Paraventricular oxytocin neurons are involved in neural modulation of breathing.

In this study, we determined the projections of oxytocin-containing neurons of the paraventricular nucleus (PVN) to phrenic nuclei and to the rostral ventrolateral medullary (RVLM) region, which is known to be involved in respiratory rhythm generation. Studies were also designed to determine oxytocin-receptor expression within the RVLM and the physiological effects of their activation on respiratory drive and arterial blood pressure. Oxytocin immunohistochemistry combined with cholera toxin B, a retrograde tracer, showed that a subpopulation of oxytocin-containing parvocellular neurons in the dorsal and medial ventral regions of the PVN projects to phrenic nuclei. Similarly, a subpopulation of pseudorabies virus-labeled neurons in the PVN coexpressed oxytocin after injection of pseudorabies virus, a transynaptic retrograde marker, into the costal region of the diaphragm. A subpopulation of oxytocin expressing neurons was also found to project to the RVLM. Activation of this site by microinjection of oxytocin into the RVLM (0.2 nmol/200 nl) significantly increased diaphragm electromyographic activity and frequency discharge (P < 0.05). In addition, oxytocin increased blood pressure and heart rate (P < 0.05). These data indicate that oxytocin participates in the regulation of respiratory and cardiovascular activity, partly via projections to the RVLM and phrenic nuclei.

[1]  E. Badoer.  Hypothalamic paraventricular nucleus and cardiovascular regulation. , 2001, Clinical and experimental pharmacology & physiology.

[2]  M. Raggenbass,et al.  Vasopressin receptors of the vasopressor (V1) type in the nucleus of the solitary tract of the rat mediate direct neuronal excitation , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  E. Badoer.  Proceedings of the Australian Physiological and Pharmacological Society Symposium: The Hypothalamus HYPOTHALAMIC PARAVENTRICULAR NUCLEUS AND CARDIOVASCULAR REGULATION , 2001 .

[4]  P. Ernsberger,et al.  Differential cardiorespiratory control elicited by activation of ventral medullary sites in mice. , 2000, Journal of applied physiology.

[5]  M. Palkovits.  Interconnections between the Neuroendocrine Hypothalamus and the Central Autonomic System Geoffrey Harris Memorial Lecture, Kitakyushu, Japan, October 1998 , 1999, Frontiers in Neuroendocrinology.

[6]  J. Santiago,et al.  Leptin concentrations in Prader‐Willi syndrome before and after growth hormone replacement , 2000, Clinical endocrinology.

[7]  M. Callahan,et al.  Central Oxytocin Mediates Stress‐Induced Tachycardia , 1995, Journal of neuroendocrinology.

[8]  P. L. Smith,et al.  Leptin, obesity, and respiratory function. , 2000, Respiration physiology.

[9]  B. Sessle,et al.  Vasopressin and oxytocin express excitatory effects on respiratory and respiration-related neurones in the nuclei of the tractus solitarius in the cat , 1989, Brain Research.

[10]  Huiqing Lu,et al.  Leptin-induced increase in sympathetic nervous and cardiovascular tone is mediated by proopiomelanocortin (POMC) products , 1999, Brain Research Bulletin.

[11]  R. Buijs,et al.  Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat , 1978, Cell and Tissue Research.

[12]  K. D. Cliffer,et al.  Evidence that Fluoro-Gold can be transported avidly through fibers of passage , 1990, Brain Research.

[13]  N. Yanaihara,et al.  Actions of vasopressin, gastrin releasing peptide and other peptides on neurons of newborn rat spinal cord in vitro , 1981, Neuroscience Letters.

[14]  D. Mutolo,et al.  Area postrema glutamate receptors mediate respiratory and gastric responses in the rabbit , 1998, Neuroreport.

[15]  M. Forsling,et al.  Vasopressin and oxytocin release during prolonged environmental hypoxia in the rat. , 1997, Thorax.

[16]  G. Gimpl,et al.  The oxytocin receptor system: structure, function, and regulation. , 2001, Physiological reviews.

[17]  M. Raggenbass,et al.  Morphological and electrophysiological evidence for postsynaptic localization of functional oxytocin receptors in the rat dorsal motor nucleus of the vagus nerve , 1992, Brain Research.

[18]  M. Haxhiu,et al.  CNS innervation of vagal preganglionic neurons controlling peripheral airways: a transneuronal labeling study using pseudorabies virus. , 1999, Journal of the autonomic nervous system.

[19]  C. Helke,et al.  Enkephalin‐immunoreactive neuronal projections from the medulla oblongata to the intermediolateral cell column: Relationship to substance P–immunoreactive neurons , 1989, The Journal of comparative neurology.

[20]  M. Sofroniew.  Morphology of vasopressin and oxytocin neurones and their central and vascular projections. , 1983, Progress in brain research.

[21]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[22]  D. Swaab,et al.  Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat , 1978, Cell and Tissue Research.

[23]  J. Coote.  Cardiovascular function of the paraventricular nucleus of the hypothalamus. , 1995, Biological signals.

[24]  D F Swaab,et al.  Prader—Willi syndrome and the hypothalamus , 1997, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[25]  J. C. Smith,et al.  Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. , 1991, Science.

[26]  G. Fontana,et al.  Respiratory responses to electrical and chemical stimulation of the area postrema in the rabbit. , 1993, The Journal of physiology.

[27]  A. Menendez.  Abnormal ventilatory responses in patients with Prader-Willi syndrome , 1999, European Journal of Pediatrics.

[28]  D. Larhammar,et al.  Neuropeptide expression in rat paraventricular hypothalamic neurons that project to the spinal cord , 2001, The Journal of comparative neurology.

[29]  P. Jones,et al.  Release of oxytocin into blood and cerebrospinal fluid by electrical stimulation of the hypothalamus or neural lobe in the rat. , 1983, Neuroendocrinology.

[30]  W. Mitzner,et al.  Leptin attenuates respiratory complications associated with the obese phenotype. , 1998, Journal of applied physiology.

[31]  R. Arens,et al.  Hypercapnic arousal responses in Prader-Willi syndrome. , 1995, Chest.

[32]  M. Tohyama,et al.  Localization of oxytocin receptor messenger ribonucleic acid in the rat brain. , 1993, Endocrinology.

[33]  K. Mori,et al.  Structure and expression of a human oxytocin receptor , 1992, Nature.

[34]  J. Feldman,et al.  Modulation of respiratory frequency by peptidergic input to rhythmogenic neurons in the preBötzinger complex. , 1999, Science.

[35]  J. Ciriello,et al.  Role of paraventricular and supraoptic nuclei in central cardiovascular regulation in the cat. , 1980, The American journal of physiology.

[36]  J. LaManna,et al.  The paraventricular nucleus of the hypothalamus influences respiratory timing and activity in the rat , 1997, Neuroscience Letters.

[37]  Jere H. Mitchell,et al.  Identification of hypothalamic vasopressin and oxytocin neurons activated during the exercise pressor reflex in cats , 1997, Brain Research.

[38]  B. Erokwu,et al.  CNS innervation of posterior cricoarytenoid muscles: a transneuronal labeling study. , 2001, Respiration physiology.

[39]  H. Kuypers,et al.  The paraventricular nucleus of the hypothalamus: Cytoarchitectonic subdivisions and organization of projections to the pituitary, dorsal vagal complex, and spinal cord as demonstrated by retrograde fluorescence double‐labeling methods , 1980, The Journal of comparative neurology.

[40]  E. Ling,et al.  Hypobaric hypoxia induces Fos and neuronal nitric oxide synthase expression in the paraventricular and supraoptic nucleus in rats , 2000, Neuroscience Letters.

[41]  L. Swanson,et al.  Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat , 1982, The Journal of comparative neurology.

[42]  Y. Jo,et al.  Oxytocin Modulates Glutamatergic Synaptic Transmission between Cultured Neonatal Spinal Cord Dorsal Horn Neurons , 1998, The Journal of Neuroscience.

[43]  D. Swaab,et al.  Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases. , 1995, The Journal of clinical endocrinology and metabolism.

[44]  N. Cherniack,et al.  CO2-induced c-fos expression in the CNS catecholaminergic neurons. , 1996, Respiration physiology.

[45]  A. Loewy,et al.  Viruses as Transneuronal Tracers for Defining Neural Circuits , 1998, Neuroscience & Biobehavioral Reviews.

[46]  G. York,et al.  Congenital and Acquired Cognitive Disorders , 1981, Neurology.

[47]  E. Schlenker,et al.  Cardiorespiratory and metabolic responses to injection of bicuculline into the hypothalamic paraventricular nucleus (PVN) of conscious rats , 2001, Brain Research.

[48]  T. Waldrop,et al.  Responses of feline caudal hypothalamic cardiorespiratory neurons to hypoxia and hypercapnia , 2004, Experimental Brain Research.

[49]  J. C. Finley,et al.  The central organization of carotid body afferent projections to the brainstem of the rat , 1992, Brain Research.

[50]  L. Swanson,et al.  Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms. , 1980, Neuroendocrinology.

[51]  A. Loewy,et al.  CNS innervation of airway-related parasympathetic preganglionic neurons: a transneuronal labeling study using pseudorabies virus , 1993, Brain Research.