(Image caption: The complex shape of individual oligodendrocytes (OLs) and myelin in adult mice injected with tamoxifen. Credit: Sarah Jolly)

Myelin vital for learning new practical skills

New evidence of myelin’s essential role in learning and retaining new practical skills, such as playing a musical instrument, has been uncovered by UCL research. Myelin is a fatty substance that insulates the brain’s wiring and is a major constituent of ‘white matter’. It is produced by the brain and spinal cord into early adulthood as it is needed for many developmental processes, and although earlier studies of human white matter hinted at its involvement in skill learning, this is the first time it has been confirmed experimentally.

The study in mice, published in Science today, shows that new myelin must be made each time a skill is learned later in life and the structure of the brain’s white matter changes during new practical activities by increasing the number of myelin-producing cells. Furthermore, the team say once a new skill has been learnt, it is retained even after myelin production stops. These discoveries could prove important in finding ways to stimulate and improve learning, and in understanding myelin’s involvement in other brain processes, such as in cognition.

For a child to learn to walk or an adult to master a new skill such as juggling, new brain circuit activity is needed and new connections are made across large distances and at high speeds between different parts of the brain and spinal cord. For this, electrical signals fire between neurons connected by “axons” – thread-like extensions of their outer surfaces which can be viewed as the ‘wire’ in the electric circuit. When new signals fire repeatedly along axons, the connections between the neurons strengthen, making them easier to fire in the same pattern in future. Neighbouring myelin-producing cells called oligodendrocytes (OLs) recognise the repeating signal and wrap myelin around the active circuit wiring. It is this activity-driven insulation that the team identified as essential for learning.

The team demonstrated that young adult mice need to make myelin to learn new motor skills but that new myelin does not need to be produced to recall and perform a pre-learned skill. They tested the ability of mice to learn to run on a complex wheel with irregularly spaced rungs. The study looked at thirty-six normal mice and thirty-two mice with a drug-controlled genetic switch to prevent new OLs and myelin from being made. They found the mice that were prevented from producing new myelin could not master the complex wheel, whereas those that could produce myelin did learn, with differences between the two groups’ abilities seen after only two hours of practice.

A second experiment looked at mice that were first allowed to learn to run on the complex wheel before being treated with the drug to prevent further myelin production. When the mice were later re-introduced to the complex wheel, they were immediately able to run at top speed without having to spend time re-learning. This shows that the inability to make new myelin did not affect the mouse’s running ability and that new myelin is not required to remember and perform a skill once learned; it is required only during the initial learning phase.

Lead researcher, Professor Bill Richardson, Director of the UCL Wolfson Institute for Biomedical Research, said: “From earlier studies of human white matter using advanced MRI technology, we thought OLs and myelin might be involved in some way in skill learning, so we decided to attack this idea experimentally. We were surprised how quickly we saw differences in the ability of mice from each group to learn how to run on complex wheel, which shows just how fast the brain can respond to wrap newly-activated circuits in myelin and how this improves learning. This rapid response suggests that a number of alternative axon pathways might already exist in the brain that could be used to drive a particular sequence of movements, but it quickly works out which of those circuits is most efficient and both selects and protects its chosen route with myelin.

“We think these findings are really exciting as they open up opportunities to investigate the role of OLs and myelin in other brain processes, such as cognitive activities (like navigating through a maze), to see if the requirement for new myelin is general or specific to motor activity. I’m keen to find out the precise sequence of changes to OLs and myelin during learning and whether these changes are needed more in some parts of the brain than others, which might shed light on some of the mysteries still surrounding how the brain adapts and learns throughout life.”

Orchestral manoeuvres: multiple sclerosis faces the music

The conductor walks to the stand and takes his place in front of the orchestra. He raises his baton and, with a dramatic flourish, one hundred individuals come to life. From nowhere, the stillness becomes a beautiful harmony as each member takes their part in a complex symphony.

Consider the workings and structure of the human brain – our most complicated organ – in terms of this orchestra. When it works, it is capable of something more remarkable than the greatest musical compositions in human history, but when it is affected by a condition such as multiple sclerosis (MS), “the brain’s tightly orchestrated biological functions become discordant – the conductor begins to fail at their job and several instruments go out of tune,” said Professor Robin Franklin, Head of Translational Science at the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute and Director of the MS Society Cambridge Centre for Myelin Repair.

