Because neurogenesis persists in the adult mammalian brain and can be regulated by physiological and pathological events, we investigated its possible involvement in the brain's response to focal cerebral ischemia. Ischemia was induced by occlusion of the middle cerebral artery in the rat for 90 min, and proliferating cells were labeled with 5-bromo-2 -deoxyuridine-5 -monophosphate (BrdUrd) over 2-day periods before sacrificing animals 1, 2 or 3 weeks after ischemia. Ischemia increased the incorporation of BrdUrd into cells in two neuroproliferative regions-the subgranular zone of the dentate gyrus and the rostral subventricular zone. Both effects were bilateral, but that in the subgranular zone was more prominent on the ischemic side. Cells labeled with BrdUrd coexpressed the immature neuronal markers doublecortin and proliferating cell nuclear antigen but did not express the more mature cell markers NeuN and Hu, suggesting that they were nascent neurons. These results support a role for ischemia-induced neurogenesis in what may be adaptive processes that contribute to recovery after stroke. D iseases of the brain have singularly adverse effects on the quality and duration of life. Unlike many other tissues, the mature brain has limited regenerative capacity, and its unusual degree of cellular specialization restricts the extent to which residual healthy tissue can assume the function of damaged brain. However, cerebral neurons are derived from precursor cells that persist in the adult brain (1-5), so stimulation of endogenous neural precursors in the adult brain could have therapeutic potential (6).Neurogenesis occurs in discrete regions of the adult brain, including the rostral subventricular zone (SVZ) of the lateral ventricles (7) and the subgranular zone (SGZ) of the dentate gyrus (DG) (8). Neurons that arise in the SVZ travel via the rostral migratory stream to the olfactory bulb (9) and also enter association neocortex (10), and new neurons leaving the SGZ migrate into the adjacent DG granule cell layer. Neurogenesis in these regions is subject to physiological regulation by glucocorticoids (11), sex hormones (12), growth factors (13-16), excitatory neurotransmission (17), learning (18), and stress (19) and can be modified pharmacologically (20).Pathological events can also stimulate neurogenesis in the adult brain. Mechanical injury to the DG granule cell layer in the rat increases proliferation of granule neuron precursors in the adjacent SGZ, as shown by enhanced incorporation of [ 3 H]thymidine and 5-bromo-2Ј-deoxyuridine-5Ј-monophosphate (BrdUrd), induction of proliferating cell nuclear antigen (PCNA), and coexpression of mature neuronal markers in [ 3 H]thymidinelabeled cells (21). Seizures also trigger neurogenesis in the SGZ, with BrdUrd-labeled cells expressing the neuronal markers TOAD-64, class III␤-tubulin, and microtubule-associated protein 2 (MAP-2) (22). Finally, apoptosis induced by oxidative stress in mouse corticothalamic neurons increases BrdUrd labeling in cells that go on to express ...

No abstract

SummaryNeurogenesis, which may contribute to the ability of the adult brain to function normally and adapt to disease, nevertheless declines with advancing age. Adult neurogenesis can be enhanced by administration of growth factors, but whether the aged brain remains responsive to these factors is unknown. We compared the effects of intracerebroventricular fibroblast growth factor (FGF)-2 and heparin-binding epidermal growth factor-like growth factor (HB-EGF) on neurogenesis in the hippocampal dentate subgranular zone (SGZ) and the subventricular zone (SVZ) of young adult (3-month) and aged (20-month) mice. Neurogenesis, measured by labelling with bromodeoxyuridine (BrdU) and by expression of doublecortin, was reduced by ∼ ∼ ∼ ∼ 90% in SGZ and by ∼ ∼ ∼ ∼ 50% in SVZ of aged mice. HB-EGF increased BrdU labelling in SGZ at 3 months by ∼ ∼ ∼ ∼ 60% and at 20 months by ∼ ∼ ∼ ∼ 450%, which increased the number of BrdU-labelled cells in SGZ of aged mice to ∼ ∼ ∼ ∼ 25% of that in young adults. FGF-2 also stimulated BrdU labelling in SGZ, by ∼ ∼ ∼ ∼ 25% at 3 months and by ∼ ∼ ∼ ∼ 250% at 20 months, increasing the number of newborn neurones in older mice to ∼ ∼ ∼ ∼ 20% of that in younger mice. In SVZ, HB-EGF and FGF-2 increased BrdU incorporation by ∼ ∼ ∼ ∼ 140% at 3 months and ∼ ∼ ∼ ∼ 170% at 20 months, so the number of BrdU-labelled cells was comparable in untreated 3-month-old and growth factor-treated 20-month-old mice. These results demonstrate that the aged brain retains the capacity to respond to exogenous growth factors with increased neurogenesis, which may have implications for the therapeutic potential of neurogenesis enhancement in age-associated neurological disorders.

No abstract

No abstract