Hypercapnia (increased CO2) is a major stimulus for breathing and is sensed by specialized neurons, called chemosensitive neurons, from several brainstem regions. We have been studying the ionic pathways by which these neurons sense CO2. Based on our findings, we have proposed a new model of chemosensitive signaling, the multiple factors model. The main tenet of this model is that the response of chemosensitive neurons to hypercapnia involves multiple signaling pathways that target multiple ion channels. The work in this revised application is divided into 4 aims: 1) test directly that there are multiple signals involved in chemosensitive signaling, by measuring the intrinsic chemosensitivity of neurons from one brainstem region, focusing especially on neuronal responses to acidic stimuli with pHi held constant and on the role of Cai;2) determine which ion channels act as targets of chemosensitive signaling and measure their properties, using a combination of immunocytochemistry and voltage clamp techniques to describe which channels are present in chemosensitive neurons and which are affected by hypercapnia;3) compare the signaling pathways studied in Aim 1 in neurons from three different brainstem regions, the locus coeruleus (low chemosensitivity), the nucleus tractus solitarius (intermediate chemosensitivity) and the retrotrapezoid nucleus (high chemosensitivity) and develop a mathematical model to describe the response of mammalian chemosensitive neurons which combines the multiple signals and ion channel targets described for the neurons from each region;and 4) determine the efferent projections of CO2-chemosensitive neurons combining retrograde labeling with intracellular recordings. These studies will be the first to employ identical techniques in neurons from several brainstem regions which have widely different intrinsic chemosensitivitv, and should yield valuable new insights into the cellular properties that determine chemosensitivity. Further, our results should define the cellular signaling pathways and ion channel targets of chemosensitivitv in neurons and serve to test the multiple factors model. Many diseases, including sleep apnea and Sudden Infant Death Syndrome (SIDS) are believed to involve, in part, disordered central respiratory control, and yet no current drug treatments are available to modify this control pathway. Our studies should suggest new potential targets for drug treatment and may well indicate that a combination of drugs is most effective in modifying central respiratory drive. Lay Summary: Increased CO2, sensed by brainstem neurons, is a major stimulus that drives breathing. Alterations of this response are thought to be involved, in part, in diseases like sleep apnea, but no drugs are now available to affect this response. We are studying the ways in which neurons respond to CO2 to identify novel drug targets and to test a new theory that this pathway involves several different signals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056683-12
Application #
7683257
Study Section
Special Emphasis Panel (ZRG1-RES-B (04))
Program Officer
Twery, Michael
Project Start
1998-07-01
Project End
2012-01-31
Budget Start
2009-08-01
Budget End
2012-01-31
Support Year
12
Fiscal Year
2009
Total Cost
$278,677
Indirect Cost
Name
Wright State University
Department
Physiology
Type
Schools of Medicine
DUNS #
047814256
City
Dayton
State
OH
Country
United States
Zip Code
45435
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Li, Ke-Yong; Putnam, Robert W (2013) Transient outwardly rectifying A currents are involved in the firing rate response to altered CO2 in chemosensitive locus coeruleus neurons from neonatal rats. Am J Physiol Regul Integr Comp Physiol 305:R780-92
Imber, Ann N; Putnam, Robert W (2012) Postnatal development and activation of L-type Ca2+ currents in locus ceruleus neurons: implications for a role for Ca2+ in central chemosensitivity. J Appl Physiol 112:1715-26
Gargaglioni, Luciane H; Hartzler, Lynn K; Putnam, Robert W (2010) The locus coeruleus and central chemosensitivity. Respir Physiol Neurobiol 173:264-73
Dean, Jay B; Putnam, Robert W (2010) The caudal solitary complex is a site of central CO(2) chemoreception and integration of multiple systems that regulate expired CO(2). Respir Physiol Neurobiol 173:274-87
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

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