Respiratory Control Network Research Articles

Noradrenergic tuning, not simple rate effects, produces temperature‐sensitivity of the respiratory network in bullfrogs

Animals match ventilation to metabolic and acid‐base regulatory demands during changes in body temperature. Across vertebrates, ventilation increases at warmer temperatures and decreases at cooler temperatures. At the organismal level this is attributed to metabolic feedback and/or alpha‐stat pH regulation; however, the cellular mechanisms that produce ventilatory output in response to brain temperature changes remain unclear. To identity mechanisms underlying temperature‐sensitivity of the respiratory control network, we used brainstem‐spinal cord preparations producing spontaneously active, rhythmic motor output similar to breathing in vivo of adult bullfrogs Lithobates catesbeianus. In vitro brainstem‐spinal cords were superfused with artificial cerebrospinal fluid (aCSF) equilibrated at 90% O2, 1.3% CO2, and balance N2. Whole nerve recordings from the trigeminal (V) and vagus (X) nerves were used for measuring respiratory‐related activity. We applied temperature ramps from 20°C to 15°C and then to 25°C; each step lasted 15 minutes. Bursting frequency was analyzed for the last 5 minutes of each step and then normalized to percent of baseline (20°C). Consistent with in vivo and in vitro data (Bícego‐Nahas and Branco, 1999; Morales and Hedrick, 2002), we demonstrate that the frequency of respiratory‐related nerve activity is stable across high temperatures, but not lower temperatures (One‐way ANOVA p=0.0013; percent of baseline significantly lower at 15°C compared to 20°C and compared to 25°C, but no difference between 20°C and 25°C; Tukey's Multiple Comparison Test). The locus coeruleus (LC) is a nucleus of the respiratory network and is the main supplier of norepinephrine in the brain. LC neurons from bullfrogs are paradoxically activated by decreases in temperature (Santin et al., 2013) suggesting that firing frequencies inversely proportional to temperature may play a role in setting the respiratory frequency across temperatures. To identify the role of norepinephrine in generating the respiratory frequency, we applied the temperature protocol while blocking the main adrenergic receptors (AR). For blocking α1AR, preparations were superfused with aCSF containing Prazosin and for blocking α2AR we used RX821002. We found that bursting stability at high temperatures is disrupted when α1AR are blocked (One‐way ANOVA p=0.0011; percent of baseline significantly lower at 15°C compared to 20°C and 25°C, and percent of baseline significantly lower at 20°C compared to 25°C; Tukey's Multiple Comparison Test). In contrast, the inhibition of bursting frequency at 15°C was lost when α2AR were blocked (One‐way ANOVA p=0.1649; percent of baseline not different at 15°C, 20°C and 25°C). These results imply that norepinephrine tuning through different receptors, rather than simple Q10 effects, plays a major role in generating the breathing frequency across temperatures to match metabolic demands and acid‐base regulation requirements at those temperatures.Support or Funding InformationSupport for this project was provided by the Department of Biological Sciences at Wright State University as well as a Biology Award for Research Excellence and a Graduate Student Assembly Original Research Grant (both to M.V.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Ventilation and neurochemical changes during µ-opioid receptor activation or blockade of excitatory receptors in the hypoglossal motor nucleus of goats.

Neuromodulator interdependence posits that changes in one or more neuromodulators are compensated by changes in other modulators to maintain stability in the respiratory control network. Herein, we studied compensatory neuromodulation in the hypoglossal motor nucleus (HMN) after chronic implantation of microtubules unilaterally ( n = 5) or bilaterally ( n = 5) into the HMN. After recovery, receptor agonists or antagonists in mock cerebrospinal fluid (mCSF) were dialyzed during the awake and non-rapid eye movement (NREM) sleep states. During day studies, dialysis of the µ-opioid inhibitory receptor agonist [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO; 100 µM) decreased pulmonary ventilation (V̇i), breathing frequency ( f), and genioglossus (GG) muscle activity but did not alter neuromodulators measured in the effluent mCSF. However, neither unilateral dialysis of a broad spectrum muscarinic receptor antagonist (atropine; 50 mM) nor unilateral or bilateral dialysis of a mixture of excitatory receptor antagonists altered V̇i or GG activity, but all of these did increase HMN serotonin (5-HT) levels. Finally, during night studies, DAMGO and excitatory receptor antagonist decreased ventilatory variables during NREM sleep but not during wakefulness. These findings contrast with previous dialysis studies in the ventral respiratory column (VRC) where unilateral DAMGO or atropine dialysis had no effects on breathing and bilateral DAMGO or unilateral atropine increased V̇i and f and decreased GABA or increased 5-HT, respectively. Thus we conclude that the mechanisms of compensatory neuromodulation are less robust in the HMN than in the VRC under physiological conditions in adult goats, possibly because of site differences in the underlying mechanisms governing neuromodulator release and consequently neuronal activity, and/or responsiveness of receptors to compensatory neuromodulators. NEW & NOTEWORTHY Activation of inhibitory µ-opioid receptors in the hypoglossal motor nucleus decreased ventilation under physiological conditions and did not affect neurochemicals in effluent dialyzed mock cerebral spinal fluid. These findings contrast with studies in the ventral respiratory column where unilateral [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) had no effects on ventilation and bilateral DAMGO or unilateral atropine increased ventilation and decreased GABA or increased serotonin, respectively. Our data support the hypothesis that mechanisms that govern local compensatory neuromodulation within the brain stem are site specific under physiological conditions.

