Posts tagged science
Articles and news from the latest research reports.
Research sheds new light on traumatic brain injuries
Even a mild injury to the brain can have long lasting consequences, including increased risk of cognitive impairment later in life. While it is not yet known how brain injury increases risk for dementia, there are indications that chronic, long-lasting, inflammation in the brain may be important. A new paper by researchers at the University of Kentucky Sanders-Brown Center on Aging (SBCoA), appearing in the Journal of Neuroscience, offers the latest information concerning a “switch” that turns “on” and “off” inflammation in the brain after trauma.
A team of researchers led by Linda Van Eldik, director of SBCoA, used a mouse model to study the role of p38a MAPK in trauma-induced injury responses in the microglia resident immune cell of the brain.
"The p38α MAPK protein is an important switch that drives abnormal inflammatory responses in peripheral tissue inflammatory disorders, including chronic debilitating diseases like rheumatoid arthritis," said Van Eldik.
"However, less is known about the potential importance of p38α MAPK in controlling inflammatory responses in the brain. Our work supports p38α MAPK as a promising clinical target for the treatment of CNS disorders associated with uncontrolled brain inflammation, including trauma, and potentially others like Alzheimer’s disease. We are excited by our findings, and are actively working to develop drugs targeting p38a MAPK designed specifically for diseases of the brain."
Lead author of the paper Adam D. Bachstetter said, “I was surprised when I looked under the microscope at the brain tissue of mice that had a diffuse brain injury. Microglia normally look like a small spider, but after suffering a brain injury the microglia become like angry spiders from a horror movie. In brain-injured mice that lack p38a MAPK there were no angry-looking microglia, only the normal small spider-like cells. When I started the study I never expected the results to be so clear and striking. I believe that the p38a MAPK is a promising clinical target for the treatment of CNS disorders with dysregulated inflammatory responses, but we are still a long way from development of CNS-active p38 inhibitor drugs. “
(Source: eurekalert.org)
Brain Development Is Guided by Junk DNA that Isn’t Really Junk
Specific DNA once dismissed as junk plays an important role in brain development and might be involved in several devastating neurological diseases, UC San Francisco scientists have found.
Their discovery in mice is likely to further fuel a recent scramble by researchers to identify roles for long-neglected bits of DNA within the genomes of mice and humans alike.
While researchers have been busy exploring the roles of proteins encoded by the genes identified in various genome projects, most DNA is not in genes. This so-called junk DNA has largely been pushed aside and neglected in the wake of genomic gene discoveries, the UCSF scientists said.
In their own research, the UCSF team studies molecules called long noncoding RNA (lncRNA, often pronounced as “link” RNA), which are made from DNA templates in the same way as RNA from genes.
“The function of these mysterious RNA molecules in the brain is only beginning to be discovered,” said Daniel Lim, MD, PhD, assistant professor of neurological surgery, a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, and the senior author of the study, published online April 11 in the journal Cell Stem Cell.
Alexander Ramos, a student enrolled in the MD/PhD program at UCSF and first author of the study, conducted extensive computational analysis to establish guilt by association, linking lncRNAs within cells to the activation of genes.
Ramos looked specifically at patterns associated with particular developmental pathways or with the progression of certain diseases. He found an association between a set of 88 long noncoding RNAs and Huntington’s disease, a deadly neurodegenerative disorder. He also found weaker associations between specific groups of long noncoding RNAs and Alzheimer’s disease, convulsive seizures, major depressive disorder and various cancers.
“Alex was the team member who developed this new research direction, did most of the experiments, and connected results to the lab’s ongoing work,” Lim said. The study was mostly funded through Lim’s grant – a National Institutes of Health (NIH) Director’s New Innovator Award, a competitive award for innovative projects that have the potential for unusually high impact.
LncRNA versus Messenger RNA
Unlike messenger RNA, which is transcribed from the DNA in genes and guides the production of proteins, lncRNA molecules do not carry the blueprints for proteins. Because of this fact, they were long thought to not influence a cell’s fate or actions.
