Unraveling the Mechanisms Underlying Irregularities in Inspiratory Rhythm Generation in a Mouse Model of Parkinson's Disease

Autor(es)

Oliveira, Luiz M. ^{[1, 2]} ; Baertsch, Nathan A. ^{[1, 3]} ; Moreira, Thiago S. ^[4] ; Ramirez, Jan-Marino ^{[1, 3, 5]} ; Takakura, Ana C. ^[2]

Afiliação do(s) autor(es)

^[1] Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98101 - USA

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Pharmacol, BR-05508 Sao Paulo - Brazil

^[3] Univ Washington, Dept Pediat, Seattle, WA 98101 - USA

^[4] Univ Sao Paulo, Inst Ciencias Biomed, Dept Physiol & Biophys, BR-05508 Sao Paulo - Brazil

^[5] Univ Washington, Dept Neurol Surg, Seattle, WA 98101 - USA

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF NEUROSCIENCE; v. 41, n. 21, p. 4732-4747, MAY 26 2021.
• Citações Web of Science: 0

Resumo

Parkinson's disease (PD) is a neurodegenerative disorder anatomically characterized by a progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). Much less known, yet clinically very important, are the detrimental effects on breathing associated with this disease. Consistent with the human pathophysiology, the 6-hydroxydopamine hydrochloride (6-OHDA) rodent model of PD shows reduced respiratory frequency (f(R)) and NK1r-immunoreactivity in the pre-Botzinger complex (preBotC) and PHOX2B(+) neurons in the retrotrapezoid nucleus (RTN). To unravel mechanisms that underlie bra-dypnea in PD, we employed a transgenic approach to label or stimulate specific neuron populations in various respiratory-related brainstem regions. PD mice were characterized by a pronounced decreased number of putatively rhythmically active excitatory neurons in the preBotC and adjacent ventral respiratory column (VRC). Specifically, the number of Dbx1 and Vglut(2) neurons was reduced by 47.6% and 17.3%, respectively. By contrast, inhibitory Vgat(+) neurons in the VRC, as well as neurons in other respiratory-related brainstem regions, showed relatively minimal or no signs of neuronal loss. Consistent with these anatomic observations, optogenetic experiments identified deficits in respiratory function that were specific to manipulations of excitatory (Dbx1/Vglut(2)) neurons in the preBotC. We conclude that the decreased number of this critical population of respiratory neurons is an important contributor to the development of irregularities in inspiratory rhythm generation in this mouse model of PD. (AU)

• Processo FAPESP: 15/23376-1 - Núcleo retrotrapezóide, quimiossensibilidade central e automaticidade respiratória
• Beneficiário: Thiago dos Santos Moreira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/09323-3 - Regulação do fluxo sanguíneo na superfície ventrolateral do bulbo em modelo animal de Doença de Parkinson
• Beneficiário: Luiz Marcelo Oliveira Santos
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 19/01236-4 - Efeitos de tratamentos farmacológicos e não farmacológicos nas alterações respiratórias observadas em um modelo murino da Doença de Parkinson
• Beneficiário: Ana Carolina Takakura Moreira
• Modalidade de apoio: Auxílio à Pesquisa - Regular