ORGANIZATION OF CENTRAL SYMPATHETIC PATHWAYS

Summary

Principal Investigator: PATRICE GUYENET
Abstract: Arterial pressure (AP)and regional blood flows are finely tuned by the central nervous system CNS) via the synpathetic system. This neural control is essential to match circulation with respiration and behavior. It is also critical to the maintenance of a stable level of AP. Most of the work will be focused on a region of the brain (rostral ventrolateral medulla, RVLM) that plays a critical role in regulating sympathetic tone and AP. RVLM also deserves intensive study because it is the main site of action of numerous drugs that have actions either beneficial or detrimental to circulation. RVLM controls sympathetic tone via a small group of neurons (BS neurons) that project to the spinal cord. A key to understanding how RVLM controls AP is to find how BS neurons are inturn regulated and what type of transmitters they release. A third of the work proposed in this renewal is to analyze with state of the art patch-clamp recording methods the local neuronal cicuitry that regulates the activity of BS neurons. We will first identify the major synaptic inputsof these neurons. We will then examine in detail how catecholamines regulate their excitatory inputs since our preliminarydata suggests that theantihypertensive clonidine and its new imidazoline congeners may work by mimicking the effect of noradrenalirie at this level. Next we will study the presynaptic regulation of the synaptic inputs of BS neurons by other substances of pharmacological or toxicological interest like neuropeptides, nicotine and opiates. We will then determine whether RVLM contains interneurons that regulate the discharges of the BS neurons and we will identify the transmitters used by these interneurons. A second major aspect of the work will be to analyze the structure of various subclasses of BS neurons and to identify the type of transmitters that they release. This will be done with a new method that permits to localize an enzyme or an mRNA within a single neuron physiologically characterized "in vivo". In the last part of the work we will examine the possibility that sympathetic tone could also be regulated by GABAergic inhibitory inputs that originate from the brainstem and,in particular, from the nucleus of the solitary tract. The research will contribute to the basic physiological knowledge needed to understand how syrr pathetic tone is regulated in health and in diseases such as arrhythmias, hypertension and dysautonomias.
Funding Period: 1989-04-01 - 2009-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 26:10305-14. 2006
  2. pmc Activation of the retrotrapezoid nucleus by posterior hypothalamic stimulation
    Michal G Fortuna
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    J Physiol 587:5121-38. 2009
  3. pmc Neurochemistry of bulbospinal presympathetic neurons of the medulla oblongata
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States of America
    J Chem Neuroanat 38:222-30. 2009
  4. pmc Retrotrapezoid nucleus and parafacial respiratory group
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908 0735, USA
    Respir Physiol Neurobiol 173:244-55. 2010
  5. pmc Central respiratory chemoreception
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Comp Neurol 518:3883-906. 2010
  6. pmc Photostimulation of Phox2b medullary neurons activates cardiorespiratory function in conscious rats
    Roy Kanbar
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
    Am J Respir Crit Care Med 182:1184-94. 2010
  7. pmc Central CO2 chemoreception and integrated neural mechanisms of cardiovascular and respiratory control
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908 0735, USA
    J Appl Physiol (1985) 108:995-1002. 2010
  8. pmc Control of breathing by raphe obscurus serotonergic neurons in mice
    Seth D DePuy
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 31:1981-90. 2011
  9. pmc Phox2b-expressing neurons of the parafacial region regulate breathing rate, inspiration, and expiration in conscious rats
    Stephen B G Abbott
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 31:16410-22. 2011
  10. pmc Regulation of visceral sympathetic tone by A5 noradrenergic neurons in rodents
    Roy Kanbar
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    J Physiol 589:903-17. 2011

Detail Information

Publications36

  1. ncbi Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 26:10305-14. 2006
    ..The presence of Phox2b in this circuit and its apparent absence from the respiratory CPG could explain why Phox2b mutations disrupt breathing automaticity during sleep without causing major impairment of respiration during waking...
  2. pmc Activation of the retrotrapezoid nucleus by posterior hypothalamic stimulation
    Michal G Fortuna
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    J Physiol 587:5121-38. 2009
    ..ccRTN neurons probably contribute both to the chemical drive of breathing and to the feed-forward control of breathing associated with emotions and or locomotion...
  3. pmc Neurochemistry of bulbospinal presympathetic neurons of the medulla oblongata
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States of America
    J Chem Neuroanat 38:222-30. 2009
    ..Although there is abundant data on potential neurotransmitters and neuropeptides contained in the presympathetic neurons, we are still unable to predict function and physiology based solely on the phenotype of these neurons...
  4. pmc Retrotrapezoid nucleus and parafacial respiratory group
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908 0735, USA
    Respir Physiol Neurobiol 173:244-55. 2010
    ..ccRTN neurons are activated by acidification via an intrinsic mechanism or via ATP released by glia. In summary, throughout life, ccRTN neurons seem to be a critical hub for the regulation of CO(2) via breathing...
  5. pmc Central respiratory chemoreception
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Comp Neurol 518:3883-906. 2010
    ..Their contribution to central respiratory chemoreception may be behavior dependent or vary according to the state of vigilance...
  6. pmc Photostimulation of Phox2b medullary neurons activates cardiorespiratory function in conscious rats
    Roy Kanbar
    Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, USA
    Am J Respir Crit Care Med 182:1184-94. 2010
    ..This preclinical study explores whether direct stimulation of central chemoreceptors could be used as an alternative method to stimulate breathing...
  7. pmc Central CO2 chemoreception and integrated neural mechanisms of cardiovascular and respiratory control
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908 0735, USA
    J Appl Physiol (1985) 108:995-1002. 2010
    ..In the case of SNA, these sites include the nucleus of the solitary tract, the ventrolateral medulla, and the preganglionic neurons...
  8. pmc Control of breathing by raphe obscurus serotonergic neurons in mice
    Seth D DePuy
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 31:1981-90. 2011
    ..In conclusion, RO serotonergic neurons activate breathing frequency and amplitude and potentiate the central respiratory chemoreflex but do not appear to have a central respiratory chemoreceptor function...
  9. pmc Phox2b-expressing neurons of the parafacial region regulate breathing rate, inspiration, and expiration in conscious rats
    Stephen B G Abbott
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 31:16410-22. 2011
    ..These results suggest that RTN-Phox2b neurons are no longer rhythmogenic in adulthood and that their average discharge rate may be far more important than their discharge pattern in driving lung ventilation...
  10. pmc Regulation of visceral sympathetic tone by A5 noradrenergic neurons in rodents
    Roy Kanbar
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    J Physiol 589:903-17. 2011
    ..A5 neurons respond weakly to hypercapnia in vivo or to changes in pH in slices suggesting that their ability to sense local variations in brain pH or Pco₂ is limited...
  11. pmc Pre-Bötzinger complex receives glutamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons
    Genrieta Bochorishvili
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Comp Neurol 520:1047-61. 2012
    ..RTN-Phox2b neurons establish classic excitatory glutamatergic synapses with pre-Bötzinger complex neurons presumed to generate the respiratory rhythm...
  12. pmc Optogenetic stimulation of c1 and retrotrapezoid nucleus neurons causes sleep state-dependent cardiorespiratory stimulation and arousal in rats
    Stephen B G Abbott
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    Hypertension 61:835-41. 2013
    ..These neurons, which are powerfully activated by chemoreceptor stimulation, may contribute to the sleep disruption associated with obstructive sleep apnea...
  13. pmc Glutamatergic neurotransmission between the C1 neurons and the parasympathetic preganglionic neurons of the dorsal motor nucleus of the vagus
    Seth D DePuy
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 33:1486-97. 2013
    ....
  14. pmc Selective optogenetic activation of rostral ventrolateral medullary catecholaminergic neurons produces cardiorespiratory stimulation in conscious mice
    Stephen B G Abbott
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    J Neurosci 33:3164-77. 2013
    ..The results also suggest that RVLM-CA neurons may underlie some of the acute respiratory response elicited by carotid body stimulation but contribute little to the central respiratory chemoreflex...
  15. pmc Cholinergic neurons in the mouse rostral ventrolateral medulla target sensory afferent areas
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia Health System, P O Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908 0735, USA
    Brain Struct Funct 218:455-75. 2013
    ....
  16. pmc C1 neurons: the body's EMTs
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908 0735, USA
    Am J Physiol Regul Integr Comp Physiol 305:R187-204. 2013
    ....
  17. pmc Monosynaptic glutamatergic activation of locus coeruleus and other lower brainstem noradrenergic neurons by the C1 cells in mice
    Benjamin B Holloway
    Departments of Pharmacology and Psychology, University of Virginia, Charlottesville, Virginia 22904
    J Neurosci 33:18792-805. 2013
    ..In conclusion, activation of RVLM catecholaminergic neurons, predominantly C1 cells, by somatic or psychological stresses has the potential to increase the firing of both peripheral and central noradrenergic neurons. ..
  18. pmc Retrotrapezoid nucleus, respiratory chemosensitivity and breathing automaticity
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
    Respir Physiol Neurobiol 168:59-68. 2009
    ..Finally, we argue that the RTN neurons are the adult form of the parafacial respiratory group in neonate rats...
  19. pmc Photostimulation of retrotrapezoid nucleus phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats
    Stephen B G Abbott
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 29:5806-19. 2009
    ..These results provide strong evidence that the Phox2b-expressing noncatecholaminergic neurons of the RTN region function as central respiratory chemoreceptors...
  20. pmc Water deprivation activates a glutamatergic projection from the hypothalamic paraventricular nucleus to the rostral ventrolateral medulla
    Sean D Stocker
    Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536 0298, USA
    J Comp Neurol 494:673-85. 2006
    ..One mechanism by which water deprivation may increase the sympathetic outflow is activation of a glutamatergic pathway from the PVH to the RVLM...
  21. ncbi Afferent and efferent connections of the rat retrotrapezoid nucleus
    Diane L Rosin
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Comp Neurol 499:64-89. 2006
    ....
  22. pmc Central chemoreceptors and sympathetic vasomotor outflow
    Thiago S Moreira
    Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, USA
    J Physiol 577:369-86. 2006
    ..Activation of the central respiratory network reduces the overall sympathetic response to CO(2), presumably by activating barosensitive CVLM neurons and inhibiting RTN chemoreceptors...
  23. pmc Peripheral chemoreceptor inputs to retrotrapezoid nucleus (RTN) CO2-sensitive neurons in rats
    Ana Carolina Thomaz Takakura
    Department of Pharmacology, University of Virginia Health System, Charlottesville, 22908 0735, USA
    J Physiol 572:503-23. 2006
    ..RTN neurons probably contribute a portion of the chemical drive to breathe...
  24. pmc Inhibitory input from slowly adapting lung stretch receptors to retrotrapezoid nucleus chemoreceptors
    Thiago S Moreira
    Department of Pharmacology, University of Virginia Health System, PO Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908 0735, USA
    J Physiol 580:285-300. 2007
    ..In conclusion, RTN chemoreceptors receive an inhibitory input from myelinated lung stretch receptors, presumably SARs. The lung input to RTN may be di-synaptic with inhibitory pump cells as sole interneurons...
  25. ncbi Serotonergic neurons activate chemosensitive retrotrapezoid nucleus neurons by a pH-independent mechanism
    Daniel K Mulkey
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 27:14128-38. 2007
    ..Thus, RTN neurons presumably contribute to the respiratory stimulation caused by serotonergic neurons, but serotonin seems without effect on the cellular mechanism by which RTN neurons detect pH...
  26. ncbi Transneuronal mapping of the CNS network controlling sympathetic outflow to the rat thymus
    R Nicholas Trotter
    Department of Microbiology, University of Virginia, PO Box 800734, Charlottesville, VA 22908, USA
    Auton Neurosci 131:9-20. 2007
    ..None of the infected animals exhibited labeling of the dorsal motor nucleus of the vagus. In summary, this study provides the first anatomic map of CNS neurons involved in control of sympathetic outflow to the thymus...
  27. ncbi Central nervous system distribution of the transcription factor Phox2b in the adult rat
    B J Kang
    Department of Anesthesiology, Dankook University College of Medicine, Chonan City, 330 714 Republic of Korea
    J Comp Neurol 503:627-41. 2007
    ..Phox2b is virtually absent from the respiratory rhythm and pattern generator (VRC and dorsolateral pons) but is highly expressed by neurons involved in the chemical drive and reflex regulation of this oscillator...
  28. ncbi GABAergic pump cells of solitary tract nucleus innervate retrotrapezoid nucleus chemoreceptors
    Ana C Takakura
    Department of Pharmacology, University of Virginia Health System, Charlottesville, VA 22908 0735, USA
    J Neurophysiol 98:374-81. 2007
    ..We demonstrate that a GABAergic subset of these pump cells innervates the RTN region. We conclude that these inhibitory neurons probably contact RTN chemoreceptors and mediate their inhibition by lung inflation...
  29. ncbi Botzinger expiratory-augmenting neurons and the parafacial respiratory group
    Michal G Fortuna
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 28:2506-15. 2008
    ....
  30. pmc Retrotrapezoid nucleus and central chemoreception
    Patrice G Guyenet
    University of Virginia Health System, P O Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908 0735, USA
    J Physiol 586:2043-8. 2008
    ....
  31. pmc Identification of neurotransmitters and co-localization of transmitters in brainstem respiratory neurons
    R L Stornetta
    Department of Pharmacology, University of Virginia Health System, P O Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908, USA
    Respir Physiol Neurobiol 164:18-27. 2008
    ..Although the purpose of the additional transmitter has not been elucidated for any of the respiratory neurons, some examples from other systems will be discussed...
  32. pmc Selective lesion of retrotrapezoid Phox2b-expressing neurons raises the apnoeic threshold in rats
    Ana C Takakura
    University of Virginia Health System, PO Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908 0735, USA
    J Physiol 586:2975-91. 2008
    ..The loss of an even greater percentage of these cells would presumably be required to produce significant breathing deficits in the awake state...
  33. pmc The 2008 Carl Ludwig Lecture: retrotrapezoid nucleus, CO2 homeostasis, and breathing automaticity
    Patrice G Guyenet
    Department of Pharmacology, University of Virginia Health System, PO Box 800735, 1300 Jefferson Park Ave, Charlottesville, VA 22908 0735, USA
    J Appl Physiol (1985) 105:404-16. 2008
    ..The working hypothesis could explain the breathing deficits experienced by CCHS patients...
  34. pmc Galanin is a selective marker of the retrotrapezoid nucleus in rats
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Comp Neurol 512:373-83. 2009
    ..In conclusion, galanin mRNA is a very specific marker of the glutamatergic Phox2b(+)/TH(-) neurons of the RTN, but galanin mRNA identifies only half of these putative central respiratory chemoreceptors...
  35. pmc Photostimulation of channelrhodopsin-2 expressing ventrolateral medullary neurons increases sympathetic nerve activity and blood pressure in rats
    Stephen B G Abbott
    University of Virginia Health System, PO Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908 0735, USA
    J Physiol 587:5613-31. 2009
    ..Photostimulation of RVLM neurons caused a sizable sympathoactivation and rise in blood pressure. These results provide the most direct evidence yet that the C1 neurons have a sympathoexcitatory function...
  36. ncbi Vesicular glutamate transporter 2 is required for the respiratory and parasympathetic activation produced by optogenetic stimulation of catecholaminergic neurons in the rostral ventrolateral medulla of mice in vivo
    Stephen B G Abbott
    Department of Pharmacology, University of Virginia, Charlottesville, VA, USA
    Eur J Neurosci 39:98-106. 2014
    ..In conclusion, two responses evoked by RVLM-CA neuron stimulation in vivo require the expression of VGLUT2 by these neurons, suggesting that the acute autonomic responses driven by RVLM-CA neurons are mediated by glutamate. ..