Posts tagged oligodendrocytes
Articles and news from the latest research reports.
(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.”
(Image caption: Neurons (blue) which have absorbed exosomes (green) have increased levels of the enzyme catalase (red), which helps protect them against peroxides. Credit: Institute of Molecular Cell Biology)
Vesicles influence the function of nerve cells
Tiny vesicles containing protective substances which they transmit to nerve cells apparently play an important role in the functioning of neurons. As cell biologists at Johannes Gutenberg University Mainz (JGU) have discovered, nerve cells can enlist the aid of mini-vesicles of neighboring glial cells to defend themselves against stress and other potentially detrimental factors. These vesicles, called exosomes, appear to stimulate the neurons on various levels: they influence electrical stimulus conduction, biochemical signal transfer, and gene regulation. Exosomes are thus multifunctional signal emitters that can have a significant effect in the brain.
The researchers in Mainz already observed in a previous study that oligodendrocytes release exosomes on exposure to neuronal stimuli. These exosomes are absorbed by the neurons and improve neuronal stress tolerance. Oligodendrocytes are a type of glial cell and they form an insulating myelin sheath around the axons of neurons. The exosomes transport protective proteins such as heat shock proteins, glycolytic enzymes, and enzymes that reduce oxidative stress from one cell type to another, but also transmit genetic information in the form of ribonucleic acids.
"As we have now discovered in cell cultures, exosomes seem to have a whole range of functions," explained Dr. Eva-Maria Krämer-Albers. By means of their transmission activity, the small bubbles that are the vesicles not only promote electrical activity in the nerve cells, but also influence them on the biochemical and gene regulatory level. "The extent of activities of the exosomes is impressive," added Krämer-Albers. The researchers hope that the understanding of these processes will contribute to the development of new strategies for the treatment of neuronal diseases. Their next aim is to uncover how vesicles actually function in the brains of living organisms.
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.”
Stem Cell Therapies Hold Promise, But Obstacles Remain
In an article appearing online today in the journal Science, a group of researchers, including University of Rochester neurologist Steve Goldman, M.D., Ph.D., review the potential and challenges facing the scientific community as therapies involving stem cells move closer to reality.
The review article focuses on pluripotent stem cells (PSCs), which are stem cells that can give rise to all cell types. These include both embryonic stem cells, and those derived from mature cells that have been “reprogrammed” or “induced” – a process typically involving a patient’s own skin cells – so that they possess the characteristics of stem cells found at the earliest stage of development. These cells can then be differentiated, through careful manipulation of chemical and genetic signaling, to become virtually any cell type found in the body.
While the process of making induced PSCs is relatively new in scientific terms – it was first demonstrated that skin cells could be successfully reprogrammed in 2007 – one of the reasons that these cells are viewed with promise by the scientific community is because they are derived from the patient’s own tissue. Consequently, cells used for transplant can be a genetic match and far less likely to be rejected, thereby potentially mitigating the need to use immune system suppressing drugs.
The article addresses the current state of efforts to apply PSCs to treat a number of diseases, including diabetes, liver disease, and heart disease. Goldman, a distinguished professor and co-director of the University of Rochester School of Medicine and Dentistry Center for Translational Neuromedicine, reviewed the current state of therapies for neurological diseases.
While progress has been made over the last several years, the authors point out that significant challenges remain. Scientists must be able to obtain the precise cell populations required to treat the target disease, and once transplanted, make sure that these cells get to where they are needed and integrate into existing tissue. The cells that are transplanted must also first be checked for purity and screened for unwanted cells that could give rise to tumors.
Goldman and his co-authors contend that “the brain is arguable the most difficult of the organs in which to employ stem cell-based therapeutics.” The complex connections and interdependency between neurons and the myriad of other support cells found in central nervous mean that a precise reconstruction of damaged areas of the brain is often impractical. Also, many degenerative neurological disorders, including Alzheimer’s, involve more than one cell type, making them difficult targets for stem cell therapies, at least in the near future.
