop prematurely within the first few weeks after birth. This accelerated maturation dramatically expands the process known as “excitability”—how often brain cells fire—in the hippocampus, a part of the brain critical for memory. The delicate balance between excitability and inhibition is especially critical during early developmental periods. However, it remained a mystery how early maturation of brain circuits could lead to lifelong cognitive and behavioral problems.

The current study shows in mice that the interruption of the synapse-regulating gene known as SYNGAP1—which can cause a devastating form of intellectual disability and increase the risk for developing autism in humans—induces early functional maturation of neural connections in two areas of the cortex. The influence of this disruption is widespread throughout the developing brain and appears to degrade the duration of these critical windows of plasticity.

“In this study, we were able to directly connect early maturation of synapses to the loss of an important plasticity window in the cortex,” Rumbaugh said. “Early maturation of synapses appears to make the brain less plastic at critical times in development. Children with these mutations appear to have brains that were built incorrectly from the ground up.”

The accelerated maturation also appeared to occur surprisingly early in the developing cortex. That, Rumbaugh added, would correspond to the first two years of a child’s life, when the brain is expanding rapidly. “Our goal now is to figure out a way to prevent the damage caused by SYNGAP1 mutations. We would be more likely to help that child if we could intervene very early on—before the mutation has done its damage,” he said.

Scientists discover previously unknown requirement for brain development

Scientists at the Salk Institute for Biological Studies have demonstrated that sensory regions in the brain develop in a fundamentally different way than previously thought, a finding that may yield new insights into visual and neural disorders.

In a paper published June 7, 2013, in Science, Salk researcher Dennis O’Leary and his colleagues have shown that genes alone do not determine how the cerebral cortex grows into separate functional areas. Instead, they show that input from the thalamus, the main switching station in the brain for sensory information, is crucially required.

O’Leary has done pioneering studies in “arealization,” the way in which the neo-cortex, the major region of cerebral cortex, develops specific areas dedicated to particular functions. In a landmark paper published in Science in 2000, he showed that two regulatory genes were critically responsible for the general pattern of the neo-cortex, and has since shown distinct roles for other genes in this process. In this new set of mouse experiments, his laboratory focused on the visual system, and discovered a new, unexpected twist to the story.

"In order to function properly, it is essential that cortical areas are mapped out correctly, and it is this architecture that was thought to be genetically pre-programmed," says O’Leary, holder of the Vincent J. Coates Chair in Molecular Neurobiology at Salk. "To our surprise, we discovered thalamic input plays an essential role far earlier in brain development."

Vision is relayed from the outside world into processing areas within the brain. The relay starts when light hits the retina, a thin strip of cells at the back of the eye that detects color and light levels and encodes the information as electrical and chemical signals. Through retinal ganglion cells, those signals are then sent into the Lateral Geniculate Nucleus (LGN), a structure in thalamus.

In the next important step in the relay, the LGN routes the signals into the primary visual area (V1) in the neo-cortex, a multi-layered structure that is divided into functionally and anatomically distinct areas. V1 begins the process of extracting visual information, which is further carried out by “higher order” visual areas in the neo-cortex that are vitally important to visual perception. Like parts in a machine, the functions of these areas are both individual and integrated. Damage in one tiny area can lead to strange visual disorders in which a person may be able to see a moving ball, and yet not perceive it is in motion.

Current dogma holds that this basic architecture is entirely genetically determined, with environmental input only playing a role later in development. One of the most famous examples of this idea is the Nobel Prize-winning work of visual neuroscientists David Hubel and Torsten Wiesel, which showed that there is a “critical period” of sensitivity in vision. Their finding was commonly interpreted as a warning that without exposure to basic visual stimuli early in life, even an individual with a healthy brain will be unable to see correctly.

Later discoveries in neural plasticity more optimistically suggested that early deprivation can be overcome, and the brain can even sprout new neurons in specific areas. Nevertheless, this still reinforced the idea that environmental influences might modify neural architecture, but only genetics could establish how cortical areas would be laid out.

In their new study, however, O’Leary and the paper’s co-first authors, Shen-Ju Chou and Zoila Babot, post-doctoral researchers in O’Leary’s laboratory, show that genetics only provides a broad field in the neo-cortex for visual areas.

When they created mouse mutants that disconnected the link between thalamus and cortex but only after early cortical development was complete, they found that the primary and higher order visual areas failed to differentiate from one another as they should.

"Our new understanding is that genes only create a rough lay-out of cortical areas," explains O’Leary. "There must be thalamic input to develop the fine differentiation necessary for proper sensory processing."

Essentially, if the brain were a house, genes would determine which areas were bedrooms. Thalamic input provides the details, distinguishing what will be the master bedroom, a child’s bedroom, a guest bedroom and so on. “The size and location of areas within the overall cortex does not change, but without thalamic input from the LGN, the critical differentiation process that creates primary and higher order visual areas does not happen,” says O’Leary.

Given that most sensory modalities—sight, hearing, touch—route through thalamus to cortex, this experiment may suggest why, when someone lacks a sensory modality from birth, that individual has a harder time processing restored sensory input than someone who lost the sense later in life. But in addition, as O’Leary says, “More subtle changes in thalamic input in humans would also likely result in changes to the neo-cortex that could well have a substantial impact on the ability to process vision, or other senses, and lead to abnormal behavior.”

O’Leary says his lab plans to continue to explore the links between how cortical areas in the brain are established and various developmental disorders, such as autism.

(Image: Nucleus Medical Art, Inc.)