Scratches on the Brain

Ora Arif

So, what does it look like? This familiar question is the follow-up to lots of other questions that are very difficult to answer. We'd like to know, for instance, how people feel when we ask if they're happy, if they've matured, or if they've changed. Pop psychology will tell us, "He looks tense," "It seems she's just been through a crisis," "Marriage suits him," or "My, how she's aged." We may notice a new sparkle in their eyes or the weight of depression on their shoulders. We look at the cover and try to figure out what's going on inside the book. It never occurs to us that the experiences people undergo in their lives are engraved on their brains. They leave actual physical marks, like scratches, and it seems that each of our brains is covered with scratches.

Dr. Adi Mizrahi, a young (35-year-old) researcher, is very curious about what goes on inside our brains as a result of all the things we experience in our lives: "Basic brain research examines how plastic our brains are. How does the brain change after we've experienced something, or when we're sleeping, studying, or developing physically? These are questions I find very interesting. At the moment, I'm concerned with the structural dimension of the brain and the extent to which the brain - composed of nerve cells - changes."

Nerve cells, says Mizrahi, are totally different from other cells in the body, not only because they are too complex to comprehend. Unlike a "regular" biological cell that is relatively "boring" structurally in the eyes of researchers, every nerve cell has thousands of synapses (connection centers) that function as extensions that process and compute information and transmit their commands to every part of the body. Think about it: every individual nerve cell acts as a super sophisticated computer and is one of ten billion such cells working in the brain simultaneously and communicating with each other.

Researchers at the Interdisciplinary Center for Neural Computation at Hebrew University are trying to learn more about the brain together with a wide-ranging team of experts, among them Adi Mizrahi. His goal is to draw a picture of the changes that take place in the synapses of nerve cells. Mizrahi is certain that these changes must be supervised, and even restricted, by a control system of some kind. If true, this would be further evidence that the brain is "plastic" - relatively flexible. After all, there is some sort of interior balance that limits the "plasticity" of the brain. As Mizrahi explains, "Thoughts and sensations pass through the brain. The brain controls our physical actions, heartbeat, breathing, and sleep patterns. The brain is in command of our responses to the environment in which we live. Therefore, there must be a balance somewhere between the ability to change and stability. What we're asking is where and when the brain changes. At this point, I'm interested in changes in individual nerve cells over long time spans ranging between a few minutes and a few weeks. We're tracing the changes that take place in the nerve cells of animals after they undergo a particular experience."

Mizrahi's research goes a giant and important step beyond previous approaches, which performed before-and-after experiments on two different groups of animals, one that experienced learning and the other that did not. Today, says Mizrahi, "We have tools to examine a single animal and record the changes taking place in its brain. There are clear advantages to this method: Beyond the statistical validity of the data obtained with the new methodology, it also significantly reduces the number of scientific experiments that make use of animals." Mizrahi's latest research performs imaging on the brain of a laboratory mouse whose cells fire repeatedly. This method, he says, allows researchers to identify very slight changes taking place within the cells.

The research uses another method that makes experimentation easier for both the laboratory animals and the scientists observing brain cells with advanced microscopic equipment. The process involves genetic coloring of the animals' brain cells, and it is performed on fetuses. After birth, the brain cells that were previously colored are now visible through a sophisticated type of microscope. This coloring method, it was found, is not harmful in any way to the mouse at any time in its life. The fluorescent color used comes from protein extracted from jellyfish. "Even today," says Mizrahi, "we can color specific cells in the brain." And borrowing the jargon of the fashion industry, he talks about producing different "lines" of mice whose genes have been infused with yellow, red, blue, and green protein. In this way, there is no need to probe into the mouse's brain, because the part of its brain that interests researchers is already highlighted by a predetermined color. All that's needed is a microscope to see what's happening within the cells; the bright fluorescent colors provide a clear picture of the living brain.

This type of special fluorescent microscopy is being employed in many fields of biology. The focus at the moment, however, is on the outer layers of the brain, since deeper areas are not yet accessible with the new method. Cells can now be observed at a depth of 0.5 mm, where the brain membrane, cerebellum, and olfactory bulb (controlling our sense of smell) are located.

"These observations open the door to a wide world of cell research, in which we can color the nerve cells of living and breathing animals and study them under the microscope," notes Mizrahi. "What we have here is a research tool that was not available to us a decade ago. With the help of genetics, we can also mark specific proteins in the cell." Part of the research is devoted to observation of animals with epilepsy, with the aim of learning what changes the disease produces in the brain and determining what (if any) effect drugs have.

Mizrahi, a native of Beersheba, remained loyal to his birthplace and completed his doctoral work (on insect brains) at Beersheba Ben-Gurion University. This followed his studies abroad at Duke University, where he learned how to use the type of microscope that is an essential part of his current research.

One of his research goals is to locate cells that play a role in memory and learning, and to discover where changes take place in these cells as a result of memory and learning processes. But that's not all. "Another question that interests me is brain development," says Mizrahi. In fact he can apply the same techniques he now uses to studying the development and dynamics of the brain. The conclusions he reaches could help scientists discover the key principles of development: "Which genes lead to normal development, and which lead to abnormal development?"

And just when things start sounding totally futuristic, Mizrahi concludes by saying, "I believe that observation of brain structure is only the beginning. In the future, we'll be able to trace its functioning at high resolution in vivo [on living cells]. The markers [colors] being developed for that purpose are designed to report on brain activity and not only brain development - on the activities occurring within whole populations of cells, and how these activities affect individual cells."

The mysterious realm in which brain researchers operate has led them, more than once, to dead ends. Laboratory results have sometimes been disappointing. Mizrahi says that "our work demands that we look into a mirror. It's a very dynamic field. I'm doing things today that people only dreamed about 20 years ago. In the past, cells were colored using electrodes rather than the current gene method. To a great extent, technological developments pave the way for scientific advancement."

And, indeed, even today Mizrahi understands that we mustn't be wedded to a concept. We need to keep our feet on the ground and proceed step by step: "I feel that molecular biology has changed the face of science, truly revolutionized it. The scientific community has made great strides in brain research in recent years. Now, with advanced imaging techniques, we have an opportunity to change the face of neurobiology."

Since the age of 22, Mizrahi has been devoting his life to study and research. For the past half year, he has been conducting research in the Life Sciences Department of Hebrew University in Jerusalem. His dreams are bound to take him to faraway places. But he expects no miracles. As he puts it, it's "one step after another."