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Developmental origins of central norepinephrine neuron diversity.

Robertson SD, Plummer NW, de Marchena J, Jensen P - Nat. Neurosci. (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

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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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(a) Schematic sagittal view of adult mouse brain compressed along the mediolateral axis (left) and representative coronal section from Hoxb1cre;DbhFlpo;RC∷FrePe mouse brain (right) injected with FluoroGold into the insular cortex. Scale bar indicates 2.5 mm. (b) Sagittal sections from adult animals corresponding to the boxed regions in (a). eGFP-positive r4(Hoxb1cre)-derived norepinephrine neurons (green) co-labeled (*) with FluoroGold (blue) and NET (red) in C2/A2 (top panel), C1/A1 (middle panel), and SubC (bottom panel). Scale bar indicates 20 μm.
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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(a) Schematic sagittal view of adult mouse brain compressed along the mediolateral axis (left) and representative coronal section from Hoxb1cre;DbhFlpo;RC∷FrePe mouse brain (right) injected with FluoroGold into the insular cortex. Scale bar indicates 2.5 mm. (b) Sagittal sections from adult animals corresponding to the boxed regions in (a). eGFP-positive r4(Hoxb1cre)-derived norepinephrine neurons (green) co-labeled (*) with FluoroGold (blue) and NET (red) in C2/A2 (top panel), C1/A1 (middle panel), and SubC (bottom panel). Scale bar indicates 20 μm.

Mentions: To precisely determine which of the r4(Hoxb1cre)-derived norepinephrine neurons situated in the SubC, A5, C1/A1 and C2/A2 nuclei provided this non-LoC input to the insular cortex, we performed in vivo retrograde labeling with FluoroGold in mature Hoxb1cre;DbhFlpo;RC∷FrePe mice. Notably, we found eGFP-positive r4(Hoxb1cre)-derived neurons co-labeled with FluoroGold in the SubC, C2/A2, and C1/A1 nuclei (Fig. 8 and Supplementary Fig. 3). To confirm the identity of these neurons we stained with an antibody against NET, which is expressed by norepinephrine neurons but not by the epinephrine neurons that populate C2 and C142. In each of the three nuclei, we observed norepinephrine neurons co-labeled with eGFP, FluoroGold, and NET (Fig. 8). The identification of a shared projection to the insular cortex by r4(Hoxb1cre)-derived norepinephrine neurons distributed throughout the hindbrain, supports the hypothesis that developmental gene expression history contributes to neuronal function. These findings underscore both the strength of the intersectional genetic strategy and the importance of genetic lineage in determining norepinephrine neuron subtype identity.


Developmental origins of central norepinephrine neuron diversity.

Robertson SD, Plummer NW, de Marchena J, Jensen P - Nat. Neurosci. (2013)

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(a) Schematic sagittal view of adult mouse brain compressed along the mediolateral axis (left) and representative coronal section from Hoxb1cre;DbhFlpo;RC∷FrePe mouse brain (right) injected with FluoroGold into the insular cortex. Scale bar indicates 2.5 mm. (b) Sagittal sections from adult animals corresponding to the boxed regions in (a). eGFP-positive r4(Hoxb1cre)-derived norepinephrine neurons (green) co-labeled (*) with FluoroGold (blue) and NET (red) in C2/A2 (top panel), C1/A1 (middle panel), and SubC (bottom panel). Scale bar indicates 20 μm.
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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(a) Schematic sagittal view of adult mouse brain compressed along the mediolateral axis (left) and representative coronal section from Hoxb1cre;DbhFlpo;RC∷FrePe mouse brain (right) injected with FluoroGold into the insular cortex. Scale bar indicates 2.5 mm. (b) Sagittal sections from adult animals corresponding to the boxed regions in (a). eGFP-positive r4(Hoxb1cre)-derived norepinephrine neurons (green) co-labeled (*) with FluoroGold (blue) and NET (red) in C2/A2 (top panel), C1/A1 (middle panel), and SubC (bottom panel). Scale bar indicates 20 μm.
Mentions: To precisely determine which of the r4(Hoxb1cre)-derived norepinephrine neurons situated in the SubC, A5, C1/A1 and C2/A2 nuclei provided this non-LoC input to the insular cortex, we performed in vivo retrograde labeling with FluoroGold in mature Hoxb1cre;DbhFlpo;RC∷FrePe mice. Notably, we found eGFP-positive r4(Hoxb1cre)-derived neurons co-labeled with FluoroGold in the SubC, C2/A2, and C1/A1 nuclei (Fig. 8 and Supplementary Fig. 3). To confirm the identity of these neurons we stained with an antibody against NET, which is expressed by norepinephrine neurons but not by the epinephrine neurons that populate C2 and C142. In each of the three nuclei, we observed norepinephrine neurons co-labeled with eGFP, FluoroGold, and NET (Fig. 8). The identification of a shared projection to the insular cortex by r4(Hoxb1cre)-derived norepinephrine neurons distributed throughout the hindbrain, supports the hypothesis that developmental gene expression history contributes to neuronal function. These findings underscore both the strength of the intersectional genetic strategy and the importance of genetic lineage in determining norepinephrine neuron subtype identity.

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

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.

Show MeSH
Related in: MedlinePlus