Neuroscience

For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small molecules that allow for complete control over a genetic defect responsible for the most common adult onset form of muscular dystrophy. These small molecules will enable scientists to investigate potential new therapies and to study the long-term impact of the disease.

“This is the first example I know of at all where someone can literally turn on and off a disease,” said TSRI Associate Professor Matthew Disney, whose new research was published June 28, 2013, by the journal Nature Communications. “This easy approach is an entirely new way to turn a genetic defect off or on.”

Myotonic dystrophy is an inherited disorder, the most common form of a group of conditions called muscular dystrophies that involve progressive muscle wasting and weakness. Myotonic dystrophy type 1 is caused a type of RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code. In this case, a cytosine-uracil-guanine (CUG) triplet repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities.

To find drug candidates that act against the defect, Disney and his colleagues analyzed the results of a National Institutes of Health (NIH)-sponsored screen of more than 300,000 small molecules that inhibit a critical RNA-protein complex in the disease.

The team divided the NIH hits into three “buckets”—the first group bound RNA, the second bound protein, and a third whose mechanism was unclear. The researchers then studied the compounds by looking at their effect on human muscle tissue both with and without the defect.

Startlingly, diseased muscle tissue treated with RNA-binding compounds caused signs of the disease to go away. In contrast, both healthy and diseased tissue treated with the protein-binding compounds showed the opposite effect—signs of the disease either appeared (in healthy tissue) or became worse.

The new compounds will serve as useful tools to study the disease on a molecular level. “In complex diseases, there are always unanticipated mechanisms,” Disney noted. “Now that we can reverse the disease at will, we can study those aspects of it.”

In addition, Disney said, with the new discovery, scientists will be able to develop a greater understanding of how to control RNA splicing with small molecules. RNA splicing can cause a host of diseases that range from sickle-cell disease to cancer, yet prior to this study, no tools were available to control specific RNA splicing.

Scientists using sophisticated imaging techniques have observed a molecular protein folding process that may help medical researchers understand and treat diseases such as Alzheimer’s, Lou Gehrig’s and cancer.

The study, reported this month in the journal Cell, verifies a process that scientists knew existed but with a mechanism they had never been able to observe, according to Dr. Hays Rye, Texas A&M AgriLife Research biochemist.

“This is a step in the direction of understanding how to modulate systems to prevent diseases like Alzheimer’s. We needed to understand the cell’s folding machines and how they interact with each other in a complicated network,” said Rye, who also is associate professor of biochemistry and biophysics at Texas A&M.

Rye explained that individual amino acids get linked together like beads on a string as a protein is made in the cell.

“But that linear sequence of amino acids is not functional,” he explained. “It’s like an origami structure that has to fold up into a three-dimensional shape to do what it has to do.”

Rye said researchers have been trying to understand this process for more than 50 years, but in a living cell the process is complicated by the presence of many proteins in a concentrated environment.

"The constraints on getting that protein to fold up into a good ‘origami’ structure are a lot more demanding,” he said. “So, there are special protein machines, known as molecular chaperones, in the cell that help proteins fold.”

But how the molecular chaperones help protein fold when it isn’t folding well by itself has been the nagging question for researchers.

“Molecular chaperones are like little machines, because they have levers and gears and power sources. They go through turning over cycles and just sort of buzz along inside a cell, driving a protein folding reaction every few seconds,” Rye said.

The many chemical reactions that are essential to life rely on the exact three-dimensional shape of folded proteins, he said. In the cell, enzymes, for example, are specialized proteins that help speed biological processes along by binding molecules and bringing them together in just the right way.

“They are bound together like a three-dimensional jigsaw puzzle,” Rye explained.  “And the proteins — those little beads on the string that are designed to fold up like origami — are folded to position all these beads in three-dimensional space to perfectly wrap around those molecules and do those chemical reactions.

“If that doesn’t happen — if the protein doesn’t get folded up right – the chemical reaction can’t be done. And if it’s essential, the cell dies because it can’t convert food into power needed to build the other structures in the cell that are needed. Chemical reactions are the structural underpinning of how cells are put together, and all of that depends on the proteins being folded in the right way.”

When a protein doesn’t fold or folds incorrectly it turns into an “aggregate,” which Rye described as “white goo that looks kind of like a mayonnaise, like crud in the test tube.

“You’re dead; the cell dies,” he said.

Over the past 20 years, he said, researchers have linked that aggregation process “pretty convincingly” to the development of diseases — Alzheimer’s disease, Lou Gehrig’s disease, Huntington’s disease, to name a few. There’s evidence that diabetes and cancer also are linked to protein folding disorders.

“One of the main roles for the molecular chaperones is preventing those protein misfolding events that lead to aggregation and not letting a cell get poisoned by badly folded or aggregated proteins,” he said.

Rye’s team focused on a key molecular chaperone — the HSP60.

“They’re called HSP for ‘heat shock protein’ because when the cell is stressed with heat, the proteins get unstable and start to fall apart and unfold,” Rye said. “The cell is built to respond by making more of the chaperones to try and fix the problem.

“This particular chaperone takes unfolded protein and goes through a chemical reaction to bind the unfolded protein and literally puts it inside a little ‘box,’” Rye said.

He added that the mystery had long been how the folding worked because, while researchers could see evidence of that happening, no one had ever seen precisely how it happened.

Rye and the team zeroed in on a chemically modified mutant that in other experiments had seemed to stall at an important step in the process that the “machine” goes through to start the folding action. This clued the researchers that this stalling might make it easier to watch.

They then used cryo-electron microscopy to capture hundreds of thousands of images of the process at very high resolutions which allowed them to reconstruct from two-dimensional flat images a three-dimensional model. A highly sophisticated computer algorithm aligns the images and classifies them in subcategories.

“If you have enough of them you can actually reconstruct and view a structure as a three-dimensional model,” Rye said.

What the team saw was this: The HSP60 chaperone is designed to recognize proteins that are not folded from the ones that are. It binds them and then has a separate co-chaperone that puts a “lid” on top of the box to keep the folding intermediate in the box. They could see the box move, and parts of the molecule moved to peel the chaperone box away from the bound protein — or “gift” in the box. But the bound protein was kept inside the package where it could then initiate a folding reaction. They saw tiny tentacles, “like a little octopus in the bottom of the box rising up and grabbing hold of the substrate protein and helping hold it inside the cavity.”

"The first thing we saw was a large amount of an unfolded protein inside of this cavity,” he said. “Even though we knew from lots and lots of other studies that it had to go in there, nobody had ever seen it like this before. We can also see the non-native protein interacting with parts of the box that no one had ever seen before. It was exciting to see all of this for the first time. I think we got a glimpse of a protein in the process of folding, which we actually can compare to other structures.”

