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

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% O), and hypercapnic (7% CO) 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.

Respiratory pattern and phrenic and hypoglossal nerve activity during normoxia and hypoxia in 6-OHDA-induced bilateral model of Parkinson’s disease

“…We can speculate that NA reduced by 28% in the brainstem could be responsible at least is some part for respiratory changes present after 6-OHDA. Substantial lesion of noradrenergic neurons of LC [46] and most of the bulbospinal catecholaminergic neurons (C1 and A5 group) resulted in blunted ventilatory response to hypoxia [50]. We observed rather tendency to increased hypoxic minute ventilation, thus this moderate depletion of NA present in our study seems to be compensated.…”

Adrenergic C1 neurons are part of the circuitry that recruits active expiration in response to hypoxia

“…Previous studies (Marina et al, 2011;Abbott et al, 2013b;Burke et al, 2014;Malheiros-Lima et al, 2017;Menuet et al, 2017;Malheiros-Lima et al, 2018b) and the present findings suggest that, in the intact adult brain, the C1 neurons recruit inspiratory and expiratory muscles in an orderly sequence that depends on the degree to which they are activated by hypoxia or by other mechanisms.…”

“…The brains were extracted, cryoprotected by overnight immersion in a 20% sucrose solution in phosphate buffered saline at 4 °C, sectioned in the coronal plane at 40 m a sliding microtome and stored in cryoprotectant solution (20% glycerol plus 30% ethylene glycol in 50 mM phosphate buffer, pH 7.4) at -20 °C until histological processing. All histochemical procedures were completed using free-floating sections according to previously described protocols (Malheiros-Lima et al, 2017, 2018b.…”

Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats

“…) (12.36 mm caudal to bregma, 2.3 mm lateral to the midline, and 8.3 mm below the dura matter) by controlled flow injection (6 nl seg −1 , syringe infusion pump, KD Scientific, Holliston, MA, USA) using a Hamilton syringe (0.5 μl) connected to an injection needle (32‐gauge, point style 3) to destroy C1 neurones (Madden & Sved ; Malheiros‐Lima et al . , b ; Andrade et al . ).…”

“…Clinically, the degree of sympathoexcitation rises abruptly as HF progresses and this correlates with increased brain levels of adrenaline and noradrenaline in HF patients (Lambert et al 1995). In addition, hyperactivation of RVLM-C1 neurones may also result in an excess glutamate release at the respiratory network (Stornetta et al 2002;Malheiros-Lima et al 2017b). (V T ) and respiratory frequency (f R ) in normoxia (F IO 2 21%) and during hypercapnic (F ICO 2 7%, balance O 2 ) stimulation of central chemoreceptors.…”