Neuroscience

Neurodegenerative diseases are not all alike. Two individuals suffering from the same disease may experience very different age of onset, symptoms, severity, and constellation of impairments, as well as different rates of disease progression. Researchers in the Perelman School of Medicine at the University of Pennsylvania have shown one disease protein can morph into different strains and promote misfolding of other disease proteins commonly found in Alzheimer’s, Parkinson’s and other related neurodegenerative diseases.

Virginia M.Y. Lee, PhD, MBA, professor of Pathology and Laboratory Medicine and director of the Center for Neurodegenerative Disease Research, with co-director, John Q. Trojanowski MD, PhD, postdoctoral fellow Jing L. Guo, PhD, and colleagues, discovered that alpha-synuclein, a protein that forms sticky clumps in the neurons of Parkinson’s disease patients, can exist in at least two different structural shapes, or “strains,” when it clumps into fibrils, despite having precisely the same chemical composition.

These two strains differ in their ability to promote fibril formation of normal alpha-synuclein, as well as the protein tau, which forms neurofibrillary tangles in individuals with Alzheimer’s disease.

Importantly, these alpha-synuclein strains are not static; they somehow evolve, such that fibrils that initially cannot promote tau tangles acquire that ability after multiple rounds of “seeded” fibril formation in test tubes.

The findings appear in the July 3rd issue of Cell.

Morphed Misfolding Proteins Found In Overlapping Neurodegenerative Diseases
Tau and alpha-synuclein protein clumps are hallmarks of separate diseases – Alzheimer’s and Parkinson’s, respectively. Yet these two proteins are often found entangled in diseased brains of patients who may manifest symptoms of both disorders.

One possible explanation for this convergence of Alzheimer’s and Parkinson’s disease pathology in the same patient is a global disruption in protein folding. But, Guo and Lee showed that one strain of alpha-synuclein fibrils which cannot promote tau fibrillization actually evolved into another strain that could efficiently cause tau to fibrillize in cultured neurons, although both strains are identical at the amino acid sequence level. Guo and Lee called the starting conformation “Strain A,” and the evolved conformation, “Strain B.”

To figure out how A and B differ, Guo showed that the two strains folded into different shapes, as indicated by their differential reactivity to antibodies and sensitivity to protein-degrading enzymes. The two strains also differed in their ability to promote tau fibrillization and pathology in mouse brains, mimicking the results from cultured cells. When analyzing post-mortem brains of Parkinson’s patients, the team found at least two distinct forms of pathological alpha-synuclein.

Lee and her team speculate that in humans, alpha-synuclein aggregates may shift their shapes as they pass from cell to cell (much like a cube of silly putty being re-shaped to form a sphere), possibly developing the ability to entangle other proteins such as tau along the way. That process, in turn, could theoretically yield distinct types of alpha-synuclein pathologies that are observed in different brain regions of Parkinson’s disease patients.

While further research is needed to confirm and extend these findings, they have potentially significant implications for patients afflicted with Parkinson’s and other neurodegenerative diseases. For example, Lee explains, they could account for some of the heterogeneity observed in Parkinson’s disease. Different strains of pathological alpha-synuclein may promote formation of distinct types of alpha-synuclein aggregates that may or may not induce tau pathology in different brain regions and in different patients. That, in turn, could explain why some Parkinson’s patients, for example, experience only motor impairments while others ultimately develop cognitive impairments.

The findings also have potential therapeutic implications, Lee says. By recognizing that pathological alpha-synuclein can exist in different forms that are linked with different impairments, researchers can now selectively target one or the other, or both, for instance with strain-selective antibodies.

“What we’ve found opens up new areas for developing therapies, and particularly immunotherapies, for Parkinson’s and other neurodegenerative diseases,” Lee says.

In a study that could change the way scientists view the process of protein production in humans, University of Chicago researchers have found a single gene that encodes two separate proteins from the same sequence of messenger RNA.

Published online July 3 in Cell, their finding elucidates a previously unknown mechanism in human gene expression and opens the door for new therapeutic strategies against a thus-far untreatable neurological disease.

"This is the first example of a mechanism in a higher organism in which one gene creates two proteins from the same mRNA transcript, simultaneously," said Christopher Gomez, MD, PhD, professor and chairman of the Department of Neurology at the University of Chicago, who led the study. "It represents a paradigm shift in our understanding of how genes ultimately encode proteins."