His research team and those led by other Stem Cell Institute researchers Drs Thóra Káradóttir, Mark Kotter and Stefano Pluchino are each looking at a different aspect of this errant orchestra. They hope that their collective knowledge will one day help ‘re-tune’ the brains of MS patients to self-repair.

In its simplest terms, MS is a disease in which the immune system turns on itself, destroying the oligodendrocytes that make a protective sheath called myelin, which encases nerve fibres. This halts the transmission of neural messages, and eventually leads to nerve fibre damage, resulting in a progressive loss of movement, speech and vision for the 100,000 people in the UK who have MS.

However, the complexities of treating the disease go beyond simply stopping the destruction of myelin, said Franklin: “The myelin damage causes a build-up of debris, which needs removing, and the environment surrounding the cells needs to be conducive to regenerating the sheath. When we think about repairing the damage, we need to be considering several different biological phenomena at the same time.”

Although there are drugs available for modifying the early stages of MS – including alemtuzumab (Lemtrada), developed in Cambridge – there are no treatments that regenerate the damaged tissue. Moreover, although the disease evolves over decades, with periods of remission followed by relapses, there is no treatment once patients have reached the progressive stage (estimated to be about 50% of current patients).

Oligodendrocytes – the master manufacturers of myelin – are formed by a type of stem cell in the brain called oligodendrocyte progenitor cells (OPCs), and are responsible for re-wrapping, or remyelinating, the bare axons with myelin in response to injuries or diseases. But this regenerative ability decreases with age and MS. “As the disease progresses, the need for intervention that galvanises the natural healing process becomes ever more important,” explained Franklin. “Working with colleagues at the Harvard Stem Cell Institute, we’ve shown that the effects of age on remyelination are reversible, which gives us some confidence that we can use the brain’s own OPCs for myelin regeneration.”

However, to understand how to stimulate the brain’s own repair mechanisms first requires an understanding of how the brain detects injury and initiates repair.

Thóra Káradóttir believes that one way the brain ‘senses’ problems are afoot is through the drop in how fast neural messages are passed across the brain. “The difference in speed between an intact neuron and a damaged one can be like comparing the speed of a cheetah to a tortoise,” she said. “I’m eavesdropping on the information superhighway by attaching electrodes to neurons and OPCs.”

Her findings show that damaged fibres release a molecule called glutamate. “It’s their ‘cry for help’ to OPCs. If it doesn’t happen, or if the OPCs don’t ‘hear’, then repair is reduced.” She is working with Numedicus, a company that specialises in developing secondary uses for existing drugs, to test drugs that she hopes will be able to amplify this signal and increase the repair process.

Meanwhile, Robin Franklin’s team has shown that it’s possible to kick-start OPCs, driving the formation of oligodendrocytes and sheath formation, using a drug that targets retinoid X receptor-gamma, a molecule found within OPCs. The results are positive and clinical trials will shortly commence in collaboration with Dr Alasdair Coles from the Department of Clinical Neurosciences and the MRC Centre for Regenerative Medicine at the University of Edinburgh.

What’s interesting about the rejuvenation of remyelination is that the treatment primarily affected inflammation in demyelinating lesions, and specifically the recruitment of cells called macrophages. These are the body’s ‘big eaters’ – their role is to search out and gobble up rubbish. “We have identified myelin debris as a potent inhibitor of stem cells. Learning how it is being sensed by stem cells enabled us to overcome this inhibition by using drugs such as ibudilast.  A clinical trial to test these effects is currently undergoing preparation,” explained Mark Kotter.

Franklin and Kotter’s work is representative of an interesting turn in MS research within the field. Increasingly, investigators are looking at how the environment around the damage can be improved to help natural remyelination. “It’s a curious paradox,” said Franklin. “MS is caused by the immune system but components of the immune system are also key to its recovery.”

