The current issue of the journal Science (November 5) marks a turning point in research on the brain. This event is fascinating not only for the wealth of new information about how the brain functions and how it fails in mental and neurological illness, but equally as a rare display of a field of science changing course. Such transitions are the lore of scientific history, but rarely do we have the opportunity to witness such pivotal moments in real time.
The journal Science is a premier international journal covering all areas of science, and this issue contains a special section on glia. Glia, in contrast to neurons, are brain cells that do not generate electrical impulses, and there are a lot of them—85 percent of the cells in the brain. Yet, these cells have been largely neglected for 100 years. I call this new frontier of neuroscience "The Other Brain," because we are only now beginning to explore it. The new findings are expanding our concept of information processing in the brain. They are leading rapidly to new treatments for diseases ranging from spinal cord injury to brain cancer to chronic pain, and Alzheimer's disease. And they are overturning a century of conventional thinking about how the brain operates at the most fundamental level.
In the past, glia were understood to support neurons; to feed them and clean up after them, and to respond to brain injury. But these functions were regarded as peripheral to the exciting functions that neurons perform in processing information and storing memories. Consequently, research on glia did not fare well in the fierce competition for the limited grant funding for brain research. Neuroscientists were not trained in glial science, and the standard texts cover glia superficially, if at all. Editors at major journals were not well versed in these odd and very complicated brain cells. As a consequence, glial research was rarely published in high-impact scientific journals. These forces dragged on glial researchers for decades. Now all of this is changing.
The functions of glia can be broadly divided into three main categories, and four very different types of glia serve these different functions. Astrocytes, glia so named because their shape reminded early anatomists of stars, fill the spaces between neurons. Astrocytes provide the energy source to neurons; they maintain the chemical environment surrounding neurons within the narrow limits required for neurons to survive and fire electrical impulses, and to communicate at synapses.
Microglia are the immune cells of the brain. The brain is isolated from the rest of the fluids in the body because the unique environment within brain tissue must be maintained. A barrier between the brain and the blood is formed by cells in the walls of blood vessels in the brain, which prevents the free diffusion of materials and cells between blood and brain. However, this barrier also prevents the immune cells of the bloodstream, which protect the entire body, from entering the brain. Microglia are the brain's private cellular guard cells, seeking out and killing germs and healing the brain after injury. As such, microglia are involved in every aspect of nervous system disease and healing.
The third important function of glia is to form the electrical insulation on nerve fibers (axons), which is essential for high speed transmission of electrical impulses. The importance of this insulation, called myelin, is clearly seen in people who suffer from multiple sclerosis, an autoimmune disorder that attacks the myelin sheath on axons, which leaves these people with serious impairments in sensory and motor function. Inside the brain and spinal cord, glial cells resembling cellular octopuses wrap up to 150 layers of compacted membrane around axons, much like electrical tape. The core of the brain—half its bulk—is comprised of millions of tightly bundled axons insulated with myelin. This brain region is called "white matter," because the color of myelin tints this brain tissue white. Although of little interest in the past, white matter is the newest area of research on learning. In the rest of the body, glial calls called Schwann cells, which resemble flattened pearls strung up on axons, form this vital insulation.
My article in this issue explains the sea change in thinking about white matter in the brain. Traditionally myelin was primarily of interest to those concerned with demyelinating disease, but new brain imaging research and cellular research showing that myelinating glia sense electrical activity in axons, is revealing that white matter changes during learning. The formation of myelin can be controlled by electrical impulse activity, and thus by experience. When a bare axon becomes myelinated, the speed of impulse transmission through the fiber increases roughly 50 times. The increased transmission speed will have profound effects on information processing in that neural circuit. A remarkable thing about the human brain is that it continues to form myelin through childhood, adolescence, and at slower rates into early adult life. After age 50, myelin begins to be lost in parallel with the normal gradual decline in cognitive function with aging. This new research is expanding thinking about the mechanisms of learning beyond the synapse, to include the transmission of information through the entire network involved in carrying out a complex cognitive function. White matter changes are seen by brain imaging after learning new skills, ranging from playing computer games, to golf, to reading, to juggling, to playing the piano, and the molecular signals from axons that control development and formation of myelin in response to electrical impulse activity are being identified.
