Control of breathing pattern: interactions between respiratory oscillators

• Grant number: 20/05045-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2021
• End date: April 30, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Daniel Breseghello Zoccal
• Grantee: Isabela de Paula Leirão
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated research grant: 15/23467-7 - Experimental pathophysiology: role of central mechanisms of the cardiovascular and respiratory control changes induced by experimental hypertension and obesity, AP.TEM
• Associated scholarship(s): 22/12416-6 - Control of abdominal expiratory activity by the preBötzinger complex, BE.EP.DR

Abstract

Rhythmogenic respiratory neurons on the ventral surface of the medulla, located in the pre-Bötzinger complex (pre-BötC), constitute the primary inspiratory oscillator and are responsible for generating the respiratory rhythm. In situations of reduced O2 (hypoxia) and/or increased CO2 (hypercapnia), the pre-BötC is stimulated to promote an increase in the respiratory frequency. In these situations of metabolic challenge, expiration becomes an active process, with the presence of rhythmic contractions in the abdominal muscles due to the recruitment of a conditional expiratory oscillator, named the parafacial respiratory group (pFRG). In conditions where expiratory motor activity is recruited, it is suggested that the inspiratory (pre-BötC) and expiratory (pFRG) oscillators operate in a coordinated manner to synchronize the inspiratory and expiratory motor activities. Although anatomical evidence suggests the presence of synaptic projections between the oscillators, there are few studies that show, functionally, how the interaction between oscillators happens, and under what conditions they are recruited. In addition to coordinating neuronal activity, the interaction between respiratory oscillators probably has relevant functional implications, due to the ventilatory changes that follow the inspiratory excitation and expiratory recruitment. Thus, in this project we consider the following questions: i) does the abdominal recruitment occur only after a certain level inspiratory excitation?; ii) if the pre-BötC is responsible for inhibiting the expiratory oscillator, would active expiration happen only after the reduction of the inspiratory oscillator activity?; iii) what are the changes in pulmonary ventilation that follow inspiratory excitation with and without the occurrence of active expiration? Therefore, in the present study, we will explore the hypothesis that the inspiratory and expiratory oscillators operate, in situations of metabolic challenges, in hierarchical and stimulus-dependent manner, where: i) during mild/moderate stimuli, there is only excitation of the inspiratory oscillator, promoting an increase in inspiratory motor activity; and ii) during intense stimuli, abdominal expiratory activity occurs (recruitment of the expiratory oscillator) to promote an additional increase in ventilation, not supported by inspiratory motor activity only. For this to happen, an important step for the emertence of active expiration will be the inhibition of specific groups of pFRG-projecting pre-BötC inhibitory neurons. For these studies, we will combine in vivo and in situ experimental approaches. The results are expected to advance our understanding about the interaction between respiratory oscillators to better understand the development of ventilatory responses to hypoxia and hypercapnia, not only in physiological conditions, but associated with pathological situations, as seen in patients with central and obstructive apneas, heart failure, Sudden Infant Death Syndrome (SIDS) and Sudden Death associated with Epilepsy (SUDEP). (AU)

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)

KARLEN-AMARANTE, MARLUSA; ISABELA, I. P.; KATAYAMA, PEDRO L.; COLOMBARI, EDUARDO; BITTENCOURT-SILVA, PALOMA G.; MENEZES, MIGUEL F.; ZOCCAL, D. B.. Sympathetic dysregulation induced by postnatal intermittent hypoxia. Sleep, v. N/A, p. 13-pg., 2023-03-02. (13/17251-6, 20/05045-6, 19/11196-0)