Neurodegeneration Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne Parkville, VIC, Australia ; Department of Neurology, Shenyang First People's Hospital Shenyang, China.
Front Cell Neurosci. 2013 Mar 1;7:13. doi: 10.3389/fncel.2013.00013. eCollection 2013.
Neurogenesis in the adult rodent brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle and subgranular zone (SGZ) of the dentate gyrus (DG). We examined whether cholecystokinin (CCK) through actions mediated by CCK1 receptors (CCK1R) is involved in regulating neurogenesis. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 h prior to death or by immunoreactivity against Ki67, were reduced by 37 and 42%, respectively, in female (but not male) mice lacking CCK1Rs (CCK1R(-/-)) compared to wild-type (WT). Generation of neuroblasts in the SVZ and rostral migratory stream (RMS) was also affected, since the number of doublecortin (DCX)-immunoreactive (ir) neuroblasts in these regions decreased by 29%. In the SGZ of female CCK1R(-/-) mice, BrdU-positive (+), and Ki67-ir cells were reduced by 38 and 56%, respectively, while DCX-ir neuroblasts were down 80%. Subsequently, the effect of reduced SVZ/SGZ proliferation on the generation and survival of mature adult-born cells in female CCK1R(-/-) mice was examined. In the OB granule cell layer (GCL), the number of neuronal nuclei (NeuN)-ir and calretinin-ir cells was stable compared to WT, and 42 days after BrdU injections, the number of BrdU+ cells co-expressing GABA- or NeuN-like immunoreactivity (LI) was similar. Compared to WT, the granule cell layer of the DG in female CCK1R(-/-) mice had a similar number of calbindin-ir cells and BrdU+ cells co-expressing calbindin-LI 42 days after BrdU injections. However, the OB glomerular layer (GL) of CCK1R(-/-) female mice had 11% fewer NeuN-ir cells, 23% less TH-ir cells, and a 38% and 29% reduction in BrdU+ cells that co-expressed TH-LI or GABA-LI, respectively. We conclude that CCK, via CCK1Rs, is involved in regulating the generation of proliferating cells and neuroblasts in the adult female mouse brain, and mechanisms are in place to maintain steady neuronal populations in the OB and DG when the rate of proliferation is altered.
成年啮齿动物大脑中的神经发生主要局限于侧脑室的室管膜下区（SVZ）和齿状回的颗粒下区（SGZ）。我们研究了胆囊收缩素（CCK）是否通过 CCK1 受体（CCK1R）介导的作用参与调节神经发生。通过在死亡前 2 小时注射 5-溴-2-脱氧尿苷（BrdU）或通过 Ki67 免疫反应测量的 SVZ 中的增殖细胞，与野生型（WT）相比，缺乏 CCK1R（CCK1R(-/-)）的雌性（但不是雄性）小鼠中的增殖细胞分别减少了 37%和 42%。SVZ 和额状迁移流（RMS）中的神经母细胞的生成也受到影响，因为这些区域中的双皮质素（DCX）免疫反应性（ir）神经母细胞的数量减少了 29%。在雌性 CCK1R(-/-)小鼠的 SGZ 中，BrdU 阳性（+）和 Ki67-ir 细胞分别减少了 38%和 56%，而 DCX-ir 神经母细胞减少了 80%。随后，我们检查了 SVZ/SGZ 增殖减少对雌性 CCK1R(-/-)小鼠中成熟的成年新生细胞的生成和存活的影响。在 OB 颗粒细胞层（GCL）中，神经元核（NeuN）-ir 和钙结合蛋白-ir 细胞的数量与 WT 相比保持稳定，并且在 BrdU 注射后 42 天，表达 GABA 或 NeuN 样免疫反应性（LI）的 BrdU+细胞的数量相似。与 WT 相比，在雌性 CCK1R(-/-)小鼠的 DG 颗粒细胞层中，在 BrdU 注射后 42 天，钙结合蛋白-ir 细胞和表达钙结合蛋白-LI 的 BrdU+细胞的数量相似。然而，CCK1R(-/-)雌性小鼠的 OB 肾小球层（GL）中的 NeuN-ir 细胞减少了 11%，TH-ir 细胞减少了 23%，表达 TH-LI 或 GABA-LI 的 BrdU+细胞分别减少了 38%和 29%。我们得出结论，CCK 通过 CCK1R 参与调节成年雌性小鼠大脑中增殖细胞和神经母细胞的生成，并且当增殖率改变时，机制可以维持 OB 和 DG 中稳定的神经元群体。