Stefano Pluchino’s team, for instance, has shown that injecting brain stem cells into mice with MS works in a surprising way. Instead of making new oligodendrocytes (or other brain cells), the cells seem to work by re-setting the damaging immune response, creating better conditions for the brain’s own stem cells to replace or restore what has been damaged. He is now developing more-efficient stem cells and new drugs, including nanomedicines, to foster the healing of the damaged brain.

Given the complex landscape of abnormal activities happening in the MS brain, will combination therapies be the way forward? “Certainly,” said Franklin. “Over the next ten years we will see an increased understanding of the fundamental biology in MS, we will identify more targets which may yield effective drugs and we’ll have more-refined strategies for running clinical trials. What makes Cambridge rare is the spectrum of skills here – from understanding the fundamental biology of myelin repair through to clinical trials.”

Turning science on its head

Harvard neuroscientists have made a discovery that turns 160 years of neuroanatomy on its head.

Myelin, the electrical insulating material in the body long known to be essential for the fast transmission of impulses along the axons of nerve cells, is not as ubiquitous as thought, according to new work led by Professor Paola Arlotta of the Harvard Stem Cell Institute (HSCI) and the University’s Department of Stem Cell and Regenerative Biology, in collaboration with Professor Jeff Lichtman of Harvard’s Department of Molecular and Cellular Biology.

“Myelin is a relatively recent invention during evolution,” says Arlotta. “It’s thought that myelin allowed the brain to communicate really fast to the far reaches of the body, and that it has endowed the brain with the capacity to compute higher-level functions.”

In fact, loss of myelin is a feature in a number of devastating diseases, including multiple sclerosis and schizophrenia.

But the new research shows that despite myelin’s essential roles in the brain, “some of the most evolved, most complex neurons of the nervous system have less myelin than older, more ancestral ones,” said Arlotta, co-director of the HSCI neuroscience program.

What this means, she said, is that the higher one looks in the cerebral cortex — closer to the top of the brain, which is its most evolved part — the less myelin one finds.  Not only that, but “neurons in this part of the brain display a brand-new way of positioning myelin along their axons that has not been previously seen. They have ‘intermittent myelin’ with long axon tracts that lack myelin interspersed among myelin-rich segments.”

“Contrary to the common assumptions that neurons use a universal profile of myelin distribution on their axons, the work indicates that different neurons choose to myelinate their axons differently,” Arlotta said. “In classic neurobiology textbooks, myelin is represented on axons as a sequence of myelinated segments separated by very short nodes that lack myelin. This distribution of myelin was tacitly assumed to be always the same, on every neuron, from the beginning to the end of the axon. This new work finds this not to be the case.”

The results of the research by Arlotta and postdoctoral fellow Giulio Srubek Tomassy, the first author on the report, are published in the latest edition of the journal Science.

The paper is accompanied by a “perspective” by R. Douglas Fields of the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, who said that Arlotta and Tomassy’s findings raise important questions about the purpose of myelin, and “are likely to spark new concepts about how information is transmitted and integrated in the brain.”

Arlotta and Tomassy collaborated closely on the new work with postdoctoral fellow Daniel Berger of the Lichtman lab, which generated one of the two massive electron microscopy databases that made the work possible.

“The fact that it is the most evolved neurons, the ones that have expanded dramatically in humans, suggest that what we’re seeing might be the ‘future.’ As neuronal diversity increases and the brain needs to process more and more complex information, neurons change the way they use myelin to achieve more,” said Arlotta.

Tomassy said it is possible that these profiles of myelination “may be giving neurons an opportunity to branch out and ‘talk’ to neighboring neurons.” For example, because axons cannot make synaptic contacts when they are myelinated, one possibility is that these long myelin gaps may be needed to increase neuronal communication and synchronize responses across different neurons. He and Arlotta postulate that the intermittent myelin may be intended to fine-tune the electrical impulses traveling along the axons, in order to allow the emergence of highly complex neuronal behaviors.

Brain activity drives dynamic changes in neural fiber insulation

The brain is a wonderfully flexible and adaptive learning tool. For decades, researchers have known that this flexibility, called plasticity, comes from selective strengthening of well-used synapses — the connections between nerve cells.

Now, researchers at the Stanford University School of Medicine have demonstrated that brain plasticity also comes from another mechanism: activity-dependent changes in the cells that insulate neural fibers and make them more efficient. These cells form a specialized type of insulation called myelin.