“By understanding the mechanism of these machines, the hope is that one of the things we can learn to do is turn them up or turn them off when we need to, like for a patient who has one of the protein folding diseases,” he said.

A single dose of a commonly-prescribed attention deficit hyperactivity disorder (ADHD) drug helps improve brain function in cocaine addiction, according to an imaging study conducted by researchers from the Icahn School of Medicine at Mount Sinai. Methylphenidate (brand name Ritalin®) modified connectivity in certain brain circuits that underlie self-control and craving among cocaine-addicted individuals. The research is published in the current issue of JAMA Psychiatry, a JAMA network publication.

Previous research has shown that oral methylphenidate improved brain function in cocaine users performing specific cognitive tasks such as ignoring emotionally distracting words and resolving a cognitive conflict. Similar to cocaine, methylphenidate increases dopamine (and norepinephrine) activity in the brain, but, administered orally, takes longer to reach peak effect, consistent with a lower potential for abuse. By extending dopamine’s action, the drug enhances signaling to improve several cognitive functions, including information processing and attention.

“Orally administered methylphenidate increases dopamine in the brain, similar to cocaine, but without the strong addictive properties,” said Rita Goldstein, PhD, Professor of Psychiatry at Mount Sinai, who led the research while at Brookhaven National Laboratory (BNL) in New York. “We wanted to determine whether such substitutive properties, which are helpful in other replacement therapies such as using nicotine gum instead of smoking cigarettes or methadone instead of heroin, would play a role in enhancing brain connectivity between regions of potential importance for intervention in cocaine addiction.”

Anna Konova, a doctoral candidate at Stony Brook University, who was first author on this manuscript, added, ”Using fMRI, we found that methylphenidate did indeed have a beneficial impact on the connectivity between several brain centers associated with addiction.”

Dr. Goldstein and her team recruited 18 cocaine addicted individuals, who were randomized to receive an oral dose of methylphenidate or placebo. The researchers used functional magnetic resonance imaging (fMRI) to measure the strength of connectivity in particular brain circuits known to play a role in addiction before and during peak drug effects. They also assessed each subject’s severity of addiction to see if this had any bearing on the results.

Methylphenidate decreased connectivity between areas of the brain that have been strongly implicated in the formation of habits, including compulsive drug seeking and craving. The scans also showed that methylphenidate strengthened connectivity between several brain regions involved in regulating emotions and exerting control over behaviors—connections previously reported to be disrupted in cocaine addiction.

“The benefits of methylphenidate were present after only one dose, indicating that this drug has significant potential as a treatment add-on for addiction to cocaine and possibly other stimulants,” said Dr. Goldstein. “This is a preliminary study, but the findings are exciting and warrant further exploration, particularly in conjunction with cognitive behavioral therapy or cognitive remediation.”

A chromosomal deletion is associated with changes in the brain’s white matter and delayed language acquisition in youngsters from Southeast Asia or with ancestral connections to the region, said an international consortium led by researchers at Baylor College of Medicine. However, many such children who can be described as late-talkers may overcome early speech and language difficulties as they grow.

The finding involved both cutting edge technology and two physicians with an eye for unusual clinical findings. Dr. Seema R. Lalani, a physician-scientist at BCM and Dr. Jill V. Hunter, professor of radiology at BCM and Texas Children’s Hospital, worked together to identify this genetic change responsible for expressive language delay and brain changes in children, predominantly from Southeast Asia.

Lalani, assistant professor of molecular and human genetics at BCM, is a clinical geneticist and also signs out diagnostic studies called chromosomal microarray analysis, a gene chip that helps identify abnormalities in specific genes and chromosomes, as part of her work at BCM’s Medical Genetics Laboratory.

"I got intrigued when I kept seeing this small (genomic) change in children from a large sample of more than 15,000 children referred for chromosomal microarray analysis at Baylor College of Medicine. These children were predominantly Burmese refugees or of Vietnamese ancestry living in the United States. It started with two children whom I evaluated at Texas Children’s Hospital and soon realized that there was a pattern of early language delay and brain imaging abnormalities in these individuals carrying this deletion from this part of the world. Within a period of two to three years, we found 13 more families with similar problems, having the same genetic change. There were some children who obviously were more affected than the others and had cognitive and neurological problems, but many of them were identified as late-talkers who had better non-verbal skills compared to verbal performance," said Lalani. Hunter, helped in determining the specific pattern of white matter abnormalities in the MRI (magnetic resonance imaging) scans in children and their parents carrying this deletion. Most of the children either came from Southeast Asia or were the offspring of people from that area. (White matter is the paler material in the brain that consists of nerve fibers covered with myelin sheaths.)

Now, in a report that appears online in the American Journal of Human Genetics, Lalani, Hunter and an international group of collaborators identify a genomic deletion on chromosome 2 that is associated with bright white spots that show up in an MRI in the white matter of the brain . The chromosomal deletion removes a portion of a gene known as TM4SF20 that encodes a protein that spans the cellular membrane. They do not know yet what the function of the protein is. They found this genetic change in children from 15 unrelated families mainly from Southeast Asia.

"This deletion could be responsible for early childhood language delay in a large number of children from this part of the world," says Lalani.

She credits Dr. Wojciech Wiszniewski, an assistant professor of molecular and human genetics at BCM with doing much of the work. Wiszniewski has an interest in genomic disorders and is working under the mentorship of Dr. James R. Lupski, vice chair of the department of molecular and human genetics.

Lupski said, “Professor Lalani has made a stunning discovery in that she provides evidence that population-specific intragenic CNV (copy number variation – a deletion or duplication of the chromosome) can contribute to genetic susceptibility of even common complex disease such as speech delay in children.”

"In a way, this is a good news story," said Hunter. There is evidence from family studies that some of these children may do quite well in the future, said Lalani.

Lalani elaborates. “This is a genetic change that is present in 2 percent of Vietnamese Kinh population (an ethnic group that makes up 90 percent of the population in that country),” she said. “In the 15 families we have identified, all children have early language delay. Some are diagnosed with autism spectrum disorder, and if you do a brain MRI study, you find white matter changes in about 70 percent of them. We have found this change in children who are Vietnamese, Burmese, Thai, Indonesian, Filipino and and Micronesian. It is very likely that children from other Southeast Asian countries within this geographical distribution also carry this genetic change.”

