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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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r2(Hoxa2-cre)- and r3&5(Krox20cre)-derived norepinephrine neurons project to limited targetsCoronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r2(Hoxa2-cre;DbhFlpo;RC∷FrePe)- derived norepinephrine neurons to the somatosensory cortex (top panel), and r3&5(Krox20cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the commissural solitary nucleus (bottom panel). The representative sections correspond to the boxed areas within the brain schematics (left). Sparse but specific projections from r2(Hoxa2-cre)-derived norepinephrine neurons are seen in the somatosensory cortex (top row, arrowheads in second panel), which is also targeted by the r1(En1cre)-derived subpopulation (top row, first panel). Strong innervation of the solitary nucleus by r3&5(Krox20cre)-derived norepinephrine neurons (bottom row, first panel) and r4(Hoxb1cre)-derived norepinephrine neurons (bottom row, second panel) is observed in the brainstem. Scale bar indicates 25 μm (cortex) and 100 μm (solitary nucleus).
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Figure 5: r2(Hoxa2-cre)- and r3&5(Krox20cre)-derived norepinephrine neurons project to limited targetsCoronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r2(Hoxa2-cre;DbhFlpo;RC∷FrePe)- derived norepinephrine neurons to the somatosensory cortex (top panel), and r3&5(Krox20cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the commissural solitary nucleus (bottom panel). The representative sections correspond to the boxed areas within the brain schematics (left). Sparse but specific projections from r2(Hoxa2-cre)-derived norepinephrine neurons are seen in the somatosensory cortex (top row, arrowheads in second panel), which is also targeted by the r1(En1cre)-derived subpopulation (top row, first panel). Strong innervation of the solitary nucleus by r3&5(Krox20cre)-derived norepinephrine neurons (bottom row, first panel) and r4(Hoxb1cre)-derived norepinephrine neurons (bottom row, second panel) is observed in the brainstem. Scale bar indicates 25 μm (cortex) and 100 μm (solitary nucleus).

Mentions: In comparison to the r1-derived norepinephrine neurons, the relatively small populations of r2(Hoxa2-cre)-, r3&5(Krox20cre)-derived norepinephrine neurons projected to limited targets. r2-derived norepinephrine neurons provided a sparse yet consistently observed input to the somatosensory cortex (Fig. 5), LoC, parvicellular and intermediate reticular nuclei, and the cerebellum (Supplementary Table 2). Projections from r3&5-derived norepinephrine neurons were restricted to the hindbrain, providing sparse to moderate input to the LoC, parabrachial nucleus (PBN), and the parvicellular and intermediate reticular nuclei; as well as substantial input to the solitary nucleus (NTS) (Fig. 5 and Supplementary Table 2). Though we were unable to distinguish norepinephrine neurons derived from r3 from those originating in r5, the narrow focus of their projections, together with their shared expression of Krox20, suggests that the r3&5-derived norepinephrine neurons form a single, functionally distinct subpopulation.


Developmental origins of central norepinephrine neuron diversity.

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

r2(Hoxa2-cre)- and r3&5(Krox20cre)-derived norepinephrine neurons project to limited targetsCoronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r2(Hoxa2-cre;DbhFlpo;RC∷FrePe)- derived norepinephrine neurons to the somatosensory cortex (top panel), and r3&5(Krox20cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the commissural solitary nucleus (bottom panel). The representative sections correspond to the boxed areas within the brain schematics (left). Sparse but specific projections from r2(Hoxa2-cre)-derived norepinephrine neurons are seen in the somatosensory cortex (top row, arrowheads in second panel), which is also targeted by the r1(En1cre)-derived subpopulation (top row, first panel). Strong innervation of the solitary nucleus by r3&5(Krox20cre)-derived norepinephrine neurons (bottom row, first panel) and r4(Hoxb1cre)-derived norepinephrine neurons (bottom row, second panel) is observed in the brainstem. Scale bar indicates 25 μm (cortex) and 100 μm (solitary nucleus).
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Figure 5: r2(Hoxa2-cre)- and r3&5(Krox20cre)-derived norepinephrine neurons project to limited targetsCoronal sections from adult mouse brains immunostained for eGFP to detect axonal inputs from r1(En1cre;DbhFlpo;RC∷FrePe)- and r2(Hoxa2-cre;DbhFlpo;RC∷FrePe)- derived norepinephrine neurons to the somatosensory cortex (top panel), and r3&5(Krox20cre;DbhFlpo;RC∷FrePe)- and r4(Hoxb1cre;DbhFlpo;RC∷FrePe)-derived norepinephrine neurons to the commissural solitary nucleus (bottom panel). The representative sections correspond to the boxed areas within the brain schematics (left). Sparse but specific projections from r2(Hoxa2-cre)-derived norepinephrine neurons are seen in the somatosensory cortex (top row, arrowheads in second panel), which is also targeted by the r1(En1cre)-derived subpopulation (top row, first panel). Strong innervation of the solitary nucleus by r3&5(Krox20cre)-derived norepinephrine neurons (bottom row, first panel) and r4(Hoxb1cre)-derived norepinephrine neurons (bottom row, second panel) is observed in the brainstem. Scale bar indicates 25 μm (cortex) and 100 μm (solitary nucleus).
Mentions: In comparison to the r1-derived norepinephrine neurons, the relatively small populations of r2(Hoxa2-cre)-, r3&5(Krox20cre)-derived norepinephrine neurons projected to limited targets. r2-derived norepinephrine neurons provided a sparse yet consistently observed input to the somatosensory cortex (Fig. 5), LoC, parvicellular and intermediate reticular nuclei, and the cerebellum (Supplementary Table 2). Projections from r3&5-derived norepinephrine neurons were restricted to the hindbrain, providing sparse to moderate input to the LoC, parabrachial nucleus (PBN), and the parvicellular and intermediate reticular nuclei; as well as substantial input to the solitary nucleus (NTS) (Fig. 5 and Supplementary Table 2). Though we were unable to distinguish norepinephrine neurons derived from r3 from those originating in r5, the narrow focus of their projections, together with their shared expression of Krox20, suggests that the r3&5-derived norepinephrine neurons form a single, functionally distinct subpopulation.

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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