Posts tagged neuroscience
Researchers at the Beckman Institute at the University of Illinois at Urbana-Champaign have developed a new technique that can noninvasively image the pulse pressure and elasticity of the arteries of the brain, revealing correlations between arterial health and aging.
Brain artery support, which makes up the cerebrovascular system, is crucial for healthy brain aging and preventing diseases like Alzheimer’s and other forms of dementia.
The researchers, led by Monica Fabiani and Gabriele Gratton, psychology professors in the Cognitive Neuroscience Group, routinely record optical imaging data by shining near-infrared light into the brain to measure neural activity. Their idea to measure pulse pressure through optical imaging came from observing in previous studies that the arterial pulse produced strong signals in the optical data, which they normally do not use to study brain function. Realizing the value in this overlooked data, they launched a new study that focused on data from 53 participants aged 55-87 years.
“When we image the brain using our optical methods, we usually remove the pulse as an artifact—we take it out in order to get to other signals from the brain,” said Fabiani. “But we are interested in aging and how the brain changes with other bodily systems, like the cardiovascular system. When thinking about this, we realized it would be useful to measure the cerebrovascular system as we worry about cognition and brain physiology.”
The initial results using this new technique find that arterial stiffness is directly correlated with cardiorespiratory fitness: the more fit people are, the more elastic their arteries. Because arterial stiffening is a cause of reduced brain blood flow, stiff arteries can lead to a faster rate of cognitive decline and an increased chance of stroke, especially in older adults.
Using this method, the researchers were able to collect additional, region-specific data.
“In particular, noninvasive optical methods can provide estimates of arterial elasticity and brain pulse pressure in different regions of the brain, which can give us clues about the how different regions of the brain contribute to our overall health,” said Gratton. “For example, if we found that a particular artery was stiff and causing decreased blood flow to and loss of brain cells in a specific area, we might find that the damage to this area is also associated with an increased likelihood of certain psychological and cognitive issues.”
The researchers are investigating ways to use this technique to measure arterial stiffness across different age groups and specific cardiovascular or stress levels. High levels of stress, especially over a long amount of time, may affect arterial health, according to the researchers.
“This is just the beginning of what we’re able to explore with this technique. We’re looking at other age groups, and in the future we intend to study people with varying levels of long-term stress,” said Fabiani. “When people are stressed for long periods of time, like if they’re caring for a sick parent, stress might generate vasoconstriction and higher blood pressure, with significant consequences for arterial function in the brain. We are interested in knowing whether this may be an important factor leading to arterial stiffness.”
The researchers are also able to gather information about pulse transit time, or how long it takes the blood to flow through the brain’s arteries, and visualize large arteries running along the brain surface.
“Our goal is to find more information about what causes arterial stiffness, and how regional arterial stiffness can lead to specific health problems. Our findings continue to bolster the idea that an important key to aging well is having good cerebrovascular health,” said Fabiani.
(Source: beckman.illinois.edu)
Filed under aging cardiorespiratory fitness cerebrovascular system neural activity neuroscience science
When investigators at the Stanford University School of Medicine applied light-driven stimulation to nerve cells in the brains of mice that had suffered strokes several days earlier, the mice showed significantly greater recovery in motor ability than mice that had experienced strokes but whose brains weren’t stimulated.
These findings, published online Aug. 18 in Proceedings of the National Academy of Sciences, could help identify important brain circuits involved in stroke recovery and usher in new clinical therapies for stroke, including the placement of electrical brain-stimulating devices similar to those used for treating Parkinson’s disease, chronic pain and epilepsy. The findings also highlight the neuroscientific strides made possible by a powerful research technique known as optogenetics.
Stroke, with 15 million new victims per year worldwide, is the planet’s second-largest cause of death, according to Gary Steinberg, MD, PhD, professor and chair of neurosurgery and the study’s senior author. In the United States, stroke is the largest single cause of neurologic disability, accounting for about 800,000 new cases each year — more than one per minute — and exacting an annual tab of about $75 billion in medical costs and lost productivity.
The only approved drug for stroke in the United States is an injectable medication called tissue plasminogen activator, or tPA. If infused within a few hours of the stroke, tPA can limit the extent of stroke damage. But no more than 5 percent of patients actually benefit from it, largely because by the time they arrive at a medical center the damage is already done. No pharmacological therapy has been shown to enhance recovery from stroke from that point on.
