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.

Reference:
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

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  1. The discoveries that neurons that mediate birdsong in canaries are replaced by new neurons produced from stem cells, and that this turnover of the neurons is regulated by testosterone in a seasonal manner, have provided important insight into the control of neurogenesis by environmental factors. In their new study, Alvarez-Borda et al. provide evidence that BDNF promotes the survival of newly generated neurons in the high vocal center of the canaries. Remarkably, there is only a very tight time window of approximately two weeks following neurogenesis in the spring when BDNF is capable of promoting the long-term survival of the newly generated neurons. These findings have important implications for the regulation of adult neurogenesis in mammals as well as for the importance of neurogenesis in learning and memory processes.

    Recent studies of neurogenesis in the hippocampus and forebrain of mice
    suggest that the continued production of new neurons is required for at
    least some aspects of learning and memory [1,2]. Presumably, newly
    generated neurons must integrate into neuronal circuits in order to
    function in learning and memory, and this requires that they migrate to
    the appropriate site, differentiate into the relevant phenotype, and form
    functional synapses. Of course, functional neurogenesis also requires that
    the neurons survive, which in many instances is not the case, as indeed many
    newly generated neurons undergo apoptosis. As in the canary, it has been
    shown that BDNF promotes the differentiation [3] and survival [4] of
    newly generated neurons in the mammalian brain.

    Might there be a role for altered neurogenesis in the cognitive
    dysfunction that occurs in Alzheimer's disease [AD]? Neurogenesis is
    decreased during aging [5], and aging is a major risk factor for AD.
    Studies of transgenic mice with amyloid deposits in their brains, and
    of cultured human neural stem cells exposed to amyloid-β peptide, suggest that
    increased levels of Aβ can impair neurogenesis [6]. However, analyses
    of brain tissue from AD patients suggested that neurogenesis is not
    reduced and even might be increased in AD [7]. It therefore remains to
    be determined whether impairment of neurogenesis contributes to cognitive
    dysfunction in mouse models or AD patients. Nevertheless, levels of BDNF,
    [8] and its high affinity receptor TrkB [9], are decreased in affected
    brain regions in AD patients, and there are indications that polymorphisms in the
    BDNF gene can affect the risk of AD [10]. A deficit in BDNF signaling
    would be expected to impair synaptic plasticity and might also suppress
    neurogenesis in AD.

    References:
    1. Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002;12[5]:578-84.
    Abstract

    2. Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Miller MW, Ware CB, Martin GM, Kim SH, Langdon RB, Sisodia SS, Tsien JZ. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces. Neuron. 2001 Dec 6;32[5]:911-26. Erratum in: Neuron 2002 Jan 17;33[2]:313.
    Abstract

    3. Cheng A, Wang S, Cai J, Rao MS, Mattson MP. Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol. 2003 Jun 15;258[2]:319-33.
    Abstract

    4. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem. 2002 Sep;82[6]:1367-75.
    Abstract

    Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996 Mar 15;16[6]:2027-33.
    Abstract

    6. Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid β-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002 Dec;83[6]:1509-24.
    Abstract

    7. Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101[1]:343-7.
    Abstract

    8. Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M. Brain-derived neurotrophic factor is reduced in Alzheimer's disease. Brain Res Mol Brain Res. 1997 Oct 3;49[1-2]:71-81.
    Abstract

    9. Allen SJ, Wilcock GK, Dawbarn D. Profound and selective loss of catalytic TrkB immunoreactivity in Alzheimer's disease. Biochem Biophys Res Commun. 1999 Nov 2;264[3]:648-51.
    Abstract

    10. Kunugi H, Ueki A, Otsuka M, Isse K, Hirasawa H, Kato N, Nabika T, Kobayashi S, Nanko S. A novel polymorphism of the brain-derived neurotrophic factor [BDNF] gene associated with late-onset Alzheimer's disease. Mol Psychiatry. 2001 Jan;6[1]:83-6.
    Abstract

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References

News Citations

  1. From Protein Trafficking to Episodic Memory: Tracing BDNF Genotypes
  2. New Neurons in Old Brains Make New Contacts

Paper Citations

  1. . Timing of brain-derived neurotrophic factor exposure affects life expectancy of new neurons. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3957-61. PubMed.

Other Citations

  1. ARF Live Discussion

Further Reading

Papers

  1. . Intraventricular infusion of TrkB-Fc fusion protein promotes ischemia-induced neurogenesis in adult rat dentate gyrus. Stroke. 2003 Nov;34(11):2710-5. PubMed.
  2. . Timing of brain-derived neurotrophic factor exposure affects life expectancy of new neurons. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3957-61. PubMed.
  3. . Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit. Neurosci Res. 2003 Sep;47(1):55-63. PubMed.
  4. . Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem. 2002 Sep;82(6):1367-75. PubMed.
  5. . Suppression of insult-induced neurogenesis in adult rat brain by brain-derived neurotrophic factor. Exp Neurol. 2002 Sep;177(1):1-8. PubMed.

News

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  3. Antiinflammatory Drugs Protect Hippocampal Neurogenesis

Primary Papers

  1. . Timing of brain-derived neurotrophic factor exposure affects life expectancy of new neurons. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3957-61. PubMed.