Category: Neuroscience

How the intricate network of blood vessels forms within the brain has long fascinated biologists. Though the human brain comprises only 2 percent of body weight it receives up to 15 percent of the cardiac output through this network, or vessel vasculature. The vasculature in the human brain consists of a complex branching network of blood vessels, in total some several hundred miles in length.

An experimental immune-based therapy more than doubled median survival of patients diagnosed with the most aggressive malignant brain tumor, Cedars-Sinai Medical Center researchers reported in Cancer Immunology, Immunotherapy, published online Aug. 3.

NewsPsychology (Aug. 15, 2012) — A new model of background noise present in the nervous system could help better understand neuronal signalling delay in response to a stimulus.

Brain scans have revealed distinctive features in the brain structure of karate experts, which could be linked to their ability to punch powerfully from close range. Researchers from Imperial College London and UCL (University College London) found that differences in the structure of white matter — the connections between brain regions — were correlated with how black belts and novices performed in a test of punching ability.

 New research conducted by biologists at Texas A&M University suggests that ZOLOFT®, one of the most widely prescribed antidepressants in the world, also packs a potential preventative bonus — potent mechanisms capable of inhibiting deadly fungal infections.

The findings are the result of a two-year investigation by Xiaorong Lin, assistant professor of biology, and Matthew S. Sachs, professor of biology, involving sertraline hydrocholoride (ZOLOFT) and its effects on Cryptococcus neoformans, the major causative agent of fungal meningitis — specifically, cryptococcal meningitis, which claims more than half a million lives worldwide each year, according to a 2009 Center for Disease Control (CDC) report.

Their research, funded with grants from the American Heart Association (AHA), the Norman Hackerman Advanced Research Program, and the National Institutes of Health (NIH), is published in the June issue of the American Society of Microbiology journal Antimicrobial Agents and Chemotherapy. Their research team includes Ph.D. candidate Bing Zhai and postdoctoral fellows Cheng Wu and Linqi Wang.

"The point here is that if there is a drug that already exists, is known to be well-tolerated, and has alternative uses, that's a good thing," Sachs says. "The billion dollars it would take to bring a drug to the market — that's already done."

C. neoformans is a potentially dangerous fungal pathogen found in many soils throughout the world that may cause systemic infections, particularly involving the central nervous system. In most cases, the microscopic, airborne fungal cells of C. neoformans cause asymptomatic colonization in the lungs. However, Lin says the fungus is particularly aggressive in people with weakened immune systems and can spread to other parts of the body, such as the brain and spinal cord, resulting in cryptococcal meningitis — a condition that, in absence of treatment, is fatal.

Lin participated in a previous study to screen a collection of FDA-approved drugs in a John Hopkins Clinical Compound Library to determine if any contained fungicidal agents. Although sertraline was shown to only moderately inhibit the effects of common fungal strains like Aspergillus nidulans, a genus of common mold often found on spoiled food, and Candida, a genus of yeast often associated with mammals, sertraline was found to be particularly effective against C. neoformans.

A follow-up investigation of sertraline in a mouse model of systemic cryptococcosis revealed that it combats infection similar to fluconazole, an antifungal drug used commonly since the early 1990s. Moreover, a drug combination of sertraline and fluconazole was found to work more efficiently than either drug alone.

Lin says that even though the infection ultimately proved fatal in the mice study, sertraline as a cryptoccol treatment still holds promise. Because sertraline reduced the overall fungal burden within the mice and also possesses the desirable ability to cross the blood-brain barrier as an antidepressant, there is still hope it can be altered to serve as a viable treatment option.

"The problem for many current antifungal drugs is that many cannot go to the brain, and it's very difficult for a lot of compounds to reach the brain in the first place," Lin says. "So, you run into the problem of not killing all the fungus or having a very low level of fungus still exist. The fact is, this antidepressant can cross the blood-brain barrier and can get into the tissue at high concentrations."

It remains unclear exactly what dosage and concentration of sertraline is necessary to completely eliminate cryptococcosis, especially cryptococcal meningitis, but Lin and Sachs hope those answers will come to light with further testing.

"If this becomes useful, it could represent a truly significant increase in our ability to help people with brain cryptococcal infections," Sachs adds.

Events that take place early in life almost certainly have consequences for later cognitive development. Establishing the connections is difficult, however, because human infants cannot be used as laboratory subjects.

Rodney Johnson and his collaborators have developed an alternative model for studying infant brain development. "Assistant professor Ryan Dilger and I became interested in establishing the neonatal piglet as a model of human brain and cognitive development 3 or 4 years ago," he said.