The article by Ben Emery, of the Florey Neuroscience Institutes in Melbourne, Australia, summarizes what is known about the mechanisms controlling development of oligodendrocytes and myelin. Both chemical signals from the environment, and internal controls regulate development of oligodendrocytes from immature "progenitor cells". These oligodendrocyte progenitor cells (OPCs), are of intense interest, because new research shows that they can transform not only into mature oligodendrocytes, but also into astrocytes and neurons under the proper conditions. These are the cells that are now being transplanted into patients with spinal cord injury in experimental studies to cure paralysis. Most intriguingly, neurons form synapses onto these cells for reasons that are not understood. A possibility that is hotly pursued is that synaptic communication could instruct these cells to form myelin, although there is no evidence for this as yet. (Also, research just published from my lab in the October 5 issue of Science Signaling reveals a new mechanism for axons to release neurotransmitter without synapses. This is especially important in communicating with myelinating glia, which are far removed from synapses.) Emery sees the major challenge of the future will be in translating our new knowledge into new therapies to treat diseases like multiple sclerosis.
Manuel Graeber, of the University of Sydney, Australia, reviews how microglia sense and respond to threats in the brain, and how they are involved in chronic pain. The involvement of microglia in Alzheimer's disease and their active monitoring of synaptic activity is reviewed. These functions of glia in remodeling the brain during disease suggest that they may carryout similar remodeling of neural circuits in the healthy brain. Research is beginning to show that microglia can unplug synapses and that they are involved in psychological disorders, such as chronic depression.
The third article is on astrocytes by Marc Freeman, of the University of Massachusetts. The article reviews the role of astrocytes in forming synapses and changing their strength, and in how astrocytes communicate with each other and with neurons. In his opinion we are only beginning to understand how astrocytes develop, grow, change forms, and respond to neurons. Astrocytes do, however, communicate among themselves with chemical signaling. This signaling can be observed using fluorescent dyes that sense calcium levels in side the cells. Astrocytes have receptors for neurontransmitters, enabling them to respond to the neurotransmitter released by neurons at synapses. Astrocytes can communicate with other astrocytes, and they release or take up neurotransmitters from distant synapses to control the transmission of information between neurons. The activity of astrocytes in controlling neurotransmitter levels at synapses implicates them in psychiatric disorders. All drugs for treating mental illnesses act by controlling the levels of different neurotransmitters, but this is the normal job of astrocytes.
A new dimension of brain science is unfolding, and as neuroscientists begin to explore it they are gaining a new understanding of the brain. At the same time neuroscientists are re-learning an age-old lesson about how science progresses through fits and fashions, and that our unconscious preconceptions can mislead "experts" until eventually new experimental data shines the way.
Image: Astrocytes are shown in red, OPCs in green, and neurons in blue. The cells are taken from rat hippocampus and grown in culture. Credit: Dr. Jonathan Cohen, NICHD
Emery, B. (2010) Regulation of Oligodendrocyte Differentiation and Myelination. Science 330: 779-782.
Fields, R.D. (2010) Change in the Brain's White Matter. Science 330: 768-769.
Fields, R.D. and Ni, Y. (2010) Nonsynaptic Communication through ATP Release from Volume-Activated Anion Channels in Axons. Science Signaling 3: ra73.
Freeman, M.R. (2010) Specification and Morphogenesis of Astrocytes. Science 330:774-778.
Graeber, M.B. (2010) Changing Face of Microglia. Science 330:783-788.
Fields, R.D. The Other Brain, published by Simon and Schuster, 2010. The first book about glia for the general audience. http://theotherbrainbook.com
Fields RD (2004) The Other Half of the Brain. Scientific American 290: 54-61.
Fields RD (2008) White Matter Matters. Scientific American 298: 42-49.
Fields RD (2009) New Culprits in Chronic Pain. Scientific American 301: 50-57.
Fields, R.D. Watching The Brain Learn, Scientific American Blog: https://www.scientificamerican.com/article.cfm?id=watching-the-brain-learn
Glia, The Other Brain Cells. Brain Briefings, Sept, 2010. The Society for Neuroscience: http://www.sfn.org/index.aspx?pagename=brainBriefings_10_glia
ABOUT THE AUTHOR
R. Douglas Fields, Ph. D. is the Chief of the Nervous System Development and Plasticity Section at the National Institute of Child Health and Human Development and Adjunct Professor at the University of Maryland, College Park. Fields, who conducted postdoctoral research at Stanford University, Yale University, and the NIH, is Editor-in-Chief of the journal Neuron Glia Biology and member of the editorial board of several other journals in the field of neuroscience. He is the author of the new book The Other Brain (Simon and Schuster), about cells in the brain (glia) that do not communicate using electricity. His hobbies include building guitars, mountain climbing, and scuba diving. He lives in Silver Spring, Md.
The views expressed are those of the author and are not necessarily those of Scientific American.