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New Findings r What is the central question of this study?This study was designed to investigate whether the Phox2b-expressing neurons in the retrotrapezoid nucleus are important to breathing and chemoreflexes in conscious rats. r What is the main finding and its importance?The high rate of destruction of a defined cell population (Phox2b + TH − ) of the retrotrapezoid nucleus by the toxin suggests that the specialized connectivity of retrotrapezoid nucleus neurons, their glutamatergic nature and their relatively high sensitivity to CO 2 are determinant factors in explaining their large contribution to the central and peripheral chemoreflexes.Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO 2 /H + . A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of Phox2b-expressing glutamatergic neurons that appear to function as important chemoreceptors. In the present study, we ask whether the destruction of a type of pH-sensitive interneuron that expresses the transcription factor Phox2b and is non-catecholaminergic (Phox2b + TH − ) could affect breathing in conscious adult rats. The injection of substance P (1 nmol in a volume of 50 nl) into the RTN increased respiratory frequency, tidal volume, minute ventilation and mean arterial pressure. Bilateral injections of the toxin substance P conjugated with saporin (SSP-SAP) into the RTN destroyed Phox2b + TH − neurons but spared facial motoneurons, catecholaminergic and serotonergic neurons and the ventral respiratory column caudal to the facial motor nucleus. Bilateral inhibition of RTN neurons with SSP-SAP (0.6 ng in 30 nl) reduced resting ventilation and the increase in ventilation produced by hypercapnia (7% CO 2 ) in conscious rats with or without peripheral chemoreceptors. In anaesthetized rats with bilateral lesions of around 90% of the Phox2b + TH − neurons, acute activation of the Bötzinger complex, the pre-Bötzinger complex or the rostral ventral respiratory group with NMDA (5 pmol in 50 nl) elicited normal cardiorespiratory output. In conclusion, the destruction of the Phox2b + TH − neurons is a plausible cause of the respiratory deficits observed after injection of SSP-SAP into the RTN. Our results also suggest that RTN neurons activate facilitatory mechanisms important to the control of breathing in resting or hypercapnic conditions in conscious adult rats.

The retrotrapezoid nucleus (RTN) contains chemosensitive cells that distribute CO2-dependent excitatory drive to the respiratory network. This drive facilitates the function of the respiratory central pattern generator (rCPG) and increases sympathetic activity. It is also evidenced that during hypercapnia, the late-expiratory (late-E) oscillator in the parafacial respiratory group (pFRG) is activated and determine the emergence of active expiration. However, it remains unclear the microcircuitry responsible for the distribution of the excitatory signals to the pFRG and the rCPG in conditions of high CO2. Herein, we hypothesized that excitatory inputs from chemosensitive neurons in the RTN are necessary for the activation of late-E neurons in the pFRG. Using the decerebrated in situ rat preparation, we found that lesions of neurokinin-1 receptor (NK1R)-expressing neurons in the RTN region with substance P-saporin conjugate (SSP-SAP) suppressed the late-E activity in abdominal (AbN) and sympathetic (SN) nerves, and attenuated the increase in phrenic nerve (PN) activity induced by hypercapnia. On the other hand, kynurenic acid (100 mM) injections in the pFRG eliminated the late-E activity in AbN and tSN, but did not modify PN response during hypercapnia. Iontophoretic injections of retrograde tracer into the pFRG of adult rats revealed labeled phox2b-expressing neurons within the RTN. Our findings are supported by mathematical modeling of chemosensitive and late-E populations within the RTN and pFRG regions as two separate but interacting populations, in a way that the activation of the pFRG late-E neurons during hypercapnia requires glutamatergic inputs from the RTN neurons that intrinsically detect changes in CO2/pH.

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Patients with Parkinson's disease (PD) exhibit both motor and non-motor symptoms. Among the non-motor symptoms, cardiovascular autonomic dysfunction is frequently observed. Here, we evaluated baroreflex function, vascular reactivity and neuroanatomical changes in brainstem regions involved in the neural control of circulation in the 6-hydroxydopamine (6-OHDA) model of PD. Male Wistar rats received a bilateral injection of 6-OHDA or vehicle into the striatum. After 61days, baroreflex function and vascular reactivity were assessed. The 6-OHDA and vehicle groups showed similar increases in mean arterial pressure (MAP) in response to phenylephrine (PE). However, the bradycardia observed in the vehicle group was blunted in the 6-OHDA-treated rats. Injection of sodium nitroprusside (SNP) decreased hypotension, tachycardia and vascular relaxation in 6-OHDA-treated rats. Bilateral intrastriatal 6-OHDA led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus of the solitary tract (NTS). 6-OHDA-treated rats also showed decreases in Phox2b-expressing neurons in the NTS and in choline acetyltransferase (ChAT) immunoreactivity in the nucleus ambiguus. Altogether, our data suggest that this model of PD includes neuroanatomical and functional changes that lead to cardiovascular impairment.