“Myelin plasticity is a fascinating concept that may help to explain how the brain adapts in response to experience or training,” said Michelle Monje, MD, PhD, assistant professor of neurology and neurological sciences.

The researchers’ findings are described in a paper published online April 10 in Science Express.

“The findings illustrate a form of neural plasticity based in myelin, and future work on the molecular mechanisms responsible may ultimately shed light on a broad range of neurological and psychiatric diseases,” said Monje, senior author of the paper. The lead authors of the study are Stanford postdoctoral scholar Erin Gibson, PhD, and graduate student David Purger.

Sending neural impulses quickly down a long nerve fiber requires insulation with myelin, which is formed by a cell called an oligodendrocyte that wraps itself around a neuron. Even small changes in the structure of this insulating sheath, such as changes in its thickness, can dramatically affect the speed of neural-impulse conduction. Demyelinating disorders, such as multiple sclerosis, attack these cells and degrade nerve transmission, especially over long distances.

Myelin-insulated nerve fibers make up the “white matter” of the brain, the vast tracts that connect one information-processing area of the brain to another. “If you think of the brain’s infrastructure as a city, the white matter is like the roads, highways and freeways that connect one place to another,” Monje said.

In the study, Monje and her colleagues showed that nerve activity prompts oligodendrocyte precursor cell proliferation and differentiation into myelin-forming oligodendrocytes. Neuronal activity also causes an increase in the thickness of the myelin sheaths within the active neural circuit, making signal transmission along the neural fiber more efficient. It’s much like a system for improving traffic flow along roadways that are heavily used, Monje said. And as with a transportation system, improving the routes that are most productive makes the whole system more efficient.

In recent years, researchers have seen clues that nerve cell activity could promote the growth of myelin insulation. There have been studies that showed a correlation between experience and myelin dynamics, and studies of isolated cells in a dish suggesting a relationship between neuronal activity and myelination. But there has been no way to show that neuronal activity directly causes myelin changes in an intact brain. “You can’t really implant an electrode in the brain to answer this question because the resulting injury changes the behavior of the cells,” Monje said.

The solution was a relatively new and radical technique called optogenetics. Scientists insert genes for a light-sensitive ion channel into a specific group of neurons. Those neurons can be made to fire when exposed to particular wavelengths of light. In the study, Monje and her colleagues used mice with light-sensitive ion channels in an area of their brains that controls movement. The scientists could then turn on and off certain movement behaviors in the mice by turning on and off the light. Because the light diffuses from a source placed at the surface of the brain down to the neurons being studied, there was no need to insert a probe directly next to the neurons, which would have created an injury.

By directly stimulating the neurons with light, the researchers were able to show it was the activation of the neurons that prompted the myelin-forming cells to respond.

Further research could reveal exactly how activity promotes oligodendrocyte-precursor-cell proliferation and maturation, as well as dynamic changes in myelin. Such a molecular understanding could help researchers develop therapeutic strategies that promote myelin repair in diseases in which myelin is degraded, such as multiple sclerosis, the leukodystrophies and spinal cord injury.

“Conversely, when growth of these cells is dysregulated, how does that contribute to disease?” Monje said. One particular area of interest for her is a childhood brain cancer called diffuse intrinsic pontine glioma. The cancer, which usually strikes children between 5 and 9 years old and is inevitably fatal, occurs when the brain myelination that normally takes place as kids become more physically coordinated goes awry, and the brain cells grow out of control.

Quality of white matter in the brain is crucial for adding and multiplying

‘Grey’ cells process information in the brain and are connected via neural pathways, the tracts through which signals are transferred.

"Neural pathways are comparable to a bundle of cables. These cables are surrounded by an isolating sheath: myelin, or ‘white matter’. The thicker the isolating sheath and the more cables there are, the more white matter. And the more white matter, the faster the signals are transferred," explains educational neuroscientist Bert de Smedt.

While the correlation between arithmetic and white matter tracts linking certain brain regions is known, very little research has been done to test this correlation in normally-developing children. Nor has previous research teased out differences in neuroactivity when carrying out different arithmetic operations, e.g., adding, subtracting, multiplying and dividing.

