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Ionic mechanisms underlying the ATP-mediated respiratory stimulation - understanding the interaction between central oxygen sensors and rhythm-generating neurons

Grant number: 18/21000-2
Support type:Scholarships abroad - Research
Effective date (Start): July 01, 2019
Effective date (End): June 30, 2020
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Daniel Breseghello Zoccal
Grantee:Daniel Breseghello Zoccal
Host: Gregory Douglas Funk
Home Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Local de pesquisa : University of Alberta, Canada  


The brain functioning depends on adequate supply of oxygen (O2) that must meet its high metabolic demand. In mammals, the partial pressure of O2 (PO2) in the blood is monitored continuously by specialized cells located in the arterial vascular system, in the carotid bodies and the aortic arc. In conditions of hypoxia (reduced PO2), these cells, named peripheral chemoreceptors, drive sensorial afferent inputs to the central nervous system that initiate a compensatory increase in pulmonary ventilation. Convention holds that the peripheral chemoreceptors are the only source of excitatory inputs to the respiratory network in conditions of hypoxia. However, recent experimental evidence challenges this convention revealing the existence of astrocytes acting as central O2 sensors that contribute to the ventilatory response to hypoxia. These O2-sensitive astrocytes in the pre-Bötzinger complex (pre-BötC) of the ventrolateral medulla - the critical region for inspiratory rhythm generation - release ATP during hypoxia which stimulates inspiratory neurons causing an increase in ventilation. This ATP-mediated excitation of the pre-BötC is mediated by the activation of P2Y1 receptors (P2Y1R). However, it remains to be elucidated the intracellular pathways and the ionic mechanisms underlying the excitation of pre-BötC by P2Y1R activation. Based upon preliminary data, in the present study we will investigate the hypothesis that ATP/ P2Y1R promotes the excitation of glutamatergic inspiratory neurons of the pre-BötC through the potentiation of hyperpolarization-activated (Ih) currents. To reach this goal, we will obtain medullary rhythmic slices and evaluate the effects of P2Y1R agonist on the hypoglossal nerve activity (network effect) and on the amplitude of P2Y1 receptor-evoked currents in the pre-BötC inspiratory neurons (cellular effect), in the presence and absence of Ih current blockers. Whole-cell recording protocols to determine the amplitude of Ih currents before and during P2Y1R activation will be also performed. The recorded neurons will be labeled for subsequent phenotypic characterization (as excitatory or inhibitory) by in situ hybridization (RNAScope). The identification of the ionic mechanism underlying the effects of ATP on the pre-BötC neurons is an important step to comprehend the mechanisms of interaction between astrocytes and neurons of the pre-BötC, and to advance our acknowledge about the functioning of central O2 sensors.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FLOR, KARINE C.; BARNETT, WILLIAM H.; KARLEN-AMARANTE, MARLUSA; MOLKOV, I, YAROSLAV; ZOCCAL, DANIEL B. Inhibitory control of active expiration by the Botzinger complex in rats. JOURNAL OF PHYSIOLOGY-LONDON, JUL 2020. Web of Science Citations: 0.

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