Posts tagged neuroscience
Articles and news from the latest research reports.
Study: Model for Brain Signaling Flawed
A new study out today in the journal Science turns two decades of understanding about how brain cells communicate on its head. The study demonstrates that the tripartite synapse – a model long accepted by the scientific community and one in which multiple cells collaborate to move signals in the central nervous system – does not exist in the adult brain.
“Our findings demonstrate that the tripartite synaptic model is incorrect,” said Maiken Nedergaard, M.D., D.M.Sc., lead author of the study and co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine. “This concept does not represent the process for transmitting signals between neurons in the brain beyond the developmental stage.”
The central nervous system is home to many different cells. While neurons tend to garner the most attention, it is only recently that the function of the brain’s other cells have been fully appreciated. Glial cells known as astrocytes, for example, had long been considered mainly the “glue” that helps hold all the other cells in the central nervous system in place. Scientists now understand that that these cells are essential to maintaining a healthy environment in the brain by helping carry out functions such as removing waste.
“Neurons are like a racing car,” said Nedergaard. “While the driver gets all the credit, there are often 20 people behind the scenes that are optimizing his or her success.”
However, when it comes to moving signals between neurons in the brain it turns out that the scientists may have vastly exaggerated the role of the astrocyte.
Neurons are connected to each other via axons or “arms” that extend from the cell’s main body. Communication between neighboring neurons takes place where axons meet other nerve cells – called a synaptic juncture – when an electrical charge causes chemicals called neurotransmitters or glutamate to be released by one cell and “read” by receptors on the surface of the opposite. The two cells do not actually touch, so the chemicals messages must pass through a gap in the synaptic juncture. The space around this gap is insulated by astrocytes.
Under the tripartite synapse model, both astrocytes and neurons were believed to play a role in the “conversation” between cells. This understanding was largely based on animal models which showed active receptors and neurotransmission between not only the nerve cells but also the nearby astrocytes.
Specifically, a key neurotransmission receptor called metabotropic glutamate receptor 5 (mGluR5) was observed to be present and active in astrocytes at the synaptic juncture. It was also observed that when the mGluR5 receptor was activated, the astrocytes would release chemical transmitters that were in turn read by the nerve cells. These findings led to the conclusion that astrocytes must in some manner modulate the signaling process between brain cells.
While this model has held sway for decades, scientists have long been frustrated by their inability to influence this process by targeting it with drugs.
“If this concept was correct, it should have given rise to a clinical trial by now,” said Nedergaard. “It has not, which tells us that with so many labs work on this for 20 years that there must be something wrong.”
One of the barriers to understanding precise mechanics of passing signals from one neuron to another has been the inability to observe this process in the adult brain. The tripartite synapse model was based – in part – by examining the activity in the brains of very young rodents. Adult rodents could not be similarly studied because the synapses in the brain would die before they could be fully analyzed. This ultimately led to the presumption that the signaling process that was witnessed in the young brain carried over to adulthood.
Collaborating with researchers at the University of Rochester’s Institute of Optics, Nedergaard and her team developed a new 2-photon microscope that enables researchers to observe glia activity in the living brain. Using both this method and by analyzing the gene and protein expression in the brain the researchers discovered that the mGluR5 largely disappear in the glial cells of adult mice meaning that these cells do not directly respond to synaptic neuronal signalling, thus calling into question the concepts that drive most of ongoing research in the field.
“The process of neuron-glial transmission as conceived by the tripartite synapse model appears to just be a simplistic signaling pathway that ‘teaches’ the synapse how to behave,” said Nedergaard. “Once the brain matures, it goes away.”
Machine Perception Lab Shows Robotic One-Year-Old on Video
The world is getting a long-awaited first glimpse at a new humanoid robot in action mimicking the expressions of a one-year-old child. The robot will be used in studies on sensory-motor and social development – how babies “learn” to control their bodies and to interact with other people.
Diego-san’s hardware was developed by leading robot manufacturers: the head by Hanson Robotics, and the body by Japan’s Kokoro Co. The project is led by University of California, San Diego full research scientist Javier Movellan.
Movellan directs the Institute for Neural Computation’s Machine Perception Laboratory, based in the UCSD division of the California Institute for Telecommunications and Information Technology (Calit2). The Diego-san project is also a joint collaboration with the Early Play and Development Laboratory of professor Dan Messinger at the University of Miami, and with professor Emo Todorov’s Movement Control Laboratory at the University of Washington.
