Sleep apnea syndrome affects at least 3% - 5% of the adult population in this country and available data suggest that significant morbidity and increased mortality result from this disorder. Despite 40 years of intensive investigation, the brainstem mechanisms responsible for, or permissive of, sleep-related apnea remain unknown. Our work to develop and characterize a rodent model of sleep-related breathing disorder makes it feasible to systematically examine the detailed brainstem mechanisms of apnea. A brainstem anatomical pathway recently has been demonstrated in which the intertrigeminal region (ITR) of the lateral pons is posited as a key regulatory site for apneic reflexes. The ITR is innervated by sensory subnuclei of the solitary tract that receive inputs from the ninth and tenth cranial nerves; each of which mediate airway-protective apneic reflexes. Moreover, the ITR sends direct projections to respiratory rhythm generating neurons in the medulla. Although the ITR thus may represent an important airway reflex integrating site, no physiological or pathophysiological role has yet been demonstrated for this region. We present novel preliminary evidence that the ITR dampens vagally-mediated reflex apnea, an effect that appears to be mediated by glutamatergic neurotransmission and may result from short term potentiation. Further, we show that focal lesions of the ITR lead to dramatically increased apnea expression during sleep. The overall goals of this proposal are 1) to identify the neural mechanisms by which the ITR modulates apneic reflexes, 2) to demonstrate the functional role of the ITR in sleep apnea genesis and 3) to establish the impact of sleep/wake state changes on ITR function. To achieve these goals, we will employ pressure microinjections to enhance and impair ITR functional activity and to test the strength of monoaminergic and cholinergic inputs on ITR function. The acute impact of these manipulations on respiratory pattern and apneic reflexes will be tested in anesthetized rats. Sustained effects following focal lesions will be tested by behavioral state and cardiorespiratory monitoring in sleeping rats. The proposed neurochemical manipulations of the ITR provide a systematic approach to define the importance of this region in modulating both reflexive and spontaneous sleep-related apnea and to identify the initial steps in the signaling pathway by which this region modulates apnea expression.
| Topchiy, Irina; Radulovacki, Miodrag; Waxman, Jonathan et al. (2011) Impact of the vagal feedback on cardiorespiratory coupling in anesthetized rats. Respir Physiol Neurobiol 175:375-82 |
| Stoiljkovic, Milan; Radulovacki, Miodrag; Carley, David W (2009) Local antagonism of intertrigeminal region metabotropic glutamate receptors exacerbates apneic responses to intravenous serotonin. Respir Physiol Neurobiol 165:137-42 |
| Topchiy, Irina; Radulovacki, Miodrag; Waxman, Jonathan et al. (2009) Cardiorespiratory effects of intertrigeminal area stimulation in vagotomized rats. Brain Res 1250:120-9 |
| Carley, David W; Radulovacki, Miodrag (2008) Pharmacology of vagal afferent influences on disordered breathing during sleep. Respir Physiol Neurobiol 164:197-203 |
| Isenovic, Esma R; Radulovacki, Miodrag; Carley, David W (2007) Impact of intertrigeminal region AMPA receptor blockade on respiratory responses in rats. Respir Physiol Neurobiol 158:39-44 |
| Radulovacki, Miodrag; Stoiljkovic, Milan; Saponjic, Jasna et al. (2007) Effects of intertrigeminal region NMDA and non-NMDA receptors on respiratory responses in rats. Respir Physiol Neurobiol 156:40-6 |
| Nakamura, Yasuhiro; Wang, Xiaohong; Xu, Chengsu et al. (2007) Xenotransplantation of long-term-cultured swine bone marrow-derived mesenchymal stem cells. Stem Cells 25:612-20 |