Because these are all within a geographic location, she suspects that there is an ancient founder effect, meaning that at some point in the distant past, the gene deletion occurred spontaneously in an individual, who then passed it on to his or her children and to succeeding generations.

"It is important to follow these children longitudinally to see how these late-talkers develop as they grow," said Lalani. "We have also seen this deletion in children whose parents clearly were late-talkers themselves, but overcame the earlier problems to become doctors and professionals. The variability within the deletion carriers is fascinating and brings into question genetic and environmental modifiers that contribute to the extent of disease in these children.

Language delays mean that they may speak only two or three words at age 2, in comparison to other children who would generally have between 75-100 word vocabulary by this age. While there is evidence that children with this deletion may catch up, it is unclear if they continue to have better non-verbal skills than verbal skills. It is also unclear how the specific brain changes correlate with communication disorders in these children.

In fact, when doctors check the parents of these children, they often find similar white matter changes in the parent carrying the deletion. “Young parents in their 30s should not have age-related white matter changes in the brain and these changes should definitely not be present in healthy children,” said Lalani. Hunter said they are not sure how the gene variation relates to the changes in brain white matter and how all of these result in delay in language.

Insights into how the brain compensates for temporary hearing loss during infancy, such as that commonly experienced by children with glue ear, have been revealed in a research study in ferrets. The Wellcome Trust-funded study could point to new therapies for glue ear and has implications for the design of hearing aid devices.

Normally, the brain works out where sounds are coming from by relying on information from both ears located on opposite sides of the head, such as differences in volume and time delay in sounds reaching the two ears. The shape of the outer ear also helps us to interpret the location of sounds by filtering sounds from different directions - so-called ‘spectral cues’.

This ability to identify where sounds are coming from not only helps us to locate the path of moving objects but also helps us to separate different sound sources in noisy environments.

Glue ear, or otitis media, is a relatively common condition caused by a build-up of fluid in the middle ear that causes temporary hearing loss. By age 10, eight out of ten children will have experienced one or more episodes of glue ear. It usually resolves itself, but more severe cases can require interventions such as the insertion of tubes (commonly known as grommets) to drain the fluid and restore hearing.

If the loss of hearing is persistent, however, it can lead to impairments in later life, even after normal hearing has returned. These impairments include ‘lazy ear’, or amblyaudia, which leaves people struggling to locate sounds or pick out sounds in noisy environments such as classrooms or restaurants.

Researchers at the University of Oxford used removable earplugs to introduce intermittent, temporary hearing loss in one ear in young ferrets, mimicking the effects of glue ear in children. The team then tested their ability to localise sounds as adults and measured activity in the brain to see how the loss of hearing affected their development.

The results show that animals raised with temporary hearing loss were still able to localise sounds accurately while wearing an earplug in one ear. They achieved this by becoming more dependent on the unchanged spectral cues from the outer part of the unaffected ear. When the plug was removed and hearing returned to normal, the animals were just as good at localising sounds as those who had never experienced hearing loss.

Professor Andrew King, a Wellcome Trust Principal Research Fellow at the University of Oxford who led the study, explains: “Our results show that, with experience, the brain is able to shift the strategy it uses to localise sounds depending on the information that is available at the time.

"During periods of hearing loss in one ear - when the spatial cues provided by comparing the sounds at each ear are compromised - the brain becomes much more reliant on the intact spectral cues that arise from the way sounds are filtered by the outer ear. But when hearing is restored, the brain returns to using information from both ears to work out where sounds are coming from."

The results contrast with previous studies that looked at the effects of enduring hearing loss - rather than recurring hearing loss - on brain development. These earlier studies found that changes in the brain that result from loss of hearing persisted even when normal hearing returned.

The new findings suggest that intermittent experience of normal hearing is important for preserving sensitivity to those cues and could offer new strategies for rehabilitating people who have experienced hearing loss in childhood. In addition, the finding that spectral cues from the outer ear are an important source of information during periods of hearing loss has important implications for the design of hearing aids, particularly those that sit behind the ear.

"Recurring periods of hearing loss are extremely common during childhood. These findings will help us to find better ways of rehabilitating those affected, which should limit the number who go on to develop more serious hearing problems in later life," adds Professor King.

The study is published today in the journal ‘Current Biology’.

A study from Karolinska Institutet shows, that our imagination may affect how we experience the world more than we perhaps think. What we imagine hearing or seeing ‘in our head’ can change our actual perception. The study, which is published in the scientific journal Current Biology, sheds new light on a classic question in psychology and neuroscience - about how our brains combine information from the different senses.

"We often think about the things we imagine and the things we perceive as being clearly dissociable," says Christopher Berger, doctoral student at the Department of Neuroscience and lead author of the study. "However, what this study shows is that our imagination of a sound or a shape changes how we perceive the world around us in the same way actually hearing that sound or seeing that shape does. Specifically, we found that what we imagine hearing can change what we actually see, and what we imagine seeing can change what we actually hear."

The study consists of a series of experiments that make use of illusions in which sensory information from one sense changes or distorts one’s perception of another sense. Ninety-six healthy volunteers participated in total. In the first experiment, participants experienced the illusion that two passing objects collided rather than passed by one-another when they imagined a sound at the moment the two objects met. In a second experiment, the participants’ spatial perception of a sound was biased towards a location where they imagined seeing the brief appearance of a white circle. In the third experiment, the participants’ perception of what a person was saying was changed by their imagination of a particular sound.

According to the scientists, the results of the current study may be useful in understanding the mechanisms by which the brain fails to distinguish between thought and reality in certain psychiatric disorders such as schizophrenia. Another area of use could be research on brain computer interfaces, where paralyzed individuals’ imagination is used to control virtual and artificial devices.

"This is the first set of experiments to definitively establish that the sensory signals generated by one’s imagination are strong enough to change one’s real-world perception of a different sensory modality", says Professor Henrik Ehrsson, the principle investigator behind the study.

A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta (Αβ) plaques that are associated with Alzheimer’s disease, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.

The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer’s disease, as well as combined deposits of amylin and Aβ plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer’s.

“We’ve known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now,” said UC Davis Alzheimer’s Disease Center Director Charles DeCarli.

“This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer’s disease,” DeCarli said. “In fact, the amylin looks like the amyloid beta protein, and they both interact. That’s why we’re calling it the second amyloid of Alzheimer’s disease.”

 ”Amylin deposition in the brain: A second amyloid in Alzheimer’s disease?” is published online today in the Annals of Neurology.

Type 2 diabetes is a chronic metabolic disorder that increases the risk for cerebrovascular disease and dementia, a risk that develops years before the onset of clinically apparent diabetes. Its incidence is far greater among people who are obese and insulin resistant.

