St. Jude Children’s Research Hospital scientists studying two rare, inherited childhood neurodegenerative disorders have identified a new, possibly common source of DNA damage that may play a role in other neurodegenerative diseases, cancer and aging. The findings appear in the current issue of the scientific journal Nature Neuroscience.
Researchers showed for the first time that an enzyme required for normal DNA functioning causes DNA damage in the developing brain. DNA is the molecule found in nearly every cell that carries the instructions needed to assemble and sustain life.
The enzyme is topoisomerase 1 (Top1). Normally, Top1 works by temporarily attaching to and forming a short-lived molecule called a Top1 cleavage complex (Top1cc). Top1ccs cause reversible breaks in one strand of the double-stranded DNA molecule. That prompts DNA to partially unwind, allowing cells to access the DNA molecule in preparation for cell division or to begin production of the proteins that do the work of cells.
Different factors, including the free radicals that are a byproduct of oxygen metabolism, result in Top1ccs becoming trapped on DNA and accumulating in cells. This study, however, is the first to link the buildup to disease. The results also broaden scientific understanding of the mechanisms that maintain brain health.
Investigators made the connection between DNA damage and accumulation of Top1cc while studying DNA repair problems in the rare neurodegenerative disorders ataxia telangiectasia (A-T) and spinocerebellar ataxia with axonal neuropathy 1(SCAN1). The diseases both involve progressive difficulty with walking and other movement. This study showed that A-T and SCAN1 also share the buildup of Top1ccs as a common mechanism of DNA damage. A-T is associated with a range of other health problems, including an increased risk of leukemia, lymphoma and other cancers.
“We are now working to understand how this newly recognized source of DNA damage might contribute to tumor development or the age-related DNA damage in the brain that is associated with neurodegenerative disorders like Alzheimer’s disease,”said co-corresponding author Peter McKinnon, Ph.D., a member of the St. Jude Department of Genetics. The co-corresponding author is Sachin Katyal, Ph.D., of the University of Manitoba Department of Pharmacology and Therapeutics and formerly of St. Jude.
A-T and SCAN1 are caused by mutations in different enzymes involved in DNA repair. Mutations in the ATM protein lead to A-T. Alterations in the Tdp1 protein cause SCAN1.
Working in nerve cells growing in the laboratory and in the nervous system of specially bred mice, researchers showed for the first time that ATM and Tdp1 work cooperatively to repair breaks in DNA. Scientists also demonstrated how the proteins accomplish the task.
The results revealed a new role for ATM in repairing single-strand DNA breaks. Until this study, ATM was linked to double-strand DNA repair. ATM was also known to work exclusively as a protein kinase. Kinases are enzymes that use chemicals called phosphate groups to regulate other proteins.
Scientists reported that when Top1ccs are trapped ATM functions as a protein kinase and alert cells to the DNA damage. But researchers found ATM also serves a more direct role by marking the trapped Top1ccs for degradation by the protein complex cells use to get rid of damaged or unnecessary proteins. ATM accomplishes that task by promoting the addition of certain proteins called ubiquitin and SUMO to the Top1cc surface.
Tdp1 then completes the DNA-repair process by severing the chemical bonds that tether Top1 to DNA.
Mice lacking either Atm or Tdp1 survived with apparently normal neurological function. But compared to normal mice, the animals missing either protein had elevated levels of Top1cc. Those levels rose sharply during periods of rapid brain development and in response to radiation, oxidation and other factors known to cause breaks in DNA.
When researchers knocked out both Atm and Tdp1, Top1cc accumulation rose substantially as did a form of programmed cell death called apoptosis. Investigators reported that apoptosis was concentrated in the developing brain and few mice survived to birth. McKinnon said the results add to evidence that the brain is particularly sensitive to DNA damage.
Researchers then used the anti-cancer drug topotecan to link elevated levels of Top1cc to the cell death and other problems seen in mice lacking Atm and Tdp1. Topotecan works by trapping Top1ccs in tumor cells, resulting in the DNA damage that triggers apoptosis. Investigators showed that the impact of Top1cc accumulation was strikingly similar whether the cause was topotecan or the loss of Atm and Tdp1.
(Source: stjude.org)
Filed under DNA damage neurodegenerative diseases topoisomerase 1 ataxia kinases neuroscience science
In a paper published in the latest issue of the neuroscience journal Neuron, McLean Hospital investigators report that a gene essential for normal brain development, and previously linked to Autism Spectrum Disorders, also plays a critical role in addiction-related behaviors.
"In our lab, we investigate the brain mechanisms behind drug addiction – a common and devastating disease with limited treatment options," explained Christopher Cowan, PhD, director of the Integrated Neurobiology Laboratory at McLean and an associate professor of Psychiatry at Harvard Medical School. "Chronic exposure to drugs of abuse causes changes in the brain that could underlie the transition from casual drug use to addiction. By discovering the brain molecules that control the development of drug addiction, we hope to identify new treatment approaches."
The Cowan lab team, led by Laura Smith, PhD, an instructor of Psychiatry at Harvard Medical School, used animal models to show that the fragile X mental retardation protein, or FMRP, plays a critical role in the development of addiction-related behaviors. FMRP is also the protein that is missing in Fragile X Syndrome, the leading single-gene cause of autism and intellectual disability. Consistent with its important role in brain function, the team found that cocaine utilizes FMRP to facilitate brain changes involved in addiction-related behaviors.
Cowan, whose work tends to focus on identifying novel genes related to conditions such as autism and drug addiction, explained that FMRP controls the remodeling and strength of connections in the brain during normal development. Their current findings reveal that FMRP plays a critical role in the changes in brain connections that occur following repeated cocaine exposure.
"We know that experiences are able to modify the brain in important ways. Some of these brain changes help us, by allowing us to learn and remember. Other changes are harmful, such as those that occur in individuals struggling with drug abuse," noted Cowan and Smith. "While FMRP allows individuals to learn and remember things in their environment properly, it also controls how the brain responds to cocaine and ends up strengthening drug behaviors. By better understanding FMRP’s role in this process, we may someday be able to suggest effective therapeutic options to prevent or reverse these changes."
(Source: eurekalert.org)
Filed under drug addiction cocaine addiction fragile x syndrome autism FMRP neuroscience science
An estimated 15-20 percent of U.S. troops returning from Iraq and Afghanistan suffer from some form of traumatic brain injury (TBI) sustained during their deployment, with most injuries caused by blast waves from exploded military ordnance. The obvious cognitive symptoms of minor TBI — including learning and memory problems — can dissipate within just a few days. But blast-exposed veterans may continue to have problems performing simple auditory tasks that require them to focus attention on one sound source and ignore others, an ability known as “selective auditory attention.”
According to a new study by a team of Boston University (BU) neuroscientists, such apparent “hearing” problems actually may be caused by diffuse injury to the brain’s prefrontal lobe — work that will be described at the 167th meeting of the Acoustical Society of America, to be held May 5-9, 2014 in Providence, Rhode Island.
"This kind of injury can make it impossible to converse in everyday social settings, and thus is a truly devastating problem that can contribute to social isolation and depression," explains computational neuroscientist Scott Bressler, a graduate student in BU’s Auditory Neuroscience Laboratory, led by biomedical engineering professor Barbara Shinn-Cunningham.
For the study, Bressler, Shinn-Cunningham and their colleagues — in collaboration with traumatic brain injury and post-traumatic stress disorder expert Yelena Bogdanova of VA Healthcare Boston — presented a selective auditory attention task to 10 vets with mild TBI and to 17 control subjects without brain injuries. Notably, on average, veterans had hearing within a normal range.
In the task, three different melody streams, each comprised of two notes, were simultaneously presented to the subjects from three different perceived directions (this variation in directionality was achieved by differing the timing of the signals that reached the left and right ears). The subjects were then asked to identify the “shape” of the melodies (i.e., “going up,” “going down,” or “zig-zagging”) while their brain activity was measured by electrodes on the scalp.
"Whenever a new sound begins, the auditory cortex responds, encoding the sound onset," Bressler explains. "Attentional focus, however, changes the strength of this response: when a listener is attending to a particular sound source, the neural activity in response to that sound is greater." This change of the neural response occurs because the brain’s "executive control" regions, located in the brain’s prefrontal cortex, send signals to the auditory sensory regions of the brain, modulating their response.
The researchers found that blast-exposed veterans with TBI performed worse on the task — that is, they had difficulty controlling auditory attention — “and in all of the TBI veterans who performed well enough for us to measure their neural activity, 6 out of our 10 initial subjects, the brain response showed weak or no attention-related modulation of auditory responses,” Bressler says.
"Our hope is that some of our findings can be used to develop methods to assess and quantify TBI, identifying specific factors that contribute to difficulties communicating in everyday settings," he says. "By identifying these factors on an individual basis, we may be able to define rehabilitation approaches and coping strategies tailored to the individual."
Some TBI patients also go on to develop chronic traumatic encephalopathy (CTE) — a debilitating progressive degenerative disease with symptoms that include dementia, memory loss and depression — which can now only be definitively diagnosed after death. “With any luck,” Bressler adds, “neurobehavioral research like ours may help identify patients at risk of developing CTE long before their symptoms manifest.”
(Source: newswise.com)
Filed under TBI brain injury selective attention auditory cortex brain activity hearing neuroscience science
Pain’s Benefit to Squid May Hold Clues to Chronic Human Pain
For the longfin inshore squid, pain can mean the difference between life and death, according to a new study. That’s because pain prompts injured squid to behave in ways that help it survive encounters with a fish predator, researchers said.
That finding may also provide hints as to why other animals, including humans, experience long-lasting or chronic pain, behavior experts say.
It’s long been thought that pain causes an animal to act self-protectively, says Robert Elwood, an animal behavior researcher at Queen’s University Belfast who was not involved in the study. Pain teaches an organism to avoid situations that will bring it on. It seems obvious, but it hasn’t really been tested until now, Elwood said in an email interview.
In a study published today in Current Biology, researchers report that the sensitivity with which injured squid reacted to aggressive moves from a predator, in this case a black sea bass, gave the squid better odds of surviving an attack.
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Filed under pain chronic pain nociception predation animal behavior neuroscience science
Your brain on speed: Walking doesn’t impair thinking and multitasking
When we’re strolling down memory lane, our brains recall just as much information while walking as while standing still—findings that contradict the popular science notion that walking hinders one’s ability to think.
University of Michigan researchers at the School of Kinesiology and the College of Engineering examined how well study participants performed a very complex spatial cognitive task while walking versus standing still.
"We’re saying that at least for this task, which is fairly complicated, walking and thinking does not compromise your thinking ability at all," said Julia Kline, a U-M doctoral candidate in biomedical engineering and first author on the study, which appears online in Frontiers in Human Neuroscience.
The finding surprised researchers, who expected to see decreased thinking performance with increased walking speed, Kline said. The 2011 best-selling book “Thinking Fast and Slow” suggests that because walking requires mental effort, walking may hinder our ability to think when compared to standing still.
"Past studies that have compared mental performance at a slow walking speed and standing have not found any differences, but our study is the first to show that the walking speed doesn’t matter," said Daniel Ferris, professor of kinesiology and biomedical engineering and senior author of the paper.
"Given the health benefits of walking, we should not discourage people from walking and thinking when they want."
Ferris offered one caveat: previous research has shown that walking performance can be impaired in the elderly when they dual-task during gait.
Ferris, Kline and Katherine Poggensee of U-M’s Human Neuromechanics Laboratory measured the ability of young, healthy participants to memorize numbers and their placement on a grid, and then enter those numbers correctly with a keypad while walking different speeds and standing still.
"Think of filling numbers one through nine on a tic-tac-toe grid and then remembering where they all are," Ferris said. "At every walking speed and standing still, participants entered about half the numbers correctly."
While speed didn’t change task performance, people took wider steps when performing the task than when they were only walking, which may be to compensate and stay balanced while concentrating, Kline said.
All participants showed increased activity in areas of the brain associated with spatial relationships and short-term memory during the cognitive task. In keeping with the U-M findings, a recent Stanford study suggested that walking fueled creativity.
In addition to good news for treadmill-desk users or people who like to think on the move, the study provides a useful scientific tool by demonstrating that it’s possible to collect accurate EEG data on moving subjects, Kline said.
This is important to researchers who study the brain and are concerned about getting accurate results when the subjects aren’t perfectly still. U-M researchers achieved their EEG results by applying different signal-processing techniques to eliminate the movement “noise” from the EEG signal.
Filed under spatial memory locomotion memory brain imaging walking multitasking neuroscience science
FDA allows marketing of first prosthetic arm that translates signals from person’s muscles to perform complex tasks
The U.S. Food and Drug Administration (FDA) today allowed marketing of the DEKA Arm System, the first prosthetic arm that can perform multiple, simultaneous powered movements controlled by electrical signals from electromyogram (EMG) electrodes.
EMG electrodes detect electrical activity caused by the contraction of muscles close to where the prosthesis is attached. The electrodes send the electrical signals to a computer processor in the prosthesis that translates them to a specific movement or movements.
The EMG electrodes in the DEKA Arm System convert electrical signals into up to 10 powered movements, and it is the same shape and weight as an adult arm. In addition to the EMG electrodes, the DEKA Arm System contains a combination of mechanisms including switches, movement sensors, and force sensors that cause the prosthesis to move.
“This innovative prosthesis provides a new option for people with certain kinds of arm amputations,” said Christy Foreman, director of the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health. “The DEKA Arm System may allow some people to perform more complex tasks than they can with current prostheses in a way that more closely resembles the natural motion of the arm.”
The FDA reviewed clinical information relating to the device, including a 4-site Department of Veterans Affairs study in which 36 DEKA Arm System study participants provided data on how the arm performed in common household and self-care tasks. The study found that approximately 90 percent of study participants were able to perform activities with the DEKA Arm System that they were not able to perform with their current prosthesis, such as using keys and locks, preparing food, feeding oneself, using zippers, and brushing and combing hair.
The DEKA Arm System can be configured for people with limb loss occurring at the shoulder joint, mid-upper arm, or mid-lower arm. It cannot be configured for limb loss at the elbow or wrist joint.
Data reviewed by the FDA also included testing of software and electrical and battery systems, mitigations to prevent or stop unintended movements of the arm and hand mechanisms, durability testing (such as ability to withstand exposure to common environmental factors such as dust and light rain), and impact testing.
The FDA reviewed the DEKA Arm System through its de novo classification process, a regulatory pathway for some novel low- to moderate-risk medical devices that are first-of-a-kind.
The DEKA Arm System is manufactured by DEKA Integrated Solutions in Manchester, N.H.
Filed under prosthetic limbs prosthetic arm DEKA arm system muscles EMG electrodes robotics neuroscience science
Listening to bipolar disorder: Smartphone app detects mood swings via voice analysis
A smartphone app that monitors subtle qualities of a person’s voice during everyday phone conversations shows promise for detecting early signs of mood changes in people with bipolar disorder, a University of Michigan team reports.
While the app still needs much testing before widespread use, early results from a small group of patients show its potential to monitor moods while protecting privacy.
The researchers hope the app will eventually give people with bipolar disorder and their health care teams an early warning of the changing moods that give the condition its name. The technology could also help people with other conditions.
"We only ask that an individual use his or her smart phone as he or she normally would," said Emily Mower Provost, assistant professor of computer science and engineering who co-led the project. "We collect speech data from the smart phone and process the data in a privacy preserving manner to learn the acoustic patterns associated with harmful mood variations."
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Filed under bipolar disorder health technology science
The science behind rewards and punishment
In a neuroimaging study, a UQ psychologist has examined whether having allegiances with someone can affect feelings of empathy when punishing and rewarding others.
An international team of researchers, including Dr Pascal Molenberghs from UQ’s School of Psychology, mapped the brain activity while volunteers where giving electroshocks or money to members within or outside their group.
Dr Molenberghs said the research was a first of its kind and demonstrated that different neural responses were involved when delivering rewards or punishment to others.
“When we reward others we activate similar brain areas as when we receive rewards ourselves,” he said.
“However, these areas become more active when we reward members from our own group.
“Previous research has shown that we prefer to give more money to people from our own group, now we can actually show that this is associated with increased activation in reward-related brain areas, which is really exciting.
“The brain responses for punishing others directly revealed a different pattern of activation, one that was typically associated with receiving and seeing others in pain,” Dr Molenberghs said.
