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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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r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons differ in their axon morphology at multiple target sites(a) Coronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the insular cortex, basolateral amygdala posterior part (BLP), paraventricular hypothalamus, and the bed nucleus of the stria terminalis (BNST) medial division ventral part (STMV). In the representative sections, corresponding to the boxed areas within the brain schematics (left), axons from r4(Hoxb1cre)-derived norepinephrine neurons appear thicker and have larger varicosities than those of r1(En1cre)-derived neurons. Scale bar indicates 56 μm (cortex, amygdala), 222 μm (hypothalamus), and 500 μm (BNST). (b) Quantitative comparison of projection fiber type from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons, confirms the link between genetic lineage and fiber morphology. The average projection pixel intensity of eGFP-positive axon fibers from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons projecting to the insular cortex and BLP amygdala is shown (insular cortex n=15 and BLP amygdala n=10 images from four mice; error bars are mean ± s.e.m.). A two tailed, unpaired t-test was used to determine significance **p=0.009 t=6.801 df =14 (insular Ctx), ***p=0.0006 t=2.808 df=28 (BLP amygdala).
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Figure 6: r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons differ in their axon morphology at multiple target sites(a) Coronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the insular cortex, basolateral amygdala posterior part (BLP), paraventricular hypothalamus, and the bed nucleus of the stria terminalis (BNST) medial division ventral part (STMV). In the representative sections, corresponding to the boxed areas within the brain schematics (left), axons from r4(Hoxb1cre)-derived norepinephrine neurons appear thicker and have larger varicosities than those of r1(En1cre)-derived neurons. Scale bar indicates 56 μm (cortex, amygdala), 222 μm (hypothalamus), and 500 μm (BNST). (b) Quantitative comparison of projection fiber type from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons, confirms the link between genetic lineage and fiber morphology. The average projection pixel intensity of eGFP-positive axon fibers from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons projecting to the insular cortex and BLP amygdala is shown (insular cortex n=15 and BLP amygdala n=10 images from four mice; error bars are mean ± s.e.m.). A two tailed, unpaired t-test was used to determine significance **p=0.009 t=6.801 df =14 (insular Ctx), ***p=0.0006 t=2.808 df=28 (BLP amygdala).

Mentions: Similar to the r1(En1cre)-derived population, axons from r4(Hoxb1cre)-derived norepinephrine neurons projected throughout the brain (Supplementary Table 2). We observed overlapping inputs, arising from both subpopulations, to multiple target areas. Within these target areas, our ability to visualize the inputs from r1- and r4-derived neurons in complete isolation revealed unique insights into the architecture of norepinephrine efferents. The morphology, density, and regional distribution of inputs arising from these two subpopulations were distinct (Fig. 6 and Supplementary Table 2). In comparison with the fine axons characteristic of the r1-derived subpopulation, r4-derived norepinephrine neurons had axons that were considerably thicker with larger varicosities. Quantification of the average pixel intensity of the two fiber types in the insular cortex and the posterior basolateral amygdaloid nucleus (BLP) confirmed that this difference was significant (Fig. 6b).


Developmental origins of central norepinephrine neuron diversity.

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

r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons differ in their axon morphology at multiple target sites(a) Coronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the insular cortex, basolateral amygdala posterior part (BLP), paraventricular hypothalamus, and the bed nucleus of the stria terminalis (BNST) medial division ventral part (STMV). In the representative sections, corresponding to the boxed areas within the brain schematics (left), axons from r4(Hoxb1cre)-derived norepinephrine neurons appear thicker and have larger varicosities than those of r1(En1cre)-derived neurons. Scale bar indicates 56 μm (cortex, amygdala), 222 μm (hypothalamus), and 500 μm (BNST). (b) Quantitative comparison of projection fiber type from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons, confirms the link between genetic lineage and fiber morphology. The average projection pixel intensity of eGFP-positive axon fibers from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons projecting to the insular cortex and BLP amygdala is shown (insular cortex n=15 and BLP amygdala n=10 images from four mice; error bars are mean ± s.e.m.). A two tailed, unpaired t-test was used to determine significance **p=0.009 t=6.801 df =14 (insular Ctx), ***p=0.0006 t=2.808 df=28 (BLP amygdala).
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Figure 6: r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons differ in their axon morphology at multiple target sites(a) Coronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the insular cortex, basolateral amygdala posterior part (BLP), paraventricular hypothalamus, and the bed nucleus of the stria terminalis (BNST) medial division ventral part (STMV). In the representative sections, corresponding to the boxed areas within the brain schematics (left), axons from r4(Hoxb1cre)-derived norepinephrine neurons appear thicker and have larger varicosities than those of r1(En1cre)-derived neurons. Scale bar indicates 56 μm (cortex, amygdala), 222 μm (hypothalamus), and 500 μm (BNST). (b) Quantitative comparison of projection fiber type from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons, confirms the link between genetic lineage and fiber morphology. The average projection pixel intensity of eGFP-positive axon fibers from r1(En1cre)- and r4(Hoxb1cre)-derived norepinephrine neurons projecting to the insular cortex and BLP amygdala is shown (insular cortex n=15 and BLP amygdala n=10 images from four mice; error bars are mean ± s.e.m.). A two tailed, unpaired t-test was used to determine significance **p=0.009 t=6.801 df =14 (insular Ctx), ***p=0.0006 t=2.808 df=28 (BLP amygdala).
Mentions: Similar to the r1(En1cre)-derived population, axons from r4(Hoxb1cre)-derived norepinephrine neurons projected throughout the brain (Supplementary Table 2). We observed overlapping inputs, arising from both subpopulations, to multiple target areas. Within these target areas, our ability to visualize the inputs from r1- and r4-derived neurons in complete isolation revealed unique insights into the architecture of norepinephrine efferents. The morphology, density, and regional distribution of inputs arising from these two subpopulations were distinct (Fig. 6 and Supplementary Table 2). In comparison with the fine axons characteristic of the r1-derived subpopulation, r4-derived norepinephrine neurons had axons that were considerably thicker with larger varicosities. Quantification of the average pixel intensity of the two fiber types in the insular cortex and the posterior basolateral amygdaloid nucleus (BLP) confirmed that this difference was significant (Fig. 6b).

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