Respiratory muscle dysfunction in animal models of hypoxic disease: antioxidant therapy goes from strength to strength.

The striated muscles of breathing play a critical role in respiratory homeostasis governing blood oxygenation and pH regulation. Upper airway dilator and thoracic pump muscles retain a remarkable capacity for plasticity throughout life, both in health and disease states. Hypoxia, whatever the cause, is a potent driver of respiratory muscle remodeling with evidence of adaptive and maladaptive outcomes for system performance. The pattern, duration, and intensity of hypoxia are key determinants of respiratory muscle structural-, metabolic-, and functional responses and adaptation. Age and sex also influence respiratory muscle tolerance of hypoxia. Redox stress emerges as the principal protagonist driving respiratory muscle malady in rodent models of hypoxic disease. There is a growing body of evidence demonstrating that antioxidant intervention alleviates hypoxia-induced respiratory muscle dysfunction, and that N-acetyl cysteine, approved for use in humans, is highly effective in preventing hypoxia-induced respiratory muscle weakness and fatigue. We posit that oxygen homeostasis is a key driver of respiratory muscle form and function. Hypoxic stress is likely a major contributor to respiratory muscle malaise in diseases of the lungs and respiratory control network. Animal studies provide an evidence base in strong support of the need to explore adjunctive antioxidant therapies for muscle dysfunction in human respiratory disease.

Engineering a solution to explore the cardiorespiratory limits to exercise performance: take a load off!

Engineering a solution to explore the cardiorespiratory limits to exercise performance: take a load off!

Anatomical and functional connections between the locus coeruleus and the nucleus tractus solitarius in neonatal rats

This study was designed to investigate brain connections among chemosensitive areas in newborn rats. Rhodamine beads were injected unilaterally into the locus coeruleus (LC) or into the caudal part of the nucleus tractus solitarius (cNTS) in Sprague–Dawley rat pups (P7–P10). Rhodamine-labeled neurons were patched in brainstem slices to study their electrophysiological responses to hypercapnia and to determine if chemosensitive neurons are communicating between LC and cNTS regions. After 7–10days, retrograde labeling was observed in numerous areas of the brainstem, including many chemosensitive regions, such as the contralateral LC, cNTS and medullary raphe. Whole-cell patch clamp was done in cNTS. In 4 of 5 retrogradely labeled cNTS neurons that projected to the LC, firing rate increased in response to hypercapnic acidosis (15% CO2), even in synaptic blockade medium (SNB) (high Mg2+/low Ca2+). In contrast, 2 of 3 retrogradely labeled LC neurons that projected to cNTS had reduced firing rate in response to hypercapnic acidosis, both in the presence and absence of SNB. Extensive anatomical connections among chemosensitive brainstem regions in newborn rats were found and at least for the LC and cNTS, the connections involve some CO2-sensitive neurons. Such anatomical and functional coupling suggests a complex central respiratory control network, such as seen in adult rats, is already largely present in neonatal rats by at least day P7–P10. Since the NTS and the LC play a major role in memory consolidation, our results may also contribute to the understanding of the development of memory consolidation.

Blast from the past! Phrenic motor memory of antecedent episodic hypercapnia is serotonin dependent: relevance to respiratory rehabilitation and sleep-disordered breathing?

Blast from the past! Phrenic motor memory of antecedent episodic hypercapnia is serotonin dependent: relevance to respiratory rehabilitation and sleep-disordered breathing?

Imaging the Respiratory Effects of Opioids in the Human Brain.

