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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