Enhancing recovery
But in this study — the first to use a light-driven stimulation technology called optogenetics to enhance stroke recovery in mice — the stimulations promoted recovery even when initiated five days after stroke occurred.
“In this study, we found that direct stimulation of a particular set of nerve cells in the brain — nerve cells in the motor cortex — was able to substantially enhance recovery,” said Steinberg, the Bernard and Ronni Lacroute-William Randolph Hearst Professor in Neurosurgery and Neurosciences.
About seven of every eight strokes are ischemic: They occur when a blood clot cuts off oxygen flow to one or another part of the brain, destroying tissue and leaving weakness, paralysis and sensory, cognitive and speech deficits in its wake. While some degree of recovery is possible — this varies greatly among patients depending on many factors, notably age — it’s seldom complete, and typically grinds to a halt by three months after the stroke has occurred.
Animal studies have indicated that electrical stimulation of the brain can improve recovery from stroke. However, “existing brain-stimulation techniques activate all cell types in the stimulation area, which not only makes it difficult to study but can cause unwanted side effects,” said the study’s lead author, Michelle Cheng, PhD, a research associate in Steinberg’s lab.
For the new study, the Stanford investigators deployed optogenetics, a technology pioneered by co-author Karl Deisseroth, MD, PhD, professor of psychiatry and behavioral sciences and of bioengineering. Optogenetics involves expressing a light-sensitive protein in specifically targeted brain cells. Upon exposure to light of the right wavelength, this light-sensitive protein is activated and causes the cell to fire.
Steinberg’s team selectively expressed this protein in the brain’s primary motor cortex, which is involved in regulating motor functions. Nerve cells within this cortical layer send outputs to many other brain regions, including its counterpart in the brain’s opposite hemisphere. Using an optical fiber implanted in that region, the researchers were able to stimulate the primary motor cortex near where the stroke had occurred, and then monitor biochemical changes and blood flow there as well as in other brain areas with which this region was in communication. “We wanted to find out whether activating these nerve cells alone can contribute to recovery,” Steinberg said.
Walking farther
By several behavioral, blood flow and biochemical measures, the answer two weeks later was a strong yes. On one test of motor coordination, balance and muscular strength, the mice had to walk the length of a horizontal beam rotating on its axis, like a rotisserie spit. Stroke-impaired mice whose primary motor cortex was optogenetically stimulated did significantly better in how far they could walk along the beam without falling off and in the speed of their transit, compared with their unstimulated counterparts.
The same treatment, applied to mice that had not suffered a stroke but whose brains had been similarly genetically altered and then stimulated just as stroke-affected mice’s brains were, had no effect on either the distance they travelled along the rotating beam before falling off or how fast they walked. This suggests it was stimulation-induced repair of stroke damage, not the stimulation itself, yielding the improved motor ability.
Stroke-affected mice whose brains were optogenetically stimulated also regained substantially more of their lost weight than unstimulated, stroke-affected mice. Furthermore, stimulated post-stroke mice showed enhanced blood flow in their brain compared with unstimulated post-stroke mice.
In addition, substances called growth factors, produced naturally in the brain, were more abundant in key regions on both sides of the brain in optogenetically stimulated, stroke-affected mice than in their unstimulated counterparts. Likewise, certain brain regions of these optogenetically stimulated, post-stroke mice showed increased levels of proteins associated with heightened ability of nerve cells to alter their structural features in response to experience — for example, practice and learning. (Optogenetic stimulation of the brains of non-stroke mice produced no such effects.)
Steinberg said his lab is following up to determine whether the improvement is sustained in the long term. “We’re also looking to see if optogenetically stimulating other brain regions after a stroke might be equally or more effective,” he said. “The goal is to identify the precise circuits that would be most amenable to interventions in the human brain, post-stroke, so that we can take this approach into clinical trials.”
(Source: med.stanford.edu)
Filed under stroke optogenetics channelrhodopsin motor cortex animal model neuroscience science
Researchers obtain key insights into how the internal body clock is tuned
Researchers at UT Southwestern Medical Center have found a new way that internal body clocks are regulated by a type of molecule known as long non-coding RNA.
The internal body clocks, called circadian clocks, regulate the daily “rhythms” of many bodily functions, from waking and sleeping to body temperature and hunger. They are largely “tuned” to a 24-hour cycle that is influenced by external cues such as light and temperature.
