Stimulation of retrotrapezoid nucleus Phox2b-expressing neurons rescues breathing dysfunction in an experimental Parkinson's disease rat model

Author(s)

Fernandes-Junior, Silvio A. ^{[1, 2]} ; Oliveira, Luiz M. ^[1] ; Czeisler, Catherine M. ^[2] ; Mo, Xiaokui ^{[3, 4]} ; Roy, Sashwati ^[5] ; Somogyi, Arpad ^[6] ; Zhang, Liewn ^[6] ; Moreira, Thiago S. ^[7] ; Otero, Jose J. ^[2] ; Takakura, Ana C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Pharmacol, 1524 Prof Lineu Prestes Ave, BR-05508000 Sao Paulo, SP - Brazil

^[2] Ohio State Univ OSU, Sch Med, Dept Pathol, Columbus, OH - USA

^[3] Ohio State Univ OSU, Dept Biostat & Bioinformat, Columbus, OH - USA

^[4] Ohio State Univ OSU, Dept Surg, Columbus, OH - USA

^[5] Ohio State Univ OSU, Dept Mol & Cellular Biochem, Columbus, OH - USA

^[6] Ohio State Univ OSU, Mass Spectrometry & Prote Facil, Columbus, OH - USA

^[7] Univ Sao Paulo, Inst Ciencias Biomed, Dept Physiol & Biophys, Sao Paulo - Brazil

• Document type: Journal article
• Source: Brain Pathology; v. 30, n. 5 JUL 2020.
• Web of Science Citations: 0

Abstract

Emerging evidence from multiple studies indicates that Parkinson's disease (PD) patients suffer from a spectrum of autonomic and respiratory motor deficiencies in addition to the classical motor symptoms attributed to substantia nigra degeneration of dopaminergic neurons. Animal models of PD show a decrease in the resting respiratory rate as well as a decrease in the number ofPhox2b-expressing retrotrapezoid nucleus (RTN) neurons. The aim of this study was to determine the extent to which substantia nigra pars compact (SNc) degeneration induced RTN biomolecular changes and to identify the extent to which RTN pharmacological or optogenetic stimulations rescue respiratory function following PD-induction. SNc degeneration was achieved in adult male Wistar rats by bilateral striatal 6-hydroxydopamine injection. For proteomic analysis, laser capture microdissection and pressure catapulting were used to isolate the RTN for subsequent comparative proteomic analysis and Ingenuity Pathway Analysis (IPA). The respiratory parameters were evaluated by whole-body plethysmography and electromyographic analysis of respiratory muscles. The results confirmed reduction in the number of dopaminergic neurons of SNc and respiratory rate in the PD-animals. Our proteomic data suggested extensive RTN remodeling, and that pharmacological or optogenetic stimulations of the diseased RTN neurons promoted rescued the respiratory deficiency. Our data indicate that despite neuroanatomical and biomolecular RTN pathologies, that RTN-directed interventions can rescue respiratory control dysfunction. (AU)

• FAPESP's process: 16/23281-3 - Encephalic regions responsible for neuroplasticity observed in respiratory response induced by hypercapnia in a modelo of Parkinson's Disease
• Grantee: Ana Carolina Takakura Moreira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/20695-6 - Analysis of the selective activation of medullary neurons in an experimental model of Parkinson's Disease: a time study of the possible mechanisms for restoration of respiratory function
• Grantee: Silvio de Araujo Fernandes Junior
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/23376-1 - Retrotrapezoid nucleus, respiratory chemosensitivity and breathing automaticity
• Grantee: Thiago dos Santos Moreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/11165-1 - Respiratory deficit in an experimental model of Parkinson's Disease may be associated with changes in the Phox2b gene at the level of the ventrolateral medulla
• Grantee: Silvio de Araujo Fernandes Junior
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate