Developmental origins of central norepinephrine neuron diversity

Nat Neurosci. 2013 Aug;16(8):1016-23. doi: 10.1038/nn.3458. Epub 2013 Jul 14.


Central norepinephrine-producing neurons comprise a diverse population of cells differing in anatomical location, connectivity, function and response to disease and environmental insult. The mechanisms that generate this diversity are unknown. Here we elucidate the lineal relationship between molecularly distinct progenitor populations in the developing mouse hindbrain and mature norepinephrine neuron subtype identity. We have identified four genetically separable subpopulations of mature norepinephrine neurons differing in their anatomical location, axon morphology and efferent projection pattern. One of the subpopulations showed an unexpected projection to the prefrontal cortex, challenging the long-held belief that the locus coeruleus is the sole source of norepinephrine projections to the cortex. These findings reveal the embryonic origins of central norepinephrine neurons and provide multiple molecular points of entry for future study of individual norepinephrine circuits in complex behavioral and physiological processes including arousal, attention, mood, memory, appetite and homeostasis.

Publication types

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

MeSH terms

  • Adrenergic Fibers / physiology
  • Adrenergic Neurons / classification*
  • Adrenergic Neurons / cytology
  • Adrenergic Neurons / enzymology
  • Afferent Pathways
  • Animals
  • Axons / ultrastructure
  • Cell Count
  • Cell Lineage
  • Dopamine beta-Hydroxylase / analysis
  • Female
  • Genes, Reporter
  • Green Fluorescent Proteins / biosynthesis
  • Green Fluorescent Proteins / genetics
  • Locus Coeruleus / cytology
  • Locus Coeruleus / embryology
  • Male
  • Mice
  • Nerve Tissue Proteins / analysis
  • Neural Stem Cells / cytology
  • Neurogenesis*
  • Norepinephrine / physiology
  • Organ Specificity
  • Prefrontal Cortex / cytology
  • Prefrontal Cortex / embryology
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • Rhombencephalon / cytology*
  • Rhombencephalon / embryology


  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Dopamine beta-Hydroxylase
  • Norepinephrine