“Although we know that long non-coding RNAs are abundant in many organisms, what they do in the body, and how they do it, has not been clear so far,” said Dr. Yi Liu, Professor of Physiology. “Our work establishes a role for long non-coding RNAs in ‘tuning’ the circadian clock, but also shows how they control gene expression.”
Determining how circadian clocks work is crucial to understanding several human diseases, including sleep disorders and depression in which the clock malfunctions. The influence of a functional clock is evident in the reduced performance of shift workers and the jet lag felt by long-distance travellers.
Dr. Liu and his team were able to learn more about the circadian rhythms by studying model systems involving the bread mold, Neurospora crassa. The researchers found that the expression of a clock gene named frequency (frq) is controlled by a long non-coding RNA named qrf (frq backwards) − an RNA molecule that is complementary, or antisense, to frq. Unlike normal RNA molecules, qrf does not encode a protein, but it can control whether and how much frq protein is produced.
Specifically, qrf RNA is produced in response to light, and can then interfere with the production of the frq protein. In this way, qrf can “re-set” the circadian clock in a light-dependent way. This regulation works both ways: frq can also block the production of qrf. This mutual inhibition ensures that the frq and qrf RNA molecules are present in opposite “phases” of the clock and allows each RNA to oscillate robustly. Without qrf, normal circadian rhythms are not sustained, indicating that the long non-coding RNA is required for clock functions.
The findings are published online in the journal Nature.
“We anticipate a similar mode of action may operate in other organisms because similar RNAs have been found for clock genes in mice. In addition, such RNAs may also function in other biological processes because of their wide presence in genomes,” said Dr. Liu, who is the Louise W. Kahn Scholar in Biomedical Research.
UT Southwestern investigators are leaders in unraveling the gene networks underlying circadian clocks and have shown that most body organs, such as the pancreas and liver, have their own internal clocks, and that virtually every cell in the human body contains a clock. It now appears that the clocks and clock-related genes – some 20 such genes have been identified – affect virtually all of the cells’ metabolic pathways, from blood sugar regulation to cholesterol production.
Other UT Southwestern researchers involved in the latest findings include Dr. Zhihong Xue, Qiaohong Ye, Dr. Juchen Yang and Dr. Guanghua Xiao. Support for this research included grants from the National Institutes of Health, the Welch Foundation, the Cancer Prevention Research Institute of Texas, and the Biotechnology and Biological Sciences Research Council.
“This study adds to an important body of work that has shown the ubiquity of a circadian clock across species, including humans, and its role in metabolic regulation in cells, organs, and organisms,” said Dr. Michael Sesma, Program Director in the Division of Genetics and Developmental Biology at the of the National Institutes of Health’s National Institute of General Medical Sciences, which partially funded the research. “These new results from Dr. Liu and his colleagues also extend beyond understanding the function of an anti-sense RNA in the fine tuning of a cell’s daily rhythm; they provide an example of the means by which anti-sense transcription likely regulates other key molecular and physiological processes in cells and organisms.”
(Image: Fotolia)
Filed under circadian rhythms qrf frq RNA molecules gene expression neuroscience science
Everyone knows that neurons are the key to how the brain operates. But it turns out they aren’t the only stars in the show; neighboring cells called astrocytes are quickly gaining increasing respect for the critical role they play in memory and learning. EPFL scientists have recently outlined the molecular mechanics of this process in an article published in Proceedings of the National Academy of Sciences (PNAS). Lactate produced by the star-shaped astrocytes accelerates the memorization process. This result, surprising until very recently, opens up new possibilities for treating cognitive and memory disorders, as well as psychiatric conditions such as depression.
Our brains are greedy, gobbling up as much as 25% of our daily energy consumption. Neurons and astrocytes thrive on glucose. Neurons use it to protect themselves from the buildup of toxic products resulting from their activity. Astrocytes, which are glial cells (as opposed to neurons), manufacture lactate; this was long thought to be a byproduct of glucose metabolism, and then as a simple energy source for neurons.
In 2011, research published in the journal Cell by EPFL’s Laboratory of Neuroenergetics and Cellular Dynamics in collaboration with a U.S. team unveiled the critical role of lactate. “In vivo, when the transfer of lactate from astrocytes to neurons is blocked, we found that the memorization process was also blocked,” explains EPFL professor Pierre Magistretti, head of the lab. “We thus knew that it was an essential fuel for that process.”