The human genome contains a similar number of protein-coding genes as the nematode worm (roughly 20,000). This disparity between biological complexity and gene count partially can be explained by the fact that individual genes can encode multiple protein variants via the production of different sequences of messenger RNA (mRNA) — short, mass-produced copies of genetic code that guide the creation of myriad cellular machinery.

Gomez and his team, which included first author Xiaofei Du, MD, discovered a new layer of complexity in this process of gene expression as they studied spinocerebellar ataxia type-6 (SCA6), a neurodegenerative disease that causes patients to slowly lose coordination of their muscles and eventually their ability to speak and stand. Human genetic studies identified its cause as a mutation in CACNA1A — a gene that encodes a calcium channel protein important for nerve cell function — resulting in extra copies of the amino acid glutamine.

However, although the gene, mutation and dysfunction are known, attempts to find the biological mechanism of the disease proved inconclusive. Calcium channel proteins with the mutation still seemed to function normally.

Suspecting another factor at play, Gomez and his team instead focused on α1ACT, a poorly understood, free-floating fragment of the CACNA1A calcium channel protein known to express extra copies of glutamine in SCA6 cells. The researchers first looked at its origin and found that, to their surprise, α1ACT was generated from the same mRNA sequence as the CACNA1A calcium channel.

For the first time, they had evidence of a human gene that coded one strand of mRNA that coded two separate, structurally distinct proteins. This occurred due to the presence of a special sequence in the mRNA known as an internal ribosomal entry site (IRES). Normally found at the beginning of an mRNA sequence, this IRES site sat in the middle, creating a second location for ribosomes, the cellular machines that read mRNA, to begin the process of protein production.

Looking at function, Gomez and his team found that normal α1ACT acted as a transcription factor and enhanced the growth of specific brain cells. Importantly, mutated α1ACT appeared to be toxic to nerve cells in a petri dish, and caused SCA6-like symptoms in an animal model.

The team hopes to discover other examples of human genes with similar IRES sites to better understand the implications of this new class of “bifunctional” genes on our basic biology. For now, they are focused on leveraging their findings toward helping SCA6 patients and already are working on ways to silence mutated α1ACT.

"We discovered this genetic phenomenon in the pursuit of a disease cause and, in finding it, immediately have a potential strategy for developing preclinical tools to treat that disease," Gomez said. "If we can target the IRES and inhibit production of this mutant form of α1ACT in SCA6, we may be able to stop the progression of the disease."

In the first study to compare all available IVF treatments and the risk of neurodevelopmental disorders in children, researchers find that IVF treatments for the most severe forms of male infertility are associated with an increased risk of intellectual disability and autism in children.

Autism and intellectual disability remain a rare outcome of IVF, and whilst some of the risk is associated with the risk of multiple births, the study provides important evidence for parents and clinicians on the relative risks of modern IVF treatments.

Published in JAMA today, the study is the largest of its kind and was led by researchers at King’s College London (UK), Karolinska Institutet (Sweden) and Mount Sinai School of Medicine in New York (USA).

By using anonymous data from the Swedish national registers, researchers analysed more than 2.5 million birth records from 1982 and 2007 and followed-up whether children had a clinical diagnosis of autism or  intellectual disability (defined as having an IQ below 70) up until 2009. Of the 2.5m children, 1.2% (30,959) were born following IVF. Of the 6,959 diagnosed with autism, 103 were born after IVF; of the 15,830 with intellectual disability, 180 were born after IVF. Multiple pregnancies are a known risk factor for pre-term birth and some neurodevelopmental disorders, so the researchers also compared single to multiple births.

Sven Sandin, co-author of the study from King’s College London’s Institute of Psychiatry says: “IVF treatments are vastly different in terms of their complexity. When we looked at IVF treatments combined, we found there was no overall increased risk for autism, but a small increased risk of intellectual disability. When we separated the different IVF treatments, we found that ‘traditional’ IVF is safe, but that IVF involving ICSI, which is specifically recommended for paternal infertility is associated with an increased risk of both intellectual disability and autism in children.”

Compared to spontaneous conception, children born from any IVF treatment were not at an increased risk of autism, but were at a small increased risk of intellectual disability (18% increase – from 39.8 to 46.3 per 100,000 person years).  However, the risk increase disappeared when multiple births were taken into account.

Secondly, the researchers compared all 6 different types of IVF procedures available in Sweden – whether fresh or frozen embryos were used; if intracytoplasmic sperm injection (ICSI) was used, and if so, whether sperm was ejaculated or surgically extracted. Developed in 1992, ICSI is recommended for male infertility and is now used in about half of all IVF treatments. The procedure involves injecting a single sperm directly into an egg, rather than fertilization happening in a dish, as in standard IVF.

