title: Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats.
abstract: Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO2/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% CO2) 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.
authors.affiliation: * Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, 1524, Prof. Lineu Prestes Avenue, 05508-900, São Paulo, SP, Brazil.    takakura@icb.usp.br.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Takakura
authors.forename: Bárbara F
authors.initials: BF
authors.lastname: Barna
authors.forename: Josiane C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Eduardo
authors.initials: E
authors.lastname: Colombari
authors.forename: Thiago S
authors.initials: TS
authors.lastname: Moreira
mesh_terms: D000758:Anesthesia; D000818:Animals; D002344:Carotid Body / Q000502:physiology; D002490:Central Nervous System / Q000502:physiology*; D003714:Denervation; D003720:Densitometry; D018398:Homeodomain Proteins / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000502:physiology*; D017933:Peripheral Nervous System / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000502:physiology; D012018:Reflex / Q000502:physiology; D012119:Respiration; D012125:Respiratory Center / Q000502:physiology; D054789:Ribosome Inactivating Proteins, Type 1 / Q000494:pharmacology; D000076985:Saporins; D011984:Sensory Receptor Cells / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; D018040:Receptors, Neurokinin-1; D054789:Ribosome Inactivating Proteins, Type 1; D014157:Transcription Factors; D013373:Substance P; D000076985:Saporins