Ultrastructural analyses of axon pathology in PHOX2b-astrocyte ablated mice

• Grant number: 18/03994-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: June 08, 2018
• End date: May 07, 2019
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Thiago dos Santos Moreira
• Grantee: Talita de Melo e Silva
• Supervisor: Jose Javier Otero
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Ohio State University, Columbus, United States

Abstract

In addition to neurons, astrocytes from ventral medullary surface are highly chemosensitive, contribute to respiratory drive and have a developmental connection with retrotrapezoid nucleus (RTN) neurons. These cells are ideally anatomically positioned, respond to decreases in inspired O2 and decreases in pH, with robust elevations in intracellular Ca2+ and vesicular release of ATP. ATP activates RTN chemoreceptor neurons, which then integrate this information with respiratory neuronal network to modify breathing patterns and adjust lung ventilation. We had reported that ultrastructural evaluation of the RTN/ parafacial respiratory group (pFRG) demonstrated that animals that underwent PHOX2B-derived astrocyte ablation showed features of neuro-axonal dystrophy in neuronal inputs to the RTN, including abnormally dilated axonal terminals, and increased percentage of axon terminals with autophagic vacuoles/phagosomes. Furthermore, selective ablation of these astrocytes also affect hypoxia-induced increase in ventilation, which raise the possibility that the O2 chemosensory response requires PHOX2B-derived astrocytes for efficient neural circuit activation of the respiratory groups. The peripheral chemoreceptors stimulate the respiratory pattern generator directly and indirectly by activating RTN via a neuronal projection from the nucleus of the solitary tract (NTS). Based on present evidences, important questions emerge: do PHOX2B-derived astrocytes ablation affect the morphology of commNTS terminals that make close appositions with RTN neurons? Astrocytes exert structural, metabolic and functional effects on neurons, therefore, could ablation PHOX2B-derived astrocytes modify autophagic mechanisms that can lead to axon degeneration and impair respiratory drive? Considering the well described commNTS inputs to RTN and the importance of these areas to the breathing control, our main aim is to better investigate the neuroanatomical, molecular and physiological role of the PHOX2B-derived astrocytes in this neural circuit and a possible relationship between astrocytes in regulation of autophagic mechanisms, that can lead to neurodegeneration and breathing impair.

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)

SILVA, TALITA M.; BORNIGER, JEREMY C.; ALVES, MICHELE JOANA; CORREA, DIEGO ALZATE; ZHAO, JING; FADDA, PAOLO; TOLAND, AMANDA EWART; TAKAKURA, ANA C.; MOREIRA, THIAGO S.; CZEISLER, CATHERINE M.; et al. Machine learning approaches reveal subtle differences in breathing and sleep fragmentation in Phox2b-derived astrocytes ablated mice. Journal of Neurophysiology, v. 125, n. 4, p. 1164-1179, APR 2021. (15/23376-1, 18/03994-0, 19/01236-4)