NEWS RELEASE, 6/5/97 UC Berkeley brain scientists locate area in mouse brains for link between the immune system and higher mental function

by Patricia McBroom

Berkeley -- UC Berkeley neuroscientists have discovered what they believe is a basic mechanism through which higher brain centers in mammals may help to regulate the immune system. The experiments on mice involve the frontal cortex, which is the most evolved structure in the brain, responsible for voluntary, purposeful behavior. It appears that this region has a direct link with the thymus gland, which is the production center for germ-fighting T-cells, and may be able to modulate levels of CD4 and CD8 T-cells. While it is too early to comment on any clinical applications, the researchers said their discovery, based on 10 years of research, brings together several different lines of evidence all pointing to one conclusion. "I think we have the mechanism for showing that there is voluntary control over the immune system," said Marian Diamond, professor of integrative biology at the University of California at Berkeley. She said the frontal cortex of the mouse is comparable to the prefrontal lobes and the motor cortex of the human brain combined. Consequently, the human equivalent to the mouse brain would include both purposeful movement, such as exercising, and planning ahead or forethought. Both might be playing a role in regulating functions of the immune system, she said. Diamond headed the research carried out by Gary O. Gaufo, now a postdoctoral fellow in immunology at the University of California, San Francisco. They published a joint paper this month in the journal, Brain Research, involving implantation of a thymus in young mice genetically bred to be immune deficient because they are born without a thymus. The scientists were able to show major effects on the forebrain of the animals due to implantation of the thymus beneath the capsule of the kidneys. The cerebral cortex of this strain of immune deficient mice is typically abnormally thin and underdeveloped. But in the mice that Gaufo altered, the frontal area became as thick as normal. It was the only part of the brain to show such changes, although this particular strain, called "nude" mice, has neurological deficits in other places. Moreover, the scientists were able to show the presence of T-cells in the blood of the surgically grafted mice, indicating that the thymus was active. The current work is the latest chapter in research that Diamond and her students have carried out for a decade. In 1985, they mapped the cerebral cortex of the mouse brain looking for links with the T-cell mediated immune system and established a probable site in the forebrain. Many experiments were conducted to find ways of implanting the tiny mouse thymus so that it would be active. "Now finally," said Diamond, "we are able to show that we can implant a thymus and reverse deficits in this area of the brain." French researchers were the first to show in the early 1980s that the cerebral cortex in general could suppress or stimulate the immune system, but it took years of work in Diamond's laboratory to localize the influence to just the frontal cortex. "We now have evidence of a direct link between these higher cognitive centers and the so-called involuntary immune system," said Gaufo. "They are not just two independent systems; they are directly linked in protecting our bodies from invasion by pathogens." Gaufo said he cannot say how much control is lodged in the frontal cortex. "We think it has a role in modulating functions of the immune system, but perhaps not a regulatory role," he said. This research also established that the messenger between thymus and frontal cortex was the hormone prolactin, well known for its role in producing mother's milk and nurturing behaviors. A product of the pituitary gland, prolactin has recently been shown to have a range of effects on systems including T-cell development, electrolyte levels and cellular survival. It was prolactin activity in the midbrain of Gaufo's thymus-implanted mice that was critical in rebuilding the forebrains of these animals. At 60 days of age when the animals were evaluated, their frontal cortex had increased in thickness to normal levels while the brains of mice not given a thymus were still deficient. When Gaufo provided extra prolactin via a pituitary implant, the cortical reconstruction was more global, while with the thymus implant, recovery was restricted to the frontal area. (Normally, nude mice have a pituitary, but the animals still develop brain deficits.) The mice were originally altered at 30 days of age, when the frontal cortex in these animals would have reached its maximum growth, which means that the mouse brains recovered while the animals were in young adulthood. Gaufo believes that the increased cortical thickness was probably due, not to growth in the number of neurons, but growth in the size of the cell body, its branches and supporting structures. The implications of the work are immense, even though research on humans has not yet been done. It was Diamond's and colleagues' work on rats over a period of 30 years that first established that enrichment in the environment could build bigger, better brains in animals at any age -- work that is only now seeing widespread application in humans. Similarly, this research offers hope for individuals to gain some voluntary control over their immune systems, the investigators said. "Even though it is a far reach from this basic research to clinical usefulness, there is hope," said Gaufo. "Certainly, there is no harm in making plans for the future and believing that even though you might be ill and depressed, there is something to be gained immunologically from exercising and thinking positively."