Instead, Goldman argues that neurological diseases that involve a single cell type – at least at the early stages – are more promising targets for PSC-based therapies. These include Parkinson’s disease and Huntington’s disease, which are characterized by the loss of dopamine-producing neurons and medium spiny neurons, respectively. In particular, diseases that involved support cells found in the brain known as glia – such as multiple sclerosis, white matter stroke, cerebral palsy, and pediatric leukodystrophies – are especially strong candidates for stem cell therapies. These diseases are characterized by the loss of a specific glial cell type called the oligodendrocyte, which makes myelin, the insulation that allows electrical signals to travel between nerve cells. In multiple sclerosis, the body’s own immune system attacks and destroys these cells and, over time, communication between cells is disrupted or even lost.
Oligodendrocytes are the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Scientists have long speculated that, if successfully transplanted into the diseased or injured brain, OPCs might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.
Goldman’s group has already shown that OPCs produced from PSCs obtained from human skin cells successfully restore myelin in the brains and spinal cords of myelin-deficient mice, and can rescue and restore function to mice that would have otherwise died. While this work demonstrated the promise of stem cell therapies, it also illustrated the challenges facing scientists. It took Goldman’s lab four years to establish the exact chemical signaling required to reprogram, produce, and ultimately purify OPCs in sufficient quantities for transplantation, and only recently has the group developed methods for producing the cells in purity and quantity sufficient to transplant into humans.
The authors contend that future progress will depend upon continued close collaboration between scientists and clinicians, and between academia, industry and regulatory bodies to overcome the remaining barriers to bringing new stem cell-based therapies to patients with these devastating diseases.
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.
Researchers Find Inherited Pathway of Risk for Schizophrenia
Schizophrenia is one of the most disabling of all psychiatric illnesses. Sadly, it is not uncommon and it strikes early in life.
Many studies have looked into causes and potential interventions, and it has been long known that genetic factors play a role in determining the risk of developing schizophrenia. However, recent work has shown that there will be no simple answers as to why some people get schizophrenia: No single gene or small number of genes explains much of the risk for illness. Instead, future studies must focus on larger numbers of interacting genes.
In a new paper published in PLOS ONE, researchers led by Bruce Cohen of Harvard Medical School and McLean Hospital report promising evidence on what one of those important groups of genes may be.
Previous studies of schizophrenia have shown abnormalities in the brain’s white matter—its wiring and insulation—but these studies could not definitively separate inherited from environmental causes. For this study, researchers used previously discovered anomalies to select likely assortments of genes that, as a group, might be highly determinative of the risk for schizophrenia. The choice of genes was based on convergent results of past studies conducted locally and around the world, and included genes that control the insulation of the nerve cells in the brain.
The results of this study strongly suggest that the abnormalities of wiring and insulation are substantially determined by genes.
“There is abundant evidence from our center and from other laboratories that this insulation is compromised in schizophrenia,” said Cohen, HMS Robertson-Steele Professor of Psychiatry and director of the Shervert Frazier Research Institute at McLean Hospital. “Based on this lead, we tested whether the genes required for the activities of the cells that make this insulation (oligodendrocytes) were associated with schizophrenia. In a primary analysis, followed by three separate means of confirmatory analysis, we found strong evidence that genes for oligodendrocytes, as a group, were indeed associated with schizophrenia.”
The findings suggest a concrete reason why insulation is disrupted in the brain in schizophrenia. This disruption in turn may explain why thinking is altered in schizophrenia: Nerve cells are unable to pass exact messages if they lack proper insulation.
Further, the findings show that the abnormality in insulation is at least in part genetically determined, rather than solely due to environmental factors such as years of treatment, different life activities or exposure to toxins.
Finally, the results identify a specific cell-level abnormality, in oligodendrocytes, in schizophrenia.
Similar findings, using different techniques, were recently reported by an independent group of investigators, working separately but contemporaneously with the authors of this study.
“Knowing that one of the pathways of risk for schizophrenia is in this set of genes and in these cells may help identify who is at risk and in what way they are at risk,” said Cohen. “The cells themselves will next be studied to define the problem and seek methods to prevent or reverse it. Thus, the findings can point us towards new ways to reduce the risk and burden of schizophrenia.”
Additional researchers from HMS, Harvard School of Public Health, McLean Hospital, Massachusetts General Hospital, The Broad Institute of MIT and Harvard, and the Cardiff University School of Medicine in Wales contributed to the study.