The idea came to Johnson when a former student, who was working for an infant formula company, asked about finding ways to determine differences in cognitive development between breast-fed infants and infants fed on formula.

"Human breast milk is the gold standard, but not every infant can be breast fed. A major goal for many infant formula companies is to improve the formulation to capture all of the benefits of breast milk," he explained.

Johnson and his group had been working with rodent models to study learning and memory; they also had done some research looking at infectious disease in pigs. They wondered if it would be possible to develop tests to look at learning and memory using neonatal piglets.

It seemed like a reasonable idea because the growth and development of the piglet brain is similar to that of the human brain. The brain growth spurt is a perinatal event in both humans and pigs. At birth, the human brain is about 25 percent of adult size. In the first 2 years of life, it reaches 85 to 90 percent of adult size. The piglet brain grows in a similar way in a shorter time.

Johnson's team first developed structural MRI methods for quantifying brain volume in the neonatal piglet. They then used these techniques to determine total brain and brain region volumes in a cohort of male and female domestic pigs, taking repeated measurements every 4 weeks starting at 2 weeks of age and finishing at near sexual maturity at 24 weeks of age.

They found that at 4 weeks, the piglet brain had grown to approximately 50 percent of its maximum volume, and it continued to grow rapidly for the next 8 weeks. Human infant brains grow in a similar way in the postnatal period. The results suggested that environmental insults during this period could affect brain structure and function.

The researchers' next task was to develop a test to assess the piglets' learning and memory, using a T-maze. They thought that this would be easy. They were wrong.

"It actually turned out to be very complicated because there were a lot of things that went wrong that we didn't predict," said Johnson. "For example, when we first started these studies, we used things like Skittles and apple slices as a reward because that's what people using older pigs had done."

The piglets, which were being fed on infant formula, had no interest in solid food, nor were they motivated to perform the tasks if the reward was the same as their regular food. They were, however, very willing to work for chocolate milk, specifically Nesquik™.

They did not receive the Nesquik™ anywhere else. "The idea is that piglets see chocolate milk only during the test and then it's back to the standard formula," said Johnson. "It helps increase their precision because it's something they look forward to."

Tests were conducted in a plus-shaped maze with one arm blocked off to leave a 'T' shape. Piglets were trained to locate the milk reward in a constant place in space as well as direction, using visual cues from outside the maze. When they learned to perform the task correctly the reward location was reversed, and the piglets were retested to assess learning and working memory. Correct choices decreased in the reversal phase but improved over time.

The results demonstrate that the T-maze can be used to measure cognitive abilities. Johnson and his collaborators will use these new tests to examine how stressors such as nutrient deficiencies and infections affect the human brain during this time of early, rapid growth.

"We want to know if this will alter the trajectory of normal development in a way that makes them more susceptible to behavioral disorders that occur later in life, such as autism and depression," Johnson said. "Exposure to environmental insults early in life may also reduce stress resilience," he added.

"There is a lot of interest in the concept of programming, the notion that things that occur early in life set that individual up for problems that occur many years later," he continued. "Because the pig brain grows so much like a human brain, we thought this could be a very attractive model."

The researchers have used the piglet model to demonstrate that an iron-deficient diet causes iron depletion in specific brain areas and is accompanied by cognitive deficits. They are using structural MRI and the T-maze task to study how viral pneumonia in the early neonatal period affects brain and cognitive development.

These data are complemented by measures of neuroinflammation, neurogenesis, and neuron morphology, procedures Johnson's group has established in the neonatal piglet. Ryan Dilger is developing novel MRI procedures to measure biochemicals in the brain and to reveal how neural connections develop.

They are hoping to receive NIH funding to look at maternal viral infections. "We will infect pregnant gilts at the beginning of what would be the third trimester in humans and then study brain and cognitive development in the offspring," Johnson said. "This is the type of interesting question we can pursue now that the piglet model is in place."

Johnson said that it would be difficult to do this kind of research anywhere else.

"The Beckman Institute has been wonderful. We're not MRI experts, nor do we want to be. However, we had a hypothesis and thought MRI technology could help us address it," he said. "The support staff at Beckman has been really critical to helping develop the protocols."

Johnson said that the other major advantages of the U of I are that the College of Agricultural, Consumer and Environmental Sciences has a unique research facility for housing pigs, and the Department of Animal Sciences maintains several swine farms that produce piglets on a regular basis.

The most recent research has been published online in Developmental Neuroscience.