Movellan and his colleagues are developing the software that allows Diego-san to learn to control his body and to learn to interact with people.
"We’ve made good progress developing new algorithms for motor control, and they have been presented at robotics conferences, but generally on the motor-control side, we really appreciate the difficulties faced by the human brain when controlling the human body," said Movellan, reporting even more progress on the social-interaction side. "We developed machine-learning methods to analyze face-to-face interaction between mothers and infants, to extract the underlying social controller used by infants, and to port it to Diego-san. We then analyzed the resulting interaction between Diego-san and adults." Full details and results of that research are being submitted for publication in a top scientific journal.
While photos and videos of the robot have been presented at scientific conferences in robotics and in infant development, the general public is getting a first peak at Diego-san’s expressive face in action. On January 6, David Hanson (of Hanson Robotics) posted a new video on YouTube.
“This robotic baby boy was built with funding from the National Science Foundation and serves cognitive A.I. and human-robot interaction research,” wrote Hanson. “With high definition cameras in the eyes, Diego San sees people, gestures, expressions, and uses A.I. modeled on human babies, to learn from people, the way that a baby hypothetically would. The facial expressions are important to establish a relationship, and communicate intuitively to people.”
Diego-san is the next step in the development of “emotionally relevant” robotics, building on Hanson’s previous work with the Machine Perception Lab, such as the emotionally responsive Albert Einstein head.
Networking Ability a Family Trait in Monkeys
Two years of painstaking observation on the social interactions of a troop of free-ranging monkeys and an analysis of their family trees has found signs of natural selection affecting the behavior of the descendants.
Rhesus macaques who had large, strong networks tended to be descendants of similarly social macaques, according to a Duke University team of researchers. And their ability to recognize relationships and play nice with others also won them more reproductive success.
"If you are a more social monkey, then you’re going to have greater reproductive success, meaning your babies are more likely to survive their first year," said post-doctoral research fellow Lauren Brent, who led the study. "Natural selection appears to be favoring pro-social behavior."
The analysis, which appears in Nature Scientific Reports, combined sophisticated social network maps with 75 years of pedigree data and some genetic analysis.
Stem Cells May Hold Promise for Lou Gehrig’s Disease (ALS)
Apparent stem cell transplant success in mice may hold promise for people with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. The results of the study were released today and will be presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego, March 16 to 23, 2013. “There have been remarkable strides in stem cell transplantation when it comes to other diseases, such as cancer and heart failure,” said study author Stefania Corti, MD, PhD, with the University of Milan in Italy and a member of the American Academy of Neurology. “ALS is a fatal, progressive, degenerative disease that currently has no cure. Stem cell transplants may represent a promising avenue for effective cell-based treatment for ALS and other neurodegenerative diseases.”
For the study, mice with an animal model of ALS were injected with human neural stem cells taken from human induced pluripotent stem cells (iPSCs). iPSC are adult cells such as skin cells that have been genetically reprogrammed to an embryonic stem cell-like state. Neurons are a basic building block of the nervous system, which is affected by ALS. After injection, the stem cells migrated to the spinal cord of the mice, matured and multiplied.
The study found that stem cell transplantation significantly extended the lifespan of the mice by 20 days and improved their neuromuscular function by 15 percent. “Our study shows promise for testing stem cell transplantation in human clinical trials,” said Corti.
(Image: ALAMY)
Eliminating useless information important to learning, making new memories
As we age, it just may be the ability to filter and eliminate old information – rather than take in the new stuff – that makes it harder to learn, scientists report.
“When you are young, your brain is able to strengthen certain connections and weaken certain connections to make new memories,” said Dr. Joe Z. Tsien, neuroscientist at the Medical College of Georgia at Georgia Regents University and Co-Director of the GRU Brain & Behavior Discovery Institute.
It’s that critical weakening that appears hampered in the older brain, according to a study in the journal Scientific Reports.
The NMDA receptor in the brain’s hippocampus is like a switch for regulating learning and memory, working through subunits called NR2A and NR2B. NR2B is expressed in higher percentages in children, enabling neurons to talk a fraction of a second longer; make stronger bonds, called synapses; and optimize learning and memory. This formation of strong bonds is called long-term potentiation. The ratio shifts after puberty, so there is more NR2A and slightly reduced communication time between neurons.
