Recent evidence indicates that gap junctions play a more prominent role in normal functioning of the mammalian central nervous system (CNS) than was once believed. Accumulating evidence from both neonatal and adult rodents indicates that gap junctions participate in multiple aspects of respiratory control, including central CO2 chemoreception. Central CO2 chemoreceptors have been demonstrated to be distributed at several sites in the mammalian brainstem, and respiratory neurophysiologists have gained tremendous insight as to how presumptive central CO2 chemoreceptor neurons work by studying the electrophysiological and anatomical properties of cells in in vitro preparations of the mammalian CNS. One feature that has been identified in CO2-chemosensitive neurons is cell-to-cell coupling which occurs via gap junctions. The presence of gap junctions between adjoining CO2-chemosensitive neurons and the demonstration of neuronal expression of the gap junction proteins (connexin; Cx) Cx26 and Cx32 in CO2-chemosensitive brainstem regions suggest that either electrical coupling and/or metabolic coupling is/are involved in respiratory control. The principle hypothesis of this proposal is that gap junctional communication plays an important role in mediating and maintaining the ventilatory response to elevated levels of CO2 (i.e., hypercapnia). The experiments proposed in this application will use both in vitro and in vivo models along with biochemical and immunohistochemical procedures to further define the role of gap junctions in CO2 chemoreception.
The specific aims of the project are: (1) investigate the effects of pharmacological blockade (i.e., uncoupling) of brainstem gap junctions on CO2-chemoreception, (2) investigate the effects of genetic manipulation (deletion) of the neuronal gap junction proteins Cx32 and Cx 36 on CO2-chemoreception in vivo, (3) identify the repertoire of neuronal and glial gap junction proteins, including regional and postnatal developmental expression, in putative CO2-chemosensitive brainstem regions, (4) investigate the effects of hypercapnia on modulation of gap junction protein expression in putative CO2-chemosensitivie regions and (5) investigate the effects of a prior hypercapnia conditioning exposure on CO2 chemoreception.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045321-03
Application #
7013123
Study Section
Respiratory Physiology Study Section (RESP)
Program Officer
Golanov, Eugene V
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$271,883
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
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
Shen, Tabitha Y; Ono, Kenichi; Solomon, Irene C (2010) Influence of extracellular [K+]o on inspiratory network complexity of phrenic and hypoglossal nerve discharge in arterially-perfused adult rat. Adv Exp Med Biol 669:181-4
Bale, Tejus A; Solomon, Irene C (2010) Influence of 5-HT2A receptor blockade on phrenic nerve discharge at three levels of extracellular K+ in arterially-perfused adult rat. Adv Exp Med Biol 669:139-42
Cordovez, Juan M; Wilson, Christopher G; Solomon, Irene C (2010) Geometrical analysis of bursting pacemaker neurons generated by computational models: comparison to in vitro pre-Bötzinger complex bursting neurons. Adv Exp Med Biol 669:45-8
Chun, Hyun Hye; Spiegel, Evan T; Solomon, Irene C (2008) Burst-to-Burst variability in respiratory timing, inspiratory-phase spectral activity, and inspiratory neural network complexity in urethane-anesthetized C57BL/6 mice in vivo. Adv Exp Med Biol 605:407-12
Warren, Kelly A; Solomon, Irene C (2008) Glutamatergic neurotransmission is not essential for, but plays a modulatory role in, the production of gasping in arterially-perfused adult rat. Adv Exp Med Biol 605:423-7
Chen, Xinnian; Chon, Ki H; Solomon, Irene C (2008) Fast oscillatory rhythms in inspiratory motor discharge: a mathematical model. Adv Exp Med Biol 605:401-6
Cordovez, Juan M; Clausen, Chris; Moore, Leon C et al. (2008) A mathematical model of pH(i) regulation in central CO2- chemoreception. Adv Exp Med Biol 605:306-11
Yu, Hui Jing; Chen, Xinnian; Foglyano, Ryan M et al. (2008) Respiratory network complexity in neonatal rat in vivo and in vitro. Adv Exp Med Biol 605:393-8
Chen, Xinnian; Solomon, Irene C; Chon, Ki H (2006) Fast oscillatory rhythms in inspiratory motor discharge: a mathematical model. Conf Proc IEEE Eng Med Biol Soc 1:4619-22

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