Many earlier investigations of regeneration of nerve cells (neurogenesis) are now being questioned. This concerns among other things reports of connections between neurogenesis and depression, learning and stroke. (Back to Arvidīs column)

Changes of neurogenesis are epiphenomena
There are a lot of reports of relations between regeneration of neurons and depressive illnesses. One hypothesis is that stress influences the hippocampus so that neurogenesis is reduced, which leads to depression. The proofs are indirect. The scientists made the observation that the volume of the hippocampus was diminished in depression, bipolar disorder and posttraumatic stress disorder. These results were interpreted as being a consequence of a reduction in neurogenesis in the hippocampus. An increased regeneration of nerve cells has also been reported following antidepressives and electroconvulsive therapy in animals.

But more and more studies of a better quality have begun to question these relations, according to an overview by Fritz Henn and Barbara Vollmayr in 2004. One such study shows for instance that no neurogenesis is required for the effect of antidepressives. Neither was neurogenesis increased by magnetic stimulation, which can also counteract depression. This study utilized a better animal model of depression than earlier investigations. Other studies of a high quality could not find that a reduced regeneration of neurons led to depression or to other kinds of altered behavior in the experimental animals. Henn regards changes in neurogenesis as an epiphenomenon rather than a cause of depression.

A connection between regeneration of nerve cells and learning has also been asserted. Mice which have been placed in an enriched environment have been reported to change their behavior and to have an increased neurogenesis in the hippocampus. The mice got less anxious, adapted faster to a new environment and learned certain tasks in a quicker way. But if the regeneration of neurons is blocked by irradiation, the animals still show a changed behavior as a consequence of the environmental enrichment, as was recently demonstrated by Dar Meshi et al. So, according to them, adult neurogenesis is not necessary for learning.

Studies using a faulty technique must be reconsidered
A special problem in many of the studies of neurogenesis, is that a great many scientists have used a faulty technique to detect new cells. This concerns for instance studies of transplantation in experimental animals and patients with Parkinsonīs disease. In these studies the scientists want to investigate the fate of the transplanted cells in the brain. So they label the cells with a substance which is a thymidine analog and resembles thymidine, one of the components of DNA. The thymidine analog is also used to track newly born cells, since it is incorporated into dividing cells where the DNA is also replicating. Therefore the scientists have believed that if they find a thymidine analog in a nerve cell, this means that the nerve cell is newly born. This is however not necessarily the case, as it appeared.

A group lead by Catherine Verfaillie has studied the fate of thymidine analogs in cells transplanted in mice. The scientists found the thymidine analog in the mouseīs own neurons. It is well known that more than 90 percent of the grafted cells may die after transplantation. The thymidine analog is then released into the environment where it may be incorporated into the receiverīs own neurons, according to Verfaillie. So what looks like transplanted cells are actually the experimental animalīs own nerve cells. As a consequence, the results of studies of for example stem cells from bone marrow must be reconsidered. In those studies stem cells from bone marrow have been used in transplantations, in order to avoid the many problems of embryonic stem cells. The scientists have reported good results where the stem cells evolved and differentiated into nerve cells after the transplantation. But since thymidine analogs were utilized in these studies the findings must be questioned. What looked like new nerve cells could have been the receiverīs own neurons.

Research has also revealed that thymidine analogs are toxic and affect the incorporating cell in many ways. A thymidine analog may for instance initiate a cell division, which would otherwise not occur. The cell division is however never completed and instead the nerve cell dies. Thymidine analogs may also induce mutations which change the cell surface. Among other things this may result in a glial cell (supporting cell) of the brain looking like a nerve cell. Thymidine analogs may also be incorporated into dying neurons. Hence, a cell which looks like a nerve cell and contains a thymidine analog is not necessarily a newly born neuron, which was previously assumed. Therefore, many studies which have used this technique become much more difficult to interpret than was earlier believed. This concerns for example Peter Erikssonīs investigation in 1998, where he reported of neurogenesis in the adult human brain.

No cell division after stroke
Another example of studies which may have been misinterpreted, because thymidine analogs were used to label newly born neurons, concerns stroke. In stroke, scientists have reported of an increased neurogenesis in rats. But in a stroke study on both adult mice and rats, Chia-Yi Kuan and his colleagues investigated what happened to neurons after the incorporation of the thymidine analogs. They found that no cell division was taking place. Certainly, the nerve cells started to divide since the DNA synthesis began. After a while however the neurons died without having divided. The scientists could also demonstrate that no thymidine analog had been incorporated in the part of the brain where the stem cells are situated. According to the researchers, the stroke provokes the DNA synthesis. Juri Katchanov, Yan Yang and many other researchers have arrived at similar results, where brain damages cause DNA synthesis and cell death.

Moreover, the thymidine analogs themselves seem to be able to influence stem cells from bone marrow, resulting in a greater number of new nerve cells, according to Ting Yu Qu et al. The scientists hope that this effect may be utilized to improve the results.

It is important to know that most of the work on "adult" neurogenesis is done in still developing rodents which are 2-3 months old. Rodents are not mature until at least 8 months, which would be equivalent to "young adults". However, the experiments relevant to Parkinsonīs disease and Alzheimerīs disease should be conducted in 20 month-old mice to more closely approximate the human postmenstrual age of 45-50 years, when these disorders usually occur.

Human stem cell production is a difficult task
Mostly, the debate of stem cell research in the media is not about unsolved scientific problems but about ethical issues concerning the use of human embryos to create stem cell lineages. But when it comes to making such cell lineages there are also big difficulties which are purely technical. It is very hard to produce human embryonic stem cell lineages, according to a statement in a Swedish Journal (Medicinsk Vetenskap 4/06) by the stem cell researcher Outi Hovatta at the Karolinska Institute. As a matter of fact, there are no such cell lineages containing only human material today. The embryonic stem cells are cultivated in media which contain animal substances. If the stem cells shall be used in therapy in patients, the animal material must be replaced by human material, which is a very expensive process that demands a great deal of work, according to Hovatta.

January, 2007
Lena Carlsson

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