Hypoxia Silences Retrotrapezoid Nucleus Respiratory Chemoreceptors via Alkalosis

Abstract

In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (⌬f R ) was larger in hyperoxia (65% FiO 2 ), smaller in 15% FiO 2 , and absent in 12% FiO 2 . Tidal volume changes (⌬V T ) followed the same trend. The effect of hypoxia on ⌬f R was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO 2 ). ⌬f R was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN.

Neural Control of Respiration by the Retrotrapezoid Nucleus.

“…When neonate RTN neurons are isolated in a dish their pH sensitivity remains (Wang et al, 2013c). When RTN neurons are inhibited under normoxic conditions in conscious rats both breathing frequency and tidal volume decrease showing that these neurons are necessary to the drive to breathe (Basting et al, 2015). This information in combination with their connectome provides evidence that the RTN is important in integrating many pH sensitive areas of the brain and plays an important role in the drive to breathe.…”

“…The retrotrapezoid nucleus is a small cluster of lower brainstem neurons that are activated by hypercapnia and regulate several aspects of breathing including inspiratory amplitude, breathing frequency and active expiration Guyenet, 2014a;Basting et al, 2015). The high responsiveness of RTN neurons to CO 2 in vivo is attributed to several mechanisms: an intrinsic sensitivity to protons, paracrine effects from surrounding pH/CO 2 -sensitive astrocytes and inputs from other chemosensory neurons and the carotid bodies (Guyenet et al, 2005;Gestreau et al, 2010;Gourine et al, 2010;Huckstepp & Dale, 2011;Ramanantsoa et al, 2011;Wang et al, 2013a).…”

Neurônios catecolaminérgicos do tronco encefálico participam dos ajustes respiratórios induzidos por hipóxia e hipercapnia.

“…Em conjunto, estes resultados sugerem que os neurônios C1 contribuem para os ajutes cardiovasculares promovidos pela hipóxia, e que durante a hipercapnia os neurônios C1 não parecem exercer uma influencia direta sobre o controle cardiovascular (Wenker et al, 2017). A hipótese mais plausível para explicar a reversão dos ajustes cardiovasculares induzidos pela hipóxia após a adição de CO2 propõe que o aumento da respiração promovido pelo CO2 decorreria de uma redução na hipoxemia arterial, o que possibilitaria a ativação dos neurônios do RTN, os quais são inibidos por alcalose (Basting et al, 2015). Tal resposta, faria com o estímulo hipóxico fosse menos intenso, reduzindo a ativação dos corspúsculos carotídeos e, consequentemente, a discarga dos neurônios C1 (Basting et al, 2015;Wenker et al, 2017).…”

“…A hipótese mais plausível para explicar a reversão dos ajustes cardiovasculares induzidos pela hipóxia após a adição de CO2 propõe que o aumento da respiração promovido pelo CO2 decorreria de uma redução na hipoxemia arterial, o que possibilitaria a ativação dos neurônios do RTN, os quais são inibidos por alcalose (Basting et al, 2015). Tal resposta, faria com o estímulo hipóxico fosse menos intenso, reduzindo a ativação dos corspúsculos carotídeos e, consequentemente, a discarga dos neurônios C1 (Basting et al, 2015;Wenker et al, 2017). No entanto, embora vários avanços tenham sido realizados no estudo da contribuição dos neurônios C1 para o controle tônico e reflexo da pressão arterial, não foram encontrados estudos que avaliaram os efeitos promovidos pela depleção dos neurônios C1, por meio de injeções da toxina anti-DH-SAP no RVLM e na medula espinal, sobre os ajustes cardiovasculares promovidos pela hipóxia e a hipercapnia, sendo um dos objetivos do presente estudo.…”

Interação entre o grupamento parafacial/núcleo retrotrapezóide e a região de kölliker-fuse na modulação do padrão respiratório.

“…Dessa maneira, gostaríamos de classificar a região do pFRG/RTN não somente como uma região do encéfalo que contém neurônios quimiossensíveis (MULKEY et al, 2004;TAKAKURA et al, 2006TAKAKURA et al, , 2008TAKAKURA et al, , 2014, mas uma região crucial para a manutenção do padrão respiratório eupneico (ABBOTT et al, 2013;BASTING et al, 2015;HUCKSTEPP et al, 2015;MARINA et al, 2010) (Fig. 17).…”