5 March 2004. In this week’s PNAS, Fernando Nottebohm and colleagues at Rockefeller University, New York, report that brain-derived neurotrophic factor (BDNF) protects newborn neurons in songbirds. BDNF has also been linked to long-term potentiation, memory, and even Alzheimer’s disease in humans (see ARF related news story; see also ARF Live Discussion).
While neurogenesis in adult mammalian brains is a relatively recent discovery (see ARF related news story), avian researchers have been singing its praises for over 20 years. In the early 1980s Nottebohm, together with Steve Goldman, showed that testosterone induces neurogenesis in adult female canaries—even making them sing male tunes. Subsequently, it turned out that a seasonal flurry of neurogenesis is responsible for new neural connections that songbirds need to learn tunes for serenading potential mates. After the breeding season, these neurons die off, to be replaced again the following year. In general, birds that don’t sing also don’t have these waves of neuron birth.
In canaries, the new neurons are derived from the ventricular zone of the lateral ventricles. From there, they migrate to a region of the brain called the high vocal center (HVC) and many of them integrate into the neural circuitry within the next 30 days. However, their lifespan depends on when they were formed. If the neurons are born in the fall, when canaries begin learning songs, half of them will last through the following spring, eight months later. But if born in the spring, almost all the neurons will be gone within four months.
Because BDNF is known to affect neuronal survival, first author Benjamin Alvarez-Borda and colleagues decided to test if it had any effect on the lifespan of new neurons in adult male canaries. Also, to test if the timing of BDNF infusion was critical, Alvarez-Borda used a type of pulse-chase experiment. For four days he dosed the birds with radioactive thymidine to label newly formed neurons; then 4-10, 14-20, and 24-30 days later, he infused BDNF directly into the HVC. Eight months later, when the authors tested the numbers of new HVC neurons (thymidine was labeled with tritium, which has a half life of 12 years), they found that birds chased on days 14-20 had about tenfold more new neurons (about two percent) than controls or the other treated birds.
The results suggest that there is a time window during which new neurons can be protected by the neurotrophic factor.
Turning to the seasonal nature of bird neurogenesis, the authors compared newborn neuron survival in fall birds to that in spring birds supplemented with BDNF. Neuronal longevity was strikingly similar in the two groups, suggesting that perhaps seasonal regulation of BDNF explains the long lifespan of fall neurons.
What this says for mammalian neurogenesis is unclear, but the authors remind us that similar winnowing of new neurons occurs in the hippocampus and olfactory bulb of adult mice. The authors suggest a provocative idea; in new neurons BDNF winds up, during a narrowly defined sensitive period, a molecular clock that then determines when that neuron will die. In mammals, one reason why many researchers suspect that adult neurogenesis contributes few functioning neurons to the brain, and why cell therapies may be difficult, is that many newly generated neurons tend to die soon after “birth.”—Tom Fagan.
Alvarez-Broda B, Haripal B, Nottebohm F. Timing of brain-derived neurotrophic factor exposure affects life expectancy of new neurons. PNAS early edition. 2004 March 1. Abstract