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The mathematics of depression

Is the cause of depression a decrease in the rate of brain cell growth?

By Marit Selvin

About a hundred years ago, a clear distinction was established between neurology and psychiatry. In the post-mortem examination of people who suffered from neurological diseases, structural changes in the brain were discovered, while in people who suffered from psychiatric diseases, the structure of the brain looked perfectly normal under a microscope. It is not for nothing that they were called in the vernacular "mental illnesses".

In recent years, it seems that this distinction is becoming irrelevant: it turns out that even in psychiatric illnesses, structural changes occur in the brain - certain areas in the brains of depressed patients are smaller than those of healthy people, and after treatment they return to their normal size. Last month, an article was published in the journal "Lancet" in which it was reported for the first time that an antidepressant drug led to an increase in the number of nerve cells in the human brain.

The disease on which most of the studies in this field are concentrated is depression. Depression manifests itself in decreased mood and appetite, sleep disturbances, lack of interest in life, physiological slowing of all body activities and suicidal thoughts. Until recently, psychiatrists believed that the cause of depression was an imbalance between certain nerve mediators (neurotransmitters) in the brain, mainly a lack of those associated with the pleasure centers. But recently, the perception is taking shape that the cause of depression is a decrease in the reproduction rate of brain cells. Until about two years ago, most neuroscientists did not take this theory seriously, because it was common to think that, unlike the rest of the body's cells, brain cells are unable to reproduce. But then it became clear that the brain continues to produce new cells even in adults. Studies have shown that new cells in the adult brain are created in specific areas, primarily in the hippocampus, which is responsible for learning and memory functions.

A study published in 1996 in the journal "Academy of Proceedings of "Sciences the National showed that the hippocampus is smaller in depressed patients by 12 to 15 percent on average compared to people who do not suffer from depression. In the last year, additional studies were conducted, which confirmed the results. "The idea of ​​growth and decay of brain cells can explain the cycle of depression more than any other theory that has been accepted so far," said Barry Jacobs, a neuroscientist at Princeton University to the journal "Science".

The decrease in the number of brain cells in those suffering from depression is apparently not limited to the hippocampus area. Researchers who last year examined the brains of dead people who suffered from depression before their death reported that in the frontal cortex, which is apparently related to emotions and consciousness, the nerve cells were less dense compared to the normal state, and in some areas there the decrease in the volume of the gray matter (which contains the nerve cells) reached up to %. 40

Many neuroscientists believe that the decrease in the number of brain cells in these areas occurs due to stressful conditions. It is known that stress is one of the factors that illustrate depression. Stressful situations cause an increase in the amount of certain hormones that increase the heart rate and the activity of the immune system and suppress the reproductive system. When the conditions of oppression prevail for years, the brain also suffers. In such a situation, cells die in certain areas of the hippocampus, and as a result it shrinks.

And now, new research shows that antidepressants increase the process of cell proliferation. In a study that will soon be published in the "Journal of Neuroscience", a group of researchers from Yale University gave antidepressants, including Prozac, to laboratory animals, and in all of them, new nerve cells appeared in the hippocampus after the treatment.

Physical activity also has an anti-depressant effect, and it, like anti-depressants, accelerates the growth of new nerve cells in the brain. A research group from the Salk Center in California reported last year that in mice that performed vigorous physical activity (they ran on a device about five kilometers a day for five months), twice as many cells were found in the brain than in mice that did not perform physical activity.

In an article published last month in the Lancet journal, researchers from the Department of Psychiatry and Behavioral Sciences in Detroit, led by neuroscientist Hosseini Manji, showed that the drug lithium, which has been given to people suffering from depression for fifty years, increased the volume of gray matter in manic-depressive patients who were in a depressive episode in the brain already after four weeks of treatment. Despite the drug's success, it was not known until now how lithium alleviates the symptoms of depression. For the first time, the researchers were able to demonstrate, through MRI tests, that lithium increases the number of brain cells in humans. This is probably where its anti-depressant effect lies.

