Kuhn H G, Dickinson-Anson H, Gage F H
Laboratory of Genetics, Salk Institute, La Jolla, California 92037, USA.
J Neurosci. 1996 Mar 15;16(6):2027-33. doi: 10.1523/JNEUROSCI.16-06-02027.1996.
The hippocampus is one of the few areas of the rodent brain that continues to produce neurons postnatally. Neurogenesis reportedly persists in rats up to 11 months of age. Using bromodeoxyuridine (BrdU) labeling, the present study confirms that in the adult rat brain, neuronal progenitor cells divide at the border between the hilus and the granule cell layer (GCL). In adult rats, the progeny of these cells migrate into the GCL and express the neuronal markers NeuN and calbindin-D28k. However, neurogenesis was drastically reduced in aged rats. Six-to 27-month-old Fischer rats were injected intraperitoneally with BrdU to detect newborn cells in vivo and to follow their fate in the dentate gyrus. When killed 4-6 weeks after BrdU labeling, 12- to 27-month-old rats exhibited a significant decline in the density of BrdU-positive cells in the granule cell layer compared with 6-month-old controls. Decreased neurogenesis in aging rats was accompanied by reduced immunoreactivity for poly-sialylated neural cell adhesion molecule, a molecule that is involved in migration and process elongation of developing neurons. When animals were killed immediately (12 hr) after BrdU injection, significantly fewer labeled cells were observed in the GCL and adjacent subgranular zone of aged rats, indicative of a decrease in mitotic activity of neuronal precursor cells. The reduced proliferation was not attributable to a general aged-related metabolic impairment, because the density of BrdU-positive cells was not altered in other brain regions with known mitotic activity (e.g., hilus and lateral ventricle wall). The decline in neurogenesis that occurs throughout the lifespan of an animal can thus be related to a decreasing proliferation of granule cell precursors.
海马体是啮齿动物大脑中少数几个在出生后仍能持续产生神经元的区域之一。据报道，大鼠的神经发生可持续到11个月大。本研究使用溴脱氧尿苷（BrdU）标记法证实，在成年大鼠大脑中，神经元祖细胞在海马齿状回门区和颗粒细胞层（GCL）之间的边界处分裂。在成年大鼠中，这些细胞的后代迁移到GCL并表达神经元标志物NeuN和钙结合蛋白-D28k。然而，老年大鼠的神经发生显著减少。对6至27月龄的Fischer大鼠腹腔注射BrdU，以在体内检测新生细胞并追踪它们在齿状回中的命运。在BrdU标记后4至6周处死大鼠时，与6月龄对照组相比，12至27月龄大鼠颗粒细胞层中BrdU阳性细胞的密度显著下降。衰老大鼠神经发生减少伴随着多唾液酸神经细胞黏附分子免疫反应性降低，该分子参与发育中神经元的迁移和轴突延伸。当在BrdU注射后立即（12小时）处死动物时，在老年大鼠的GCL和相邻的颗粒下区观察到标记细胞明显减少，这表明神经元前体细胞的有丝分裂活性降低。增殖减少并非归因于与年龄相关的一般代谢损伤，因为在其他已知有丝分裂活性的脑区（如门区和侧脑室壁），BrdU阳性细胞的密度没有改变。因此，动物一生中发生的神经发生下降可能与颗粒细胞前体增殖减少有关。