The research is described in more detail in the following articles:

Conrad, M.S., R.N. Dilger and R.W. Johnson. 2012. "Brain growth of the Domestic Pig (Sus scrofa) from 2 to 24 weeks of Age: A Longitudinal MRI Study." Developmental Neuroscience (in press, online first).

Elmore, M.R.P., R.N. Dilger, R.W. Johnson. 2012. "Place and Direction Learning in a Spatial T-maze test." Animal Cognition 15:667-676.

Conrad, M.S., R.N. Dilger, A. Nickolls, and R.W. Johnson. 2012. "Magnetic Resonance Imaging of the Neonatal Piglet Brain." Pediatric Research 71:179-184.

— Scientists at the University of Manchester have uncovered how the internal mechanisms in nerve cells wire the brain. The findings open up new avenues in the investigation of neurodegenerative diseases by analysing the cellular processes underlying these conditions.

Dr Andreas Prokop and his team at the Faculty of Life Sciences have been studying the growth of axons, the thin cable-like extensions of nerve cells that wire the brain. If axons don't develop properly this can lead to birth disorders, mental and physical impairments and the gradual decay of brain capacity during aging.

Axon growth is directed by the hand shaped growth cone which sits in the tip of the axon. It is well documented how growth cones perceive signals from the outside to follow pathways to specific targets, but very little is known about the internal machinery that dictates their behaviour.

Dr Prokop has been studying the key driver of growth cone movements, the cytoskeleton. The cytoskeleton helps to maintain a cell's shape and is made up of the protein filaments, actin and microtubules. Microtubules are the key driving force of axon growth whilst actin helps to regulate the direction the axon grows.

Dr Prokop and his team used fruit flies to analyse how actin and microtubule proteins combine in the cytoskeleton to coordinate axon growth. They focussed on the multifunctional proteins called spectraplakins which are essential for axonal growth and have known roles in neurodegeneration and wound healing of the skin.

What the team demonstrate in this recent paper is that spectraplakins link microtubules to actin to help them extend in the direction the axon is growing. If this link is missing then microtubule networks show disorganised criss-crossed arrangements instead of parallel bundles and axon growth is hampered.

By understanding the molecular detail of these interactions the team made a second important finding. Spectraplakins collect not only at the tip of microtubules but also along the shaft, which helps to stabilise them and ensure they act as a stable structure within the axon.

This additional function of spectraplakins relates them to a class of microtubule-binding proteins including Tau. Tau is an important player in neurodegenerative diseases, such as Alzheimer's, which is still little understood. In support of the author's findings, another publication has just shown that the human spectraplakin, Dystonin, causes neurodegeneration when affected in its linkage to microtubules.

Talking about his research Dr Prokop said: "Understanding cytoskeletal machinery at the cell level is a holy grail of current cell research that will have powerful clinical applications. Thus, cytoskeleton is crucially involved in virtually all aspects of a cell's life, including cell shape changes, cell division, cell movement, contacts and signalling between cells, and dynamic transport events within cells. Accordingly, the cytoskeleton lies at the root of many brain disorders. Therefore, deciphering the principles of cytoskeletal machinery during the fundamental process of axon growth will essentially help research into the causes of a broad spectrum of diseases. Spectraplakins like at the heart of this machinery and our research opens up new avenues for its investigation"

What Dr Prokop's paper in the Journal of Neuroscience also demonstrates is the successful research technique using the fruit fly Drosophila. The team was able to replicate its findings regarding axon growth in mice which in turn means the findings can be translated to humans.

Dr Prokop points out fruit flies provide ideal means to make sense of these findings and essentially help to unravel the many mysteries of neurodegeneration.

Dr Prokop continues: "Understanding how spectraplakins perform their cellular functions has important implications for basic as well as biomedical research. Thus, besides their roles during axon growth, spectraplakins of mice and humans are clinically important for a number of conditions and processes including skin blistering, neuro-degeneration, wound healing, synapse formation and neuron migration during brain development. Understanding spectraplakins in one biological process will instruct research on the other clinically relevant roles of these proteins."

The recently published paper represents six years of work by Dr Prokop and his dedicated team.

Researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital have identified several gene mutations responsible for the most common childhood brain tumor, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.

"We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumors are at the molecular level," said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children's and the senior author of the new research. "This paper represents a finer-grained view of the genetic landscape of these tumors and provides us with some leads on how to develop new therapies."

The research, which appeared online in Nature July 22, is part of a large, ongoing effort to characterize genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children's, the Broad Institute, Children's Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.

Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumor as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumor's genetic characteristics.

Cho's team extracted DNA from 92 medulloblastoma tumors and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant "point mutations" — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.

Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumors. "Mutations in this gene have now also been identified in other tumor types, such as chronic lymphocytic leukemia, and head and neck tumors," he said.

However, the researchers found that it was rare for the same gene mutated in several different patients' tumors. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumors — a pattern that is emerging across cancer genome sequencing efforts.

Though no single tumor in the study carried all 12 mutations, the researchers were able to categorize the tumors according to which mutations they possessed. "We now understand that there are certain tumors with particular genetic signatures that are really resistant to standard treatments," Cho said. Children with medulloblastoma do not routinely have their tumors' genetic signatures characterized, but Cho believes that such characterization coupled with targeted therapies could greatly enhance tumor treatment.

About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumor's genetic profile have the potential to save more patients while reducing side effects, Cho said.

Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. "The dysregulation of these 'epigenetic programs' is becoming a common theme not only in medulloblastoma but across cancer," Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma.

Cho is the co-chair of a committee within the Pediatric Brain Tumor Consortium that guides which drugs should be moved into clinical trials next. "Our plan is that within the next one to two years we will be able to offer kids a new set of compounds that have a clear biological rationale based on our genomic studies." Cho said. "We want to make sure we're being careful of what we move forward with, but at the same time, for some of these kids we don't have many, if any, effective and durable treatment options."

Cho's collaborators at Stanford included research associate Furong Yu; Gerald Crabtree, PhD, professor of pathology and of developmental biology and a member of the Stanford Cancer Institute; and life science research assistant Amanda Kautzman.

The research was funded by the National Institutes of Health, a St. Baldrick's Foundation Career Development Award, the Beirne Faculty Scholar endowment at Stanford University, German Cancer Aid, the BMBF ICGC-PedBrain project, the Howard Hughes Medical Institute, the Pediatric Brain Tumor Foundation, the Canadian Institutes of Health Research, the Hospital for Sick Children and the Mullarkey Research Fund. Cho consults for Novartis to help develop biomarkers for the company's clinical trial design.

NewsPsychology (July 23, 2012) — Snack consumption and BMI are linked to both brain activity and self-control, new research has found.

The research, carried out by academics from the Universities of Exeter, Cardiff, Bristol, and Bangor, discovered that an individual’s brain ‘reward centre’ response to pictures of food predicted how much they subsequently ate. This had a greater effect on the amount they ate than their conscious feelings of hunger or how much they wanted the food,

A strong brain response was also associated with increased weight (BMI), but only in individuals reporting low levels of self-control on a questionnaire. For those reporting high levels of self-control a stronger brain response to food was actually related to a lower BMI.

This study, which is now published in the journal NeuroImage, adds to mounting evidence that overeating and increased weight are linked, in part, to a region of the brain associated with motivation and reward, called the nucleus accumbens. Responses in this brain region have been shown to predict weight gain in healthy weight and obese individuals, but only now have academics discovered that this is independent of conscious feelings of hunger, and that self-control also plays a key role.

Following these results, academics at the University of Exeter and Cardiff have begun testing ‘brain training’ techniques designed to reduce the influence of food cues on individuals who report low levels of self-control. Similar tests are being used to assist those with gambling or alcohol addiction.

Dr Natalia Lawrence of Psychology at the University of Exeter, lead researcher in both the original research and the new studies, said: “Our research suggests why some individuals are more likely to overeat and put on weight than others when confronted with frequent images of snacks and treats. Food images, such as those used in advertising, cause direct increases in activity in brain ‘reward areas’ in some individuals but not in others. If those sensitive individuals also struggle with self-control, which may be partly innate, they are more likely to be overweight. We are now developing computer programs that we hope will counteract the effects of this high sensitivity to food cues by training the brain to respond less positively to these cues.”

Twenty-five young, healthy females with BMIs ranging from 17-30 were involved in the study. Female participants were chosen because research shows females typically exhibit stronger responses to food-related cues. The hormonal changes during the menstrual cycle affect this reaction, so all participants were taking the monophasic combined oral contraceptive pill. Participants had not eaten for at least six hours to ensure they were hungry at the time of the scan and were given a bowl containing 150 g (four and a half packets) of potato chips to eat at the end of the study; they were informed that potato chip intake had been measured afterwards.

Researchers used MRI scanning to detect the participants’ brain activity while they were shown images of household objects, and food that varied in desirability and calorific content. After scanning, participants rated the food images for desirability and rated their levels of hunger and food craving. Results showed that participants’ brain responses to food (relative to objects) in the nucleus accumbens predicted how many potato chips they ate after the scan. However, participants’ own ratings of hunger and how much they liked and wanted the foods, including potato chips, were unrelated to their potato chip intake.

This study was funded by the Wales Institute of Cognitive Neuroscience.

What this study shows:

• Brain responses to food images vary considerably between individuals.
• Brain responses to food images but not conscious feelings of hunger or desire to eat predict subsequent potato chip consumption.
• Individuals’ reported levels of self-control influence whether this brain response is associated with a higher or lower BMI.

What this study does NOT show:

• Brain responses to food cues cause overeating.
• The associations reported here are true in everyone — only healthy young women were included.
• Whether our brain response and levels of self-control are learned or innate.

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Story Source:

The above story is reprinted from materials provided by University of Exeter, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Natalia S. Lawrence, Elanor C. Hinton, John A. Parkinson, Andrew D. Lawrence. Nucleus accumbens response to food cues predicts subsequent snack consumption in women and increased body mass index in those with reduced self-control. NeuroImage, 2012; DOI: 10.1016/j.neuroimage.2012.06.070

Neural precursor cells (NPC) in the young brain suppress certain brain tumors such as high-grade gliomas, especially glioblastoma (GBM), which are among the most common and most aggressive tumors. Now researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité — Universitätsmedizin Berlin have deciphered the underlying mechanism of action with which neural precursor cells protect the young brain against these tumors. They found that the NPC release substances that activate TRPV1 ion channels in the tumor cells and subsequently induce the tumor cells to undergo stress-induced cell-death.

Despite surgery, radiation or chemotherapy or even a combination of all three treatment options, there is currently no cure for glioblastoma. In an earlier study the research group led by Professor Helmut Kettenmann (MDC) showed that neural precursor cells migrate to the glioblastoma cells and attack them. The neural precursor cells release a protein belonging to the family of BMP proteins (bone morphogenetic protein) that directly attacks the tumor stem cells. The current consensus of researchers is that tumor stem cells are the actual cause for continuous tumor self-renewal.

Kristin Stock, Jitender Kumar, Professor Kettenmann (all MDC), Dr. Michael Synowitz (MDC and Charité), Professor Rainer Glass (Munich University Hospitals, formerly MDC) and Professor Vincenzo Di Marzo (Istituto di Chimica Biomolecolare Pozzuoli, Naples, Italy) now report a new mechanism of action of NPC in astrocytomas. Like glioblastomas, astrocytomas are brain tumors that belong to the family of gliomas. Gliomas are most common in older people and are almost invariably fatal.

As the MDC researchers showed, the NPC also migrate to the astrocytomas. There they do not secrete proteins, but rather release fatty-acid substances (endovanilloids) which are harmful to the cancer cells. However, in order to exert their lethal effect, the endovanilloids need the aid of a specific ion channel, the TRPV1 channel (transient receptor potential vanilloid type 1), also called the vanilloid receptor 1. TRPV1 is already known to researchers as a transducer of painful stimuli. It has, among other things, a binding site for capsaicin, the irritant of hot chili peppers, and is responsible for the hot sensation after eating them. Clinical trials are currently underway to develop new pain treatments by blocking or desensitizing this ion channel.

MDC researchers describe an additional role of the TRPV1 ion channel

In contrast to its use in pain management, this ion channel, which is located on the surface of glioblastoma cells and is much more abundant there than on normal glial cells, must be activated to trigger cell death in gliomas. The activated ion channel mediates stress-induced cell-death in tumor cells. If however TRPV1 is downregulated or blocked, the glioma cells are not destroyed. The MDC researchers are thus the first to identify neural precursor cells as the source of fatty acids that induce tumor cell death and to describe the role of the TRPV1 ion channel in the fight against gliomas.

However, the activity of neural precursor cells in the brain and thus of the body's own protective mechanism against gliomas diminishes with increasing age. This could explain why these tumors usually develop in older adults and not in children and young people. How can the natural protection of neural precursor cells be harnessed for older brains? According to the researchers, neural precursor cell therapy is not a solution. The benefit this obviously brings in the treatment of young people can have the opposite effect in older adults and may trigger brain tumors.

One possible treatment would be to use drugs to activate the TRPV1 channels. In mice, the group showed that a synthetic substance (arvanil), which is similar to capsaicin, reduced tumor growth. However, this substance has not yet been approved as a drug because the adverse side effects for humans are too severe. It is only used in basic research on mice, which tolerate the substance well. "In principle, however," the researchers suggest, "synthetic vanilloid compounds may have clinical potential for brain tumor treatment."