Children born after IVF treatments with ICSI (with either fresh or frozen embryos) were at an increased risk of intellectual disability (51% increase – 62 to 93 per 100,000). This association was even higher when a preterm birth also occurred (73% increase – 96 to 167 per 100,000). Even when multiple and pre-term births were taken into account, IVF treatment with ICSI and fresh embryos was associated with an increased risk of intellectual disability (66% increase for singleton birth, term birth following ICSI with fresh embryos– 48 to 76 per 100,000).

Children born after IVF with ICSI using surgically extracted sperm and fresh embryos were at an increased risk of autism (360% increase - 29 to 136 per 100,000) but the association disappeared when multiple births were taken into account.

An existing FDA-approved drug improves cognitive function in a mouse model of Down syndrome, according to a new study by researchers at the Stanford University School of Medicine.

The drug, an asthma medication called formoterol, strengthened nerve connections in the hippocampus, a brain center used for spatial navigation, paying attention and forming new memories, the study said. It also improved contextual learning, in which the brain integrates spatial and sensory information.

Both hippocampal function and contextual learning, which are impaired in Down syndrome, depend on the brain having a good supply of the neurotransmitter norepinephrine. This neurotransmitter sends its signal via several types of receptors on the neurons, including a group called beta-2 adrenergic receptors.

“This study provides the initial proof-of-concept that targeting beta-2 adrenergic receptors for treatment of cognitive dysfunction in Down syndrome could be an effective strategy,” said Ahmad Salehi, MD, PhD, the study’s senior author and a clinical associate professor of psychiatry and behavioral sciences. The study was published online July 2 in Biological Psychiatry.

Down syndrome, which is caused by an extra copy of chromosome 21, results in both physical and cognitive problems. While many of the physical issues, such as vulnerability to heart problems, can now be treated, no treatments exist for poor cognitive function. As a result, children with Down syndrome fall behind their peers’ cognitive development. In addition, adults with Down syndrome develop Alzheimer’s-type pathology in their brains by age 40. Down syndrome affects about 400,000 people in the United States and 6 million worldwide.

In prior Down syndrome research, scientists have seen deterioration of the brain center that manufactures norepinephrine in both people with Down syndrome and its mouse model. Earlier work by Salehi’s team found that giving a norepinephrine precursor could improve cognitive function in a mouse model genetically engineered to mimic Down syndrome.

Studies have shown that children with autism often struggle socially and now new research suggests that a corresponding lack of motor skills – including catching and throwing – may further contribute to that social awkwardness.

The findings, published in the July issue of Adapted Physical Activity Quarterly, add to the growing body of research highlighting the link between autism and motor skill deficits.

Lead author Megan MacDonald is an assistant professor in the College of Public Health and Human Sciences at Oregon State University. She is an expert on the movement skills of children with autism spectrum disorder.

In the study, researchers looked a group of young people ages 6 to 15 diagnosed with autism spectrum disorder. All 35 of the students were considered high-functioning and attended typical classrooms. The researchers looked at two types of motor skills – “object-control” motor skills, which involve more precise action such as catching or throwing – and “locomotion” skills, such as running or walking. Students who struggled with object-control motor skills were more likely to have more severe social and communication skills than those who tested higher on the motor skills test.

“So much of the focus on autism has been on developing social skills, and that is very crucial,” MacDonald said. “Yet we also know there is a link between motor skills and autism, and how deficits in these physical skills play into this larger picture is not clearly understood.”

Developing motor skills can be crucial for children because students often “mask” their inability to participate in basic physical activities. A student with autism may not be participating on the playground because of a lack of social skills, but the child may also be unsure of his or her physical ability to play in these activities.

“Something which seems as simple as learning to ride a bike can be crucial for a child with autism,” MacDonald said. “Being able to ride a bike means more independence and autonomy. They can ride to the corner store or ride to a friend’s house. Those kind of small victories are huge.”

She said the ability to run, jump, throw and catch isn’t just for athletic kids – physical activity is linked not only to health, but to social skills and mental well-being.

“I often show people photos of what I like to do in my spare time – canoeing, hiking, snowshoeing, and then point out that these require relatively proficient motor skills,” she said. “But that is not why I do those things. I’m doing it because I’m with my friends and having fun.”

MacDonald said the positive news for parents and educators is that motor skills can be taught.

