Discovering Nerve Cell Replacement in the Brains of Adult Birds

Nottebohm, Fernando

Until recently, scientific dogma held that at birth or soon after humans and other vertebrates possess all the brain cells they will ever have—and furthermore, if any of these cells died, they could not be replaced. This dogma was challenged by a series of papers in the 1980s in which Rockefeller neuroscientist Fernando Nottebohm (1940 - ) provided the first incontrovertible evidence that new neurons were added to the brain of adult canaries. Although this finding initially was greeted with skepticism, a description of the anatomy of the cells, their neurophysiological responses to external stimuli, and of their time of birth left little doubt that this was a case of adult neurogenesis in which the new neurons were put to use.

In addition, Nottebohm's laboratory identified the place of birth of the new neurons (the walls of the lateral ventricle), the stem cells that gave origin to the new neurons, and the manner of migration of the new neurons from the site of birth to their final destination. These findings have since been extended by other researchers who have found that neurogenesis in the adult brain of mammals, including humans, happens in much the same manner as in birds. Further studies found similar neurogenesis in the embryos of vertebrates in general. In subsequent years Nottebohm showed that spontaneous neurogenesis in birds is part of a process of constant neuronal replacement that takes place through much of the forebrain and affects as many as five percent of the classes of neurons found in the brain. This replacement occurs when the brain has to process much new information. A better understanding of how new neurons are generated and of the way in which they replace older ones that have died may suggest new therapies for brain injury and neurodegenerative disorders, as well as ways to rejuvenate brain circuits that deteriorate with aging.

Nottebohm's studies of adult neurogenesis stemmed from his work on song learning in canaries. Beginning in the 1970s, his pioneering studies had mapped the brain anatomy and circuitry responsible for vocal learning in songbirds, known as the song system. He noticed that canaries, which learn new and complex songs each spring, showed striking seasonal changes in brain anatomy. Certain areas, known to be involved with the production of learned song, were large in the spring when the learned song was produced in a very stereotypic manner; after the breeding season, as song became more variable and eventually stopped, the areas shrank in size. Nottebohm wondered whether these changes could be explained by the addition of new neurons in the brain. He and colleagues injected canaries with 3H-thymidine, a marker that becomes incorporated into newly synthesized DNA as cells divide, and thus serves as a marker for newborn cells. They discovered cells dividing in the wall of the brain cavity known as the lateral ventricle, from which daughter cells migrated into the main song control nucleus. The recruitment of new neurons, which replaced older ones that had died, peaked at the very time that canaries acquired the song they would use in the following breeding season. This temporal correlation observed in adult canaries was subsequently seen to occur also in juveniles, when they first learned their song! Based on these studies Nottebohm suggested that the process seen in adults is one of self-rejuvenation.

Nottebohm's laboratory continues to study the basic biology of neuronal replacement in adult brain, using behavioral, anatomical, neurophysiological, endocrinological, cellular, and molecular methods. Research is carried out both in laboratories at The Rockefeller University Manhattan campus and at the Field Research Center in Millbrook, NY, where behavior and brain function can be studied under natural conditions.

Neurons that die in Alzhe have unusually low levels of protein called UCHL1

Fernando Nottebohm earned the BA (1962) and the PhD (1966) at the University of California, Berkeley. He spent a year at Cambridge University as part of his doctoral training before joining Rockefeller in 1967 as assistant professor. He became associate professor in 1971 and professor in 1976. In 1996 he was named Dorothea L. Leonhardt Professor. Since 1981 Nottebohm has been director of the Rockefeller University Field Research Center for Ethology and Ecology. Among many awards and prizes, Nottebohm's achievements have been recognized with the Ipsen Foundation Neuronal Plasticity Prize (1999), the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science (2004), the Karl Spencer Lashley Award of the American Philosophical Society (2005), and the Benjamin Franklin Medal in Life Science (2006).  Nottebohm received the MERIT Award from the National Institute of Mental Health. He is an elected member of the U.S. National Academy of Sciences (1988) and the American Philosophical Society, and a fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science.

Selected Publications

Nottebohm F. A brain for all seasons: cyclical anatomical changes in song control nuclei of the canary brain. Science, 1981, 214: 1368-1370

Goldman SA and Nottebohm F. Neuronal production, migration and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci USA, 1983, 80: 2390-2394

Paton JA and Nottebohm F. Neurons generated in adult brain are recruited into functional circuits. Science, 1984, 225: 1046-1048

Burd GD and Nottebohm F. Ultrastructural characterization of synaptic terminals formed on newly generated neurons in a song control nucleus of the adult canary forebrain. J Comp Neurol, 1985, 240: 143-152

Nottebohm F. Neuronal replacement in adulthood. Ann NY Acad Sci, 1985, 457: 143-161

Alvarez-Buylla A and Notebohm F. Migration of young neurons in adult avian brain. Nature, 1988, 335: 353-354

Kirn J and Nottebohm F. Direct evidence for loss and replacement of projection neurons in adult canary brain. J Neurosci 1993, 13: 1654-1663

Barnea A and Nottebohm F. Seasonal recruitment of new neurons in the hippocampus of adult, free-ranging black-capped chickadees. Proc Natl Acad Sci USA, 1994, 91: 11217-11221

Further Reading

Nottebohm F. The road we travelled: Discovery, choreography, and significance of brain replaceable neurons. Ann NY Acad Sci, 2004, 1016: 628-658

Nottebohm F. The neural basis of birdsong. PLoS Biology, 2005, 3(5): 759-761

Nottebohm F.  The anatomy and timing of vocal learning in birds. In: The Design of Animal Communication, Hauser MD and Konishi M, eds. Cambridge, MA: MIT Press, 1999, 3: 63-110


Fernando Nottebohm, Laboratory of Animal Behavior

2006 Benjamin Franklin Medal in Life Science A resource for brain researchers