Amylin, or islet amyloid polypeptide, is a hormone produced by the pancreas that circulates in the bloodstream with insulin and plays a critical role in glycemic regulation by slowing gastric emptying, promoting satiety and preventing post-prandial spikes in blood glucose levels. Its deposition in the pancreas is a hallmark of type 2 diabetes.

When over-secreted, some proteins have a higher propensity to stick to one another, forming small aggregates, called oligomers, fibrils and amyloids. These types of proteins are called amyloidogenic and include amylin and Aβ. There are about 28 amyloidogenic proteins, each of which is associated with diseases.                

The study was conducted by examining brain tissue from individuals who fell into three groups: those who had both diabetes and dementia from cerebrovascular or Alzheimer’s disease; those with Alzheimer’s disease without diabetes; and age-matched healthy individuals who served as controls.

The research found numerous amylin deposits in the gray matter of the diabetic patients with dementia, as well as in the walls of the blood vessels in their brains, suggesting amylin influx from blood circulation. Surprisingly, the researchers also found amylin in the brain tissue of individuals with Alzheimer’s who had not been diagnosed with diabetes; they postulate that these individuals may have had undiagnosed insulin resistance. They did not find amylin deposits in the brains of the healthy control subjects.

“We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the Aβ, which is the suspected cause of Alzheimer’s disease,” said Florin Despa, assistant professor-in-residence in the UC Davis Department of Pharmacology. “It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels.

“It is accumulating in the brain and we found signs that amylin is killing neurons similar to Aβ,” he continued. “And that might be the answer to the question of ‘What makes obese and type 2 diabetes patients more prone to developing dementia?’”

The researchers undertook the investigation after Despa and his colleagues found that amylin accumulates in the blood vessels and muscle of the heart. From this evidence, he hypothesized that the same thing might be happening in the brain. To test the hypothesis he received a pilot research grant through the Alzheimer’s Disease Center.

The research was conducted using tissue from the brains of individuals over 65 donated to the UC Davis Alzheimer’s Disease Center: 15 patients with Alzheimer’s disease and type 2 diabetes; 14 Alzheimer’s disease patients without diabetes; and 13 healthy controls. A series of tests, including Western blot, immunohistochemistry and ELISA (enzyme-linked immunosorbent assay) were used to test amylin accumulation in specimens from the temporal cortex.

In contrast with the healthy brains, the brain tissue infiltrated with amylin showed increased interstitial spaces, cavities within the tissue, sponginess, and blood vessels bent around amylin accumulation sites.

Despa said that the finding may offer a therapeutic target for drug development, either by increasing the rate of amylin elimination through the kidneys, or by decreasing its rate of oligomerization and deposition in diabetic patients.

"If we’re smart about the treatment of pre-diabetes, a condition that promotes increased amylin secretion, we might be able to reduce the risk of complications, including Alzheimer’s and dementia,” Despa said.

In a perspective piece appearing today in the journal Science, researchers at University of Rochester Medical Center (URMC) point to a newly discovered system by which the brain removes waste as a potentially powerful new tool to treat neurological disorders like Alzheimer’s disease. In fact, scientists believe that some of these conditions may arise when the system is not doing its job properly. 

“Essentially all neurodegenerative diseases are associated with the accumulation of cellular waste products,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the URMC Center for Translational Neuromedicine and author of the article. “Understanding and ultimately discovering how to modulate the brain’s system for removing toxic waste could point to new ways to treat these diseases.”   

The body defends the brain like a fortress and rings it with a complex system of gateways that control which molecules can enter and exit. While this “blood-brain barrier” was first described in the late 1800s, scientists are only now just beginning to understand the dynamics of how these mechanisms function. In fact, the complex network of waste removal, which researchers have dubbed the glymphatic system, was only first disclosed by URMC scientists last August in the journal Science Translational Medicine.  

The removal of waste is an essential biological function and the lymphatic system – a circulatory network of organs and vessels – performs this task in most of the body. However, the lymphatic system does not extend to the brain and, consequently, researchers have never fully understood what the brain does its own waste. Some scientists have even speculated that these byproducts of cellular function where somehow being “recycled” by the brain’s cells.  

One of the reasons why the glymphatic system had long eluded comprehension is that it cannot be detected in samples of brain tissue. The key to discovering and understanding the system was the advent of a new imaging technology called two-photon microscopy which enables scientists to peer deep within the living brain. Using this technology on mice, whose brains are remarkably similar to humans, Nedergaard and her colleagues were able to observe and document what amounts to an extensive, and heretofore unknown, plumbing system responsible for flushing waste from throughout the brain. 

The brain is surrounded by a membrane called the arachnoid and bathed in cerebral spinal fluid (CSF). CSF flows into the interior of the brain through the same pathways as the arteries that carry blood. This parallel system is akin to a donut shaped pipe within a pipe, with the inner ring carrying blood and the outer ring carrying CSF. The CSF is draw into brain tissue via a system of conduits that are controlled by a type support cells in the brain known as glia, in this case astrocytes. The term glymphatic was coined by combining the words glia and lymphatic.

The CSF is flushed through the brain tissue at a high speed sweeping excess proteins and other waste along with it. The fluid and waste are exchanged with a similar system that parallels veins which carries the waste out of the brain and down the spine where it is eventually transferred to the lymphatic system and from there to the liver, where it is ultimately broken down.

While the discovery of the glymphatic system solved a mystery that had long baffled the scientific community, understanding how the brain removes waste – both effectively and what happens when this system breaks down – has significant implications for the treatment of neurological disorders.

One of the hallmarks of Alzheimer’s disease is the accumulation in the brain of the protein beta amyloid. In fact, over time these proteins amass with such density that they can be observed as plaques on scans of the brain. Understanding what role the glymphatic system plays in the brain’s inability to break down and remove beta amyloid could point the way to new treatments. Specifically, whether certainly key ‘players’ in the glymphatic system, such as astrocytes, can be manipulated to ramp up the removal of waste.

“The idea that ‘dirty brain’ diseases like Alzheimer may result from a slowing down of the glymphatic system as we age is a completely new way to think about neurological disorders,” said Nedergaard. “It also presents us with a new set of targets to potentially increase the efficiency of glymphatic clearance and, ultimately, change the course of these conditions.”

The power of the brain lies in its trillions of intercellular connections, called synapses, which together form complex neural “networks.” While neuroscientists have long sought to map these complex connections to see how they influence specific brain functions, traditional techniques have yet to provide the desired resolution. Now, by using an innovative brain-tracing technique, scientists at the Gladstone Institutes and the Salk Institute have found a way to untangle these networks. Their findings offer new insight into how specific brain regions connect to each other, while also revealing clues as to what may happen, neuron by neuron, when these connections are disrupted.

