Developmental Neuroscience Blossoming In The 1990s

Midway into the 1990s--the "Decade of the Brain," as declared by the United States Congress--scientists are touting major, exciting breakthroughs in the neurosciences. Researchers continue to uncover new aspects of the structure, development, and function of the brain and nervous system. Society for Neuroscience 11 Dupont Circle, N.W.Suite 500 Washington, D.C. 20036 Phone: (202) 462-6688 Nancy Beang, executive director Carla Shatz, president 23,000 members International Society for Developmental Neuroscience University of Texas Medical Branch Galveston, Texas 77550-0652 Phone: (409) 772-3667 Fax: (409) 772-8028 E-mail: regino@beach.utmb.edu Arne Schousboe, president Regino Perez-Polo, secretary-general 1,000 members According to neurophysiologist Zach Hall, director of the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Md., a particularly active topic of research has been developmental neuroscience. The study of the formation and maturation of the nervous system, this subdiscipline encompasses a broad range of investigations, from the expression of specific genes to the formation of nerve cells and the organization of the entire system. As such, this expanding field draws from a number of basic areas, including genetics and gene regulation, molecular and cell biology, biochemistry, and physiology. The wealth of information to arise from advances in these disciplines, coupled with increased sophistication in such technologies as imaging, microscopy, and tissue culture, has enabled both developmental biologists and neuroscientists to pose hitherto unasked questions. For example, Eugene Major, who heads the Laboratory of Molecular Medicine and Neuroscience at NINDS, points out that "molecular technologies--gene amplification and expression systems--are much further along now than they were five to 10 years ago." Such technologies allow developmental neuroscientists to work with molecules that are otherwise produced in very low amounts. "The whole biology of neurotrophic factors and how they control the genes in developing nerve cells" can be studied now that scientists can produce and analyze these factors in their labs, he adds. "The whole field of developmental biology is very promising- many basic problems are now being solved," says Carlos Lois, a physician currently working toward his Ph.D. in neuroscience at Rockefeller University in New York. Thus, scientists interested in the development of specific tissues and organ systems are now able to apply these basic findings toward answering their particular questions. Developmental neuroscience, Lois notes, is especially attractive in that "the nervous system is uncharted territory--many investigators [in-cluding developmental biologists] are attracted by its complexity." But the same intricacies that attract and intrigue investigators have also posed obstacles--in designing and performing experiments--to the progress of the neurosciences, researchers say. "To some extent, the nervous system has been technically difficult to work with until recently," says Major. "We now have nervous-system-derived cell cultures with representative populations of neuronal cells that are reproducible." For Major, who works on viruses that have a specific predilection for certain brain cells, for example, such cell cultures are essential for investigating the mechanisms by which the viruses infect and reside in the brain. A boon to the field, he adds, has been the availability of fetal tissue for research. "Human fetal tissue has played a significant role in drawing attention to experiments that can be done; we don't have to rely totally on [animal] model systems," he says. Because of the high degree of variation in the brains of different animals, he explains, the results of experiments on animals cannot always be extrapolated to human disease. One of Major's areas of research is investigating cell lineage namely the course of development and differentiation--of various cells in the brain, and using this information to study the pathogenesis of viral infections of the nervous system. For example, his laboratory has studied the mechanisms of disease processes of viral-induced leucoencephal-opathies-- a group of infections of non-neuronal brain cells, called glia, in the brain's white matter often associated with AIDS. Most recently, the group discovered that HIV-1 is capable of infecting cells called astrocytes in the developing nervous system. The researchers postulate that astrocytes probably act as reservoirs for the virus in cases of AIDS-associated leucoencephalitis (C. Tornatore et al., Neurology, 44:481-7, 1994). The virus lies latent in the astrocytes until it reactivates in response to certain cytokines. The next step, Major anticipates, is "to understand the mechanism of the [virus-nerve cell] interaction," and investigate possible intervention strategies based on blocking either infection of the cells or the reactivation of the virus. A long-standing belief in the scientific community about the development of the nervous system in mammals has been that neuronal cells could grow only prenatally, and that cells were incapable of migrating over long distances and differentiating into neurons after birth. Indeed, this dogma was so deeply entrenched in the research community that an early report documenting neurogenesis in the brains of adult rats and mice (J. Altman, G.D. Das, Journal of Comparative Neurology, 124:319, 1965) went largely ignored, says Lois. "The generation of new neurons was demonstrated in adult canaries in the 1980s, by which time there were significant technical advances in the field as well as a change in attitudes," remarks Lois. "But there was still very little known about neurogenesis in mammals. "Certain cells in the lateral ventricles of the [mammalian] brain were known to divide, but their fate was not known," he explains, adding that these cells were commonly thought to die or become glia. Lois investigated the fate of the dividing brain cells from rats, both in vitro and in vivo, using a combination of labeling techniques on transgenic animal models. Recently, Lois and his adviser, Arturo Alvarez-Buylla, a professor of neuroscience at Rockefeller, published evidence that neurogenesis does occur in adult mammals. They reported that a population of dividing cells in the lateral ventricles of the brain migrate to the olfactory bulb region, where the cells then differentiate into neurons (C. Lois, A. Alvarez- Buylla, Science, 264:1145-8, 1994). These findings may have implications in therapeutic approaches to various neurodegenerative diseases and transplantation, AlvarezBuylla and Lois speculate. For instance, by directing precursor cells to specific parts of a brain, it may be possible to replace dying cells in the targeted region. But to do this, Lois says, "it is important to generate specific types of neurons, and as yet we have no clue on how to do that." These results have also opened up some interesting questions in fundamental neurobiology--for example, "Why is the olfactory bulb targeted for cell replacement?"--he adds. "Even more puzzling is how memories are maintained when the structure of the cell is changing as it undergoes differentiation. Normally, we think of memory as being stored in the synapses between various neurons. These are all questions to which the answers are completely unknown." Leading researchers see the upcoming decades yielding answers to these and other intriguing questions about how the nervous system is formed and how it matures. The development of the nervous system, more than any other system in the body, is particularly fascinating because of its potential to yield answers to questions about behavior, memory, and intelligence, scientists say. Pasco Rakic, chairman of the neuroanatomy section at the Yale University School of Medicine, New Haven, Conn., likens the advance of this field to a house of bricks. "You build up a house with thousands of bricks--all of them are equally important but no one is really more important than anything else. Developmental neuroscience is a whole discipline, not just one area of research. There are many, many important and exciting things going on."

Developmental Neuroscience Blossoming In The 1990s

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