Naloxone Facilitates Contextual Learning and Memory in a Receptor-Independent and Tet1 -Dependent Manner
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ORIGINAL RESEARCH
Naloxone Facilitates Contextual Learning and Memory in a Receptor‑Independent and Tet1‑Dependent Manner Fei Meng1,2 · Yuan Li2,4,5 · Hao Sun2,3,4,5 · Changpeng Li2,4,5 · Qian Li2,4,5,6 · Ping‑Yee Law7 · Horace H. Loh4 · Lining Liang2,4,5 · Hui Zheng2,3,4,5,8 Received: 28 May 2020 / Accepted: 23 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Opioids, like morphine and naloxone, regulate the proliferation and neuronal differentiation of neural stem cells (NSCs) in a receptor-independent and ten-eleven translocation methylcytosine dioxygenase (TET1)-dependent manner in vitro. Whether naloxone regulates hippocampal NSCs and contextual learning in vivo in a similar manner was determined. Naloxone infusion increased the Ki67 and Doublecortin positive cells in subgranular zone of wild type mice, which suggested the increased proliferation and differentiation of hippocampal NSCs in vivo and was consistent with the in vitro functions of naloxone. In addition, naloxone infusion also facilitated the contextual learning and memory of wild type mice. To determine the contribution of μ-opioid receptor (OPRM1) and TET1 to these functions of naloxone, several types of knockout mice were used. Since Tet1−/− mice have high deficiency in contextual learning and memory, Tet1+/− mice were used instead. The abilities of naloxone to regulate NSCs and to facilitate contextual learning were significantly impaired in Tet1+/− mice. In addition, these abilities of naloxone were not affected in Oprm1−/− mice. Therefore, naloxone facilitates contextual learning and memory in a receptor-independent and Tet1-dependent manner, which provides new understanding on the receptorindependent functions of opioids. Keywords Naloxone · Receptor-independent · TET1-dependent · Contextual learning and memory
Introduction Adult neurogenesis mainly happens in the subventricular zone (SVZ) of lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. The Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-020-00970-8) contains supplementary material, which is available to authorized users.
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Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510700, China
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University of Science and Technology of China, Hefei 230026, Anhui, China
Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou 510530, China
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Guangzhou Medical University, Guangzhou 511436, China
CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Ave., Science City, Guangzhou 510530, China
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Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
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Institutes for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
* Lining Liang [email protected] * Hui Zheng [email protected] 1
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