In the latest issue of Neuron, a team led by Gladstone Investigator Anatol Kreitzer, PhD, and Salk Investigator Edward Callaway, PhD, combined mouse models with a sophisticated tracing technique—known as the monosynaptic rabies virus system—to assemble brain-wide maps of neurons that connect with the basal ganglia, a region of the brain that is involved in movement and decision-making. Developing a better understanding of this region is important as it could inform research into disorders causing basal ganglia dysfunction, including Parkinson’s disease and Huntington’s disease.

“Taming and harnessing the rabies virus—as pioneered by Dr. Callaway—is ingenious in the exquisite precision that it offers compared with previous methods, which were messier with a much lower resolution,” explained Dr. Kreitzer, who is also an associate professor of neurology and physiology at the University of California, San Francisco, with which Gladstone is affiliated. “In this paper, we took the approach one step further by activating the tracer genetically, which ensures that it is only turned on in specific neurons in the basal ganglia. This is a huge leap forward technologically, as we can be sure that we’re following only the networks that connect to particular kinds of cells in the basal ganglia.”

At Gladstone, Dr. Kreitzer focuses his research on the role of the basal ganglia in Parkinson’s and other neurological disorders. Last year, he and his team published research that revealed clues to the relationship between two types of neurons found in the region—and how they guide both movement and decision-making. These two types, called direct-pathway medium spiny neurons (dMSNs) and indirect-pathway medium spiny neurons (iMSNs), act as opposing forces. dMSNs initiate movement, like the gas pedal, and iMSNs inhibit movement, like the brake. The latest research from the Kreitzer lab further found that these two types are also involved in behavior, specifically decision-making, and that a dysfunction of dMSNs or iMSNs is associated with addictive or depressive behaviors, respectively. These findings were important because they provided a link between the physical neuronal degeneration seen in movement disorders, such as Parkinson’s, and some of the disease’s behavioral aspects. But this study still left many questions unanswered.

“For example, while that study and others like it revealed the roles of dMSNs and iMSNs in movement and behavior, we knew very little about how other brain regions influenced the function of these two neuron types,” said Salk Institute Postdoctoral Fellow Nicholas Wall, PhD, the paper’s first author. “The monosynaptic rabies virus system helps us address that question.”

The system, originally developed in 2007 and refined by Wall and Callaway for targeting specific cell types in 2010, uses a modified version of the rabies virus to “infect” a brain region, which in turn targets neurons that are connected to it. When the system was applied in genetic mouse models, the team could see specifically how sensory, motor, and reward structures in the brain connected to MSNs in the basal ganglia. And what they found was surprising.

“We noticed that some regions showed a preference for transmitting to dMSNs versus iMSNs, and vice versa,” said Dr. Kreitzer. “For example, neurons residing in the brain’s motor cortex tended to favor iMSNs, while neurons in the sensory and limbic systems preferred dMSNs. This fine-scale organization, which would have been virtually impossible to observe using traditional techniques, allows us to predict the distinct roles of these two neuronal types.”

“These initial results should be treated as a resource not only for decoding how this network guides the vast array of very distinct brain functions, but also how dysfunctions in different parts of this network can lead to different neurological conditions,” said Dr. Callaway. “If we can use the rabies virus system to pinpoint distinct network disruptions in distinct types of disease, we could significantly improve our understanding of these diseases’ underlying molecular mechanisms—and get even closer to developing solutions for them.”

The day of the big barbecue arrives and it’s time to fire up the grill. But rather than toss the hamburgers and hotdogs haphazardly onto the grate, you wait for the heat to reach an optimal temperature, and then neatly lay them out in their apportioned areas according to size and cooking times. Meanwhile, your friend is preparing the beverages. Cups are grabbed face down from the stack, turned over, and – using the other hand – filled with ice.

While these tasks – like countless, everyday actions – may seem trivial at first glance, they are actually fairly complex, according to Robrecht van der Wel, an assistant professor of psychology at Rutgers–Camden. “For instance, the observation that you grab a glass differently when you are filling a beverage than when you are stacking glasses suggests that you are thinking about the goal that you want to achieve,” he says. “How do you manipulate the glass? How do you coordinate your actions so that the liquid goes into the cup?  These kinds of actions are not just our only way to accomplish our intentions, but they reveal our intentions and mental states as well.”

van der Wel and his research partners, Marlene Meyer and Sabine Hunnius, turned their attention to how action planning generalizes to collaborative actions performed with others in a study, titled Higher-order planning for individual and joint object manipulations, published recently in Experimental Brain Research.

According to van der Wel, the researchers were especially interested in determining whether people’s actions exhibit certain social capabilities when performing multiple-action sequences in concert with a partner. “It is a pretty astonishing ability that we, as people, are able to plan and coordinate our actions with others,” says van der Wel. “If people plan ahead for themselves, what happens if they are now in a task where their action might influence another person’s comfort? Do they actually take that into account or not, even though, for their personal action, it makes no difference?”

In the research study, participants first completed a series of individual tasks requiring them to pick up a cylindrical object with one hand, pass it to their other hand, and then place it on a shelf. In the collaborative tasks, individuals picked up the object and handed it to their partner, who placed it on the shelf. The researchers varied the height of the shelf, to test whether people altered their grasps to avoid uncomfortable end postures. The object could only be grasped at one of two positions, implying that the first grasp would determine the postures – and comfort – of the remaining actions.

According to the researchers, the results from both the individual and joint performances show that participants altered their grasp location relative to the height of the shelf.  The participants in both scenarios were thus more likely to use a low-grasp location when the shelf was low, and vice versa. Doing so implied that the participants ended the sequences in comfortable postures. The researchers conclude that, in both individual and collaborative scenarios, participants engaged in extended planning to finish the object-transport sequences in a relatively comfortable posture. Given that participants did plan ahead for the sake of their action partner, it indicates an implicit social awareness that supports collaboration across individuals.

van der Wel notes that, while such basic actions may seem insignificant, it is important to understand how people perform basic tasks such as manipulating objects when considering those populations that aren’t able to complete them so efficiently. “How to pick up an object seems like a really trivial problem when you look at healthy adults, but as soon as you look at children, or people suffering from a stroke, it takes some time to develop that skill properly,” says van der Wel. “When someone has a stroke, it is not that they have damage to the musculature involved in doing the task; rather, damage to action planning areas in the brain results in an inability to perform simple actions. A better understanding of the mechanisms involved in action planning may guide rehabilitation strategies in such cases.”