Nonetheless, lncRNAs also are transcribed from DNA in the same way as messenger RNA, and they, too, consist of unique sequences of nucleic acid building blocks.
Evidence indicates that lncRNAs can tether structural proteins to the DNA-containing chromosomes, and in so doing indirectly affect gene activation and cellular physiology without altering the genetic code. In other words, within the cell, lncRNA molecules act “epigenetically” — beyond genes — not through changes in DNA.
The brain cells that the scientists focused on the most give rise to various cell types of the central nervous system. They are found in a region of the brain called the subventricular zone, which directly overlies the striatum. This is the part of the brain where neurons are destroyed in Huntington’s disease, a condition triggered by a single genetic defect.
Ramos combined several advanced techniques for sequencing and analyzing DNA and RNA to identify where certain chemical changes happen to the chromosomes, and to identify lncRNAs on specific cell types found within the central nervous system. The research revealed roughly 2,000 such molecules that had not previously been described, out of about 9,000 thought to exist in mammals ranging from mice to humans.
In fact, the researchers generated far too much data to explore on their own. The UCSF scientists created a website through which their data can be used by others who want to study the role of lncRNAs in development and disease.
“There’s enough here for several labs to work on,” said Ramos, who has training grants from the California Institute for Regenerative Medicine (CIRM) and the NIH.
“It should be of interest to scientists who study long noncoding RNA, the generation of new nerve cells in the adult brain, neural stem cells and brain development, and embryonic stem cells,” he said.
Bad decisions arise from faulty information, not faulty brain circuits
Making decisions involves a gradual accumulation of facts that support one choice or another. A person choosing a college might weigh factors such as course selection, institutional reputation and the quality of future job prospects.
But if the wrong choice is made, Princeton University researchers have found that it might be the information rather than the brain’s decision-making process that is to blame. The researchers report in the journal Science that erroneous decisions tend to arise from errors, or “noise,” in the information coming into the brain rather than errors in how the brain accumulates information.
These findings address a fundamental question among neuroscientists about whether bad decisions result from noise in the external information — or sensory input — or because the brain made mistakes when tallying that information. In the example of choosing a college, the question might be whether a person made a poor choice because of misleading or confusing course descriptions, or because the brain failed to remember which college had the best ratings.
Previous measurements of brain neurons have indicated that brain functions are inherently noisy. The Princeton research, however, separated sensory inputs from the internal mental process to show that the former can be noisy while the latter is remarkably reliable, said senior investigator Carlos Brody, a Princeton associate professor of molecular biology and the Princeton Neuroscience Institute (PNI), and a Howard Hughes Medical Institute Investigator.
"To our great surprise, the internal mental process was perfectly noiseless. All of the imperfections came from noise in the sensory processes," Brody said. Brody worked with first author Bingni Brunton, now a postdoctoral research associate in the departments of biology and applied mathematics at the University of Washington; and Matthew Botvinick, a Princeton associate professor of psychology and PNI.
The research subjects — four college-age volunteers and 19 laboratory rats — listened to streams of randomly timed clicks coming into both the left ear and the right ear. After listening to a stream, the subjects had to choose the side from which more clicks originated. The rats had been trained to turn their noses in the direction from which more clicks originated.
The test subjects mostly chose the correct side but occasionally made errors. By comparing various patterns of clicks with the volunteers’ responses, researchers found that all of the errors arose when two clicks overlapped, and not from any observable noise in the brain system that tallied the clicks. This was true in experiment after experiment utilizing different click patterns, in humans and rats.
The researchers used the timing of the clicks and the decision-making behavior of the test subjects to create computer models that can be used to indicate what happens in the brain during decision-making. The models provide a clear window into the brain during the “mulling over” period of decision-making, the time when a person is accumulating information but has yet to choose, Brody said.
"Before we conducted this study, we did not have a way of looking at this process without inserting electrodes into the brain," Brody said. "Now thanks to our model, we have an estimation of what is going on at each moment in time during the formation of the decision."
The study suggests that information represented and processed in the brain’s neurons must be robust to noise, Brody said. “In other words, the ‘neural code’ may have a mechanism for inherent error correction,” he said.
