Heads of Laboratories
Songbirds learn their song in a manner reminiscent of how humans learn the sounds of speech, and the song system has provided an animal model for studying the biology of vocal learning. Work on this system revealed the existence of replaceable neurons in the adult brain, an observation that has raised basic questions about the biology of memory and the brain’s capacity for self-repair. Dr. Nottebohm is now using this same system in transgenic songbirds to gain insights on the basic biology of Huntington’s disease, a neurodegenerative motor disorder.
The Nottebohm laboratory set out to understand the biology of vocal learning using all possible approaches. Early on, it identified a “song system” composed of discreet nuclei and pathways devoted to the acquisition and production of learned song; this system was present in vocal learners but absent in non-learners. In addition, it noted that vocal learners come in two kinds: 1) open-ended learners, such as the canary, that learned new songs in adulthood; and 2) sensitive period learners, such as the zebra finch, that learn their song before sexual maturity. Soon thereafter, it became clear that the song system was hormone sensitive and sexually dimorphic: the high vocal center (HVC) of canaries, for example, was four times larger in males than in females, but as females were treated with testosterone and began to sing in a male-like manner, their HVC size doubled. This led to the realization that the size of male song nuclei changed seasonally. It became clear that testosterone could induce dendritic growth and with it, the formation of many new synapses. In addition, though, use of radioactively labeled thymidine as a birth-date marker suggested that new, neuron-like cells were also added.
Eventually, it was possible to record from the new cells and establish beyond reasonable doubt that they joined existing circuits and became functioning neurons. The birth site and the neuronal stem cells that gave rise to the new neurons were identified, as were their manner and time of migration, their life expectancy and the variables that affected them. It was shown that new neurons were added not just to the song system, but throughout the forebrain. In this manner, the new discipline of adult neurogenesis became established.
Further work showed that adult neurogenesis can occur in either of two contexts: as numerical replacement and as net addition. In the first case, new neurons replace older neurons that have died. The new “ephemeral cells” can last from a few weeks to a few months to a year before they, in turn, are replaced, and peak addition occurs at times of peak memory load, as has been demonstrated in the context of vocal learning in canaries and following changes in visual, spatial and social complexity in other species. In the second case, net addition, demonstrated in the HVC of zebra finches, new neurons persist, with an eventual doubling in neuron numbers, reduction in their size and increased packing density with no net change in HVC volume. Taken together, these observations have challenged several widely held beliefs: 1) that no new neurons are added to the adult brain; 2) that neurons lost cannot be replaced; and 3) that changes in the number and efficacy of existing synapses provide all the plasticity necessary for learning.
Most recently, the Nottebohm laboratory has begun to use the song system of canaries and zebra finches as sensitive material to report on the mechanisms of late onset neurodegenerative motor disorders, such as Huntington’s disease. The human mutant huntingtin gene, responsible for the disease, has been inserted into the genome of embryos of both species, giving rise to transgenic individuals and lines of their descendants. The Nottebohm lab hopes that, as for other basic issues in brain science, the song system will again provide useful information.
Born in Buenos Aires, Dr. Nottebohm earned his undergraduate degree in 1962 and his Ph.D. in 1966 at the University of California, Berkeley. He spent a year at the University of Cambridge as part of his doctoral training before joining Rockefeller in 1967 as assistant professor. He became associate professor in 1971 and professor in 1976.
Dr. Nottebohm’s many awards and honors include the The Mortimer D. Sackler Prize for Distinguished Achievement in Developmental Psychobiology in 2011, the 2006 Benjamin Franklin Medal in Life Science, the 2005 Karl Spencer Lashley Award of the American Philosophical Society, the 2004 Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Science, the 1999 Ipsen Foundation Prize in Neuronal Plasticity, the 1997 McKnight Foundation Senior Investigator Award in neuroscience and the Charles A. Dana Award for Pioneering Achievement in Health Sciences in 1992. He was elected to the National Academy of Sciences in 1988.
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