Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors

Abstract

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.

Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories

“…Increasing evidence suggests that the hippocampus and its dentate gyrus subregion are important in reward‐associated behavior. On a correlative level, the reward‐context associations produced by morphine conditioned place preference (CPP; Bardo & Bevins, ; Tzschentke, ) modify indices of hippocampal plasticity (Zheng, Zhang, Li, Loh, & Law, ; Portugal et al, ; Rivera et al, ; Zhang, Xu, Zheng, Loh, & Law, ; Alvandi, Bourmpoula, Homberg, & Fathollahi, ), and after psychostimulant or opiate CPP dentate gyrus neurons are activated by re‐exposure to the drug‐paired context (Barr & Unterwald, ; Rivera et al, ). Notably, during CPP testing, entrance to the drug‐paired context is preceded by phase‐locked hippocampal theta rhythm (Takano, Tanaka, Takano, & Hironaka, ), suggesting the involvement of the hippocampus in reward memory retrieval of contextual cues.…”

“…ABGCs are implicated in many aspects of hippocampal‐dependent function, including stages of context‐associated learning and memory, such as retrieval, forgetting, extinction, reinstatement (Akers et al, ; Deng, Aimone, & Gage, ; Kitamura & Inokuchi, ; Saxe et al, ; Suárez‐Pereira, Canals, & Carrión, ). ABGCs have also begun to be examined for their potential role in reward‐associated learning and memory (Canales, ; Eisch et al, ; Deschaux et al, ; Castilla‐Ortega et al, ; Zhang et al, ; Alvandi et al, ; Barr, Bray, & Forster, ). For example, ABGC deletion via image guided, hippocampal‐targeted X‐ray irradiation (IG‐IR) directed at the hippocampus results in increased subsequent intravenous (i.v.)…”

Morphine modulates hippocampal neurogenesis and contextual memory extinction via miR-34c/Notch1 pathway in male ICR mice

“…Similar results have been reported in several studies by counter-regulating factors in several pathways. Reversing morphine-induced decreases in NeuroD activities and neurogenesis [30], and prolonged the time required for extinction of morphine-induced CPP without affecting its acquisition. Upregulating Prox1 exhibited similar effects [31].…”

Chronic pain and adult hippocampal neurogenesis: translational implications from preclinical studies

“…Indeed since the initial report, 29 extensive experimental data have been accumulated on the negative impact of chronic morphine administration on ahNG mainly via µ-opioid receptors (MORs). 31 , 46 – 51 The deleterious effect of morphine on hippocampal neurogenesis may potentially represent, among others, one mechanism by which morphine and other opiates exert long-lasting effects on the neural circuitries involved with cognition and mood regulation. Incidentally, cognitive dysfunction has been often reported in opiate drug abusers.…”