"The new work from the Brody lab is important for a few reasons," said Anne Churchland, an assistant professor of biological sciences at Cold Spring Harbor Laboratory who studies decision-making and was not involved in the study. "First, the work was very innovative because the researchers were able to study carefully controlled decision-making behavior in rodents. This is surprising in that one might have guessed rodents were incapable of producing stable, reliable decisions that are based on complex sensory stimuli.
"This work exposed some unexpected features of why animals, including humans, sometimes make incorrect decisions," Churchland said. "Specifically, the researchers found that errors are mostly driven by the inability to accurately encode sensory information. Alternative possibilities, which the authors ruled out, included noise associated with holding the stimulus in mind, or memory noise, and noise associated with a bias toward one alternative or the other."
(Source: princeton.edu)
Taste of beer, without effect from alcohol, triggers dopamine release in the brain
The taste of beer, without any effect from alcohol itself, can trigger dopamine release in the brain, which is associated with drinking and other drugs of abuse, according to Indiana University School of Medicine researchers.
Using positron emission tomography (PET), the researchers tested 49 men with two scans, one in which they tasted beer, and the second in which they tasted Gatorade, looking for evidence of increased levels of dopamine, a brain neurotransmitter long associated with alcohol and other drugs of abuse. The scans showed significantly more dopamine activity following the taste of beer than the sports drink. Moreover, the effect was significantly greater among participants with a family history of alcoholism.
Results of the study were published online Monday by the journal Neuropsychopharmacology.
"We believe this is the first experiment in humans to show that the taste of an alcoholic drink alone, without any intoxicating effect from the alcohol, can elicit this dopamine activity in the brain’s reward centers," said David A. Kareken, Ph.D., professor of neurology at the IU School of Medicine and the deputy director of the Indiana Alcohol Research Center.
The stronger effect in participants with close alcoholic relatives suggests that the release of dopamine in response to such alcohol-related cues may be an inherited risk factor for alcoholism, said Dr. Kareken.
Research for several decades has linked dopamine to the consumption of various drugs of abuse, although researchers have differing interpretations of the neurotransmitter’s role. Sensory cues that are closely associated with drug intoxication (ranging from tastes and smells to the sight of a tavern) have long been known to spark cravings and induce treatment relapse in recovering alcoholics. Many neuroscientists believe that dopamine plays a critical role in such cravings.
The study participants received a very small amount of their preferred beer — 15 milliliters — over a 15-minute time period, enabling them to taste the beer without resulting in any detectable blood alcohol level or intoxicating effect.
Using a PET scanning compound that targets dopamine receptors in the brain, the researchers were able to assess changes in dopamine levels occurring after the participants tasted the liquids.
In addition to the PET scan results, participants reported an increased beer craving after tasting beer, without similar responses after tasting the sports drink — even though many thought the Gatorade actually tasted better, said Brandon G. Oberlin, Ph.D., post-doctoral fellow and first author of the paper.
(Image: iStockphoto)
Ordinary Skin Cells Morphed into Functional Brain Cells
Scientists at CWRU School of Medicine Discover New Technique that Holds Promise for the Treatment of Multiple Sclerosis and Cerebral Palsy
Researchers at Case Western Reserve School of Medicine have discovered a technique that directly converts skin cells to the type of brain cells destroyed in patients with multiple sclerosis, cerebral palsy and other so-called myelin disorders.
This discovery appears today in the journal Nature Biotechnology.
This breakthrough now enables “on demand” production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced.
The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes, the type of cell responsible for myelinating the neurons of the brain.
“Its ‘cellular alchemy,’” explained Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy.”
In a process termed “cellular reprogramming,” researchers manipulated the levels of three naturally occurring proteins to induce fibroblast cells to become precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).
Tesar’s team, led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, rapidly generated billions of these induced OPCs (called iOPCs). Even more important, they showed that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.
When oligodendrocytes are damaged or become dysfunctional in myelinating diseases, the insulating myelin coating that normally coats nerves is lost. A cure requires the myelin coating to be regenerated by replacement oligodendrocytes.
Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but with limitations.