When Tsien and his colleagues genetically modified mice that mimic the adult ratio – more NR2A, less NR2B – they were surprised to find the rodents were still good at making strong connections and short-term memories but had an impaired ability to weaken existing connections, called long-term depression, and to make new long-term memories as a result. It’s called information sculpting and adult ratios of NMDA receptor subunits don’t appear to be very good at it.
“If you only make synapses stronger and never get rid of the noise or less useful information then it’s a problem,” said Tsien, the study’s corresponding author. While each neuron averages 3,000 synapses, the relentless onslaught of information and experiences necessitates some selective whittling. Insufficient sculpting, at least in their mouse, meant a reduced ability to remember things short-term – like the ticket number at a fast-food restaurant – and long-term – like remembering a favorite menu item at that restaurant. Both are impacted in Alzheimer’s and age-related dementia.
All long-term depression was not lost in the mice, rather just response to the specific electrical stimulation levels that should induce weakening of the synapse. Tsien expected to find the opposite: that long-term potentiation was weak and so was the ability to learn and make new memories. “What is abnormal is the ability to weaken existing connectivity.”
Acknowledging the leap, this impaired ability could also help explain why adults can’t learn a new language without their old accent and why older people tend to be more stuck in their ways, the memory researcher said.
“We know we lose the ability to perfectly speak a foreign language if we learn than language after the onset of sexual maturity. I can learn English but my Chinese accent is very difficult to get rid of. The question is why,” Tsien said.
Tsien and his colleagues already have learned what happens when NR2B is overexpressed. He and East China Normal University researchers announced in 2009 the development of Hobbie-J, a smarter than average rat. A decade earlier, Tsien reported in the journal Nature the development of a smart mouse dubbed Doogie using the same techniques to over-express the NR2B gene in the hippocampus.
Doogie, Hobbie-J and their descendants have maintained superior memory as they age. Now Tsien is interested in following the NR2A over-expressing mouse to see what happens.
(Source: news.georgiahealth.edu)
Newly found ‘volume control’ in the brain promotes learning, memory
Scientists have long wondered how nerve cell activity in the brain’s hippocampus, the epicenter for learning and memory, is controlled — too much synaptic communication between neurons can trigger a seizure, and too little impairs information processing, promoting neurodegeneration. Researchers at Georgetown University Medical Center say they now have an answer. In the January 10 issue of Neuron, they report that synapses that link two different groups of nerve cells in the hippocampus serve as a kind of “volume control,” keeping neuronal activity throughout that region at a steady, optimal level.
"Think of these special synapses like the fingers of God and man touching in Michelangelo’s famous fresco in the Sistine Chapel," says the study’s senior investigator, Daniel Pak, PhD, an associate professor of pharmacology. "Now substitute the figures for two different groups of neurons that need to perform smoothly. The touching of the fingers, or synapses, controls activity levels of neurons within the hippocampus."
The hippocampus is a processing unit that receives input from the cortex and consolidates that information in terms of learning and memory. Neurons known as granule cells, located in the hippocampus’ dentate gyrus, receive transmissions from the cortex. Those granule cells then pass that information to the other set of neurons (those in the CA3 region of the hippocampus, in this study) via the synaptic fingers.
Those fingers dial up, or dial down, the volume of neurotransmission from the granule cells to the CA3 region to keep neurotransmission in the learning and memory areas of the hippocampus at an optimal flow — a concept known as homeostatic plasticity. “If granule cells try to transmit too much activity, we found, the synaptic junction tamps down the volume of transmission by weakening their connections, allowing the proper amount of information to travel to CA3 neurons,” says Pak. “If there is not enough activity being transmitted by the granule cells, the synapses become stronger, pumping up the volume to CA3 so that information flow remains constant.”
There are many such touching fingers in the hippocampus, connecting the so-called “mossy fibers” of the granule cells to neurons in the CA3 region. But importantly, not every one of the billions of neurons in the hippocampus needs to set its own level of transmission from one nerve cell to the other, says Pak.
To explain, he uses another analogy. “It had previously been thought that neurons act separately like cars, each working to keep their speed at a constant level even though signal traffic may be fast or slow. But we wondered how these neurons could process learning and memory information efficiently, while also regulating the speed by which they process and communicate that information.
"We believe, based on our study, that only the mossy fiber synapses on the CA3 neurons control the level of activity for the hippocampus — they are like the engine on a train that sets the speed for all the other cars, or neurons, attached to it," Pak says. "That frees up the other neurons to do the job they are tasked with doing — processing and encoding information in the forms of learning and memory."
Not only does the study offer a new model for how homeostatic plasticity in the hippocampus can co-exist with learning and memory, it also suggests a new therapeutic avenue to help patients with uncontrollable seizures, he says.
"The CA3 region is highly susceptible to seizures, so if we understand how homeostasis is maintained in these neurons, we could potentially manipulate the system. When there is an excessive level of CA3 neuronal activity in a patient, we could learn how to therapeutically turn it down."
(Source: eurekalert.org)
Pannexins are abundant in the central nervous system of vertebrates
Pannexins traverse the cell membrane of vertebrate animals and form large pored channels. They are permeable for certain signalling molecules, such as the energy storage molecule ATP (adenosine triphosphate). The best known representative is Pannexin1, which occurs in abundance in the brain and spinal cord and among others in the hippocampus - a brain structure that is critical for long-term memory. Malfunctions of the pannexins play a role in the development of epilepsy and strokes.
No more scope in long-term potentiation
The research team studied mice in which the gene for Pannexin1 was lacking. Using cell recordings carried out on isolated brain sections, they analysed the long-term potentiation in the hippocampus. Long-term potentiation usually occurs when new memory content is built - the contacts between nerve cells are strengthened; they communicate more effectively with each other. In mice without Pannexin1, the long-term potentiation occurred earlier and was more prolonged than in mice with Pannexin1. “It looks at first glance like a gain in long-term memory”, says Nora Prochnow. “But precise analysis shows that there was no more scope for upward development.” Due to the lack of Pannexin1, the cell communication in general was increased to such an extent that a further increase through the learning of new knowledge was no longer possible. The synaptic plasticity was thus extremely restricted. “The plasticity is essential for learning processes in the brain”, Nora Prochnow explains. “It helps you to organise, keep or even to forget contents in a positive sense, to gain room for new inputs.”
Autistic-like behaviour without Pannexin1
The absence of Pannexin1 also had an impact on behaviour: when solving simple problems, the animals were quickly overwhelmed in terms of content. Their spatial orientation was limited, their attention impaired and an increased probability for seizure generation occurred. “The behavioural patterns are reminiscent of autism. We should therefore consider the Pannexin1 channel more closely with regard to the treatment of such diseases”, says the neurobiologist from Bochum.
Theory: feedback regulation gets out of hand without Pannexin1
According to the scientists’ theory, nerve cells lack a feedback mechanism without Pannexin1. Normally the channel protein releases ATP, which binds to specific receptors and thus reduces the release of the neurotransmitter glutamate. Without Pannexin1 more glutamate is released, which leads to increased long-term potentiation. This causes the cell to lose its dynamic equilibrium, which is needed for an efficient learning process.
Mass. Eye and Ear Researchers Regenerate Sensory Hair Cells, Restore Hearing to Noise-Damaged Ears
Hearing loss is a significant public health problem affecting almost 50 million people in the United States alone. Sensorineural hearing loss is the most common form and is caused by the loss of sensory hair cells in the cochlea. Hair cell loss results from a variety of factors including noise exposure, aging, toxins, infections, and certain antibiotics and anti-cancer drugs. Although hearing aids and cochlear implants can ameliorate the symptoms somewhat, there are no known treatments to restore hearing, because auditory hair cells in mammals, unlike those in birds or fish, do not regenerate once lost. Auditory hair cell replacement holds great promise as a treatment that could restore hearing after loss of hair cells.
In the Jan. 10 issue of Neuron, Massachusetts Eye and Ear and Harvard Medical School researchers demonstrate for the first time that hair cells can be regenerated in an adult mammalian ear by using a drug to stimulate resident cells to become new hair cells, resulting in partial recovery of hearing in mouse ears damaged by noise trauma. This finding holds great potential for future therapeutic application that may someday reverse deafness in humans.
“Hair cells are the primary receptor cells for sound and are responsible for the sense of hearing,” explains senior author, Dr. Albert Edge, of Harvard Medical School and Mass. Eye and Ear. “We show that hair cells can be generated in a damaged cochlea and that hair cell replacement leads to an improvement in hearing.”
In the experiment, the researchers applied a drug to the cochlea of deaf mice. The drug had been selected for its ability to generate hair cells when added to stem cells isolated from the ear. It acted by inhibiting an enzyme called gamma-secretase that activates a number of cellular pathways. The drug applied to the cochlea inhibited a signal generated by a protein called Notch on the surface of cells that surround hair cells. These supporting cells turned into new hair cells upon treatment with the drug. Replacing hair cells improved hearing in the mice, and the improved hearing could be traced to the areas in which supporting cells had become new hair cells.
