Involvement of the pontine peduncle tegmentanucleus in the control of the breathing pattern.

Author(s)

Janayna Dias Lima

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2021-07-02

Examining board members

Thiago dos Santos Moreira; Vagner Roberto Antunes; Benedito Honório Machado; Monica Akemi Sato

• Advisor: Thiago dos Santos Moreira

Abstract

The pedunculopontine tegmental nucleus (PPTg) has been shown to have important functions to the regulation of behavioral states and various motor control systems, including breathing control. The PPTg contains a variety of cell types, is considered a major cholinergic nucleus and also expresses transcription factors not only for the choline acetyltransferase enzyme (ChAT), but also for glutamate (VGluT2) or GABA (GAD) vesicles. These ChAT cells project to the rostral aspect of the ventrolateral medula. In addition, cholinergic signaling in the retrotrapezoid nucleus (RTN), a region that contains neurons that regulate breathing in response to changes in CO2/H+, has been shown to activate chemosensitive neurons and increase inspiratory activity. Our major goal is to identify the source of cholinergic input to the RTN and also investigate the respiratory effects caused by the cholinergic and glutamatergic stimulation of PPTg in animals without anesthesia. The neuroanatomical experiments showed projections of cholinergic neurons from the PPTg and the post-inspiratory complex (PiCo) to the RTN. In unrestrained awake rats, unilateral injection of the glutamate (10 mM - 100 nl) in the PPTg decreased tidal volume (VT), but otherwise increased respiratory rate (fR) and net respiratory output as evidenced by an increase in ventilation (VE). All respiratory responses elicited by PPTg stimulation were blunted by prior injection of methyl-atropine (5 mM/50-75 nl) into the RTN. In another group of the unrestrained awake rats, unilateral injection of the cholinergic muscarinic agonist carbachol (10 mM - 100 nL) in the PPTg decreased fR, and increase VT, without changing VE. The changes in fR and VT elicited by carbachol into the PPTg are abolished by previous blockade of the M4 muscarinic cholinergic receptors tropicamide into the PPTg. Interestingly, in mouse, the chemogenetic activation of PPTg glutamatergic neurons increased respiratory frequency and ventilation, without change tidal volume. In contrast, stimulation of PPTg cholinergic neurons did not change respiratory parameters. Our results identify key components of the signaling pathway that associate muscarinic receptor activation with changes in neuronal excitability and thus offer potential avenues for the therapeutic treatment of respiratory control problems associated with disordered breathing in sleep situations. (AU)

• FAPESP's process: 17/01380-2 - Pedunculo pontine tegmental nucleus and brainstem respiratory interactions in breathing
• Grantee: Janayna Dias Lima
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)