Neurodegeneration Division, Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia.
PLoS One. 2012;7(2):e31549. doi: 10.1371/journal.pone.0031549. Epub 2012 Feb 21.
Neurogenesis in the adult brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle, olfactory bulb (OB) and the dentate subgranular zone, and survival of adult-born cells in the OB is influenced by factors including sensory experience. We examined, in mice, whether survival of adult-born cells is also regulated by the rate of precursor proliferation in the SVZ. Precursor proliferation was decreased by depleting the SVZ of dopamine after lesioning dopamine neurons in the substantia nigra compacta with 6-hydroxydopamine. Subsequently, we examined the effect of reduced SVZ proliferation on the generation, migration and survival of neuroblasts and mature adult-born cells in the SVZ, rostral migratory stream (RMS) and OB. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 47% or 36%, respectively, 7 days after dopamine depletion, and by 29% or 31% 42 days after dopamine depletion, compared to sham-treated animals. Neuroblast generation in the SVZ and their migration along the RMS were not affected, neither 7 nor 42 days after the 6-hydroxydopamine injection, since the number of doublecortin-immunoreactive neuroblasts in the SVZ and RMS, as well as the number of neuronal nuclei-immunoreactive cells in the OB, were stable compared to control. However, survival analysis 15 days after 6-hydroxydopamine and 6 days after BrdU injections showed that the number of BrdU+ cells in the SVZ was 70% higher. Also, 42 days after 6-hydroxydopamine and 30 days after BrdU injections, we found an 82% increase in co-labeled BrdU+/γ-aminobutyric acid-immunoreactive cell bodies in the granular cell layer, while double-labeled BrdU+/tyrosine hydroxylase-immunoreactive cell bodies in the glomerular layer increased by 148%. We conclude that the number of OB interneurons following reduced SVZ proliferation is maintained through an increased survival of adult-born precursor cells, neuroblasts and interneurons.
成年大脑中的神经发生主要局限于侧脑室的室管膜下区（SVZ）、嗅球（OB）和齿状回颗粒下区，而 OB 中成年新生细胞的存活受到包括感觉体验在内的多种因素的影响。我们在小鼠中研究了 SVZ 中前体细胞增殖速度是否也会调节成年新生细胞的存活。通过用 6-羟多巴胺损伤黑质致密部中的多巴胺神经元，耗尽 SVZ 中的多巴胺，从而减少前体细胞增殖。随后，我们研究了 SVZ 增殖减少对 SVZ、穹窿迁移流（RMS）和 OB 中神经前体细胞、迁移神经母细胞和成熟成年新生细胞的生成、迁移和存活的影响。通过在死亡前 2 小时注射 5-溴-2-脱氧尿苷（BrdU）或用 Ki67 免疫反应测量 SVZ 中的增殖细胞，发现多巴胺耗竭 7 天后分别减少 47%或 36%，多巴胺耗竭 42 天后分别减少 29%或 31%，与假手术处理的动物相比。6-羟多巴胺注射后 7 天或 42 天，SVZ 中神经母细胞的生成及其沿 RMS 的迁移均不受影响，因为 SVZ 和 RMS 中双皮质素免疫反应性神经母细胞的数量以及 OB 中神经元核免疫反应性细胞的数量与对照相比均保持稳定。然而，6-羟多巴胺后 15 天和 BrdU 注射后 6 天的生存分析显示，SVZ 中 BrdU+细胞的数量增加了 70%。此外，6-羟多巴胺后 42 天和 BrdU 注射后 30 天，我们发现颗粒细胞层中 BrdU+/γ-氨基丁酸免疫反应性细胞体的共标记物增加了 82%，而肾小球层中 BrdU+/酪氨酸羟化酶免疫反应性细胞体增加了 148%。我们得出结论，SVZ 增殖减少后 OB 中间神经元的数量通过增加成年新生前体细胞、神经母细胞和中间神经元的存活来维持。
