Dentate gyrus \u03bc-opioid receptor-mediated neurogenic processes are associated with alterations in morphine self-administration

Haolin Zhang,Xue-Wei Wang,Meng Jia,Na Wang,Cailian Cui,Felice Elefant,Yijing Li,Hui Ma,Can Ye

doi:10.1038/s41598-018-37083-8

Abstract

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.

Highlights

Accumulating evidence shows that neurogenesis comprising both proliferation and differentiation exists in the adult brain of mammals, in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) near the lateral ventricles[1]
We show that in response to morphine self-administration (MSA), rats show an increase in neural stem cells (NSCs) neuronal differentiation and dendrite growth in the adult DG, in parallel with a two-fold elevation of the NSC MOR
To elucidate the effects of morphine on neuronal differentiation, we first asked how voluntary morphine intake affected the differentiation of BrdU-labeled NSCs in rat DG by 2-week MSA paradigm (Fig. 1a)

Summary

Introduction

Accumulating evidence shows that neurogenesis comprising both proliferation and differentiation exists in the adult brain of mammals, in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) near the lateral ventricles[1]. Studies on neuronal differentiation in opiate addiction that do exist are limited in that they utilize either morphine pellet implantation[2,3,5] or morphine intraperitoneal injection[10,11], both paradigms that do not effectively model human opiate addiction To date, these studies[3,10] all label NSCs after opiate administration, and opiate-induced effects on NSC neuronal differentiation and subsequent dendritogenesis during drug exposure currently remain unknown. To overcome limitations on previous paradigms used to study NSC differentiation in opiate addiction, here we use a rat morphine self-administration (MSA) that effectively mimics human opiate addiction. Our findings shed light on the ongoing efforts to understand the opiate addictive processes and support the concept that selectively targeting MOR in the DG NSC population might offer a novel therapeutic intervention for morphine addiction

Methods

Results

Conclusion