According to van der Wel, the researchers are currently working on modifying the task to determine the age at which children begin planning their actions with respect to other peoples’ comfort. In particular, they want to understand how the development of social action planning links with the development of other cognitive and social abilities.

New work at the University of California, Davis, shows for the first time how visual attention affects activity in specific brain cells. The paper, published June 26 in the journal Nature, shows that attention increases the efficiency of signaling into the brain’s cerebral cortex and boosts the ratio of signal over noise.

It’s the first time neuroscientists have been able to look at the behavior of synaptic circuits at such a fine-grained level of resolution while measuring the effects of attention, said Professor Ron Mangun, dean of social sciences at UC Davis and a researcher at the UC Davis Center for Mind and Brain.

Our brains recreate an internal map of the world we see through our eyes, mapping our visual field onto specific brain cells. Humans and our primate relatives have the ability to pay attention to objects in the visual scene without looking at them directly, Mangun said.

"Essentially, we ‘see out of the corner of our eyes,’ as the old saying goes. This ability helps us detect threats, and react quickly to avoid them, as when a car running a red light at high speed is approach from our side," he said.

Postdoctoral scholar Farran Briggs worked with Mangun and Professor Martin Usrey at the UC Davis Center for Neuroscience to measure signaling through single nerve connections, or synapses, in monkeys while they performed a standard cognitive test for attention: pressing a joystick in response to seeing a stimulus appear in their field of view.

By taking measurements on each side of a synapse leading into the cerebral cortex, the team could measure when neurons were firing, the strength of the signal and the signal-to-noise ratio.

The researchers found that when the animals were paying attention to an area within their field of view, the signal strength through corresponding synapses leading into the cortex became more effective, and the signal was boosted relative to background noise.

Combining established cognitive psychology with advanced neuroscience, the technique opens up new possibilities for research.

"There are a lot of questions about attention that we can now investigate, such as which brain mechanisms are disordered in diseases that affect attention," Usrey said.

The method could be used, for example, to probe the cholinergic nervous system, which is impacted by Alzheimer’s disease. It could also help to better understand developmental disorders that involve defects in attention, such as attention deficit hyperactivity disorder and autism.

"It’s going to turn out to be important for understanding and treating all kinds of diseases," Mangun predicted.

Vision and Hearing Work Together in the Brain to Help Us Catch a Moving Target

A new study has found that chasing down a moving object is not only a matter of sight or of sound, but of mind.

The study found that people who are blindfolded employ the same strategy to intercept a running ball carrier as people who can see, which suggests that multiple areas of the brain cooperate to accomplish the task.

Regardless of whether they could see or not, the study participants seemed to aim ahead of the ball carrier’s trajectory and then run to the spot where they expected him or her to be in the near future. Researchers call this a “constant target-heading angle” strategy, similar to strategies used by dogs catching Frisbees and baseball players catching fly balls.

It’s also the best way to catch an object that is trying to evade capture, explained Dennis Shaffer, assistant professor of psychology at The Ohio State University at Mansfield.

“The constant-angle strategy geometrically guarantees that you’ll reach your target, if your speed and the target’s speed stay constant, and you’re both moving in a straight line. It also gives you leeway to adjust if the target abruptly changes direction to evade you,” Shaffer said.

“The fact that people run after targets at a constant angle regardless of whether they can see or not suggests that there are brain mechanisms in place that we would call ‘polymodal’—areas of the brain that serve more than one form of sensory modality. Sight and hearing may be different senses, but within the brain the results of the sensory input for this task may be the same.”

The study appears in the journal Psychonomic Bulletin and Review.

Nine people participated in the study—mainly students at Ohio State and Arizona State University, where the study took place. Some had experience playing football, either at a high school or collegiate intramural level, while others had limited or no experience with football.

The nine of them donned motion-capture equipment and took turns in pairs, one running a football across a 20-meter field (nearly 22 yards), and one chasing. They randomly assigned participants to sighted and blindfolded conditions. In the blindfolded condition, participants wore a sleep mask and the runner carried a foam football with a beeping device inside, so that the chaser had a chance to locate them by sound. The runners ran in the general direction of the chasers at different angles, and sometimes the runner would cut right or left halfway through the run.

The study was designed so that the pursuer wouldn’t have time to consciously think about how to catch the runner.

“We were just focused on trying to touch the runner as soon as possible and before they exited the field,” Shaffer said. “The idea was to have the strategy emerge by instinct.”

About 97 percent of the time, the person doing the chasing used the constant-angle strategy—even when they were blindfolded and only able to hear the beeping football.

The results were surprising, even to Shaffer.

“I knew that this seemed to be a universal strategy across species, but I expected that people’s strategies would vary more when they were blindfolded, just because we aren’t used to running around blindfolded. I didn’t expect that the blindfolded strategies would so closely match the sighted ones.”

The findings suggest that there’s some common area in the brain that processes sight and sound together when we’re chasing something.

There is another strategy for catching moving targets. Researchers call it the pursuit or aiming strategy, because it involves speeding directly at the target’s current location. It’s how apex predators such as sharks catch prey.

“As long as you are much faster than your prey, the pursuit strategy is great. You just overtake them,” Shaffer said.

In a situation where the competition is more equal, the constant-angle strategy works better—the pursuer doesn’t have to be faster than the target, and if the target switches direction, the pursuer has time to adjust.

The study builds on Shaffer’s previous work with how collegiate-level football players chase ball carriers. He’s also studied how people catch baseballs and dogs catch Frisbees. All appear to use strategies similar to the constant target-heading angle strategy, which suggests that a common neural mechanism could be at work.

UC Berkeley researchers have found that a lack of sleep, which is common in anxiety disorders, may play a key role in ramping up the brain regions that contribute to excessive worrying.

Neuroscientists have found that sleep deprivation amplifies anticipatory anxiety by firing up the brain’s amygdala and insular cortex, regions associated with emotional processing. The resulting pattern mimics the abnormal neural activity seen in anxiety disorders. Furthermore, their research suggests that innate worriers – those who are naturally more anxious and therefore more likely to develop a full-blown anxiety disorder – are acutely vulnerable to the impact of insufficient sleep.

“These findings help us realize that those people who are anxious by nature are the same people who will suffer the greatest harm from sleep deprivation,” said Matthew Walker, a professor of psychology and neuroscience at UC Berkeley and senior author of the paper, which was published in the Journal of Neuroscience.

