Cell Reports
Volume 23, Issue 8, 22 May 2018, Pages 2225-2235
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Molecular and Functional Sex Differences of Noradrenergic Neurons in the Mouse Locus Coeruleus

https://doi.org/10.1016/j.celrep.2018.04.054Get rights and content
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Highlights

  • >3,000 genes highly expressed in adult mouse locus coeruleus (LC) are identified

  • Norepinephrine neurons of LC sex-differentially express >100 genes

  • PGE2 receptor Ptger3 is more highly expressed in female LC

  • PTGER3 agonism inhibits LC firing and LC-driven anxiety behavior only in female mice

Summary

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

norepinephrine
locus coeruleus
sex differences
sexual dimorphism
gene expression
open-field task

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