“The missing hair cells had been replaced by new hair cells after the drug treatment, and analysis of their location allowed us to correlate the improvement in hearing to the areas where the hair cells were replaced,” Dr. Edge said.
This is the first demonstration of hair cell regeneration in an adult mammal. “We’re excited about these results because they are a step forward in the biology of regeneration and prove that mammalian hair cells have the capacity to regenerate,” Dr. Edge said. “With more research, we think that regeneration of hair cells opens the door to potential therapeutic applications in deafness.”
Does listening to Mozart really boost your brainpower?
It is said that classical music could make children more intelligent, but when you look at the scientific evidence, the picture is more mixed.
You have probably heard of the Mozart effect. It’s the idea that if children or even babies listen to music composed by Mozart they will become more intelligent. A quick internet search reveals plenty of products to assist you in the task. Whatever your age there are CDs and books to help you to harness the power of Mozart’s music, but when it comes to scientific evidence that it can make you more clever, the picture is more mixed.
The phrase “the Mozart effect” was coined in 1991, but it is a study described two years later in the journal Nature that sparked real media and public interest about the idea that listening to classical music somehow improves the brain. It is one of those ideas that feels plausible. Mozart was undoubtedly a genius himself, his music is complex and there is a hope that if we listen to enough of it, a little of that intelligence might rub off on us.
The idea took off, with thousands of parents playing Mozart to their children, and in 1998 Zell Miller, the Governor of the state of Georgia in the US, even asked for money to be set aside in the state budget so that every newborn baby could be sent a CD of classical music. It’s not just babies and children who were deliberately exposed to Mozart’s melodies. When Sergio Della Sala, the psychologist and author of the book Mind Myths, visited a mozzarella farm in Italy, the farmer proudly explained that the buffalos were played Mozart three times a day to help them to produce better milk.
I’ll leave the debate on the impact on milk yield to farmers, but what about the evidence that listening to Mozart makes people more intelligent? Exactly what was it was that the authors of the initial study discovered that took public imagination by storm?
When you look back at the original paper, the first surprise is that the authors from the University of California, Irvine are modest in their claims and don’t even use the “Mozart effect” phrase in the paper. The second surprise is that it wasn’t conducted on children at all: it was in fact conducted with those stalwarts of psychological studies – young adult students. Only 36 students took part. On three occasions they were given a series of mental tasks to complete, and before each task, they listened either to ten minutes of silence, ten minutes of a tape of relaxation instructions, or ten minutes of Mozart’s sonata for two pianos in D major (K448).
The students who listened to Mozart did better at tasks where they had to create shapes in their minds. For a short time the students were better at spatial tasks where they had to look at folded up pieces of paper with cuts in them and to predict how they would appear when unfolded. But unfortunately, as the authors make clear at the time, this effect lasts for about fifteen minutes. So it’s hardly going to bring you a lifetime of enhanced intelligence.
Brain arousal
Nevertheless, people began to theorise about why it was that Mozart’s music in particular could have this effect. Did the complexity of music cause patterns of cortical firing in the brain similar to those associated with solving spatial puzzles?
More research followed, and a meta-analysis of sixteen different studies confirmed that listening to music does lead to a temporary improvement in the ability to manipulate shapes mentally, but the benefits are short-lived and it doesn’t make us more intelligent.
Then it began to emerge that perhaps Mozart wasn’t so special after all. In 2010 a larger meta-analysis of a greater number of studies again found a positive effect, but that other kinds of music worked just as well. One study found that listening to Schubert was just as good, and so was hearing a passage read out aloud from a Stephen King novel. But only if you enjoyed it. So, perhaps enjoyment and engagement are key, rather than the exact notes you hear.
Although we tend to associate the Mozart effect with babies and small children, most of these studies were conducted on adults, whose brains are of course at a very different stage of development. But in 2006 a large study was conducted in Britain involving eight thousand children. They listened either to ten minutes of Mozart’s String Quintet in D Major, a discussion about the experiment or to a sequence of three pop songs: Blur’s “Country House,” “Return of the Mack,” by Mark Morrison and PJ and Duncan’s “Stepping Stone”. Once again music improved the ability to predict paper shapes, but this time it wasn’t a Mozart effect, but a Blur effect. The children who listened to Mozart did well, but with pop music they did even better, so prior preference could come into it.