(Source: hms.harvard.edu)
New evidence that chronic stress predisposes brain to mental illness
University of California, Berkeley, researchers have shown that chronic stress generates long-term changes in the brain that may explain why people suffering chronic stress are prone to mental problems such as anxiety and mood disorders later in life.
Their findings could lead to new therapies to reduce the risk of developing mental illness after stressful events.
Doctors know that people with stress-related illnesses, such as post-traumatic stress disorder (PTSD), have abnormalities in the brain, including differences in the amount of gray matter versus white matter. Gray matter consists mostly of cells – neurons, which store and process information, and support cells called glia – while white matter is comprised of axons, which create a network of fibers that interconnect neurons. White matter gets its name from the white, fatty myelin sheath that surrounds the axons and speeds the flow of electrical signals from cell to cell.
How chronic stress creates these long-lasting changes in brain structure is a mystery that researchers are only now beginning to unravel.
In a series of experiments, Daniela Kaufer, UC Berkeley associate professor of integrative biology, and her colleagues, including graduate students Sundari Chetty and Aaron Freidman, discovered that chronic stress generates more myelin-producing cells and fewer neurons than normal. This results in an excess of myelin – and thus, white matter – in some areas of the brain, which disrupts the delicate balance and timing of communication within the brain.
“We studied only one part of the brain, the hippocampus, but our findings could provide insight into how white matter is changing in conditions such as schizophrenia, autism, depression, suicide, ADHD and PTSD,” she said.
The hippocampus regulates memory and emotions, and plays a role in various emotional disorders.
Kaufer and her colleagues published their findings in the Feb. 11 issue of the journal Molecular Psychiatry.
Does stress affect brain connectivity?
Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain’s fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses.
“You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.”
She is involved in a study to test this hypothesis in PTSD patients, and continues to study brain changes in rodents subjected to chronic stress or to adverse environments in early life.
Stress tweaks stem cells
Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells.
The finding, which they demonstrated in rats and cultured rat brain cells, suggests a key role for oligodendrocytes in long-term and perhaps permanent changes in the brain that could set the stage for later mental problems. Oligodendrocytes also help form synapses – sites where one cell talks to another – and help control the growth pathway of axons, which make those synapse connections.
The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said.
Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones.
How the brain makes myelination activity-dependent
A major question regarding how axons acquire a coat of myelin, is the role of spiking activity. It is known that in culture systems oligodendrocytes will at least try to wrap anything that feels like an axon—even dead axons and artificial tubes. As axons acquire additional layers of myelin they conduct signals faster, and presumably become more efficient. It would therefore seem logical that the nervous system should apportion the most myelin to those neurons that are seeing the greatest activity. In that way the brain gets the most bang for its buck, energetically speaking. A new study in PLOS Biology suggests that while myelination is in many cases activity-independent at first, neurons can significantly ramp things up by flipping various molecular switches, one which appears to be Neuregulin (NRG).
How Infections in Newborns are Linked to Later Behavior Problems
In animal study, inflammation stops cells from accessing iron needed for brain development
Researchers exploring the link between newborn infections and later behavior and movement problems have found that inflammation in the brain keeps cells from accessing iron that they need to perform a critical role in brain development.
Specific cells in the brain need iron to produce the white matter that ensures efficient communication among cells in the central nervous system. White matter refers to white-colored bundles of myelin, a protective coating on the axons that project from the main body of a brain cell.
The scientists induced a mild E. coli infection in 3-day-old mice. This caused a transient inflammatory response in their brains that was resolved within 72 hours. This brain inflammation, though fleeting, interfered with storage and release of iron, temporarily resulting in reduced iron availability in the brain. When the iron was needed most, it was unavailable, researchers say.
“What’s important is that the timing of the inflammation during brain development switches the brain’s gears from development to trying to deal with inflammation,” said Jonathan Godbout, associate professor of neuroscience at The Ohio State University and senior author of the study. “The consequence of that is this abnormal iron storage by neurons that limits access of iron to the rest of the brain.”
The research is published in the Oct. 9, 2013, issue of The Journal of Neuroscience.
The cells that need iron during this critical period of development are called oligodendrocytes, which produce myelin and wrap it around axons. In the current study, neonatal infection caused neurons to increase their storage of iron, which deprived iron from oligodendrocytes.