In this study, the researchers had 25 children solve a series of different arithmetic operations while undergoing a brain scan. They then compared the quality of the children’s white matter tracts with their arithmetic test performance.

"We found that a better quality of the arcuate fasciculus anterior – a white matter tract that connects brain regions often used for arithmetic – corresponds to better performance in adding and multiplying, while there is no correlation for subtracting and dividing.”

“A possible explanation for this is that this white matter bundle is involved in rote memorization, whereas when we subtract and divide, such memorization plays less of a role. When subtracting and dividing we are more likely to use intermediary steps to calculate the solution, even as adults.”

Nursery rhymes

These findings also add insight into the link between reading and arithmetic, explains Professor De Smedt: “Reading proficiency and arithmetic proficiency often go hand-in-hand. The white matter tract that we studied also plays an important role in reading: when we learn to read, we have to memorize the correspondence between particular letters and the sound they represent. It is likely that a similar process occurs for addition and multiplication. Just think of the notorious times-table drills we all memorized as schoolchildren; it is almost like learning a nursery rhyme. Some of us can even auto-recall these sums.”

"This also might explain why we often see arithmetic problems in children with dyslexia. Likewise, children with dyscalculia often have trouble reading," says Professor De Smedt.

The researchers now aim to explore how these results relate to children with impairments such as dyscalculia or head trauma. In a next step, the team will also investigate how white matter tracts can be strengthened through extra arithmetic training.

Connections in the brains of young children strengthen during sleep

While young children sleep, connections between the left and the right hemispheres of their brain strengthen, which may help brain functions mature, according to a new study by the University of Colorado Boulder.

The research team—led by Salome Kurth, a postdoctoral researcher, and Monique LeBourgeois, assistant professor in integrative physiology—used electroencephalograms, or EEGs, to measure the brain activity of eight sleeping children multiple times at the ages of 2, 3 and 5 years.

“Interestingly, during a night of sleep, connections weakened within hemispheres but strengthened between hemispheres,” Kurth said.

Scientists have known that the brain changes drastically during early childhood: New connections are formed, others are removed and a fatty layer called “myelin” forms around nerve fibers in the brain. The growth of myelin strengthens the connections by speeding up the transfer of information.

Maturation of nerve fibers leads to improvement in skills such as language, attention and impulse control. But it is still not clear what role sleep plays in the development of such brain connections.

In the new study, appearing online in the journal Brain Sciences, the researchers looked at differences in brain activity during sleep as the children got older and differences in brain activity of each child over a night’s sleep. They found that connections in the brain generally became stronger during sleep as the children aged. They also found that the strength of the connections between the left and right hemispheres increased by as much as 20 percent over a night’s sleep.

“There are strong indications that sleep and brain maturation are closely related, but at this time, it is not known how sleep leads to changes in brain structure,” Kurth said.

Future studies will be aimed at determining how sleep disruption during childhood may affect brain development and behavior.

“I believe inadequate sleep in childhood may affect the maturation of the brain related to the emergence of developmental or mood disorders,” Kurth said.

Quantity, not just quality, in new Stanford brain scan method

Researchers used magnetic resonance imaging to quantify brain tissue volume, a critical measurement of the progression of multiple sclerosis and other diseases.

Imagine that your mechanic tells you that your brake pads seem thin, but doesn’t know how long they will last. Or that your doctor says your child has a temperature, but isn’t sure how high. Quantitative measurements help us make important decisions, especially in the doctor’s office. But a potent and popular diagnostic scan, magnetic resonance imaging (MRI), provides mostly qualitative information.

An interdisciplinary Stanford team has now developed a new method for quantitatively measuring human brain tissue using MRI. The team members measured the volume of large molecules (macromolecules) within each cubic millimeter of the brain. Their method may change the way doctors diagnose and treat neurological diseases such as multiple sclerosis.

"We’re moving from qualitative – saying something is off – to measuring how off it is," said Aviv Mezer, postdoctoral scholar in psychology. The team’s work, funded by research grants from the National Institutes of Health, appears in the journal Nature Medicine.

