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Brain electrical activity spurs insulation of brain’s wiring
NIH study identifies trigger that speeds brain cell communication
Researchers at the National Institutes of Health have discovered in mice a molecular trigger that initiates myelination, the process by which brain cell networks are reinforced with an insulating material called myelin that speeds their ability to transmit messages.
The myelination process is an essential part of brain development. Myelin formation is necessary for brain cells to communicate and it may contribute to development of skills and learning.
The researchers showed that an electrical signal passing through a brain cell (neuron) results in the brain cell releasing the molecule glutamate. Glutamate, in turn, triggers another type of brain cell, called an oligodendrocyte, to form a point of contact with the neuron. Signals transmitted through this contact point stimulate the oligodendrocyte to make myelin protein and begin the process of myelination. In this process, the oligodendrocyte wraps myelin around axons— the long, cable-like projections that extend from each neuron. The myelination process is analogous to wrapping electrical tape around bare wires.
Myelin formation
Electrical signals transmitted from one neuron to the next are a basic form of communication in the brain. The myelin layers that oligodendrocytes wrap around neurons boost these signals so that they travel 50 times faster than before.
The study was conducted by Hiroaki Wake, Philip R. Lee, and R. Douglas Fields of the Nervous System Development and Plasticity Section of the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Their findings appear online in Science Express.
“Insulation begins to form on axons in the late stages of fetal development, but the process continues through childhood, adolescence, and into early adulthood,” said Dr. Fields, the study’s senior author. “For example, infants cannot hold up their heads or walk until the appropriate motor axons become myelinated, and the frontal lobes of the brain, responsible for judgment and higher-level complex reasoning, are not fully myelinated until the early twenties.”
Understanding how oligodendrocytes generate and help repair myelin could provide insight into how only the appropriate axons in the brain become insulated during development as people acquire skills, with the eventual goal of helping them do so more efficiently, Dr. Fields explained. Similarly, understanding the myelination process could lead to insights into disorders like multiple sclerosis, in which myelin is either damaged or destroyed. Moreover, understanding myelination may allow researchers to speed myelination— and repair— of axons recovering from injury.
Throughout the brain, oligodendrocytes and neurons exist side by side. The researchers placed mouse nerve cells and myelin-making oligodendrocytes together in a dish and stimulated the nerve cells with electrical pulses. After three weeks, they found that the nerve cells were wrapped in a myelin covering.
In a separate culture of neurons and oligodendrocytes, the researchers blocked the release of the molecule glutamate, a neurotransmitter. Neurotransmitters make it possible for signals to pass between cells. When glutamate release was blocked, very little myelin coating formed. Further experiments showed that after the electrical pulses and the release of glutamate, nerve cells and the neighboring oligodendrocytes began sending chemical signals back and forth. Then the oligodendrocytes started to make the protein used to form the myelin sheath. Specifically, receptors on the cell membrane of oligodendrocytes detect glutamate released by the axon, and this triggers the formation of what the researchers termed specialized adhesive signaling junctions—points of contact between oligodendrocytes and axons that enable signals to be passed between the cells. Then the oligodentrocytes began depositing myelin on electrically active axons, but not on axons that were not electrically active.
“This shows that axons that are transmitting electrical signals will become preferentially insulated by myelin,” Dr. Fields said.
In a previous study, Dr. Fields and his coauthors found that electrical activity in neurons stimulates other cells, called astrocytes, that also are involved in the myelination process.
The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s website at http://www.nichd.nih.gov/.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Electrical Impulses Foster Insulation of Brain Cells, Speeding Communications
Electrical impulses foster myelination, the insulation process that speeds communication among brain cells, report researchers at two institutes of the National Institutes of Health.
"This finding provides important information that may lead to a greater understanding of disorders such as multiple sclerosis that affect myelin, as well as a greater understanding of the learning process," said Duane Alexander, M.D., Director of the NICHD.
The study appears in the March 16 Neuron and was conducted by researchers at the National Institute of Child Health and Human Development and the National Cancer Institute.
Neurons—specialized cells of the brain and nervous system—communicate via a relay system of electrical impulses and specialized molecules called neurotransmitters, explained the study's senior author, R. Douglas Fields, Ph.D., Head of NICHD's Nervous System Development and Plasticity Section.
A neuron generates an electrical impulse, causing the cell to release its neurotransmitters, he said. The neurotransmitters, in turn, bind to nearby neurons. The recipient neurons then generate their own electrical impulses and release their own neurotransmitters, triggering the process in still more neurons, and so on.
Neurons conduct electrical impulses more efficiently if they are covered with an insulating material known as myelin, Dr. Fields added. Layers of myelin are wrapped around the fiber-like projections of neurons like electrical tape wrapped spiral-fashion around an electrical cable. Human beings are born with comparatively little myelin, and neurons become coated with the material as they develop. Moreover, mental activity appears to influence myelination, Dr Fields said. For example, neglected children have less myelin in certain brain regions than do other children.
However, raising animals in stimulating environments increases their myelin production. Also, mastering an activity, such as learning to play the piano, fosters myelination, and myelin is decreased in several mental disorders, including schizophrenia and bipolar disorder.
Dr Fields said that these phenomena implied that the cells forming myelin must somehow sense electrical impulse activity in neurons and regulate myelination accordingly.
To conduct their study, Dr. Fields and his coworkers isolated neurons from mouse brains and grew them in laboratory cultures with two other kinds of brain cells, oligodendrocytes and astrocytes. Previous studies had determined that oligodendrocytes deposit myelin on neurons, but how electrical impulse activity might stimulate them to do so was unknown.
In their laboratory cultures, the researchers stimulated the neurons by passing an electrical current through them. This electrical stimulation was designed to mimic the normal activity that takes place in the brain when neurons communicate with each other.
The researchers found that the electrical stimulation caused the neurons to release adenosine triphosphate (ATP), a high-energy molecule essential to many biological processes. In this instance, however, the ATP bound to special sites, or receptors, on the surface of the astrocytes, causing them to release a substance known as leukemia inhibitory factor (LIF). LIF, in turn, bound to the oligodendrocytes, stimulating those cells to deposit myelin around the neurons.
Dr. Fields explained that the finding has implications for disorders affecting myelination, such as Alexander disease, which is a fatal neurological disorder of childhood caused by a genetic defect in astrocytes. The brains of children who have Alexander disease also have severe myelin defects. The finding that astrocytes indirectly relay signals from neurons to oligodendrocytes provides a possible explanation for the lack of myelin characteristic of the disorder. Researchers may be able to provide treatment for demylinating diseases, such as multiple sclerosis, by developing drugs that mimic the actions of ATP and LIF on their target cells. Similarly, an understanding of how myelination takes place may offer insight into the learning process.
Other authors of the study are: Tomoko Ishibashi, Kelly A. Dakin, Beth Stevens and Philip R. Lee, of the NICHD; and Serguei V. Kozlov and Colin L. Stewart of the NCI.
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The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
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