Focusing their attention on the molecular mechanism, the scientists discovered that lactate provides more than just energy. It acts as a moderator of one type of glutamate receptor (NMDA receptors), the nervous system’s primary neurotransmitter. This glutamate receptor is involved in the memorization process, and the research demonstrates that lactate gives them what amounts to a turbo-boost. “Glutamate lets you drive in first gear; with lactate, you can shift into fourth and travel at 100 km/h,” says Magistretti.
Palliating cognitive deficits
The scientists did their initial research in vitro. They exposed mice neurons to various substances and measured their effect on the expression of genes involved in memory. Glucose and pyruvate (another glucose derivative) didn’t have any effect. A lactate supplement, on the other hand, triggered the expression of four genes involved in cerebral plasticity that are essential to memorization.
They followed this work with in vivo studies, which confirmed their results. They administered lactate into the brains of living mice, and then extracted the tissues and measured gene expression. Once again, the expression of genes involved in cerebral plasticity increased significantly.
Could we take lactate supplements and develop encyclopedic memory? Magistretti’s lab has just received a grant to study the effects of artificial lactate supplementation. “We have identified a series of molecules that can make astrocytes produce more lactate. Now the idea is to see in vivo if we can mitigate cognitive deficits and memory disorders.” In addition, since conditions such as depression are often accompanied by cognitive problems, “lactate could also have an antidepressant effect,” says Magistretti, who also conducts research at the National Center for Competence in Research Synapsy, dedicated to the understanding of the synaptic basis of psychiatric disease.
(Source: actu.epfl.ch)
Filed under astrocytes memory glucose NMDA receptors lactate synaptic plasticity neuroscience science
Our individual genetic make-up determines the effect that stress has on our emotional centres. These are the findings of a group of researchers from the MedUni Vienna. Not every individual reacts in the same way to life events that produce the same degree of stress. Some grow as a result of the crisis, whereas others break down and fall ill, for example with depression. The outcome is determined by a complex interaction between depression gene versions and environmental factors.
The Vienna research group, together with international cooperation partners, have demonstrated that there are interactions between stressful life events and certain risk gene variants that subsequently change the volume of the hippocampus forever.
The hippocampus is a switching station in the processing of emotions and acts like a central interface when dealing with stress. It is known to react very sensitively to stress. In situations of stress that are interpreted as a physical danger (‘distress’), it shrinks in size, which is a phenomenon observed commonly in patients with depression and one which is responsible for some of their clinical symptoms. By contrast, positive stress (‘eustress’), of the kind that can occur in emotionally exciting social situations can actually cause the hippocampus to increase in size.
According to the results of the study, just how stressful life events impact on the size of the hippocampus depends on more than just environmental factors. There are genes that determine whether the same life event causes an increase or decrease in the volume of the hippocampus, and which therefore defines whether the stress is good or bad for our brain. The more risk genes an individual has, the more negative an impact the “life events” have on the size of the hippocampus. Where there are no or only a few risk genes, this life event can actually have a positive effect.
Examining life crises
As part of the study, carried out at the University Department of Psychiatry and Psychotherapy (led by Siegfried Kasper), the study team obtained quantitative information from healthy test subjects about stressful life events, such as deaths in the family, divorce, unemployment, financial losses, relocations, serious illnesses or accidents.
A high-resolution anatomical magnetic resonance scan was also carried out (at the High-Field MR Centre of Excellence, Department of MR Physics, led by Ewald Moser). The University Department of Laboratory Medicine (Harald Esterbauer and colleagues) carried out the gene analyses (COMT Val158Met, BDNF Val66Met, 5-HTTLPR). At the University Department of Psychiatry and Psychotherapy, primary author Ulrich Rabl measured the volume of the test subjects’ hippocampi using computer-assisted techniques and analysed the results in the context of the genetic and environmental data.
"People with the three gene versions believed to encourage depression had a smaller hippocampus than those with fewer or none of these gene versions, even though they had the same number of stressful life events," says study leader Lukas Pezawas, describing the results. People with only one or even none of the risk genes, on the other hand, had an enlarged hippocampus with similar life events.