Mezer, whose background is in biophysics, found inspiration in seemingly unrelated basic research from the 1980s. In theory, he read, magnetic resonance could quantitatively discriminate between different types of tissues.

"Do the right modifications to make it applicable to humans," he said of adapting the previous work, "and you’ve got a new diagnostic."

Previous quantitative MRI measurements required uncomfortably long scan times. Mezer and psychology Professor Brian Wandell unearthed a faster scanning technique, albeit one noted for its lack of consistency.

"Now we’ve found a way to make the fast method reliable," Mezer said.

Mezer and Wandell, working with neuroscientists, radiologists and chemical engineers, calibrated their method with a physical model – a radiological “phantom” – filled with agar gel and cholesterol to mimic brain tissue in MRI scans.

The team used one of Stanford’s own MRI machines, located in the Center for Cognitive and Neurobiological Imaging, or CNI. Wandell directs the two-year-old center. Most psychologists, he said, don’t have that level of direct access to their MRI equipment.

"Usually there are many people between you and the instrument itself," Wandell said.

This study wouldn’t have happened, Mezer said, without the close proximity and open access to the instrumentation in the CNI.

Their results provided a new way to look at a living brain.

MRI images of the brain are made of many “voxels,” or three-dimensional elements. Each voxel represents the signal from a small volume of the brain, much like a pixel represents a small volume of an image. The fraction of each voxel filled with brain tissue (as opposed to water) is called the macromolecular tissue volume, or MTV. Different areas of the brain have different MTVs. Mezer found that his MRI method produced MTV values in agreement with measurements that, until now, could only come from post-mortem brain specimens.

This is a useful first measurement, Mezer said. “The MTV is the most basic entity of the structure. It’s what the tissue is made of.”

The team applied its method to a group of multiple sclerosis patients. MS attacks a layer of cells called the myelin sheath, which protects neurons the same way insulation protects a wire. Until now, doctors typically used qualitative MRI scans (displaying bright or dark lesions) or behavioral tests to assess the disease’s progression.

Myelin comprises most of the volume of the brain’s “white matter,” the core of the brain. As MS erodes myelin, the MTV of the white matter changes. Just as predicted, Mezer and Wandell found that MS patients’ white matter tissue volumes were significantly lower than those of healthy volunteers. Mezer and colleagues at Stanford School of Medicine are now following up with the patients to evaluate the effect of MS drug therapies. They’re using MTV values to track individual brain tissue changes over time.

The team’s results were consistent among five MRI machines.

Mezer and Wandell will next use MRI measurements to monitor brain development in children, particularly as the children learn to read. Wandell’s previous work mapped the neural connections involved in learning to read. MRI scans can measure how those connections form.

"You can compare whether the circuits are developing within specified limits for typical children," Wandell said, "or whether there are circuits that are wildly out of spec, and we ought to look into other ways to help the child learn to read."

Tracking MTV, the team said, helps doctors better compare patients’ brains to the general population – or to their own history – giving them a chance to act before it’s too late.

New Strategy to Treat Multiple Sclerosis Shows Promise in Mice

Scientists at The Scripps Research Institute (TSRI) have identified a set of compounds that may be used to treat multiple sclerosis (MS) in a new way. Unlike existing MS therapies that suppress the immune system, the compounds boost a population of progenitor cells that can in turn repair MS-damaged nerve fibers.

One of the newly identified compounds, a Parkinson’s disease drug called benztropine, was highly effective in treating a standard model of MS in mice, both alone and in combination with existing MS therapies.

“We’re excited about these results, and are now considering how to design an initial clinical trial,” said Luke L. Lairson, an assistant professor of chemistry at TSRI and a senior author of the study, which is reported online in Nature on October 9, 2013.

Lairson cautioned that benztropine is a drug with dose-related adverse side effects, and has yet to be proven effective at a safe dose in human MS patients. “People shouldn’t start using it off-label for MS,” he said.

A New Approach

An autoimmune disease of the brain and spinal cord, MS currently affects more than half a million people in North America and Europe, and more than two million worldwide. Its precise triggers are unknown, but certain infections and a lack of vitamin D are thought to be risk factors. The disease is much more common among those of Northern European heritage, and occurs about twice as often in women as in men.

