Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus

Cell Rep. 2018 May 22;23(8):2225-2235. doi: 10.1016/j.celrep.2018.04.054.


Preclinical work has long focused on male animals, though biological sex clearly influences risk for certain diseases, including many psychiatric disorders. Such disorders are often treated by drugs targeting the CNS norepinephrine system. Despite roles for noradrenergic neurons in behavior and neuropsychiatric disease models, their molecular characterization has lagged. We profiled mouse noradrenergic neurons in vivo, defining over 3,000 high-confidence transcripts expressed therein, including druggable receptors. We uncovered remarkable sex differences in gene expression, including elevated expression of the EP3 receptor in females-which we leverage to illustrate the behavioral and pharmacologic relevance of these findings-and of Slc6a15 and Lin28b, both major depressive disorder (MDD)-associated genes. Broadly, we present a means of transcriptionally profiling locus coeruleus under baseline and experimental conditions. Our findings underscore the need for preclinical work to include both sexes and suggest that sex differences in noradrenergic neurons may underlie behavioral differences relevant to disease.

Keywords: gene expression; locus coeruleus; norepinephrine; open-field task; sex differences; sexual dimorphism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Neurons / metabolism*
  • Animals
  • Behavior, Animal
  • Female
  • Gene Expression Regulation
  • Lipopolysaccharides
  • Locus Coeruleus / metabolism*
  • Male
  • Mice
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Protein Biosynthesis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Prostaglandin E, EP3 Subtype / metabolism
  • Reproducibility of Results
  • Ribosomes / metabolism
  • Sex Characteristics*
  • Transcription, Genetic


  • Lipopolysaccharides
  • Norepinephrine Plasma Membrane Transport Proteins
  • Ptger3 protein, mouse
  • RNA, Messenger
  • Receptors, Prostaglandin E, EP3 Subtype
  • Slc6a2 protein, mouse