Have we really come to understand the connection between the structure of the brain and "mental" disorders?
Jacobs believes that the answer is positive, and as evidence, depressed patients often complain of memory disturbances, and this is probably due to the shrinking of the hippocampus region, which is involved as mentioned in memory functions. Many Alzheimer's patients suffer from depression, and the hippocampus is also damaged in this disease.
{Appeared in Haaretz newspaper, 15/11/2000{

Photo: The Hebrew University

A nerve cell that the research team created in the laboratory from an embryonic stem cell. The work only
in its infancy, and it is difficult to estimate when they will begin to be applied to humans

Science 1

A team led by an Israeli researcher succeeded for the first time in causing human embryonic stem cells to turn into brain and liver cells

All it takes is the right letter

by Tamara Traubman

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Researchers have succeeded in making human embryonic stem cells turn into brain cells, liver cells and many other cells. In doing so, they took an important step towards acquiring the ability to produce transplant tissues to order. The research team, which was published in the scientific journal "of the National Academy of Proceedings,"Sciences, is headed by Prof. Nissim Benvanisti from the Hebrew University, and his partners are doctoral student Maya Shuldiner, Prof. Douglas Melton, head of the Department of Molecular Biology at Harvard University, and Prof. Yosef Itzkovic from The Rambam hospitals. The research will be presented today at an international conference being held in Israel and dealing with genetics in the era after the decoding of the human genome.

So far, most experiments have been done in mouse embryonic stem cells, very few studies have been done in human cells; In 1996, for example, researchers from Indiana University showed that it was possible to turn stem cells from mice into heart muscle cells and transplant them into mice. The team of researchers led by Prof. Benvanisti succeeded for the first time in directing the growth of human stem cells into a wide variety of cell types. However, Prof. Benvanisti clarifies that the work is only in its beginning and it is difficult to estimate when it will start to be applied to humans.

Fetal stem cells, which were isolated for the first time about two years ago, are "identity-less" cells, which can turn into any of the cell types in the body. When stem cells divide, they also form mature cells (cells of a certain type, such as skin cells, kidney, intestine, etc.), as well as stem cells. Therefore, they can divide many times, compared to mature cells, the number of times they can divide is limited. "We have no doubt that there is something programmed in these cells, which know how to differentiate into all types of cells," says Prof. Benvanisti. The big question is what is the signal that keeps the embryonic stem cells from differentiating into a certain cell type.

No one knows how to produce a brain, but if researchers manage to find out what signal should be given to the stem cells in order for them to become nerve cells, they will be able to transplant these cells into the brains of people who have had a stroke, or degenerative diseases such as Parkinson's and Alzheimer's, and replace the damaged tissues with new, healthy tissues. In many diseases, experts believe, it will be possible to transplant only the cells damaged by the disease, such as beta cells in the pancreas of diabetic patients or heart muscle cells in the hearts of people who have had a heart attack or heart failure.

In a series of experiments that has been going on for about a year and a half, Prof. Benvanisti and his colleagues are trying to trace the signals that determine the differentiation of the cells.
Initially, they allowed the cells to spontaneously transform into the three embryonic germ tissues (mesoderm, ectoderm, and endoderm) from which all cell types later develop. Then they injected the cells with different growth factors - substances that encourage the creation of new cells - and checked how the growth factors affect the development of the cells.

In total, they tested the effect of eight different tumor factors. They managed to create about a dozen types of cells, including nerve cells, liver cells, pancreatic cells and muscle cells. "We still haven't been able to get some of the tissues in culture and we are trying to get them by combinations of different factors," says Prof. Benvanisti.

The researchers discovered that sometimes the growth factors direct the differentiation of cells not only by encouraging a certain differentiation pathway, but by inhibiting other differentiation pathways. Embryo development appears to be a complex mechanism, in which growth factors are secreted with remarkably precise timing. Growth factors, on the one hand, encourage the creation of certain tissues, and on the other hand, suppress the creation of other tissues, which should be created at a later stage of the embryo's development.

Some of the types of cells that the researchers had difficulty creating are found in the body in small quantities, because only a few of them are necessary for the proper functioning of the body. According to one hypothesis, they may be difficult to produce in the laboratory because certain growth factors inhibit their development. The researchers hypothesize that it may be possible to produce them precisely by inhibiting the growth factors that delay their creation.

"Besides its importance as a source of human cells for transplantation, the research is also important for understanding the developmental pathways of embryos," says Prof. Hermona Sorek, a molecular biologist from the Hebrew University who did not participate in the research. It is possible that an understanding of cell differentiation will help to understand the molecular roots of miscarriages, which at least in part stem from abnormal development of the fetus.
{Appeared in Haaretz newspaper, 15/11/2000{

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