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Developmental origins of central norepinephrine neuron diversity

Nature Neuroscience volume 16, pages 1016–1023 (2013)Cite this article

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Abstract

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.

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Figure 1: Intersectional genetic fate mapping strategy distinguishes r1(En1cre)-derived from non-r1-derived norepinephrine neurons.
Figure 2: Complementary fate maps reveal the distribution of rhombomere-derived norepinephrine subpopulations in the pontine norepinephrine nuclei.
Figure 3: r3&5(Krox20cre)- and r4(Hoxb1cre)-derived norepinephrine neurons populate the medullary C1/A1 and C2/A2 brainstem nuclei.
Figure 4: Distribution of central norepinephrine neurons defined by genetic lineage differs from the traditional anatomical subdivisions.
Figure 5: r2(Hoxa2-cre)- and r3&5(Krox20cre)-derived norepinephrine neurons project to limited targets.
Figure 6: r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons differ in their axon morphology at multiple target sites.
Figure 7: Genetically defined norepinephrine subpopulations project to unique sets of targets.
Figure 8: Identification of a shared projection to the insular cortex from r4(Hoxb1cre)-derived norepinephrine neurons residing in the C2/A2, C1/A1 and SubC nuclei.

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Acknowledgements

We thank S. Dymecki (Harvard Medical School) for Hoxa2-cre and RC::FrePe mice and P. Charnay (INSERM) for Krox20cre mice. We thank T. Wolfgang, G. Keeley and the National Institute of Environmental Health Sciences Fluorescence Microscopy, Vivarium, Knockout Mice and Statistics services for assistance. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Environmental Health Sciences (ZIA-ES-102805).

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  1. Sabrina D Robertson and Nicholas W Plummer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Health and Human Services, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

    Sabrina D Robertson, Nicholas W Plummer, Jacqueline de Marchena & Patricia Jensen

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  1. Sabrina D Robertson
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Contributions

S.D.R. and P.J. conceived the project and designed the experiments. S.D.R. contributed to the execution and analysis of all of the experiments and prepared the figures. N.W.P. designed, generated and characterized the DbhFlpo mouse allele and prepared Supplementary Figure 1. J.d.M. designed and conducted the retrograde labeling study. S.D.R., N.W.P. and P.J. wrote the manuscript.

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Correspondence to Patricia Jensen.

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The authors declare no competing financial interests.

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Robertson, S., Plummer, N., de Marchena, J. et al. Developmental origins of central norepinephrine neuron diversity. Nat Neurosci 16, 1016–1023 (2013). https://doi.org/10.1038/nn.3458

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