Myelin plasticity in ventral tegmental area is required for opioid reward

Abstract

All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance use disorders. Here, we demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by either optogenetic stimulation or by morphine administration specifically within the reward center ventral tegmental area (VTA), but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens (NAc). Genetic blockade of oligodendrogenesis dampens NAc dopamine release dynamics, which is critical for reward learning, and impairs behavioral conditioning to morphine. Our findings identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.

Differential gene expression and chromatin accessibility in the medial prefrontal cortex associated with individual differences in rat behavioral models of opioid use disorder

“…Taken together, these results suggest a reduced oligodendroglial and myelination process during withdrawal from the initial morphine exposure to be protective against OUD-like behaviors. Supporting the functional relevance of these correlational effects, a recent report indicates that blockade of oligodendrogenesis in the mouse ventrotegmental area (VTA) reduced dopamine release in the nucleus accumbens and induction of a conditioned place preferences for morphine (Yalçın et al, 2022). Furthermore, these findings are consistent with reduced white matter in the PFC of rats exposed to oxycodone, and in OUD patients (Fan et al, 2018;Gaudreault et al, 2022) While resilience was most closely associated with differential activity in oligodendrogenesis-related pathways in the WIA paradigm, resilience in males in the Demand paradigm was most strongly associated with increased activity in gene pathways associated with neuroimmune function.…”

“…Taken together, these results suggest a reduced oligodendroglial and myelination process during withdrawal from the initial morphine exposure to be protective against OUD-like behaviors. Supporting the functional relevance of these correlational effects, a recent report indicates that blockade of oligodendrogenesis in the mouse ventrotegmental area (VTA) reduced dopamine release in the nucleus accumbens and induction of a conditioned place preferences for morphine (Yalçin et al, 2022). Furthermore, these findings are consistent with reduced white matter in the PFC of rats exposed to oxycodone, and in OUD patients (Fan et al, 2018; Gaudreault et al, 2022)…”

Single Nucleus Transcriptomics Reveals Pervasive Glial Activation in Opioid Overdose Cases

“…The canonical cell-type marker genes were expected to be highly expressed in the corresponding clusters (Figure S1E-F gene family tend to be highly enriched in the cluster 4; (7) pericytes-marker genes (MYO1B, NR4A2, PDGFRB and RGS5) are highly expressed in the cluster 6; (8) While endothelial-specific genes such as (CDH5, CLDN5, FLT1, KDR, PECAM1 and PTPRB) are highly expressed in cluster 8; (8) We also identified some T cell specific genes including CD96, IL7R, SKAP1 and THEMIS highly expressed in the cluster 9; (9) For the cluster 12 with very few number of cells, the genes including HTR2C and TTR are highly enriched, which are related to the function of ependymal cell.…”

“…Likewise, VM astrocytes play an essential role in drug-induced synaptic plasticity in DA neurons 6 , a reflection of astrocytic regulation of neuronal glutamine supply and glutamatergic neurotransmission 7 . Finally, oligodendrogenesis in VM is essential for morphine-mediated reward behavior, and proliferation and differentiation of VM oligodendrocytes is regulated by the firing activity of their surrounding dopaminergic neurons, in addition to direct effects exerts by activated opioid receptors expressed on the oligodendrocytes 8 . However, despite these intriguing mechanistic studies in animal models, the functional and clinical significance of VM glial populations in subjects diagnosed with substance use disorder remains unexplored.…”

Ablation of oligodendrogenesis in adult mice alters brain microstructure and activity independently of behavioural deficits

“…Additionally, reduced opioid reward learning (Yalçın et al, 2022) and impaired training-induced improvements in spatial working memory have also been reported (Shimizu et al, 2023). However, if and how the disruption of oligodendrogenesis in adulthood affects the CNS, independent of experience in a specific task, remains understudied.…”