In other mice, the scientists confirmed that neonatal E. coli infection was associated with motor coordination problems and hyperactivity two months later – the equivalent to young adulthood in humans. The brains of these same mice contained lower levels of myelin and fewer oligodendrocytes, suggesting that brief reductions in brain-iron availability during early development have long-lasting effects on brain myelination.
The timing of infection in newborn mice generally coincides with the late stages of the third trimester of pregnancy in humans. The myelination process begins during fetal development and continues after birth.
Though other researchers have observed links between newborn infections and effects on myelin and behavior, scientists had not figured out why those associations exist. Godbout’s group focuses on understanding how immune system activation can trigger unexpected interactions between the central nervous system and other parts of the body.
“We’re not the first to show early inflammatory events can change the brain and behavior, but we’re the first to propose a detailed mechanism connecting neonatal inflammation to physiological changes in the central nervous system,” said Daniel McKim, a lead author on the paper and a student in Ohio State’s Neuroscience Graduate Studies Program.
The neonatal infection caused several changes in brain physiology. For example, infected mice had increased inflammatory markers, altered neuronal iron storage, and reduced oligodendrocytes and myelin in their brains. Importantly, the impairments in brain myelination corresponded with behavioral and motor impairments two months after infection.
Though it’s unknown if these movement problems would last a lifetime, McKim noted that “since these impairments lasted into what would be young adulthood in humans, it seems likely to be relatively permanent.”
The reduced myelination linked to movement and behavior issues in this study has also been associated with schizophrenia and autism spectrum disorders in previous work by other scientists, said Godbout, also an investigator in Ohio State’s Institute for Behavioral Medicine Research (IBMR).
“More research in this area could confirm that human behavioral complications can arise from inflammation changing the myelin pattern. Schizophrenia and autism disorders are part of that,” he said.
This current study did not identify potential interventions to prevent these effects of early-life infection. Godbout and colleagues theorize that maternal nutrition – a diet high in antioxidants, for example – might help lower the inflammation in the brain that follows a neonatal infection.
“The prenatal and neonatal period is such an active time of development,” Godbout said. “That’s really the key – these inflammatory challenges during critical points in development seem to have profound effects. We might just want to think more about that clinically.”
Sleep Boosts Production of Brain Support Cells
Animal study shows genes involved in brain repair, growth turned on during slumber
Sleep increases the reproduction of the cells that go on to form the insulating material on nerve cell projections in the brain and spinal cord known as myelin, according to an animal study published in the September 4 issue of The Journal of Neuroscience. The findings could one day lead scientists to new insights about sleep’s role in brain repair and growth.
Scientists have known for years that many genes are turned on during sleep and off during periods of wakefulness. However, it was unclear how sleep affects specific cells types, such as oligodendrocytes, which make myelin in the healthy brain and in response to injury. Much like the insulation around an electrical wire, myelin allows electrical impulses to move rapidly from one cell to the next.
In the current study, Chiara Cirelli, MD, PhD, and colleagues at the University of Wisconsin, Madison, measured gene activity in oligodendrocytes from mice that slept or were forced to stay awake. The group found that genes promoting myelin formation were turned on during sleep. In contrast, the genes implicated in cell death and the cellular stress response were turned on when the animals stayed awake.
“These findings hint at how sleep or lack of sleep might repair or damage the brain,” said Mehdi Tafti, PhD, who studies sleep at the University of Lausanne in Switzerland and was not involved with this study.
Additional analysis revealed that the reproduction of oligodendrocyte precursor cells (OPCs) — cells that become oligodendrocytes — doubles during sleep, particularly during rapid eye movement (REM), which is associated with dreaming.
“For a long time, sleep researchers focused on how the activity of nerve cells differs when animals are awake versus when they are asleep,” Cirelli said. “Now it is clear that the way other supporting cells in the nervous system operate also changes significantly depending on whether the animal is asleep or awake.”
Additionally, Cirelli speculated the findings suggest that extreme and/or chronic sleep loss could possibly aggravate some symptoms of multiple sclerosis (MS), a disease that damages myelin. Cirelli noted that future experiments may examine whether or not an association between sleep patterns and severity of MS symptoms exists.