Whatever your musical choice, it seems that all you need to do a bit better at predictive origami is some cognitive arousal. Your mind needs to get a little more active, it needs something to get it going and that’s going to be whichever kind of music appeals to you. In fact, it doesn’t have to be music. Anything that makes you more alert should work just as well – doing a few star jumps or drinking some coffee, for instance.
There is a way in which music can make a difference to your IQ, though. Unfortunately it requires a bit more effort than putting on a CD. Learning to play a musical instrument can have a beneficial effect on your brain. Jessica Grahn, a cognitive scientist at Western University in London, Ontario says that a year of piano lessons, combined with regular practice can increase IQ by as much as three points.
So listening to Mozart won’t do you or your children any harm and could be the start of a life-long love of classical music. But unless you and your family have some urgent imaginary origami to do, the chances are that sticking on a sonata is not going to make you better at anything.
(Source: bbc.com)
First Oral Drug for Spinal Cord Injury Improves Movement in Mice
An experimental oral drug given to mice after a spinal cord injury was effective at improving limb movement after the injury, a new study shows.
The compound efficiently crossed the blood-brain barrier, did not increase pain and showed no toxic effects to the animals.
“This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model,” said Sung Ok Yoon, associate professor of molecular & cellular biochemistry at Ohio State University and lead author of the study. “So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement.”
The small molecule in this study was tested for its ability to prevent the death of cells called oligodendrocytes. These cells surround and protect axons, long projections of a nerve cell, by wrapping them in myelin. In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.
The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon’s lab previously discovered that p75 is linked to the death of these specialized cells after a spinal cord injury. When they die, axons that are supported by them degenerate.
“Because we know that oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons,” she said. “Many researchers in the field are focusing on regeneration of neurons, but we specifically targeted a different type of cells because it allows a relatively long therapeutic window.”
An additional benefit of targeting oligodendrocytes is that it can amplify the therapeutic effect because a single oligodendrocyte myelinates multiple axons.
A current acute treatment for humans, methylprednisolone, must be administered within eight but not more than 24 hours after the injury to be effective at all. An estimated 1.3 million people in the United States are living with spinal cord injuries, experiencing paralysis and complications that include bladder, bowel and sexual dysfunction and chronic pain.
The experimental drug, called LM11A-31, was developed by study co-author Frank Longo, professor of neurology and neurological sciences at Stanford University. The drug is the first to be developed with a specific target, p75, as a potential therapy for spinal cord injury.
The research is published in the Jan. 9, 2013, issue of The Journal of Neuroscience.
Researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42-day experimental period. The scientists analyzed the compound’s effectiveness at improving limb movement and preventing myelin loss.
The spinal cord injuries in mice mimicked those caused in humans by the application of extensive force and pressure, resulting in loss of hind-limb and bladder function andexperimentally calibrated baseline difficulty in walking and swimming.
The researchers determined that the mice did not experience more pain than the placebo group at all the doses tested, suggesting that LM11A-31 does not worsen nerve pain after spinal cord injury.
Analysis showed that the extent of myelin sparing was dependent on the dose of the drug. Each dose – 10, 25 or 100 milligrams per kilogram of body weight – led to increasing myelin sparing, with the highest dose demonstrating the greatest effect.
The injury in the animals caused a loss of about 75 percent of myelinated axons in the lesion area in the placebo group. This loss was reduced so that myelinated axons reached more than half of the normal levels with LM11A-31 at 100 mg/kg. That was correlated with about a 50 percent increase in surviving oligodendrotcytes compared to those in the placebo group, Yoon said.
In behavior tests, only the highest dose of the compound led to improvements in motor function. Mice were tested in both weight-bearing and non-weight-bearing activities over the 42 days to evaluate their functional recovery.
Mice receiving the highest dose could walk with well-coordinated steps. In swimming tests, scientists saw similar improvements, with mice receiving the highest dose most able to coordinate hind-limb crisscross movement. The other treatment groups exhibited difficulty in walking and swimming.
Yoon said the findings may suggest that myelin sparing needs to reach a threshold of roughly 50 percent of normal levels before motor function improvements become measurable.
“The cellular analysis of the myelin profile detects small changes. Behavior is more complex, and we don’t think functional behavior necessarily improves in a linear fashion,” she said. “Still, these results clearly show that this is the first oral drug in spinal cord injury that works alone to improve function.”
(Source: researchnews.osu.edu)