Opioid analgesia is limited by the potentially fatal side effect of respiratory depression. In humans the brain mechanisms of opioid-induced respiratory depression are poorly understood. Investigating pharmacological influences upon breathing helps us to understand better the brain's respiratory control networks. Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (FMRI) maps neuronal activity in the brain, and is therefore a potentially useful, noninvasive technique to investigate the functional neuroanatomy of respiratory control in humans. Contrast in FMRI is derived from the vascular response to brain activity (neurovascular coupling). Therefore, FMRI studies of the neuronal effects of opioids are rendered more complex by the nonneuronal effects of opioids including those on systemic physiology, cerebral blood flow, and direct effects on the cerebral vasculature such as altered vascular reactivity. Here we review our series of studies that dissect the vascular and neuronal breathing-related effects of opioids in the brain. These methodological considerations have enabled successful FMRI studies revealing the brain networks responsible for opioid effects upon respiratory awareness. Similar considerations would be necessary for FMRI studies in hypoxia or in disease states that affect the physiological state of the brain.

Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs.

The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

Respiratory manifestations of panic disorder in animals and humans: A unique opportunity to understand how supramedullary structures regulate breathing

The control of breathing is commonly viewed as being a “brainstem affair”. As the topic of this special issue of Respiratory Physiology and Neurobiology indicates, we should consider broadening this notion since the act of breathing is also tightly linked to many functions other than close regulation of arterial blood gases. Accordingly, “non-brainstem” structures can exert a powerful influence on the core elements of the respiratory control network and as it is often the case, the importance of these structures is revealed when their dysfunction leads to disease. There is a clear link between respiration and anxiety and key theories of the psychopathology of anxiety (including panic disorders; PD) focus on respiratory control and related CO2 monitoring system. With that in mind, we briefly present the respiratory manifestations of panic disorder and discuss the role of the dorso-medial/perifornical hypothalamus, the amygdalar complex, and the periaqueductal gray in respiratory control. We then present recent advances in basic research indicating how adult rodent previously subjected to neonatal stress may provide a very good model to investigate the pathophysiology of PD.

Pontine μ-opioid receptors mediate bradypnea caused by intravenous remifentanil infusions at clinically relevant concentrations in dogs

Life-threatening side effects such as profound bradypnea or apnea and variable upper airway obstruction limit the use of opioids for analgesia. It is yet unclear which sites containing μ-opioid receptors (μORs) within the intact in vivo mammalian respiratory control network are responsible. The purpose of this study was 1) to define the pontine region in which μOR agonists produce bradypnea and 2) to determine whether antagonism of those μORs reverses bradypnea produced by intravenous remifentanil (remi; 0.1-1.0 μg·kg(-1)·min(-1)). The effects of microinjections of agonist [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO; 100 μM) and antagonist naloxone (NAL; 100 μM) into the dorsal rostral pons on the phrenic neurogram were studied in a decerebrate, vagotomized, ventilated, paralyzed canine preparation during hyperoxia. A 1-mm grid pattern of microinjections was used. The DAMGO-sensitive region extended from 5 to 7 mm lateral of midline and from 0 to 2 mm caudal of the inferior colliculus at a depth of 3-4 mm. During remi-induced bradypnea (~72% reduction in fictive breathing rate) NAL microinjections (~500 nl each) within the region defined by the DAMGO protocol were able to reverse bradypnea by 47% (SD 48.0%) per microinjection, with 13 of 84 microinjections producing complete reversal. Histological examination of fluorescent microsphere injections shows that the sensitive region corresponds to the parabrachial/Kölliker-Fuse complex.

Chronic serotonin–norepinephrine reuptake transporter inhibition modifies basal respiratory output in adult mouse in vitro and in vivo

Respiratory disturbances are a common feature of panic disorder and present as breathing irregularity, hyperventilation, and increased sensitivity to carbon dioxide. Common therapeutic interventions, such as tricyclic (TCA) and selective serotonin reuptake inhibitor (SSRI) antidepressants, have been shown to ameliorate not only the psychological components of panic disorder but also the respiratory disturbances. These drugs are also prescribed for generalized anxiety and depressive disorders, neither of which are characterized by respiratory disturbances, and previous studies have demonstrated that TCAs and SSRIs exert effects on basal respiratory activity in animal models without panic disorder symptoms. Whether serotonin–norepinephrine reuptake inhibitors (SNRIs) have similar effects on respiratory activity remains to be determined. Therefore, the current study was designed to investigate the effects of chronic administration of the SNRI antidepressant venlafaxine (VHCL) on basal respiratory output. For these experiments, we recorded phrenic nerve discharge in an in vitro arterially-perfused adult mouse preparation and diaphragm electromyogram (EMG) activity in an in vivo urethane-anesthetized adult mouse preparation. We found that following 28-d VHCL administration, basal respiratory burst frequency was markedly reduced due to an increase in expiratory duration (TE), and the inspiratory duty cycle (TI/Ttot) was significantly shortened. In addition, post-inspiratory and spurious expiratory discharges were seen in vitro. Based on our observations, we suggest that drugs capable of simultaneously blocking both 5-HT and NE reuptake transporters have the potential to influence the respiratory control network in patients using SNRI therapy.