The study highlights the importance of gene and environment interaction as a determining factor for the volume of the hippocampus. “These results are important for understanding neurobiological processes in stress-associated illnesses such as depression or post-traumatic stress disorder. It is ultimately our genes that determine whether stress makes us psychologically unwell or whether it encourages our mental health,” explains Pezawas.
The study, published in the highly respected “Journal of Neuroscience”, was funded by a special research project of the FWF (Austrian Science Fund) (SFB-35, led by Harald Sitte) and presented as a highlight at the international conference on “Organization for Human Brain Mapping”.
(Source: meduniwien.ac.at)
Filed under stress hippocampus genes environment genetics neuroscience science
(Image Caption: Human neurons differentiated from induced pluripotent stem cells, with cell nuclei shown in blue and synapses in red and green. Credit: Credit: Zhexing Wen/Johns Hopkins Medicine)
Stem Cells Reveal How Illness-Linked Genetic Variation Affects Neurons
A genetic variation linked to schizophrenia, bipolar disorder and severe depression wreaks havoc on connections among neurons in the developing brain, a team of researchers reports. The study, led by Guo-li Ming, M.D., Ph.D., and Hongjun Song, Ph.D., of the Johns Hopkins University School of Medicine and described online Aug. 17 in the journal Nature, used stem cells generated from people with and without mental illness to observe the effects of a rare and pernicious genetic variation on young brain cells. The results add to evidence that several major mental illnesses have common roots in faulty “wiring” during early brain development.
“This was the next best thing to going back in time to see what happened while a person was in the womb to later cause mental illness,” says Ming. “We found the most convincing evidence yet that the answer lies in the synapses that connect brain cells to one another.”
Previous evidence for the relationship came from autopsies and from studies suggesting that some genetic variants that affect synapses also increase the chance of mental illness. But those studies could not show a direct cause-and-effect relationship, Ming says.
One difficulty in studying the genetics of common mental illnesses is that they are generally caused by environmental factors in combination with multiple gene variants, any one of which usually could not by itself cause disease. A rare exception is the gene known as disrupted in schizophrenia 1 (DISC1), in which some mutations have a strong effect. Two families have been found in which many members with the DISC1 mutations have mental illness.
To find out how a DISC1 variation with a few deleted DNA “letters” affects the developing brain, the research team collected skin cells from a mother and daughter in one of these families who have neither the variation nor mental illness, as well as the father, who has the variation and severe depression, and another daughter, who carries the variation and has schizophrenia. For comparison, they also collected samples from an unrelated healthy person. Postdoctoral fellow Zhexing Wen, Ph.D., coaxed the skin cells to form five lines of stem cells and to mature into very pure populations of synapse-forming neurons.
After growing the neurons in a dish for six weeks, collaborators at Pennsylvania State University measured their electrical activity and found that neurons with the DISC1 variation had about half the number of synapses as those without the variation. To make sure that the differences were really due to the DISC1 variation and not to other genetic differences, graduate student Ha Nam Nguyen spent two years making targeted genetic changes to three of the stem cell lines.
In one of the cell lines with the variation, he swapped out the DISC1 gene for a healthy version. He also inserted the disease-causing variation into one healthy cell line from a family member, as well as the cell line from the unrelated control. Sure enough, the researchers report, the cells without the variation now grew the normal amount of synapses, while those with the inserted mutation had half as many.
“We had our definitive answer to whether this DISC1 variation is responsible for the reduced synapse growth,” Ming says.
To find out how DISC1 acts on synapses, the researchers also compared the activity levels of genes in the healthy neurons to those with the variation. To their surprise, the activities of more than 100 genes were different. “This is the first indication that DISC1 regulates the activity of a large number of genes, many of which are related to synapses,” Ming says.
The research team is now looking more closely at other genes that are linked to mental disorders. By better understanding the roots of mental illness, they hope to eventually develop better treatments for it, Ming says.
Filed under stem cells brain cells synapses DISC1 mental health neuroscience science
New research sheds light on how children’s brains memorize facts
As children learn basic arithmetic, they gradually switch from solving problems by counting on their fingers to pulling facts from memory. The shift comes more easily for some kids than for others, but no one knows why.
Now, new brain-imaging research gives the first evidence drawn from a longitudinal study to explain how the brain reorganizes itself as children learn math facts. A precisely orchestrated group of brain changes, many involving the memory center known as the hippocampus, are essential to the transformation, according to a study from the Stanford University School of Medicine.
