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Acetylcholine and ventilation: Modulation by cholinergic inputs from pedunculopontine tegmental nucleus to the retrotrapezoid nucleus

Grant number: 15/12827-2
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2016
Effective date (End): January 31, 2019
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Thiago dos Santos Moreira
Grantee:Cleyton Roberto Sobrinho
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):16/23077-7 - Postinspiratory complex and retrotrapezoid nucleus: role of cholinergic signaling, BE.EP.PD


Neurons with chemosensory properties are specialized structures located in the central nervous system (CNS), which are able to detect changes in CO2 concentrations and plasma pH and promote appropriate adjustments in ventilation to restore blood gas homeostasis. Located near the ventrolateral surface of medulla oblongata, the retrotrapezoid nucleus (RTN) receives prominent role by fulfil all the requirements to be considered a chemosensitive neural group. The RTN neurons have the ability to sense CO2 / H + in vivo and in vitro, excitatory neurochemical phenotype and send inputs to the respiratory pattern generator centers. Furthermore, the RTN neurons also receive important paracrine contribution elicited by astrocytes, which detect changes in CO2 and pH and release ATP as signaling molecule. The RTN neurons respond to a variety of neurotransmitter, and in this sense, through in vitro experiments (patch clamp) we observed that the RTN chemosensitive neurons are highly responsive to acetylcholine (Ach) by activation of cholinergic muscarinic receptors M1 and / or M3 . The application of Ach on RTN in anesthetized animals produces increase in ventilation, and methyl-atropine (muscarinic cholinergic antagonist) injections in the RTN promoted reduction of basal ventilation and ventilatory response during a hypercapnia. Interestingly, the same responses were not observed when the animals were conscious, i.e. without the presence of anesthesia. Associating our findings to the literature, showing that the urethane is able to mimic the REM stage of sleep and respiratory oscillations and sensitivity to CO2 are dependent on the level of brain activity, we suggest that in different states of sleep-wake could have a greater contribution of cholinergic signaling in RTN region. In addition, the literature and previous data from our laboratory have shown that the region of pedunculopontine tegmental nucleus (PPT) is the main source of cholinergic projection to the rostral ventrolateral medulla, especially the RTN region.Cholinergic neurons of the PPT appear to be involved in maintaining the sleep-wake cycle, specifically the REM sleep phase. In anesthetized animals, PPT activation produces tachypnea and tonic activity of the genioglossus muscle. However, these experiments were not performed in a manner to indicate any direct relation to the RTN or demonstrating with which respiratory group the PPT was related. In this project, we seek to better understand the interaction between the PPT and the RTN in cholinergic signaling during the sleep-wake cycle. To this purpose, we propose to investigate the non-selective stimulation (pharmacological) or selective stimulation (optogenetic) of PPT is capable of promoting respiratory changes and if these changes depend on cholinergic signaling in the RTN region of anesthetized animals. We will also assess the effects on breathing pattern produced by selective stimulation of cholinergic neurons of the PPT that send inputs to the RTN simultaneously with polysomnography in non-anesthetized rats.

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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)
LIMA, JANAYNA D.; SOBRINHO, CLEYTON R.; SANTOS, LEONARDO K.; TAKAKURA, ANA C.; MOREIRA, THIAGO S.. M4-muscarinic acetylcholine receptor into the pedunculopontine tegmental nucleus mediates respiratory modulation of conscious rats. Respiratory Physiology & Neurobiology, v. 269, . (16/23281-3, 15/23376-1, 15/12827-2, 17/01380-2)
LIMA, JANAYNA D.; SOBRINHO, CLEYTON R.; FALQUETTO, BARBARA; SANTOS, LEONARDO K.; TAKAKURA, ANA C.; MULKEY, DANIEL K.; MOREIRA, THIAGO S.. Cholinergic neurons in the pedunculopontine tegmental nucleus modulate breathing in rats by direct projections to the retrotrapezoid nucleus. JOURNAL OF PHYSIOLOGY-LONDON, v. 597, n. 7, p. 1919-1934, . (15/23376-1, 16/23281-3, 15/12827-2, 16/22069-0, 17/01380-2)
SOBRINHO, CLEYTON R.; GONCALVES, CHRISTOPHER M.; TAKAKURA, ANA C.; MULKEY, DANIEL K.; MOREIRA, THIAGO S.. Fluorocitrate-mediated depolarization of astrocytes in the retrotrapezoid nucleus stimulates breathing. Journal of Neurophysiology, v. 118, n. 3, p. 1690-1697, . (14/22406-1, 11/13462-7, 15/23376-1, 15/12827-2, 16/22069-0)

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