NeuroD Modulates Opioid Agonist-Selective Regulation of Adult Neurogenesis and Contextual Memory Extinction

Abstract

Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of neurogenic differentiation 1 (NeuroD) activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate or magnitude. Fentanyl-induced CPP required much longer time for extinction than morphine-induced CPP. We observed a parallel decrease in NeuroD activities and neurogenesis after morphine-induced CPP, but not after fentanyl-induced CPP. Increasing NeuroD activities with NeuroD-lentivirus (nd-vir) injection at the dentate gyrus before CPP training reversed morphine-induced decreases in NeuroD activities and neurogenesis, and prolonged the time required for extinction of morphine-induced CPP. On the other hand, decreasing NeuroD activities via injection of miRNA-190-virus (190-vir) reversed the fentanyl effect on NeuroD and neurogenesis and shortened the time required for extinction of fentanyl-induced CPP. Another contextual memory task, the Morris Water Maze (MWM), was affected similarly by alteration of NeuroD activities. The reduction in NeuroD activities either by morphine treatment or 190-vir injection decreased MWM task retention, while the increase in NeuroD activities by nd-vir prolonged MWM task retention. Thus, by controlling NeuroD activities, opioid agonists differentially regulate adult neurogenesis and subsequent contextual memory retention. Such drug-related memory regulation could have implications in eventual context-associated relapse.

Neurod1 Modulates Opioid Antinociceptive Tolerance via Two Distinct Mechanisms

“…Similar to previous reports (5,7), 190-vir and nd-sh-vir decreased the protein and mRNA levels of Neurod1 , the amount of phosphorylated Neurod1 , and the expression of two Neurod1 downstream targets, Doublecortin and Neurod4 (27), whereas nd-vir had the opposite effects and could rescue the effects of 190-vir almost completely (Figure S1 in Supplement 1). The lentiviruses 190-vir and nd-sh-vir decreased Neurod1 activity, and nd-vir could block such decrease.…”

“…Because opioid tolerance has long been considered to involve associative learning (10,11) and NeuroD1 activity is critical for maintaining contextual memory (7), we hypothesized that decrease in NeuroD1 activity affects development of tolerance by impairing adult neurogenesis and subsequent contextual learning. As indicated in Figure 5A and C, the rates to learn the position of the submerged platform in all six groups of mice injected with various viruses were similar to each other when the MWM tests were initiated on day 7 or day 14 after virus injection.…”

“…NeuroD1 has also been identified to regulate adult neurogenesis in the subgranular zone of hippocampal dentate gyrus (DG) (6). Reducing NeuroD1 activity in DG with lentivirus encoding miR-190 , a microRNA targeting Neurod1 , impairs adult neurogenesis and the abilities of mice to retain drug-associated contextual memory (7). Because adult neurogenesis is associated with contextual learning and memory (8,9), which is implicated in development of opioid tolerance (10,11), we hypothesized that NeuroD1 could be one of the many transcription factors involved in development of opioid tolerance.…”

“…Morphine decreases the overall activity of NeuroD1, whereas fentanyl maintains it at the basal level (5,12). The inhibitory effects of morphine on NeuroD1 activity were applied to explain its ability to decrease adult neurogenesis in the hippocampus (7,13,14). …”

“…We examined opioid antinociception tolerance after manipulating NeuroD1 activity in the hippocampus with a previous reported lentivirus system (5,7). Although the hippocampus is not considered as the major brain structure in mediating opioid antinociception, it has been implicated in the affective-motivation component of pain sensation.…”