The results suggest that people suffering from such maladies as generalized anxiety disorder, panic attacks and post-traumatic stress disorder, may benefit substantially from sleep therapy. At UC Berkeley, psychologists such as Allison Harvey, a co-author on the Journal of Neuroscience paper, have been garnering encouraging results in studies that use sleep therapy on patients with depression, bipolar disorder and other mental illnesses.

“If sleep disruption is a key factor in anxiety disorders, as this study suggests, then it’s a potentially treatable target,” Walker said. “By restoring good quality sleep in people suffering from anxiety, we may be able to help ameliorate their excessive worry and disabling fearful expectations.”

While previous research has indicated that sleep disruption and psychiatric disorders often occur together, this latest study is the first to causally demonstrate that sleep loss triggers excessive anticipatory brain activity associated with anxiety, researchers said.

“It’s been hard to tease out whether sleep loss is simply a byproduct of anxiety, or whether sleep disruption causes anxiety,” said Andrea Goldstein, a UC Berkeley doctoral student in neuroscience and lead author of the study. “This study helps us understand that causal relationship more clearly.”

In their experiments, performed at UC Berkeley’s Sleep and Neuroimaging Laboratory, Walker and his research team scanned the brains of 18 healthy young adults as they viewed dozens of images, first after a good night’s rest, and again after a sleepless night. The images were either neutral, disturbing or alternated between both.

Participants in the experiments reported a wide range of baseline anxiety levels, but none fit the criteria for a clinical anxiety disorder. After getting a full night’s rest at the lab, which researchers monitored by measuring neural electrical activity, their brains were scanned via functional MRI as they waited to be shown, and then viewed 90 images during a 45-minute session.

To trigger anticipatory anxiety, researchers primed the participants using one of three visual cues prior to each series of images. A large red minus sign signaled to participants that they were about to see a highly unpleasant image, such as a death scene. A yellow circle portended a neutral image, such as a basket on a table. Perhaps most stressful was a white question mark, which indicated that either a grisly image or a bland, innocuous one was coming, and kept participants in a heightened state of suspense.

When sleep-deprived and waiting in suspenseful anticipation for a neutral or disturbing image to appear, activity in the emotional brain centers of all the participants soared, especially in the amygdala and the insular cortex. Notably, the amplifying impact of sleep deprivation was most dramatic for those people who were innately anxious to begin with.

“This discovery illustrates how important sleep is to our mental health,” said Walker. “It also emphasizes the intimate relationship between sleep and psychiatric disorders, both from a cause and a treatment perspective.”

Researchers with the UC Davis MIND Institute and Agilent Laboratories have found that Prader-Willi syndrome — a genetic disorder best known for causing an insatiable appetite that can lead to morbid obesity — is associated with the loss of non-coding RNAs, resulting in the dysregulation of circadian and metabolic genes, accelerated energy expenditure and metabolic differences during sleep.

The research was led by Janine LaSalle, a professor in the UC Davis Department of Medical Microbiology and Immunology who is affiliated with the MIND Institute. It is published online in Human Molecular Genetics.

“Prader-Willi syndrome children do not sleep as well at night and have daytime sleepiness,” LaSalle said. “Parents have to lock up their pantries because the kids are rummaging for food in the middle of the night, even breaking into their neighbors’ houses to eat.”

The study found that these behaviors are rooted in the loss of a long non-coding RNA that functions to balance energy expenditure in the brain during sleep. The finding could have a profound effect on how clinicians treat children with Prader-Willi, as well as point the way to new, innovative therapies, LaSalle said.

The leading cause of morbid obesity among children in the United States, Prader-Willi involves a complex, and sometimes contradictory, array of symptoms. Shortly after birth children with Prader-Willi experience failure to thrive. Yet after they begin to feed themselves, they have difficulty sleeping and insatiable appetites that lead to obesity if their diets are not carefully monitored.

The current study was conducted in a mouse model of Prader-Willi syndrome. It found that mice engineered with the loss of a long non-coding RNA showed altered energy use and metabolic differences during sleep.

Prader-Willi has been traced to a specific region on chromosome 15 (SNORD116), which produces RNAs that regulate gene expression, rather than coding for proteins. When functioning normally, SNORD116 produces small nucleolar (sno) RNAs and a long non-coding RNA (116HG), as well as a third non-coding RNA implicated in a related disorder, Angelman syndrome. The 116HG long non-coding RNA forms a cloud inside neuronal nuclei that associates with proteins and genes regulating diurnal metabolism in the brain, LaSalle said.

“We thought the cloud would be activating transcription, but in fact it was doing the opposite,” she said. “Most of the genes were dampened by the cloud. This long non-coding RNA was acting as a decoy, pulling the active transcription factors away from genes and keeping them from being expressed.”

As a result, losing snoRNAs and 116HG causes a chain reaction, eliminating the RNA cloud and allowing circadian and metabolic genes to get turned on during sleep periods, when they should be dampened down. This underlies a complex cycle in which the RNA cloud grew during sleep periods (daytime for nocturnal mice), turning down genes associated with energy use, and receded during waking periods, allowing these genes to be expressed. Mice without the 116HG gene lacked the benefit of this neuronal cloud, causing greater energy expenditure during sleep.

The researchers said that the work provides a clearer picture of why children with Prader-Willi syndrome can’t sleep or feel satiated and may change therapeutic approaches. For example, many such children have been treated with growth hormone because of short stature, but this actually may boost other aspects of the disease.

“People had thought the kids weren’t sleeping at night because of the sleep apnea caused by obesity,” said LaSalle. “What this study shows is that the diurnal metabolism is central to the disorder, and that the obesity may be as a result of that. If you can work with that, you could improve therapies, for example figuring out the best times to administer medications.”

Myelin, the fatty coating that protects neurons in the brain and spinal cord, is destroyed in diseases such as multiple sclerosis. Researchers have been striving to determine whether oligodendrocytes, the cells that produce myelin, can be stimulated to make new myelin. Using live imaging in zebrafish to track oligodendrocytes in real time, researchers reporting in the June 24 issue of the Cell Press journal Developmental Cell discovered that individual oligodendrocytes coat neurons with myelin for only five hours after they are born. If the findings hold true in humans, they could lead to new treatment strategies for multiple sclerosis.

"The study could help improve our understanding of the triggers needed to encourage cells to produce myelin," says senior author Dr. David Lyons, of the University of Edinburgh, UK. For example, if scientists could determine what is blocking the cells from making myelin after five hours, they might be able to remove that blockage. Alternatively, treatments could focus on creating more new oligodendrocytes rather than trying to stimulate existing oligodendrocytes.