“We have programs and interventions that we know work, and have measurable impact on motor skill development,” MacDonald said. “We need to make sure we identify the issue and get a child help as early as possible.”

The results of the study may bear significance in the treatment of Alzheimer’s disease and cancer

Dysfunction of the ubiquitin-proteasome system is related to many severe neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, and certain types of cancer. Such dysfunction is also believed to be related to some degenerative muscle diseases.

The proteasome is a large protein complex that maintains cellular protein balance by degrading and destroying damaged or expired proteins. The ubiquitin is a small protein that labels proteins for destruction for the proteasome. If the system does not work effectively enough, expired and damaged proteins accumulate in the cell. If the system is overly active, it destroys necessary proteins in addition to unnecessary ones. In both cases, cell function is disturbed, and the cell may even die.

Proteasome activity is believed to decrease with ageing. However, not much is yet known about how proteasome activity is regulated in an aging multicellular organism. The research team of Academy Research Fellow, Docent Carina Holmberg-Still has discovered an important proteasome regulatory mechanism. The study was published in Cell Reports, a highly esteemed scientific journal.

"We examined whether proteasome activity is affected by insulin/IGF-1 signalling [IIS], which regulates aging in many organisms. The results show that decreased IIS increases proteasome activity," says Holmberg-Still.

Proteasome activity was studied in C. elegans, a free-living roundworm. Decreased IIS increases proteasome activity through the FOXO transcription factor DAF-16 and the UBH-4 enzyme. DAF-16 represses the expression of ubh-4 in certain cell types. The ubh-4 enzyme slows proteasome activity, which means that its repression accelerates proteasome activity.

"Using a cell culture model, we proved that the same mechanism works in human cells," says Holmberg-Still. When the expression of the uchl5 enzyme – the human equivalent of ubh-4 – was decreased, proteasome activity and the degradation of harmful proteins increased.

"Our study shows that the effect of ageing and the related signalling pathway on proteasome activity is tissue-specific. This was a new and interesting discovery that bears great significance in terms of treatment opportunities," says researcher Olli Matilainen, who prepared his dissertation in Holmberg-Still’s research team.

The identification of proteins that regulate proteasome activity and an understanding of the regulatory mechanism offer new opportunities in treating diseases that involve proteasome dysfunction. According to Holmberg-Still, proteins that regulate proteasome activity are particularly interesting in terms of medicine development.

"An ability to accelerate proteasome activity could be beneficial in the treatment of neurodegenerative diseases. Targeted proteasome inhibitors would be useful in the treatment of cancer – general proteasome inhibitors are already used as cancer medication to some extent, but they often have harmful side effects, because they cannot be targeted to a specific tissue."

Holmberg-Still’s team continues to investigate tissue-specific mechanisms that regulate proteasome activity. The team collaborates with clinical researchers to confirm whether its research results can be refined for clinical use.

Researchers at NYU Langone Medical Center have discovered a mechanism that triggers chronic inflammation in Alzheimer’s, atherosclerosis and type-2 diabetes. The results, published today in Nature Immunology, suggest a common biochemical thread to multiple diseases and point the way to a new class of therapies that could treat chronic inflammation in these non-infectious diseases without crippling the immune system. Alzheimer’s, atherosclerosis and type-2 diabetes—diseases associated with aging and inflammation—affect more than 100 million Americans.

When the body encounters a pathogen, it unleashes a rush of chemicals known as cytokines that draws immune cells to the site of infection and causes inflammation. Particulate matter in the body, such as the cholesterol crystals associated with vascular disease and the amyloid plaques that form in the brain in Alzheimer’s disease, can also cause inflammation but the exact mechanism of action remains unclear. Researchers previously thought that these crystals and plaques accumulate outside of cells, and that macrophages—immune cells that scavenge debris in the body—induce inflammation as they attempt to clear them.

“We’ve discovered that the mechanism causing chronic inflammation in these diseases is actually very different,” says Kathryn J. Moore, PhD, senior author of the study and associate professor of medicine and cell biology, Leon H. Charney Division of Cardiology at NYU Langone Medical Center.

The researchers found that particulate matter does not linger on the outside of cells. Instead, a receptor called CD36 present on macrophages draws the soluble forms of these particles inside the cell where they are transformed into substances that trigger an inflammatory response. Says Dr. Moore, “What we found is that CD36 binds soluble cholesterol and protein matter associated with these diseases, pulls them inside the cell, and then transforms them. The resulting insoluble crystals and amyloid damage the macrophage and trigger a powerful cytokine, called interleukin-1B, linked to a chronic inflammatory response.”

