Matsumoto Minako, Nakamachi Tomoya, Watanabe Jun, Sugiyama Koichi, Ohtaki Hirokazu, Murai Norimitsu, Sasaki Shun, Xu Zhifang, Hashimoto Hitoshi, Seki Tamotsu, Miyazaki Akira, Shioda Seiji
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan.
J Mol Neurosci. 2016 Jun;59(2):270-9. doi: 10.1007/s12031-016-0731-x. Epub 2016 Feb 24.
In the subgranular zone (SGZ) of the hippocampus, neurogenesis persists throughout life and is upregulated following ischemia. Accumulating evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to recovery after stroke. However, the mechanisms underlying the upregulation of neurogenesis are unclear. We have demonstrated that a neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exerts a wide range of effects on neural stem cells (NSCs) during neural development. Here, we examined the effects of endogenous and exogenous PACAP in adult NSCs of the SGZ. Immunostaining showed expression of the PACAP receptor PAC1R in nestin-positive NSCs of adult naive mice. PACAP injection into the lateral ventricle increased bromodeoxyuridine (BrdU)-positive proliferative cells in the SGZ. These data suggest that PACAP promoted the proliferation of NSCs. In global ischemia model mice, the number of BrdU-positive cells was increased in wild-type mice but not in PACAP heterozygous knockout mice. The BrdU-positive cells that increased in number after ischemia were immunopositive for SOX2, a marker of NSCs, and differentiated into NeuN-positive mature neurons at 4 weeks after ischemia. These findings suggest that PACAP contributes to the proliferation of NSCs and may be associated with recovery after brain injury.
在海马体的颗粒下区（SGZ），神经发生在整个生命过程中持续存在，并且在缺血后会上调。越来越多的证据表明，缺血性损伤刺激增强的神经发生有助于中风后的恢复。然而，神经发生上调的潜在机制尚不清楚。我们已经证明，一种神经肽，垂体腺苷酸环化酶激活多肽（PACAP），在神经发育过程中对神经干细胞（NSCs）发挥广泛作用。在这里，我们研究了内源性和外源性PACAP对成年SGZ区神经干细胞的影响。免疫染色显示成年未处理小鼠巢蛋白阳性神经干细胞中PACAP受体PAC1R的表达。向侧脑室注射PACAP可增加SGZ区溴脱氧尿苷（BrdU）阳性增殖细胞。这些数据表明PACAP促进了神经干细胞的增殖。在全脑缺血模型小鼠中，野生型小鼠中BrdU阳性细胞数量增加，而PACAP杂合敲除小鼠中则没有增加。缺血后数量增加的BrdU阳性细胞对神经干细胞标志物SOX2呈免疫阳性，并在缺血后4周分化为NeuN阳性成熟神经元。这些发现表明PACAP有助于神经干细胞的增殖，并且可能与脑损伤后的恢复有关。