In MS, immune cells known as T cells infiltrate the upper spinal cord and brain, causing inflammation and ultimately the loss of an insulating coating called myelin on some nerve fibers. As nerve fibers lose this myelin coating, they lose their ability to transmit signals efficiently, and in time may begin to degenerate. The resulting symptoms, which commonly occur in a stop-start, “relapsing-remitting” pattern, may include limb weakness, numbness and tingling, fatigue, vision problems, slurred speech, memory difficulties and depression, among other problems.

Current therapies, such as interferon beta, aim to suppress the immune attack that de-myelinates nerve fibers. But they are only partially effective and are apt to have significant adverse side effects.

In the new study, Lairson and his colleagues decided to try a complementary approach, aimed at restoring a population of progenitor cells called oligodendrocytes. These cells normally keep the myelin sheaths of nerve fibers in good repair and in principle could fix these coatings after MS damages them. But oligodendrocyte numbers decline sharply in MS, due to a still-mysterious problem with the stem-like precursor cells that produce them. “Oligodendrocyte precursor cells (OPCs) are present during progressive phases of MS, but for unknown reasons don’t mature into functional oligodendrocytes,” Lairson said.

A 100,000-Molecule Screen

Using a sophisticated small-molecule screening laboratory that TSRI manages in conjunction with the California Institute of Regenerative Medicine and in collaboration with the California Institute for Biomedical Research (Calibr), Lairson and his team screened a library of about 100,000 diverse compounds for any that could potently induce OPCs to mature or “differentiate.”

Several compounds scored well as OPC differentiation-inducers. Most were compounds of unknown activity —but one, benztropine, had been well characterized and indeed was already FDA-approved for treating Parkinson’s disease. “That was a surprise, and it meant that we could move forward relatively quickly in testing it,” said graduate student Vishal A. Deshmukh, first author of the paper who performed most of these experiments.

With the help of Brian R. Lawson, a senior author of the paper and assistant professor of immunology at TSRI, and his colleague Research Associate Virginie Tardif, Deshmukh set up tests of benztropine in mice with an induced MS-like autoimmune disease—a model commonly used for testing prospective MS drugs.

In these tests, benztropine showed a powerful ability to prevent autoimmune disease and also was effective in treating it after symptoms had arisen—virtually eliminating the disease’s ability to relapse. Although benztropine on its own worked about as well as existing treatments, it also showed a remarkable ability to complement these existing treatments, in particular two first-line immune-suppressant therapies, interferon-beta and fingolimod.

“Adding even a suboptimal level of benztropine effectively allowed us, for example, to cut the dose of fingolimod by 90%—and achieve the same disease-modifying effect as a normal dose of fingolimod,” said Lawson. “In a clinical setting that dose-lowering could translate into a big reduction in fingolimod’s potentially serious side effects.”

In further analyses, the researchers confirmed that benztropine works against disease in this mouse model by boosting the population of mature oligodendrocytes, which in turn restore the myelin sheaths of damaged nerves—even as the immune attack continues. “The benztropine-treated mice showed no change in the usual signs of inflammation, yet their myelin was mostly intact, suggesting that it was probably being repaired as rapidly as it was being destroyed,” said Lawson.

Benztropine is known to have multiple specific effects on brain cells, including the blocking of activity at acetylcholine and histamine receptors and a boosting of activity at dopamine receptors. But Lairson and his colleagues found evidence that the drug stimulates OPCs to differentiate mainly by blocking M1 or M3 acetylcholine receptors on these cells.

In addition to setting up initial clinical trials, Lairson and his team hope to learn more about how benztropine induces OPC maturation, and how its molecular structure might be optimized for this purpose. “We’re also looking at some of the other, relatively unknown molecules that we identified in our initial screen, to see if any of those has better clinical potential than benztropine,” he said.

“This work, like our previous studies with hematopoietic and mesenchymal stem cells, illustrates the power of small molecules to control stem and precursor cells in ways that may ultimately lead to a new generation of drugs for regenerative medicine,” said Peter G. Schultz, the Scripps Family Chair Professor in the Department of Chemistry at TSRI and one of the study’s senior authors.