Intermittent hypoxic episodes are typically a consequence of immature respiratory control and remain a troublesome challenge for the neonatologist. Furthermore, their frequency and magnitude are underestimated by clinically employed pulse oximeter settings. In extremely low birth weight infants the incidence of intermittent hypoxia progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks 6–8. Such episodic hypoxia/reoxygenation has the potential to sustain a proinflammatory cascade with resultant multisystem morbidity. This morbidity includes retinopathy of prematurity and impaired growth, as well as possible longer-term cardiorespiratory instability and poor neurodevelopmental outcome. Therapeutic approaches for intermittent hypoxic episodes comprise determination of optimal baseline saturation and careful titration of supplemental inspired oxygen, as well as xanthine therapy to prevent apnea of prematurity. In conclusion, characterization of the pathophysiologic basis for such intermittent hypoxic episodes and their consequences during early life is necessary to provide an evidence-based approach to their management.

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...

The hypothalamic paraventricular nucleus (PVN) coordinates autonomic and neuroendocrine systems to maintain homeostasis and to respond to stress. Neuroanatomic and neurophysiologic experiments have provided insight into the mechanisms by which the PVN acts. The PVN projects directly to the spinal cord and brainstem and, specifically, to sites that control cardiorespiratory function: the intermediolateral cell columns and phrenic motor nuclei in the spinal cord and rostral ventrolateral medulla (RVLM) and the rostral nuclei in the ventral respiratory column (rVRC) in the brainstem. Activation of the PVN increases ventilation (both tidal volume and frequency) and blood pressure (both heart rate and sympathetic nerve activity). Excitatory and inhibitory neurotransmitters including glutamate and GABA converge in the PVN to influence its neuronal activity. However, a tonic GABAergic input to the PVN directly modulates excitatory outflow from the PVN. Further, even within the PVN, microinjection of GABA A receptor blockers increases glutamate release suggesting an indirect mechanism by which GABA control contributes to PVN functions. PVN activity alters blood pressure and ventilation during various stresses, such as maternal separation, chronic intermittent hypoxia (CIH), dehydration and hemorrhage. Among the several PVN neurotransmitters and neurohormones, vasopressin and oxytocin modulate ventilation and blood pressure. Here, we review our data indicating that increases in vasopressin and vasopressin type 1A (V 1A ) receptor signaling in the RVLM and rVRC are mechanisms increasing blood pressure and ventilation after exposure to CIH. That blockade of V 1A receptors in the medulla normalizes baseline blood pressure as well as blunts PVN-evoked blood pressure and ventilatory responses in CIH-conditioned animals indicate the role of vasopressin in cardiorespiratory control. In summary, morphological and functional studies have found that the PVN integrates sensory input and projects to the sympathetic and respiratory control systems with descending projections to the medulla and spinal cord. KeywordsRostral ventrolateral medulla; Intermediolateral cell column of the spinal cord; Ventilatory control; Blood pressure; Sympathetic nerve activity

A co-morbidity of sleep apnoea is hypertension associated with elevated sympathetic nerve activity (SNA) which may result from conditioning to chronic intermittent hypoxia (CIH). Our hypothesis is that SNA depends on input to the rostral ventrolateral medulla (RVLM) from neurons in the paraventricular nucleus (PVN) that release arginine vasopressin (AVP) and specifically, that increased SNA evoked by CIH depends on this excitatory input. In two sets of neuroanatomical experiments, we determined if AVP neurons project from the PVN to the RVLM and if arginine vasopressin (V 1A ) receptor expression increases in the RVLM after CIH conditioning (8 h per day for 10 days). In the first set, cholera toxin β subunit (CT-β) was microinjected into the RVLM to retrogradely label the PVN neurons. Immunohistochemical staining demonstrated that 14.6% of CT-β-labelled PVN neurons were double-labelled with AVP. In the second set, sections of the medulla were immunolabelled for V 1A receptors, and the V 1A receptor-expressing cell count was significantly greater in the RVLM (P < 0.01) and in the neighbouring rostral ventral respiratory column (rVRC) from CIH-than from room air (RA)-conditioned rats. In a series of physiological experiments, we determined if blocking V 1A receptors in the medulla would normalize blood pressure in CIH-conditioned animals and attenuate its response to disinhibition of PVN. Blood pressure (BP), heart rate (HR), diaphragm (D EMG ) and genioglossus muscle (GG EMG ) activity were recorded in anaesthetized, ventilated and vagotomized rats. The PVN was disinhibited by microinjecting a GABA A receptor antagonist, bicuculline (BIC, 0.1 nmol), before and after blocking V 1A receptors within the RVLM and rVRC with SR49059 (0.2 nmol). In RA-conditioned rats, disinhibition of the PVN increased BP, HR, minute D EMG and GG EMG activity and these increases were attenuated after blocking V 1A receptors. In CIH-conditioned rats, a significantly greater dose of blocker (0.4 nmol) was required to blunt these physiological responses (P < 0.05). Further, this dose normalized the baseline BP. In summary, AVP released by a subset of PVN neurons modulates cardiorespiratory output via V 1A receptors in the RVLM and rVRC, and increased SNA in CIH-conditioned animals depends on up-regulation of V 1A receptors in the RVLM. Abbreviations Ang II, angiotensin II; AT1, angiotensin 1 receptor; AVP, arginine vasopressin; BIC, bicuculline; CIH, chronic intermittent hypoxia; CT-β, cholera toxin β subunit; D EMG , diaphragm electromyographic recording; ET-1, endothelin 1; FITC, fluorescein isothiocyanate; GG EMG , genioglossal electromyographic recording; HO-1, haem oxygenase 1; HPA, hypothalamic pituitary axis; HR, heart rate; IML, intermediolateral; L-NAME, N G -nitro-L-arginine methyl ester; MAP, mean arterial pressure; MDA, malondialdehyde; nNOS, neuronal nitric oxide synthase; NO, Sadly Musa A. Haxhiu died before this work was published.

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This review summarizes recent work on two basic processes of central nervous system (CNS) control of cholinergic outflow to the airways: 1) transmission of bronchoconstrictive signals from the airways to the airway-related vagal preganglionic neurons (AVPNs) and 2) regulation of AVPN responses to excitatory inputs by central GABAergic inhibitory pathways. In addition, the autocrine-paracrine modulation of AVPNs is briefly discussed. CNS influences on the tracheobronchopulmonary system are transmitted via AVPNs, whose discharge depends on the balance between excitatory and inhibitory impulses that they receive. Alterations in this equilibrium may lead to dramatic functional changes. Recent findings indicate that excitatory signals arising from bronchopulmonary afferents and/or the peripheral chemosensory system activate second-order neurons within the nucleus of the solitary tract (NTS), via a glutamate-AMPA signaling pathway. These neurons, using the same neurotransmitter-receptor unit, transmit information to the AVPNs, which in turn convey the central command to airway effector organs: smooth muscle, submucosal secretory glands, and the vasculature, through intramural ganglionic neurons. The strength and duration of reflex-induced bronchoconstriction is modulated by GABAergic-inhibitory inputs and autocrine-paracrine controlling mechanisms. Downregulation of GABAergic inhibitory influences may result in a shift from inhibitory to excitatory drive that may lead to increased excitability of AVPNs, heightened airway responsiveness, and sustained narrowing of the airways. Hence a better understanding of these normal and altered central neural circuits and mechanisms could potentially improve the design of therapeutic interventions and the treatment of airway obstructive diseases.