These findings hold exciting clinical implications.When the researchers blocked the CD36 receptor in mice with atherosclerosis (in which cholesterol thickens the arteries), the cytokine response declined, fewer cholesterol crystals formed in plaques, and inflammation decreased. Consequently, atherosclerosis also abated.

Other less-targeted strategies to control inflammation may hamper the immune response, but the CD36 strategy spares certain cytokines to fight off pathogens, while blocking CD36’s ability to trigger interleukin-1B.

“Our findings identify CD36 as a central regulator of the immune response in these conditions and suggest that blocking CD36 might be a common therapeutic option for all three diseases,” says Dr. Moore.

Identification of a protein that appears to play an important role in the immune system’s removal of amyloid beta (A-beta) protein from the brain could lead to a new treatment strategy for Alzheimer’s disease. The report from researchers at Massachusetts General Hospital (MGH) has been published online in Nature Communications.

"We identified a receptor protein that mediates clearance from the brain of soluble A-beta by cells of the innate immune system," says Joseph El Khoury, MD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Infectious Diseases, co-corresponding author of the report. "We also found that deficiency of this receptor in a mouse model of Alzheimer’s disease leads to greater A-beta deposition and accelerated death, while upregulating its expression enhanced A-beta clearance from the brain."

The brain’s immune system – which includes cells like microglia, monocytes and macrophages that engulf and remove foreign materials – appears to play a dual role in neurodegenerative disorders like Alzheimer’s disease. At early stages, these cells mount a response against the buildup of A-beta, the primary component of the toxic plaques found in the brains of patients with the devastating neurological disorder. But as the disease progresses and A-beta plaques become larger, not only do these cells lose their ability to take up A-beta, they also release inflammatory chemicals that cause further damage to brain tissue.

In their investigation of factors that may underlie the breakdown of the immune system’s clearance of A-beta, El Khoury’s team with the hypothesis that, in addition to recognizing and binding to the insoluble form of A-beta found in amyloid plaques, the brain’s immune cells might also interact with soluble forms of A-beta that could begin accumulating in the brain before plaques appear. The researchers first examined a group of receptor proteins known to be used by microglia, monocytes and macrophages to interact with insoluble A-beta. Although any role for these proteins in Alzheimer’s disease has not been known, the MGH investigators previously found that their expression in a mouse model of the disease dropped as the animals aged.

After they first identified the involvement of a receptor called Scara1 in the uptake of soluble A-beta by monocytes and macrophages, the researchers then confirmed that Scara1 appears to be the major receptor for recognition and clearance of A-beta by the innate immune system, the body’s first line of defense. In a mouse model of Alzheimer’s, animals that were missing one or both copies of the Scara1 gene died several months earlier than did those with two functioning copies. By the age of 8 months, Alzheimer’s mice with no functioning Scara1 genes had double the A-beta in their brains as did a control group of Alzheimer’s mice, while normal mice had virtually none.

To investigate possible therapeutic application of the role of Scara1 in A-beta clearance, the MGH team treated cultured immune cells with Protollin, a compound that has been used to enhance the immune response to certain vaccines. Application of Protollin to immune cells tripled their expression of Scara1 and also increased levels of a protein that attracts other immune cells. Adding Protollin-stimulated microglia to brain samples from Alzheimer’s mice reduced the size and number of A-beta deposits in the hippocampus, an area particularly damaged by the disease, but that reduction was significantly less when microglia from Scara1-deficient mice were used.

El Khoury notes that previous research showed that Protollin treatment reduced A-beta deposits in Alzheimer’s mice and the current study reveals the probable mechanism behind that finding. “Upregulating Scara1 expression is a promising approach to treating Alzheimer’s disease,” he says. “First we need to duplicate these studies using human cells and identify new classes of molecules that can safely increase Scara1 expression or activity. That could potentially lead to ways of harnessing the immune system to delay the progression of this disease.” El Khoury is an associate professor of Medicine at Harvard Medical School.

A key brain structure that regulates emotions works differently in preschoolers with depression compared with their healthy peers, according to new research at Washington University School of Medicine in St. Louis.

The differences, measured using functional magnetic resonance imaging (fMRI), provide the earliest evidence yet of changes in brain function in young children with depression. The researchers say the findings could lead to ways to identify and treat depressed children earlier in the course of the illness, potentially preventing problems later in life.

