Severe brain hypoxia results in respiratory excitation, which takes the form of gasping. If gasps sufficiently reoxygenate the lungs and heart, cardiorespiratory function will rapidly improve;thus, survival during severe hypoxic exposures appears to be critically dependent upon gasping, which functionally promotes autoresuscitation. Although gasping is important for survival, the underlying neural mechanisms responsible for the genesis of hypoxia-induced gasping remain unclear. Recent work, including work from our laboratory, has demonstrated that the pre-Botzinger complex (pre-B6tC), which is essential for the generation of normal breathing, is hypoxia chemosensitive, and therefore, may participate in the genesis of hypoxia related gasping. The mechanism(s) by which pre-BotC neurons """"""""sense"""""""" hypoxia, leading to respiratory excitation (gasping), however, is not known. Numerous modalities have been suggested to participate in O2 sensing in other """"""""hypoxia chemosensors"""""""", including direct effects on ion channel conductance and release of excitatory and inhibitory neurotransmitters and neuromodulators. Recent observations, for example, have suggested that K+ATp channels may be part of the molecular substrate for O2 detection in hypoxia-sensitive central nervous system (CMS) neurons, and that persistent sodium channels may act as Oz sensors. Although both of these types of channels are present in pre-BotC neurons, it remains to be determined whether these channels participate in the hypoxia-sensing function of this region. Recent studies have also proposed that substance P (SP)and nitric oxide (NO),both of which are released during severe brain hypoxia in some CNS regions, may play a role in the hypoxia-sensing function of the carotid body. Although neurokinin-1 (SP) receptors and NO synthase (i.e., enzyme for NO production) are expressed by pre-BotC neurons, it remains to be determined whether these neuroactive agents participate in the hypoxia-sensing function of this region. The major objective of the work proposed in this application is to investigate whether these potential mechanisms participate in the hypoxia-sensing function of the pre-BotC, and the subsequent generation of hypoxia-induced gasping. The experiments proposed in this application will use an in vivo vagotomized, deafferented, decerebrate or anesthetized adult cat model to assess the roles of K+ATp channels, persistent sodium channels, SP, and NO in the hypoxia-sensing function of the pre- BotC. The effects of both focal and systemic hypoxic stimuli will be examined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063175-09
Application #
7782724
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Laposky, Aaron D
Project Start
2000-09-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2010
Total Cost
$301,010
Indirect Cost
Name
State University New York Stony Brook
Department
Physiology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Horn, Kyle G; Solomon, Irene C (2014) Effects of calcium (Ca(2+)) extrusion mechanisms on electrophysiological properties in a hypoglossal motoneuron: insight from a mathematical model. Prog Brain Res 212:77-97
Horn, Kyle G; Memelli, Heraldo; Solomon, Irene C (2012) Emergent central pattern generator behavior in gap-junction-coupled Hodgkin-Huxley style neuron model. Comput Intell Neurosci 2012:173910
Warren, Kelly A; Solomon, Irene C (2012) Chronic serotonin-norepinephrine reuptake transporter inhibition modifies basal respiratory output in adult mouse in vitro and in vivo. Respir Physiol Neurobiol 184:9-15
Memelli, Heraldo; Horn, Kyle G; Wittie, Larry D et al. (2012) Analyzing the effects of gap junction blockade on neural synchrony via a motoneuron network computational model. Comput Intell Neurosci 2012:575129
Ono, Kenichi; Shen, Tabitha Y; Chun, Hyun Hye et al. (2010) Upper airway and abdominal motor output during sneezing: is the in vivo decererate rat an adequate model? Adv Exp Med Biol 669:173-6
O'Neal 3rd, Marvin H; Spiegel, Evan T; Chon, Ki H et al. (2005) Time-frequency representation of inspiratory motor output in anesthetized C57BL/6 mice in vivo. J Neurophysiol 93:1762-75
Chen, Xinnian; Chon, Ki H; Solomon, Irene C (2005) Chemical activation of pre-Botzinger complex in vivo reduces respiratory network complexity. Am J Physiol Regul Integr Comp Physiol 288:R1237-47
Solomon, Irene C (2005) Glutamate neurotransmission is not required for, but may modulate, hypoxic sensitivity of pre-Botzinger complex in vivo. J Neurophysiol 93:1278-84
Solomon, Irene C (2004) Ionotropic excitatory amino acid receptors in pre-Botzinger complex play a modulatory role in hypoxia-induced gasping in vivo. J Appl Physiol 96:1643-50
Solomon, Irene C (2003) Connexin36 distribution in putative CO2-chemosensitive brainstem regions in rat. Respir Physiol Neurobiol 139:1-20

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