The results, published online Aug. 17 in Nature Neuroscience, explain brain reorganization during normal development of cognitive skills and will serve as a point of comparison for future studies of what goes awry in the brains of children with learning disabilities.
“We wanted to understand how children acquire new knowledge, and determine why some children learn to retrieve facts from memory better than others,” said Vinod Menon, PhD, the Rachael L. and Walter F. Nichols, MD, Professor and professor of psychiatry and behavioral sciences, and the senior author of the study. “This work provides insight into the dynamic changes that occur over the course of cognitive development in each child.”
The study also adds to prior research into the differences between how children’s and adults’ brains solve math problems. Children use certain brain regions, including the hippocampus and the prefrontal cortex, very differently from adults when the two groups are solving the same types of math problems, the study showed.
“It was surprising to us that the hippocampal and prefrontal contributions to memory-based problem-solving during childhood don’t look anything like what we would have expected for the adult brain,” said postdoctoral scholar Shaozheng Qin, PhD, who is the paper’s lead author.
Charting the shifting strategy
In the study, 28 children solved simple math problems while receiving two functional magnetic resonance imaging brain scans; the scans were done about 1.2 years apart. The researchers also scanned 20 adolescents and 20 adults at a single time point. At the start of the study, the children were ages 7-9. The adolescents were 14-17 and the adults were 19-22. The participants had normal IQs. Because the study examined normal math learning, potential participants with math-related learning disabilities and attention deficit hyperactivity disorder were excluded. The children and adolescents were studying math in school; the researchers did not provide any math instruction.
During the study, as the children aged from an average of 8.2 to 9.4 years, they became faster and more accurate at solving math problems, and relied more on retrieving math facts from memory and less on counting. As these shifts in strategy took place, the researchers saw several changes in the children’s brains. The hippocampus, a region with many roles in shaping new memories, was activated more in children’s brains after one year. Regions involved in counting, including parts of the prefrontal and parietal cortex, were activated less.
The scientists also saw changes in the degree to which the hippocampus was connected to other parts of children’s brains, with several parts of the prefrontal, anterior temporal cortex and parietal cortex more strongly connected to the hippocampus after one year. Crucially, the stronger these connections, the greater was each individual child’s ability to retrieve math facts from memory, a finding that suggests a starting point for future studies of math-learning disabilities.
Although children were using their hippocampus more after a year, adolescents and adults made minimal use of their hippocampus while solving math problems. Instead, they pulled math facts from well-developed information stores in the neocortex.
Memory scaffold
“What this means is that the hippocampus is providing a scaffold for learning and consolidating facts into long-term memory in children,” said Menon, who is also the Rachel L. and Walter F. Nichols, MD, Professor at the medical school. Children’s brains are building a schema for mathematical knowledge. The hippocampus helps support other parts of the brain as adultlike neural connections for solving math problems are being constructed. “In adults this scaffold is not needed because memory for math facts has most likely been consolidated into the neocortex,” he said. Interestingly, the research also showed that, although the adult hippocampus is not as strongly engaged as in children, it seems to keep a backup copy of the math information that adults usually draw from the neocortex.
The researchers compared the level of variation in patterns of brain activity as children, adolescents and adults correctly solved math problems. The brain’s activity patterns were more stable in adolescents and adults than in children, suggesting that as the brain gets better at solving math problems its activity becomes more consistent.
The next step, Menon said, is to compare the new findings about normal math learning to what happens in children with math-learning disabilities.
“In children with math-learning disabilities, we know that the ability to retrieve facts fluently is a basic problem, and remains a bottleneck for them in high school and college,” he said. “Is it that the hippocampus can’t provide a reliable scaffold to build good representations of math facts in other parts of the brain during the early stages of learning, and so the child continues to use inefficient strategies to solve math problems? We want to test this.”
Filed under learning hippocampus memory neuroimaging child development cognitive development mathematics neuroscience science
A team led by researchers at the University of Exeter Medical School and King’s College London has uncovered some of the strongest evidence yet that epigenetic changes in the brain play a role in Alzheimer’s disease.
Epigenetic changes affect the expression or activity of genes without changing the underlying DNA sequence and are believed to be one mechanism by which the environment can interact with the genome. Importantly, epigenetic changes are potentially reversible and may therefore provide targets for the development of new therapies.