“The findings really hammer home that these kids are suffering from a very real disorder that requires treatment,” said lead author Michael S. Gaffrey, PhD. “We believe this study demonstrates that there are differences in the brains of these very young children and that they may mark the beginnings of a lifelong problem.”

The study is published in the July issue of the Journal of the American Academy of Child & Adolescent Psychiatry.

Depressed preschoolers had elevated activity in the brain’s amygdala, an almond-shaped set of neurons important in processing emotions. Earlier imaging studies identified similar changes in the amygdala region in adults, adolescents and older children with depression, but none had looked at preschoolers with depression.

For the new study, scientists from Washington University’s Early Emotional Development Program studied 54 children ages 4 to 6. Before the study began, 23 of those kids had been diagnosed with depression. The other 31 had not. None of the children in the study had taken antidepressant medication.

Although studies using fMRI to measure brain activity by monitoring blood flow have been used for years, this is the first time that such scans have been attempted in children this young with depression. Movements as small as a few millimeters can ruin fMRI data, so Gaffrey and his colleagues had the children participate in mock scans first. After practicing, the children in this study moved less than a millimeter on average during their actual scans.

While they were in the fMRI scanner during the study, the children looked at pictures of people whose facial expressions conveyed particular emotions. There were faces with happy, sad, fearful and neutral expressions.

“The amygdala region showed elevated activity when the depressed children viewed pictures of people’s faces,” said Gaffrey, an assistant professor of psychiatry. “We saw the same elevated activity, regardless of the type of faces the children were shown. So it wasn’t that they reacted only to sad faces or to happy faces, but every face they saw aroused activity in the amygdala.”

Looking at pictures of faces often is used in studies of adults and older children with depression to measure activity in the amygdala. But the observations in the depressed preschoolers were somewhat different than those previously seen in adults, where typically the amygdala responds more to negative expressions of emotion, such as sad or fearful faces, than to faces expressing happiness or no emotion.

In the preschoolers with depression, all facial expressions were associated with greater amygdala activity when compared with their healthy peers.

Gaffrey said it’s possible depression affects the amygdala mainly by exaggerating what, in other children, is a normal amygdala response to both positive and negative facial expressions of emotion. But more research will be needed to prove that. He does believe, however, that the amygdala’s reaction to people’s faces can be seen in a larger context.

“Not only did we find elevated amygdala activity during face viewing in children with depression, but that greater activity in the amygdala also was associated with parents reporting more sadness and emotion regulation difficulties in their children,” Gaffrey said. “Taken together, that suggests we may be seeing an exaggeration of a normal developmental response in the brain and that, hopefully, with proper prevention or treatment, we may be able to get these kids back on track.”

Scientists at Karolinska Institutet have identified the neuronal circuits in the spinal cord of mice that control the ability to produce the alternating movements of the legs during walking. The study, published in the journal Nature, demonstrates that two genetically-defined groups of nerve cells are in control of limb alternation at different speeds of locomotion, and thus that the animals’ gait is disturbed when these cell populations are missing.

Most land animals can walk or run by alternating their left and right legs in different coordinated patterns. Some animals, such as rabbits, move both leg pairs simultaneously to obtain a hopping motion. In the present study, the researchers Adolfo Talpalar and Julien Bouvier together with professor Ole Kiehn and colleagues, have studied the spinal networks that control these movement patterns in mice. By using advanced genetic methods that allow the elimination of discrete groups of neurons from the spinal cord, they were able to remove a type of neurons characterized by the expression of the gene Dbx1.

"It was classically thought that only one group of nerve cells controls left right alternation", says Ole Kiehn who leads the laboratory behind the study at the Department of Neuroscience. "It was then very interesting to find that there are actually two specific neuronal populations involved, and on top of that that they each control different aspect of the limb coordination."

Indeed, the researchers found that the gene Dbx1 is expressed in two different groups of nerve cells, one of which is inhibitory and one that is excitatory. The new study shows that the two cellular populations control different forms of the behaviour. Just like when we change gear to accelerate in a car, one part of the neuronal circuit controls the mouse’s alternating gait at low speeds, while the other population is engaged when the animal moves faster. Accordingly, the study also show that when the two populations are removed altogether in the same animal, the mice were unable to alternate at all, and hopped like rabbits instead.

There are some animals, such as desert mice and kangaroos, which only hop. The researchers behind the study speculate that the locomotive pattern of these animals could be attributable to the lack of the Dbx1 controlled alternating system.

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.