The Locus coeruleus (LC) has been suggested as a CO(2) chemoreceptor site in mammals. In the present study, we assessed the role of LC noradrenergic neurons in the cardiorespiratory and thermal responses to hypercapnia. To selectively destroy LC noradrenergic neurons, we administered 6-hydroxydopamine (6-OHDA) bilaterally into the LC of male Wistar rats. Control animals had vehicle (ascorbic acid) injected (sham group) into the LC. Pulmonary ventilation (plethysmograph), mean arterial pressure (MAP), heart rate (HR), and body core temperature (T (c), data loggers) were measured followed by 60 min of hypercapnic exposure (7% CO(2) in air). To verify the correct placement and effectiveness of the chemical lesions, tyrosine hydroxylase immunoreactivity was performed. Hypercapnia caused an increase in pulmonary ventilation in all groups, which resulted from increases in respiratory frequency and tidal volume (V (T)) in sham-operated and 6-OHDA-lesioned groups. The hypercapnic ventilatory response was significantly decreased in 6-OHDA-lesioned rats compared with sham group. This difference was due to a decreased V (T) in 6-OHDA rats. LC chemical lesion or hypercapnia did not affect MAP, HR, and T (c). Thus, we conclude that LC noradrenergic neurons modulate hypercapnic ventilatory response but play no role in cardiovascular and thermal regulation under resting conditions.

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The lateral parafacial region (pF L ; which encompasses the parafacial respiratory group, pFRG) is a conditional oscillator that drives active expiration during periods of high respiratory demand, and increases ventilation through the recruitment of expiratory muscles. The pF L activity is highly modulated, and systematic analysis of its afferent projections is required to understand its connectivity and modulatory control. We combined a viral retrograde tracing approach to map direct brainstem projections to the putative location of pF L , with RNAScope and immunofluorescence to identify the neurochemical phenotype of the projecting neurons. Within the medulla, retrogradely-labeled, glutamatergic, glycinergic and GABAergic neurons were found in the ventral respiratory column (Bötzinger and preBötzinger Complex [preBötC], ventral respiratory group, ventral parafacial region [pF V ] and pF L), nucleus of the solitary tract (NTS), reticular formation (RF), pontine and midbrain vestibular nuclei, and medullary raphe. In the pons and midbrain, retrogradely-labeled neurons of the same phenotypes were found in the Kölliker-Fuse and parabrachial nuclei, periaqueductal gray, pedunculopontine nucleus (PPT) and laterodorsal tegmentum (LDT). We also identified somatostatin-expressing neurons in the preBötC and PHOX2B immunopositive cells in the pF V , NTS, and part of the RF. Surprisingly, we found no catecholaminergic neurons in the NTS, A5 or Locus Coeruleus, no serotoninergic raphe neurons nor any cholinergic neurons in the PPT and LDT that projected to the pF L. Our results indicate that pF L neurons receive extensive excitatory and inhibitory inputs from several respiratory and nonrespiratory related brainstem regions that could contribute to the complex modulation of the conditional pF L oscillator for active expiration.