Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.
Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.
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DOI：
10.1371/journal.pone.0153628
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Law PY
中科院分区：
文献类型：
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作者：
Zhang Y;Xu C;Zheng H;Loh HH;Law PY
阿片类药物对成人神经发生的调节与调节不同的成瘾周期有关。阿片类药物在哪个神经发生阶段发挥作用仍悬而未决。我们尝试通过使用 POMC-EGFP 小鼠模型来定义吗啡对成年神经发生的抑制作用的时间窗口，其中可以在有丝分裂后 3-28 天之间观察到新生颗粒细胞 (GC)。 POMC-EGFP 小鼠在 3 室条件位置偏好 (CPP) 范式下用盐水或吗啡进行训练。我们观察到，用盐水进行 CPP 训练 4 天后，与在笼子里注射盐水的小鼠相比，海马颗粒下区 (SGZ) 中 EGFP 标记的新生 GC 的数量显着增加。用吗啡进行 CPP 训练显着减少了 EGFP 标记的 GC 数量，而注射相同剂量吗啡的家笼小鼠观察到 EGFP 标记的 GC 数量没有显着差异。使用细胞类型选择标记，我们观察到吗啡减少了 SGZ 中晚期祖细胞和未成熟神经元的数量，例如双皮质素 (DCX) 和 βIII 微管蛋白 (TuJ1) 阳性细胞的数量，但没有减少早期祖细胞的数量，例如巢蛋白、SOX2 或神经源性分化-1 (NeuroD1) 阳性细胞的数量。对不同细胞标记物之间共定位的分析表明，吗啡通过干扰早期祖细胞的分化而不是诱导细胞凋亡来减少成年GC的数量。此外，当通过立体定向注射慢病毒在DG中过度表达NeuroD1时，它挽救了未成熟神经元的损失并延长了吗啡训练的CPP的消退时间。这些结果表明，在CPP训练范式条件下，吗啡通过涉及NeuroD1的机制影响神经祖细胞/干细胞向未成熟神经元的转变。
The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine’s inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3–28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1.