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December 21, 1999

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Molecule Looks Like Crucial Link Between Life, Mood System

"If I had to make a signal that could write messages on the brain from the environment, that would be BDNF."

Scientists at Johns Hopkins and the National Cancer Institute have found a "missing link" brain chemical that rises and falls quickly in response to stress, fear or an upbeat mood, and then sculpts nerve circuits in the brain accordingly.

Their report, on work done in genetically engineered mice, appears in the Dec. 21 issue of the Proceedings of the National Academy of Sciences (PNAS).

"What we believe we've found is a link between what happens to a person on a daily basis and the way the brain responds, from an emotional standpoint, over the long term," says Hopkins neuropathologist Vassilis E. Koliatsos, M.D., with the research team.

Beyond establishing what may be the first of many such links, the study could have far-reaching implications, the researchers say: from quelling side-effects of schizophrenia drugs to offering a sought-after animal model for impulse-driven psychiatric problems like bulimia and suicide, to explaining, in part, how cognitive therapy works for depression.

It also suggests an unusual, pivotal role in the brain for an already-known class of molecules, offering a possible new therapeutic approach to mental illness.

Scientists have long known that a chemical called BDNF (for brain-derived neurotrophic factor) acts as a neurotrophin -- a class of molecules that prompts growth of nerve cells and their proper "wiring" during development. In large amounts in an embryo's brain, for example, BDNF choreographs cells' proper migration to form the cerebellum.

"But we also see BDNF in adult brains," Koliatsos says, "and we never suspected the pivotal role it may play there."

In this as well as in earlier work by team researcher Laura Mamounas, Ph.D., the scientists showed that BDNF works specifically on a network of nerves that communicates through the chemical transmitter serotonin. Serotonin is the molecule most closely implicated in depression, and raising levels of it in the brain is the goal of Prozac and many other antidepressants. Brain researchers have long known that serotonin plays a major part in other psychiatric diseases as well, such as impulsive behavior, aggressiveness, eating disorders and, more recently, schizophrenia. More generally, the serotonin network holds the brain's major pathways dedicated to mood, sleep and appetite.

More important, however, the study shows that BDNF, working directly on the serotonin system, can regulate behavior of the sort linked with that system. "We don't have any other molecular signal in psychiatry that likely has such a direct behavioral impact," says Koliatsos.

Further, because research at Hopkins and elsewhere shows, in animals, that BDNF levels vary with experience it goes down in stressful situations; it goes up when depression leaves; it goes up during exercise the scientists suggest the molecule may link the environment and the mood/appetite centers of the brain. "BDNF has all the right features to be the critical signal by which environmental and psychosocial interactions impact on the brain," says Koliatsos. "It's very rapid, it's sensitive, and it affects a system critical for emotional life and behavior. If I had to make a signal that could write messages on the brain from the environment, that would be BDNF."

In the study, the researchers genetically engineered mice in order to shed light on BDNF's role in the brain. (The mouse serotonin system closely resembles humans.) By destroying or "knocking out" the normal BDNF gene and by selective breeding, team neuroscientists W. Ernest Lyons, Ph.D., and Lino Tessarollo, Ph.D., created mice with half the normal amount of BDNF . Mice with no BDNF died shortly after birth.

The altered mouse brains at first looked normal, but two sets of experiments showed the serotonin system was damaged: One showed unusual amounts of the protein receptors for serotonin, a classic sign that serotonin activity has dropped below normal. Another test showed that activity of a specific gene normally turned on by healthy nerve cells was sluggish -- a sign of injury.

In addition, the BDNF-deprived mice appeared noticeably more aggressive and impulsive. "They were much more likely to fight with other mice at the drop of a hat," says Lyons. Further, he adds, the mice had become almost twice normal size because of compulsive, almost bulimic eating. "There's an impulsive quality to their eating and to their aggression that ties into the damaged serotonin system. Impulse control is a well-documented casualty of low serotonin." This same impulsivity is seen in depressed people who commit suicide, the researchers say, which suggests these mice could be a model for testing drugs to lessen suicide or bulimia.

When the researchers treated the mice with Prozac, which increases available serotonin, the fighting and compulsive eating stopped.

Because one of the major side effects of the most potent schizophrenia medications is obesity with a bulimic aspect, says Koliatsos, the study may offer ways to tone down that behavior while maintaining the therapy's helpful effects.

Other researchers in the study were George A. Ricaurte, M.D., Ph.D., Susan Bora and Cornelia Wihler at Johns Hopkins, and Vincenzo Coppola,, M.D., and Susan W. Reid with the Neural Development Group and the National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Md.

The work was funded by grants from the National Cancer Institute, the National Institute of Mental Health and a Javits Neuroscience Investigator Award.

Footage showing overweight, aggressive BDNF-deprived mice in action is available.

A Web site showing pictures of overweight vs. normal mice and cross-sections of brains with/without BDNF showing obvious differences in the density of nerves is set up at: http://hopkins.med.jhu.edu/news/brainlink.html

The study is published in the Dec. 21, 1999 Proceedings of the National Academy of Sciences, vol. 96, no. 26 pp. 15239-15244.

Also helpful: "Brain-derived neurotropic factor promotes the survival and sprouting of serotonergic axons in rat brains," L. Mamounas and others, Journal of Neuroscience, 1995 vol. 15, pp. 7929-39

NOTE: Photos and B-roll available

Related Web site: http://www.med.jhu.edu/methylation

The article is in the September issue of Cardiovascular Research, vol 43, no.4, pp. 985-991.

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