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Impaired chemosensory control of breathing after depletion of bulbospinal catecholaminergic neurons in rats

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Abstract

Bulbospinal catecholaminergic neurons located in the rostral aspect of the ventrolateral medulla (C1 neurons) or within the ventrolateral pons (A5 neurons) are involved in the regulation of blood pressure and sympathetic outflow. A stimulus that commonly activates the C1 or A5 neurons is hypoxia, which is also involved in breathing activation. Although pharmacological and optogenetic evidence suggests that catecholaminergic neurons also regulate breathing, a specific contribution of the bulbospinal neurons to respiratory control has not been demonstrated. Therefore, in the present study, we evaluated whether the loss of bulbospinal catecholaminergic C1 and A5 cells affects cardiorespiratory control during resting, hypoxic (8% O2), and hypercapnic (7% CO2) conditions in unanesthetized rats. Thoracic spinal cord (T4-T8) injections of the immunotoxin anti-dopamine β-hydroxylase-saporin (anti-DβH-SAP—2.4 ng/100 nl) and the retrograde tracer Fluor-Gold or ventrolateral pontine injections of 6-OHDA were performed in adult male Wistar rats (250–280 g, N = 7–9/group). Anti-DβH-SAP or 6-OHDA eliminated most bulbospinal C1 and A5 neurons or A5 neurons, respectively. Serotonergic neurons and astrocytes were spared. Depletion of the bulbospinal catecholaminergic cells did not change cardiorespiratory variables under resting condition, but it did affect the response to hypoxia and hypercapnia. Specifically, the increase in the ventilation, the number of sighs, and the tachycardia were reduced, but the MAP increased during hypoxia in anti-DβH-SAP-treated rats. Our data reveal that the bulbospinal catecholaminergic neurons (A5 and C1) facilitate the ventilatory reflex to hypoxia and hypercapnia.

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Acknowledgements

This work was supported by the São Paulo Research Foundation (FAPESP; grants: 2014/22406-1 to ACT; 2015/23376-1 to TSM) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; grant: 471263/2013-3 to ACT and 471283/2012-6 to TSM). FAPESP fellowship (2014/07698-6 to MRML) and CNPq fellowship (301219/2016-8 to ACT and 301904/2015-4 to TSM).

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  1. Department of Physiology and Biophysics, Institute of Biomedical Science, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, SP, 05508-000, Brazil

    Milene R. Malheiros-Lima, Leonardo T. Totola & Thiago S. Moreira

  2. Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, SP, 05508-000, Brazil

    Ana C. Takakura

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  1. Milene R. Malheiros-Lima
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  2. Leonardo T. Totola
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  3. Ana C. Takakura
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  4. Thiago S. Moreira
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MRML, ACT, and TSM designed the research; MRML and LTT performed the research; MRML, LTT, and TSM analyzed the data; and MRML, ACT, and TSM wrote the paper.

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Correspondence to Thiago S. Moreira.

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Malheiros-Lima, M.R., Totola, L.T., Takakura, A.C. et al. Impaired chemosensory control of breathing after depletion of bulbospinal catecholaminergic neurons in rats. Pflugers Arch - Eur J Physiol 470, 277–293 (2018). https://doi.org/10.1007/s00424-017-2078-8

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