Barnett WH, Molkov YI, Lemes E, Falqueto B, Colombari E, Takakura AT, Moreira TS, Zoccal DB (2017) Local glutamatergic transmission in the RTN/pFRG is critical for active expiration and sympathetic overactivity during hypercapnia. Neuroscience 2017 Abstracts 233.1 / FF22. Society for Neuroscience, Washington, DC.
Summary: The retrotrapezoid nucleus (RTN) contains chemosensitive cells that distribute CO -dependent excitatory drive to the brainstem respiratory network. This drive facilitates the function of the respiratory central pattern generator (CPG), modulates sympathetic activity and determines the emergence of active expiration during hypercapnia via activation of the late expiratory (late-E) oscillator in the parafacial respiratory group (pFRG). However, the microcircuitry responsible for distribution of the chemoreflex signal to the pFRG and the respiratory CPG is not well understood. Previously, we developed a computational model of the brainstem respiratory network, which was subsequently extended to include the central and peripheral chemoreflexes as well as presympathetic circuits. We present here experiments performed on the decerebrated, arterially-perfused in situ rat, aimed to test a key assumption of this model that chemosensitive and late-E neurons in the RTN/pFRG are two distinct populations, and the latter receives local glutamatergic input from the former. The model predicts: (1) suppression of RTN chemosensitive neurons will diminish the changes to the respiratory pattern and the emergence of active expiration associated with hypercapnia; (2) the disruption of local glutamatergic neurotransmission in the RTN will specifically suppress active expiration and the appearance of late-E discharges in the sympathetic motor output. To test prediction (1) we lesioned NK1 -positive chemosensitive neurons of the RTN with microinjections of substance P-saporin (SSP-SAP) conjugate. This suppressed the emergence of late-E activity in abdominal (AbN) and sympathetic nerves, and attenuated the increase in phrenic burst amplitude during hypercapnia. However, SSP-SAP and control animals exhibited late-E AbN activity in response to peripheral chemoreflex activation. Prediction (2) was tested with bilateral microinjections of kynurenic acid (Kyn, 100 mM) in the RTN/pFRG, which suppressed the emergence of late-E AbN activity but not the change in phrenic nerve amplitude during hypercapnia. Our results support the notion that RTN chemosensitive neurons are critical for inspiratory and expiratory reflex responses to hypercapnia. Our findings indicate that activation of late-E neurons in the pFRG during hypercapnia requires glutamatergic inputs from a separate neuronal population in the RTN that intrinsically detects changes in CO . During peripheral chemoreflex stimulation, pFRG late-E neurons are activated via excitatory pathways bypassing the RTN central chemoreceptors. We recapitulate these results in our computational model.
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