“The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes,” explained co-author and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine and the university’s vice president for research. “The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells.”
This initial study used mouse cells. The critical next step is to demonstrate feasibility and safety using human cells in a lab setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.
“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” said Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center. “It is a real breakthrough.”
(Source: newswise.com)
Gene sequencing project finds new mutations to blame for a majority of brain tumor subtype
The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.
The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.
Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.
The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.
“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.
The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.
“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”
The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.
Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.
This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.
Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.
Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.
Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.
“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”
(Source: stjude.org)
Signature of circulating breast tumor cells that spread to the brain found
Some breast tumor circulating cells in the bloodstream are marked by a constellation of biomarkers that identify them as those destined to seed the brain with a deadly spread of cancer, said researchers led by those at Baylor College of Medicine in a report that appears online in the journal Science Translational Medicine.
"What prompted us to initiate this study was our desire to understand the characteristics of these cells," said Dr. Dario Marchetti, professor of pathology at BCM, director of the CTC (circulating tumor cell) Core Facility at BCM and a member of the NCI-designated Dan L. Duncan Cancer Center at BCM. Often, he said, circulating tumor cells (CTCs) from breast cancer patients which spread or metastasize to the brain are not identified by the current method for identifying such cells approved by the U.S. Food and Drug Administration (CellSearch® platform).
While this system is based on the detection of antibodies that target the epithelial cell adhesion molecule (EpCAM), the biomarkers identified by Marchetti and his colleagues include human epidermal growth factor receptor 2 (HER2+), epidermal growth factor receptor (EGFR), heparanase (HPSE) and Notch1 - and not EpCAM. Together, said Marchetti, these four proteins, previously known to be associated with cancer metastasis, spell out the signature of circulating tumors cells that travel to the brain.
Marchetti, using sophisticated techniques to test samples provided by Dr. Morris D. Groves of The University of Texas MD Anderson Cancer Center, also found this same pattern of proteins in the tissue taken from brain metastases of animals injected with breast cancer circulating tumor cells (CTCs).
They tested these special circulating tumor cells in laboratory models and found that they are highly invasive and capable of spread in live animals. They also found cells with this signature in the metastatic tumors of animals with breast cancer.
"We were able to grow these cells in vitro (in the laboratory in culture) for the first time ever," said Marchetti.
Circulating tumor cells are a promising method of identifying and monitoring solid tumors and could replace tumor biopsies in some cases. However, the promise is still being studied by experts such as Marchetti. In this case, he has identified a new signature for such cells - one that directs their activities toward spreading cancer to brain - an outcome with frequently fatal consequences.
The study not only identifies a novel signature of circulating tumor cells, it shows the limitations of currently approved platforms used to identify cancer in this way. Understanding such cells can help scientist understand how the disease spreads - an initial step in developing new methods of treating metastatic disease.
"We don’t claim that these biomarkers are the only important ones," said Marchetti. "We hope to find novel markers in brain metastasis that will make diagnosis and monitoring even more targeted."
They are also trying to find ways to link these circulating tumor cells back to the signature of the original or primary tumor.
(Source: bcm.edu)
Tapeworm-Linked Seizures May Be Rising in U.S.
Tapeworm infection in the brain that can trigger seizures is a growing health concern, doctors say.
But the infection, which leads to swelling in the brain, is usually treatable with medication, according to a leading association of neurologists.
Estimated cases of neurocysticercosis, as the tapeworm infection is called, range from 40,000 to 160,000 each year in the United States, said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston. “It’s been around a long time, affecting people living in severe poverty, but the disease is not well-studied or understood,” Hotez said.
Texas is one area of the country with many cases. “The disease has now become a leading cause of epilepsy in Houston,” Hotez said. “Every [week], we have patients come into our tropical medicine clinic with it.”
Concerns about an apparent increase of neurocysticercosis within the United States led the American Academy of Neurology to issue treatment guidelines for doctors and patients in the April 9 issue of the journal Neurology.
The recommendations are based on a review of 10 studies published between 1980 and 2010 that evaluated so-called cysticidal drugs for treatment of tapeworm infections. The infection involves infestation of the brain with the larvae of the Taenia solium tapeworm. In severe cases, it can cause death.
Tapeworm infection is common in Third World countries because of inadequate sanitation and hygiene, and an estimated 2 million people worldwide have epilepsy as a result. The good news is that good hygiene and food preparation can prevent it.
People develop the tapeworm infection when they consume improperly cooked meat, such as pork, or any food or drink that contains the tapeworm eggs or larvae (also known as cysts). Touching the fecal matter of an infected person is another means of transmission. The larvae then transform into full-sized tapeworms, which can grow to several feet, Hotez said.
In pigs, tapeworm larvae travel to the brain and await transmission to another animal (a human, for instance) when the pigs are eaten, he said. The parasites do the same thing in humans, but there’s nowhere to go from the human brain. Ultimately, the larvae die, and that’s when the trouble begins.
As the larvae die, they lose the ability to hide from the body’s immune system. The immune system responds by causing inflammation, which leads to epileptic seizures and brain swelling, Hotez said.
The guidelines for children and adults recommend using the medication albendazole to kill the cysts if they’re alive and treating brain swelling with corticosteroid drugs that dampen the immune system. The study found that albendazole (Albenza), used with or without the corticosteroids, reduced seizure frequency and the number of brain lesions seen in imaging scans. Not enough data was available to evaluate another drug, praziquantel, the researchers said.
Only limited evidence exists to support specific treatment approaches, however, and the treatments may produce side effects, such as abdominal complaints, according to the guidelines. It’s also unclear whether anti-epileptic medications may help prevent the seizures caused by the inflammation.
For now, the key is physician awareness, said Dr. Karen Roos, a professor of neurology at the Indiana University School of Medicine and lead author of the guidelines. “Physicians from areas of the world where this infection is endemic are very knowledgeable about this infection,” she said. “They know more than U.S. physicians.”
Infection with the tapeworm is preventable through proper sanitation, good hygiene and thorough cooking of meat.
(Source: nlm.nih.gov)
Molecular hub links obesity, heart disease to high blood pressure
Obesity, heart disease, and high blood pressure (hypertension) are all related, but understanding the molecular pathways that underlie cause and effect is complicated.
A new University of Iowa study identifies a protein within certain brain cells as a communications hub for controlling blood pressure, and suggests that abnormal activation of this protein may be a mechanism that links cardiovascular disease and obesity to elevated blood pressure.
"Cardiovascular diseases are the leading cause of death worldwide, and hypertension is a major cardiovascular risk factor," says Kamal Rahmouni, UI associate professor of pharmacology and internal medicine, and senior study author. "Our study identifies the protein called mTORC1 in the hypothalamus as a key player in the control of blood pressure. Targeting mTORC1 pathways may, therefore, be a promising strategy for the management of cardiovascular risk factors."
The hypothalamus is a small region of the brain that is responsible for maintaining normal function for numerous bodily processes, including blood pressure, body temperature, and glucose levels. Signaling of mTORC1 protein in the hypothalamus has previously been shown to affect food intake and body weight.
The new study, which was published April 2 in the journal Cell Metabolism, shows that the mTORC1 protein is activated by small molecules and hormones that are associated with obesity and cardiovascular disease, and this activation leads to dramatic increases in blood pressure.
Leucine is an amino acid that we get from food, which is known to activate mTORC1. The UI researchers showed that activating mTORC1 in rat brains with leucine increased activity in the nerves that connect the brain to the kidney, an important organ in blood pressure control. The increased nerve activity was accompanied by a rise in blood pressure. Conversely, blocking this mTORC1 activation significantly blunted leucine’s blood pressure-raising effect.
This finding may have direct clinical relevance as elevated levels of leucine have been correlated with an increased risk of high blood pressure in patients with cardiovascular disease.
"Our new study suggests a mechanism by which leucine in the bloodstream might increase blood pressure,” Rahmouni says.
Previous work has also suggested that mTORC1 is a signaling hub for leptin, a hormone produced by fat cells, which has been implicated in obesity-related hypertension.