Dr. Lyons and his team used zebrafish to study the formation of myelin sheaths by oligodendrocytes because this laboratory animal is transparent at early stages of its development, which allows investigators to directly observe cells within the organism. It is also known that zebrafish and humans have very similar genes, and these similarities extend to more than 80% of the genes associated with human disease. Zebrafish therefore respond in very similar ways to most drugs used for therapeutic purposes in humans.

"In the future, zebrafish will be used to identify new genes and drugs that can influence myelin formation and myelin repair," says Dr. Lyons.

A UC San Francisco-led research team has identified the likely genetic mechanism that causes some patients with multiple sclerosis (MS) to progress more quickly than others to a debilitating stage of the disease. This finding could lead to the development of a test to help physicians tailor treatments for MS patients.

Researchers found that the absence of the gene Tob1 in CD4+ T cells, a type of immune cell, was the key to early onset of more serious disease in an animal model of MS.

Senior author Sergio Baranzini, PhD, a UCSF associate professor of neurology, said the potential development of a test for the gene could predict the course of MS in individual patients.

The study, done in collaboration with UCSF neurology researchers Scott Zamvil, MD, and Jorge Oksenberg, PhD, was published on June 24 in the Journal of Experimental Medicine.

MS is an inflammatory disease in which the protective myelin sheathing that coats nerve fibers in the brain and spinal cord is damaged and ultimately stripped away – a process known as demyelination. During the highly variable course of the disease, a wide range of cognitive, debilitating and painful neurological symptoms can result.

In previously published work, Baranzini and his research team found that patients at an early stage of MS, known as clinically isolated syndrome, who expressed low amounts of Tob1 were more likely to exhibit further signs of disease activity – a condition known as relapsing-remitting multiple sclerosis – earlier than those who expressed normal levels of the gene.

The current study, according to Baranzini, had two goals: to recapitulate in an animal model what the researchers had observed in humans, and uncover the potential mechanism by which it occurs.

The authors were successful on both counts. They found that when an MS-like disease was induced in mice genetically engineered to be deficient in Tob1, the mice had significantly earlier onset compared with wild-type mice, and developed a more aggressive form of the disease.

Subsequent experiments revealed the probable cause: the absence of Tob1 in just CD4+ T cells. The scientists demonstrated this by transferring T cells lacking the Tob1 gene into mice that had no immune systems but had normal Tob1 in all other cells. They found that the mice developed earlier and more severe disease than mice that had normal Tob1 expression in all cells including CD4+.

“This shows that Tob1 only needs to be absent in this one type of immune cell in order to reproduce our initial observations in mice lacking Tob1 in all of their cells,” said Baranzini.

Personalized Treatments for MS Patients

The researchers also found the likely mechanism of disease progression in the Tob1-deficient mice: higher levels of Th1 and Th17 cells, which cause an inflammatory response against myelin, and lower levels of Treg cells, which normally regulate inflammatory responses. The inflammation results in demyelination.

The research is significant for humans, said Baranzini, because the presence or absence of Tob1 in CD4+ cells could eventually serve as a prognostic biomarker that could help clinicians predict the course and severity of MS in individual patients. “This would be useful and important,” he said, “because physicians could decide to switch or modify therapies if they know whether the patient is likely to have an aggressive course of disease, or a more benign course.”

Ultimately, predicted Baranzini, “This may become an example of personalized medicine. When the patient comes to the clinic, we will be able to tailor the therapy based on what the tests tell us. We’re now laying the groundwork for this to happen.”

A rare, inherited form of mental retardation has led scientists at Washington University School of Medicine in St. Louis to three important “travel agents” at work in the developing brain.

The agents — two individual proteins and a tightly bound cluster of four additional proteins — make it possible for brain neurons to travel from the area where they are born to other brain regions where they will reside permanently and integrate into neuronal circuits. Inhibiting any of these proteins in embryonic mice reduces the ability of neurons, which process and transmit information, to reach their final destinations and, presumably, to hardwire the brain.

“That kind of misplacement of brain cells is likely to seriously disrupt mental functions,” said Azad Bonni, MD, PhD, the Edison Professor and chairman of the Department of Anatomy and Neurobiology. “This is just one of many ways that brain development can go awry. To understand intellectual disability and develop treatments, we need to understand the many problems that can arise as the brain develops and its circuitry is established.”

The results appeared June 19 in Neuron.

The new work began as an inquiry into PHF6, a gene that is mutated in patients with Börjeson-Forssman-Lehmann syndrome. This disorder causes mental retardation, developmental delays and skeletal abnormalities. More than a decade ago, scientists identified a link between the condition and PHF6, but they did not know what the gene did in the brain.

Bonni’s laboratory added green fluorescent protein to brain cells to track their development and movement in embryonic mice. Then the researchers inhibited PHF6 in some mice.

In normal mice, as expected, brain neurons migrated from the ventricular zone, where they were born, to the cortical plate, the precursor site of the cerebral cortex. In the mature brain, the cerebral cortex is responsible for higher brain functions such as processing of sensory data, attention and decision-making. In mice whose brain cells lacked PHF6, many brain cells either stayed in the ventricular zone or only completed part of their journey.

In a series of additional experiments, Bonni’s research group showed that the PHF6 protein operates in the nucleus of brain neurons, the command center of the cell. The scientists found that the PHF6 protein interacts with the PAF1 complex, a tightly bound cluster of four proteins that regulates programs of gene expression. This cluster then turns on a cell surface protein called neuroglycan C in brain neurons.

If any of these factors were inhibited, mouse brain neurons were unable to complete their normal migration. The researchers could “rescue” the neurons by restoring the missing protein, allowing the cells to complete their journey.

Disrupting proper brain structure and organization may not be the only problem caused by the PHF6 mutation. A portion of patients with Börjeson-Forssman-Lehmann syndrome also have epilepsy.

In tests in mice, Bonni’s group found that the misplaced brain neurons were more excitable. This might result from changes in the activity of other proteins regulated by PHF6 and could make the brain more susceptible to seizures.

The researchers also learned that increasing the production of neuroglycan C in brain neurons overcomes the harmful effects of PHF6 loss on the migration of neurons.

“Cell surface proteins such as neuroglycan C are in good position to help cells move through their environment,” Bonni said. “The protein’s position on the cell surface of neurons also one day might make it an accessible target for drug treatments for developmental cognitive disorders.”

Bonni suspects there might be additional problems in brain cells that develop without normal PHF6 and that errors in the gene might even impair function in neurons that make it to their final destinations. Further studies are underway.