The study also found that personality traits influenced activity in these punishment-related brain areas.
People who did not care as much about others, showed less activation in these areas when shocking others, especially when they were shocking out-group members.
Co-author Professor Jean Decety, from the University of Chicago, said the results provided important insights into why some people don’t care as much when hurting others.
“Empathy and sympathy are necessary abilities to understand the potential consequences decisions will have on the feelings and emotions of others, even if the recipients of those decisions belong to a different group,” he said.
Filed under brain activity empathy striatum reward-punishment psychopathy psychology neuroscience science
Scientists have found that pressure from the fluid surrounding the brain plays a role in maintaining proper eye function, opening a new direction for treating glaucoma — the second leading cause of blindness worldwide. The research is being presented at the 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) this week in Orlando, Fla. (Abstract Title: Effect of translaminar pressure modification on the rat optic nerve head).
Using a rat model, researchers found that elevating the pressure of the fluid surrounding the brain can counterbalance elevated pressure in the eye, preventing the optic nerve from bending backward. Rats with higher fluid pressure from the brain maintained their ability to respond to light better than rats with lower pressure.
The brain and eye are connected by the optic nerve. In diseases like glaucoma — where vision loss is associated with elevated pressure within the eye — the optic nerve bows backward, away from the eye and toward the brain. This investigation might explain why some people with normal eye pressure develop glaucoma, and why people with intraocular pressure never develop the condition.
(Source: newswise.com)
Filed under vision optic nerve glaucoma animal model neuroscience medicine science
Students ‘print’ pink prosthetic arm for teen girl
Thirteen-year-old Sydney Kendall had one request for the Washington University in St. Louis students building her a robotic prosthetic arm: Make it pink.
Kendall Gretsch, Henry Lather and Kranti Peddada, seniors studying biomedical engineering in the School of Engineering & Applied Science, accomplished that and more. Using a 3-D printer, they created a robotic prosthetic arm out of bright-pink plastic. Total cost: $200, a fraction of the price of standard prosthetics, which start at $6,000.
“Currently, prosthetics are very expensive, and because kids keep growing, it is too costly for them to have the latest technology,” said Sydney’s mother, Beth Kendall. “With the 3-D printer, a prosthetic can be made much less expensive. The possibilities of what can be done to improve prosthetics using this technology is very exciting.”
Sydney lost her right arm in a boating accident when she was six years old. She learned to write with her left hand, but found most tasks difficult to accomplish with her prosthetic arm. Sydney said her new arm is easy to manipulate. By moving her shoulder, she can direct the arm to throw a ball, move a computer mouse and perform other tasks.
Peddada said it was thrilling to observe Sydney use her arm.
“It really showed us the great things you can accomplish when you bridge medicine and technology,” Peddada said.
The students developed the robotic hand as part of their engineering design course with Joseph Klaesner, PhD, associate professor of physical therapy at the School of Medicine. Several local medical practitioners, including orthopedic hand surgeons Charles A. Goldfarb, MD, and Lindley Wall, MD, both associate professors of orthopaedic surgery at the School of Medicine, served as mentors.
“They brought their engineering expertise, and we shared our practical experience with prosthetics and the needs of children,” Goldfarb wrote in a recent blog post about the project. “It was a valuable experience as Kendall, Henry and Kranti had no prosthetic experience and were able to think about the issues in a very different way.”
As Goldfarb explained, the WUSTL student design offers two key design differences that set it apart from similar “Robohand” devices that have been invented recently — the motor and the working thumb.
This prosthetic is battery-powered and controlled with an accelerometer (like in the iPhone). The thumb moves with a slightly different trigger (compared with finger motion).
Prosthetic limbs are tricky for patients of any age, and especially for children, noted Goldfarb, because they’re still growing and need to move to larger-sized devices on a regular basis. Since prosthetics have no sensation, some kids are more comfortable making do with their existing natural limbs, he added.
While 3-D printers can cost about $2,500, they are capable of producing artificial limbs at a relatively low individual cost.
“These prosthetic hands are really exciting because they are inexpensive, can be remade when the child grows, and they do offer functional abilities,” he said.
Filed under prosthetic limbs 3-D printing robotics technology neuroscience science
