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.

stimulates breathing via medullary and spinal pathways. J Appl Physiol 98: 1387-1395, 2005. First published November 19, 2004 doi:10.1152/japplphysiol.00914.2004.-A central neuronal network that regulates respiration may include hypothalamic neurons that produce orexin, a peptide that influences sleep and arousal. In these experiments, we investigated 1) projections of orexin-containing neurons to the pre-Bötzinger region of the rostral ventrolateral medulla that regulates rhythmic breathing and to phrenic motoneurons that innervate the diaphragm; 2) the presence of orexin A receptors in the pre-Bötzinger region and in phrenic motoneurons; and 3) physiological effects of orexin administered into the pre-Bötzinger region and phrenic nuclei at the C3-C4 levels. We found orexin-containing fibers within the pre-Bötzinger complex. However, only 0.5% of orexincontaining neurons projected to the pre-Bötzinger region, whereas 2.9% of orexin-containing neurons innervated the phrenic nucleus. Neurons of the pre-Bötzinger region and phrenic nucleus stained for orexin receptors, and activation of orexin receptors by microperfusion of orexin in either site produced a dose-dependent, significant (P Ͻ 0.05) increase in diaphragm electromyographic activity. These data indicate that orexin regulates respiratory activity and may have a role in the pathophysiology of sleep-related respiratory disorders.hypothalamus; pre-Bötzinger region; phrenic motor neurons; orexin-1 receptors; sleep apnea BREATHING IS AN ACTIVE NEURALLY controlled process that is regulated by neural mechanisms that adjust respiratory-related drive to the behavioral state and to the metabolic demands of an organism. Hypothalamic neurons are part of this controlling system and play an important role in the regulation of breathing rate and depth (14,26).Neurons in the lateral hypothalamus synthesize orexin A and orexin B, also called hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2). These peptide neurotransmitters are processed from a common precursor, prepro-orexin, encoded by a gene localized to human chromosome 17q2. Orexin-containing neurons affect autonomic, neuroendocrine, and sleep-wakefulness neuroregulatory systems that in turn could potentially influence breathing (9,13,16,19).The orexins stimulate target cells via two orexin G proteincoupled receptors, orexin R1 and orexin R2 (40). It has been proposed that orexin-containing neurons promote wakefulness by excitation of cholinergic neurons in the basal forebrain, which release acetylcholine and thereby contribute to the cortical activation of wakefulness. However, the causality of these associations remains to be determined because wakefulness is often accompanied by behavioral activation. Suppression of rapid eye movement sleep occurs through an inhibition of the cholinergic neurons in the laterodorsal tegmental and pedunculopontine nuclei (49).In the central nervous system, orexin-containing neurons innervate multiple sites, including cell groups in the brain stem and spinal cord that are involved in t...

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Previously we reported that oxytocin (OT)-containing neurons of the hypothalamic paraventricular nucleus (PVN) project to the preBötzinger complex (preBötC) region and phrenic motoneurons innervating the diaphragm (D). The aim of these studies was to determine pathways involved in PVN stimulation-induced changes in upper airway and chest wall pumping muscle activity. In addition, we determined the role of OT-containing neurons in the PVN in mediating increased respiratory output elicited by PVN stimulation. Neuroanatomical experiments, using pseudorabies virus (PRV) as a transneuronal tracer in C8 spinalectomized animals showed that PVN neurons project to hypoglossal motoneurons innervating the genioglossus (GG) muscle. Furthermore, microinjection of the PVN with bicuculline, a GABA A receptor antagonist, significantly increased (P<0.05) peak electromyographic activity of GG (GG EMG ) and of D EMG , frequency discharge, and arterial blood pressure (BP) and heart rate. Prior injection of oxytocin antagonist [d-(CH2)5, Tyr(Me)2,Orn8]-vasotocin(OVT) intracisternally or blockade of oxytocin receptors in the preBötC region with oxytocin antagonist L-368,899, diminished GG EMG and D EMG responses and blunted the increase in BP and heart rate to PVN stimulation. These data show that PVN stimulation affects central regulatory mechanisms via the preBötC region controlling both respiratory and cardiovascular functions. The parallel changes induced by PVN stimulation were mediated mainly through an OT-OT receptor signaling pathway.

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