Globally, more than 26 million people are currently affected by Alzheimer’s Disease. As this number grows in line with an increasingly aging population, the need to identify new disease mechanisms is more important than ever. Post-mortem examinations have revealed much about how Alzheimer’s damages the brain, with some regions, such as the entorhinal cortex, being particularly susceptible, while others, such as the cerebellum, remain virtually unscathed. However, little is yet known about how and why the disease develops in specific brain regions.
The current study found that chemical modifications to DNA within the ANK1 gene are strongly associated with measures of neuropathology in the brain. The study, published in Nature Neuroscience, found that people with more Alzheimer’s disease-related neuropathology in their brains had higher levels of DNA modifications within the ANK1 gene. The finding was particularly strong in the entorhinal cortex, and also detected in other cortical regions affected by the disease. In contrast, no significant changes were observed in less affected brain regions or blood.
Professor Jonathan Mill, of the University of Exeter Medical School and King’s College London, who headed the study, said: “This is the strongest evidence yet to suggest that epigenetic changes in the brain occur in Alzheimer’s disease, and offers potential hope for understanding the mechanisms involved in the onset of dementia. We don’t yet know why these changes occur – it’s possible that they are involved in disease onset, but they may also reflect changes induced by the disease itself.”
Dr Katie Lunnon, first author on the study, from the University of Exeter Medical School, added: “It’s intriguing that we find changes specifically in the regions of the brain involved in Alzheimer’s disease. Future studies will focus on isolating different cell-types from the brain to see whether these changes are neuron-specific.”
In addition to the University of Exeter Medical School and King’s College London, the team included contributors from The Icahn School of Medicine at Mount Sinai, the JJ Peters VA Medical Center, The Johns Hopkins University School of Medicine, Harvard Medical School, the University of Oxford, and Rush University Medical Center, Chicago. They used cutting-edge technology to examine brain tissue from different areas of the brain across three cohorts - the MRC London Brain Bank for Neurodegenerative Disease, the Oxford Thomas Willis Brain Bank, and the Mount Sinai Alzheimer’s Disease and Schizophrenia Brain Bank. They analysed three cortical regions, cerebellum, and blood obtained from several hundred individuals representing the spectrum of disease; from those with no evidence of dementia and neurodegeneration, through to patients with very advanced disease.
The research was primarily funded by the National Institutes of Health (NIH), U.S. Department of Health and Human Services, as part of its Epigenomics Roadmap Initiative (grant number R01-AG036039 awarded to Jonathan Mill). To learn more about the NIH initiative that seeks to accelerate research into the relatively new and fast-developing area of epigenetics, go to: https://commonfund.nih.gov/epigenomics/index.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, who also provided funding for the study said:“We know that changes to the DNA code of certain genes are associated with an increased risk of developing Alzheimer’s disease. Investigating how epigenetic changes influence genes in Alzheimer’s is still a relatively new area of study. The importance of understanding this area of research is highlighted by the fact that epigenetic changes have been associated with development of other diseases, including cancer.
“This innovative research has discovered a potential new mechanism involved in Alzheimer’s by linking the ANK1 gene to the disease. We will be interested to see further research into the role of ANK1 in Alzheimer’s and whether other epigenetic changes may be involved in the disease.
“Alzheimer’s affects millions of people worldwide and we need pioneering research to understand exactly why the disease occurs. Alzheimer’s Research UK is helping to fund research which will take us a step closer to understanding and defeating this devastating disease.”
(Source: exeter.ac.uk)
Filed under alzheimer's disease neurodegeneration epigenetics ANK1 entorhinal cortex neuroscience science
A new study led by researchers at Brigham and Women’s Hospital (BWH) and Rush University Medical Center, reveals how early changes in brain DNA methylation are involved in Alzheimer’s disease. DNA methylation is a biochemical alteration of the building blocks of DNA and is one of the markers that indicate whether the DNA is open and biologically active in a given region of the human genome.
The study is published online August 17, 2014 in Nature Neuroscience.
According to the researchers, this is the first large-scale study employing epigenome-wide association (EWAS) studies—which look at chromosomal make-up and changes—in relation to the brain and Alzheimer’s disease.
