Department of Neurobiology, School of Basic Medical Sciences, Key Laboratory for Neuroscience of the Ministry of Education and National Health and Family Planning Commission, Neuroscience Research Institute, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
Department of Biology, Drexel University, 3245 Chestnut Street, Philadelphia, 19104, USA.
Sci Rep. 2019 Feb 6;9(1):1471. doi: 10.1038/s41598-018-37083-8.
Adult hippocampal dentate gyrus (DG) neural stem cells (NSCs) continuously undergo proliferation and differentiation, producing new functional neurons that remodel existing synaptic circuits. Although proliferation of these adult DG NSCs has been implicated in opiate dependence, whether NSC neuronal differentiation and subsequent dendritogenesis are also involved in such addictive behavior remains unknown. Here, we ask whether opiate exposure alters differentiation and dendritogenesis of DG NSCs and investigate the possibility that these alterations contribute to opiate addiction. We show that rat morphine self-administration (MSA), a paradigm that effectively mimics human opiate addiction, increases NSC neuronal differentiation and promotes neuronal dendrite growth in the adult DG. Further, we demonstrate that the μ-opioid receptor (MOR) is expressed on DG NSCs and that MSA leads to a two-fold elevation of endogenous MOR levels in doublecortin expressing (DCX) NSC progenies in the rat DG. MOR expression is also detected in the cultured rat NSCs and morphine treatment in vitro increases NSC neuronal differentiation and dendritogenesis, suggesting that MOR mediates the effect of morphine on NSC neuronal differentiation and maturation. Finally, we show that conditional overexpression of MOR in DG NSCs under a doxycycline inducible system leads to facilitation of the acquisition of MSA in rats, without affecting the extinction process. We advocate that targeting MOR selectively in the DG NSC population might offer a novel therapeutic intervention for morphine addiction.
成年海马齿状回（DG）神经干细胞（NSC）持续增殖和分化，产生新的功能性神经元，重塑现有的突触回路。尽管这些成年 DG NSC 的增殖与阿片类药物依赖有关，但 NSC 神经元分化和随后的树突发生是否也参与这种成瘾行为尚不清楚。在这里，我们研究了阿片类药物暴露是否改变 DG NSC 的分化和树突发生，并探讨了这些改变是否有助于阿片类药物成瘾。我们发现，大鼠吗啡自我给药（MSA），一种有效模拟人类阿片类药物成瘾的范式，增加了 NSC 神经元分化，并促进了成年 DG 中的神经元树突生长。此外，我们证明 DG NSCs 上表达 μ-阿片受体（MOR），并且 MSA 导致大鼠 DG 中双皮质素表达（DCX）NSC 后代内源性 MOR 水平升高两倍。MOR 表达也在培养的大鼠 NSCs 中检测到，并且吗啡处理体外增加 NSC 神经元分化和树突发生，表明 MOR 介导了吗啡对 NSC 神经元分化和成熟的影响。最后，我们表明，在 DG NSCs 中，在强力霉素诱导系统下条件过表达 MOR 会促进大鼠 MSA 的获得，而不影响消退过程。我们主张，选择性地针对 DG NSC 群体中的 MOR 可能为吗啡成瘾提供一种新的治疗干预。
