Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination
Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination
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DOI：
10.1523/jneurosci.2751-04.2004
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发表时间：
2004-09-22
影响因子：
5.3
通讯作者：
Weiss, S
中科院分区：
文献类型：
--
作者：
Enwere, E;Shingo, T;Weiss, S
先前的研究表明，嗅觉中间神经元参与嗅觉辨别，并且随着年龄的增长，前脑室下区的增殖减少，这让我们想知道老年小鼠的嗅觉神经发生以及嗅觉辨别是否受到损害。脉冲标记显示，老年小鼠（24 个月大）的嗅球中新的中间神经元比年轻的成年小鼠（2 个月大）少。然而，老年小鼠比年轻小鼠拥有更多的嗅觉中间神经元。老年小鼠在区分两种不同气味的能力方面与年轻成年小鼠没有差异，但在区分相似气味（精细嗅觉辨别）方面明显较差。与野生型小鼠相比，白血病抑制因子受体杂合子小鼠的神经发生和嗅觉中间神经元较少，在精细嗅觉辨别方面的表现比野生型更差，这表明嗅觉神经发生，而不是中间神经元的总数，负责精细嗅觉辨别。免疫组织化学和蛋白质印迹分析显示，老年前脑室下区表皮生长因子（EGF）受体（EGFR）信号元件的表达水平选择性降低。 Waved-1 突变小鼠的转化生长因子-α（成年期的主要 EGFR 配体）表达量减少，老年小鼠的嗅觉神经发生和精细嗅觉辨别任务的表现均有所下降。这些结果表明，随着年龄的增长，精细嗅觉辨别力的受损可能是由于 EGF 依赖性嗅觉神经发生的减少所致。
Previous studies demonstrating olfactory interneuron involvement in olfactory discrimination and decreased proliferation in the forebrain subventricular zone with age led us to ask whether olfactory neurogenesis and, consequently, olfactory discrimination were impaired in aged mice. Pulse labeling showed that aged mice ( 24 months of age) had fewer new interneurons in the olfactory bulb than did young adult ( 2 months of age) mice. However, the aged mice had more olfactory interneurons in total than their younger counterparts. Aged mice exhibited no differences from young adult mice in their ability to discriminate between two discrete odors but were significantly poorer at performing discriminations between similar odors ( fine olfactory discrimination). Leukemia inhibitory factor receptor heterozygote mice, which have less neurogenesis and fewer olfactory interneurons than their wild-type counterparts, performed more poorly at fine olfactory discrimination than the wild types, suggesting that olfactory neurogenesis, rather than the total number of interneurons, was responsible for fine olfactory discrimination. Immunohistochemistry and Western blot analyses revealed a selective reduction in expression levels of epidermal growth factor (EGF) receptor ( EGFR) signaling elements in the aged forebrain subventricular zone. Waved-1 mutant mice, which express reduced quantities of transforming growth factor-alpha, the predominant EGFR ligand in adulthood, phenocopy aged mice in olfactory neurogenesis and performance on fine olfactory discrimination tasks. These results suggest that the impairment in fine olfactory discrimination with age may result from a reduction in EGF-dependent olfactory neurogenesis.