"Our study approach may help us to better understand the biological impact of environmental risk factors and life experiences on Alzheimer’s disease," said Philip L. De Jager, MD, PhD, Program in Translational Neuropsychiatric Genomics, BWH Departments of Neurology and Psychiatry, lead study author. "There are certain advantages to studying the epigenome, or the chemical changes that occur in DNA. The epigenome is malleable and may harbor traces of life events that influence disease susceptibility, such as smoking, depression and menopause, which may influence susceptibility to Alzheimer’s and other diseases."
The researchers analyzed samples from 708 donated brains from subjects in the Religious Orders Study and Rush Memory and Aging Project, conducted by study co-author, David A. Bennett, MD, Rush Alzheimer’s Disease Center in Chicago. They found that methylation levels correlated with Alzheimer’s disease in 71 of 415,848 CpG markers analyzed (these are a pair of DNA building blocks consisting of a cytosine and a guanine nucleotide that are located next to each other). These 71 markers were found in the ANK1 and RHBDF2 genes, as well as ABCA7 and BIN1 which harbor known Alzheimer’s disease susceptibility variants.
Further, investigation of these CpG associations revealed nearby genes whose RNA expression was altered in brain samples with Alzheimer’s disease: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. This suggests that the CpG associations identify genes whose function is altered in Alzheimer’s disease.
Further, “because these findings are also found in the subset of subjects that are not cognitively impaired at the time of death, it appears that these DNA methylation changes may play a role in the onset of Alzheimer’s disease,” said De Jager. “Moreover, our work has helped identify regions of the human genome that are altered over the life-course in a way that is associated with Alzheimer’s disease. This may provide clues to treating the disease by using drugs that influence epigenomic function.”
(Source: eurekalert.org)
Filed under alzheimer's disease DNA methylation human genome neuroscience science
According to the CDC, unintentional injuries are the leading cause of death for adolescents. Compared to the two leading causes of death for all Americans, heart disease and cancer, a pattern of questionable decision-making in dire situations comes to light in teen mortality. New research from the Center for BrainHealth at The University of Texas at Dallas investigating brain differences associated with risk-taking teens found that connections between certain brain regions are amplified in teens more prone to risk.
“Our brains have an emotional-regulation network that exists to govern emotions and influence decision-making,” explained the study’s lead author, Sam Dewitt. “Antisocial or risk-seeking behavior may be associated with an imbalance in this network.”
The study, published June 30 in Psychiatry Research: Neuroimaging, looked at 36 adolescents ages 12-17; eighteen risk-taking teens were age- and sex-matched to a group of 18 non-risk-taking teens. Participants were screened for risk-taking behaviors, such as drug and alcohol use, sexual promiscuity, and physical violence and underwent functional MRI (fMRI) scans to examine communication between brain regions associated with the emotional-regulation network. Interestingly, the risk-taking group showed significantly lower income compared to the non-risk taking group.
“Most fMRI scans used to be done in conjunction with a particular visual task. In the past several years, however, it has been shown that performing an fMRI scan of the brain during a ‘mind-wandering’ state is just as valuable,”said Sina Aslan, Ph.D., President of Advance MRI and Adjunct Assistant Professor at the Center for BrainHealth at The University of Texas at Dallas.“In this case, brain regions associated with emotion and reward centers show increased connection even when they are not explicitly engaged.”
The study, conducted by Francesca Filbey, Ph.D., Director of Cognitive Neuroscience Research of Addictive Behaviors at the Center for BrainHealth and her colleagues, shows that risk-taking teens exhibit hyperconnectivity between the amygdala, a center responsible for emotional reactivity, and specific areas of the prefrontal cortex associated with emotion regulation and critical thinking skills. The researchers also found increased activity between areas of the prefrontal cortex and the nucleus accumbens, a center for reward sensitivity that is often implicated in addiction research.
“Our findings are crucial in that they help identify potential brain biomarkers that, when taken into context with behavioral differences, may help identify which adolescents are at risk for dangerous and pathological behaviors in the future,” Dewitt explained.
He also points out that even though the risk-taking group did partake in risky behavior, none met clinical criteria for behavioral or substance use disorders.
By identifying these factors early on, the research team hopes to have a better chance of providing effective cognitive strategies to help risk-seeking adolescents regulate their emotions and avoid risk-taking behavior and substance abuse.
(Source: brainhealth.utdallas.edu)
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