Rahmouni and his colleagues showed that leptin activates mTORC1 in a specific part of the hypothalamus causing increased nerve activity and a rise in blood pressure. These effects are blocked by inhibiting activation of mTORC1.
“Our study shows that when this protein is either activated or inhibited in a very specific manner, it can cause dramatic changes in blood pressure,” Rahmouni says. “Given the importance of this protein for the control of blood pressure, any abnormality in its activity might explain the hypertension associated with certain conditions like obesity and cardiovascular disease.”
Rahmouni and his team hope that uncovering the details of the pathways linking mTORC1 activation and high blood pressure might lead to better treatments for high blood pressure in patients with cardiovascular disease and obesity.
(Source: now.uiowa.edu)
Babies’ brains to be mapped in the womb and after birth
UK scientists have embarked on a six-year project to map how nerve connections develop in babies’ brains while still in the womb and after birth.
By the time a baby takes its first breath many of the key pathways between nerves have already been made. And some of these will help determine how a baby thinks or sees the world, and may have a role to play in the development of conditions such as autism, scientists say.
But how this rich neural network assembles in the baby before birth is relatively unchartered territory.
Researchers from Guy’s and St Thomas’ Hospital, King’s College London, Imperial College and Oxford University aim to produce a dynamic wiring diagram of how the brain grows, at a level of detail that they say has been impossible until now.
They hope that by charting the journeys of bundles of nerves in the final three months of pregnancy, doctors will be able to understand more about how they can help in situations when this process goes wrong.
Prof David Edwards, director of the Centre for the Developing Brain, who is leading the research, says: “There is a distressing number of children in our society who grow up with problems because of things that happen to them around the time of birth or just before birth.
"It is very important to be able to scan babies before they are born, because we can capture a period when an awful lot is changing inside the brain, and it is a time when a great many of the things that might be going wrong do seem to be going wrong."
'Neural networks'
The study - known as the Developing Human Connectome Project - hopes to look at more than 1,500 babies, studying many aspects of their neurological development.
By examining the brains of babies while they are still growing in the womb, as well as those born prematurely and at full term, the scientists will try to define baselines of normal development and investigate how these may be affected by problems around birth.
And they plan to share their map with the wider research community.
Central to this project are advanced MRI scanning techniques, which the scientists say are able to pick up on details of the growing brain that have been difficult to capture until now.
While in the womb, foetuses are free to somersault in their amniotic sacs, and this constant movement has so far hindered clear images of growing brains.
But researchers at the Centre for the Developing Brain have found ways to counter the effects of these movements, building up full three-dimensional pictures while the foetus is in motion.
And by placing the MRI machine in the neonatal intensive care unit at Evelina Children’s Hospital in London they are one of the few centres in the world to have a scanner in such close proximity to the babies who often need it most, Prof Edwards says.
This means the same scanning system can be used to find out more about the brains of the sickest and smallest newborn babies, he says.
'Macro level'
Daniel Rueckert, professor of visual information processing at Imperial College London, who is also involved in the research, says: “We are trying to look at brain connectivity in two ways: firstly, from a structural perspective, to find out which parts of the brain are wired to other parts. And secondly we are looking at functional connectivity - how strongly two brain regions are linked across time and activity.”
But Prof Partha Mitra, a neuroscientist at Cold Spring Harbor Laboratory, New York state, says we need to be aware of the limitations of the technology in use.
"It would obviously be a very good thing to know more about the circuits in the developing human brain. Much of what we know hasn’t changed in a hundred years and has come from dissection studies.
"But we need to keep in mind the imaging techniques we have are indirect - we can’t open up a human brain and look at the connections while someone is alive so we rely on these non-invasive methods. But there is a big gap between the real circuits in the brain and what images can show us."
Prof Rueckert acknowledges that this map will provide a “macro-level” view of the developing brain and not be the “final answer”.
But he points to early results from the adult version of this project - the Human Connectome Project, based in the US: “There is so much evidence already from the adult project that there are significant changes in the brain that can be mapped with the technology we have now.
"It will be incredibly useful to be able to do this with the still growing and developing brain - perhaps giving us more time to intervene when things go wrong."