Single-Cell RNA-Seq Uncovers a Robust Transcriptional Response to Morphine by Glia

Cell Rep. 2018 Sep 25;24(13):3619-3629.e4. doi: 10.1016/j.celrep.2018.08.080.

Abstract

Molecular and behavioral responses to opioids are thought to be primarily mediated by neurons, although there is accumulating evidence that other cell types play a prominent role in drug addiction. To investigate cell-type-specific opioid responses, we performed single-cell RNA sequencing (scRNA-seq) of the nucleus accumbens of mice following acute morphine treatment. Differential expression analysis uncovered unique morphine-dependent transcriptional responses by oligodendrocytes and astrocytes. We examined the expression of selected genes, including Cdkn1a and Sgk1, by FISH, confirming their induction by morphine in oligodendrocytes. Further analysis using RNA-seq of FACS-purified oligodendrocytes revealed a large cohort of morphine-regulated genes. The affected genes are enriched for roles in cellular pathways intimately linked to oligodendrocyte maturation and myelination, including the unfolded protein response. Altogether, our data illuminate the morphine-dependent transcriptional response by oligodendrocytes and offer mechanistic insights into myelination defects associated with opioid abuse.

Keywords: RNA-seq; UPR; addiction; glucocorticoid; morphine; myelin; nucleus accumbens; oligodendrocyte; opioid; single-cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine / pharmacology*
  • Neuroglia / drug effects*
  • Neuroglia / metabolism
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Single-Cell Analysis
  • Transcriptome*

Substances

  • Analgesics, Opioid
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Immediate-Early Proteins
  • RNA, Messenger
  • Morphine
  • Protein-Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase