Evidence of CO2 chemosensitivity has been found in at least five brainstem sites: the rostroventral medulla (RVM, which contains the retrotrapezoid nucleus), the caudal raphe, the locus coeruleus, the nucleus tractus solitarius (NTS) and the preBotzinger complex of the nucleus ambiguus. When studies have been done in anesthetized or decerebrate animals, unilateral lesions of any one of these sites profoundly reduced ventilatory output, but lesions in awake animals have remarkably modest, even transient effects. The presence of widespread sites of CO2 chemosensitivity in bilaterally symmetrical nuclei (except the raphe) immediately raises two questions: How is chemosensory activity coordinated among these sites, and what is the role of this redundancy of CO2 chemosensory function? Studies in anesthetized animals make it look as if every site is essential (unilateral inhibition of even one site dramatically reduces ventilatory output), but studies of intact awake or sleeping animals suggest that the predominant site(s) is dynamic and depends on arousal state - suggesting a relationship among chemosensory sites that is more democratic and robust. Our own studies point to an important, possibly dominant role for the NTS in CO2 chemosensitivity in intact animals, and an important role for gap junctions in the NTS in central chemosensory function in younger animals. Using the isolated perfused juvenile rat brainstem and intact, chronically instrumented rats, we will examine coordination of CO2 chemosensitivity within the NTS and coordination between the NTS and disparate CO2 chemosensory nuclei in the brainstem.
In Specific Aim I, we will test the hypothesis that gap junctions provide an important amplification of signal intensity within the NTS.
In Specific Aim II, we will examine the effect of acute unilateral inhibition within the locus coeruleus and rostroventral medulla on chemosensitivity within the NTS to test the hypothesis that coordination among chemosensitive sites is hierarchical. We believe that the dominant control site lies within the NTS.
In Specific Aim III, we will examine the effect of chronic unilateral lesions within the NTS on CO2 chemosensitivity to test the hypothesis that relationships between chemoreceptor sites are plastic over time.
| Erlichman, Joseph S; Leiter, J C; Gourine, Alexander V (2010) ATP, glia and central respiratory control. Respir Physiol Neurobiol 173:305-11 |
| Erlichman, Joseph S; Leiter, J C (2010) Glia modulation of the extracellular milieu as a factor in central CO2 chemosensitivity and respiratory control. J Appl Physiol 108:1803-11 |
| Erlichman, Joseph S; Boyer, Andrew C; Reagan, Patrick et al. (2009) Chemosensory responses to CO2 in multiple brain stem nuclei determined using a voltage-sensitive dye in brain slices from rats. J Neurophysiol 102:1577-90 |
| Erlichman, Joseph S; Hewitt, Amy; Damon, Tracey L et al. (2008) Inhibition of monocarboxylate transporter 2 in the retrotrapezoid nucleus in rats: a test of the astrocyte-neuron lactate-shuttle hypothesis. J Neurosci 28:4888-96 |
| Erlichman, Joseph S; Putnam, Robert W; Leiter, J C (2008) Glial modulation of CO2 chemosensory excitability in the retrotrapezoid nucleus of rodents. Adv Exp Med Biol 605:317-21 |
| Chernov, Mykyta; Putnam, Robert W; Leiter, J C (2008) A computer model of mammalian central CO2 chemoreception. Adv Exp Med Biol 605:301-5 |
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| John, Trentini F; French, Larry G; Erlichman, Joseph S (2006) The antinociceptive effect of salvinorin A in mice. Eur J Pharmacol 545:129-33 |
| Putnam, Robert W; Conrad, Susan C; Gdovin, M J et al. (2005) Neonatal maturation of the hypercapnic ventilatory response and central neural CO2 chemosensitivity. Respir Physiol Neurobiol 149:165-79 |
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