Synaptic and Intrinsic Activation of GABAergic Neurons in the Cardiorespiratory Brainstem Network

GABAergic pathways in the brainstem play an essential role in respiratory rhythmogenesis and interactions between the respiratory and cardiovascular neuronal control networks. However, little is known about the identity and function of these GABAergic inhibitory neurons and what determines their activity. In this study we have identified a population of GABAergic neurons in the ventrolateral medulla that receive increased excitatory post-synaptic potentials during inspiration, but also have spontaneous firing in the absence of synaptic input. Using transgenic mice that express GFP under the control of the Gad1 (GAD67) gene promoter, we determined that this population of GABAergic neurons is in close apposition to cardioinhibitory parasympathetic cardiac neurons in the nucleus ambiguus (NA). These neurons fire in synchronization with inspiratory activity. Although they receive excitatory glutamatergic synaptic inputs during inspiration, this excitatory neurotransmission was not altered by blocking nicotinic receptors, and many of these GABAergic neurons continue to fire after synaptic blockade. The spontaneous firing in these GABAergic neurons was not altered by the voltage-gated calcium channel blocker cadmium chloride that blocks both neurotransmission to these neurons and voltage-gated Ca2+ currents, but spontaneous firing was diminished by riluzole, demonstrating a role of persistent sodium channels in the spontaneous firing in these cardiorespiratory GABAergic neurons that possess a pacemaker phenotype. The spontaneously firing GABAergic neurons identified in this study that increase their activity during inspiration would support respiratory rhythm generation if they acted primarily to inhibit post-inspiratory neurons and thereby release inspiration neurons to increase their activity. This population of inspiratory-modulated GABAergic neurons could also play a role in inhibiting neurons that are most active during expiration and provide a framework for respiratory sinus arrhythmia as there is an increase in heart rate during inspiration that occurs via inhibition of premotor parasympathetic cardioinhibitory neurons in the NA during inspiration.

Pontine μ‐opioid receptors mediate the bradypnea caused by clinically relevant rates of intravenous remifentanil in dogs

Life‐threatening side effects such as profound bradypnea or apnea and variable upper airway obstruction limit the use of opioids for analgesia. It is yet unclear which sites containing mu‐opioid receptors (MORs) within the respiratory control network are responsible. The purpose of this study was 1) to define the pontine region in which MOR agonists produce bradypnea and 2) to determine whether antagonism of those MORs reverses bradypnea produced by IV remifentanil (remi; 0.1–1.0 μg/kg/min). The effects of microinjections of agonist [D‐Ala2, N‐Me‐Phe4, Gly‐ol5]‐enkephalin (DAMGO; 100 μM) and antagonist naloxone (NAL; 100 μM) into the dorsal rostral pons on the phrenic neurogram were studied in a decerebrate, vagotomized, ventilated, paralyzed canine preparation during hyperoxia. A 1‐mm grid pattern of microinjections was used. The DAMGO sensitive region extended from 5–7 mm lateral of midline and from 0–2 mm caudal of the inferior colliculus at a depth of 3–4 mm. During remi‐induced bradypnea (71.5±3.6% reduction in breathing rate; 21 dogs) NAL microinjections (860±69 nl each) within the region defined by the DAMGO protocol were able to reverse bradypnea (47.2±5.2%/injection) with 13 of 84 injections producing complete reversal. Histological examination of dye injections shows that the sensitive region corresponds to the parabrachial Kölliker‐Fuse complex. Supported by VA Medical Research Funds.

Swallow remodeling of respiratory neural networks

Swallow is defined as the coordinated neuromuscular activity of the mouth, pharynx, larynx, and esophagus. Movement of a bolus and air must be coordinated by swallow remodeling of the respiratory pattern. The brainstem contains respiratory and swallow neural control networks that generate the pattern for breathing and swallow. Swallow control of respiration is proposed to be through recruitment of swallow neural elements that retask existing respiratory neural network elements. Swallow reconfiguration of the respiratory neural network is fundamental to airway protection and integrated with other airway protective reflexes. Thus, swallow, breathing, cough, and other airway defensive behaviors are produced by a central neural motor system that shares elements. It is hypothesized that swallow and airway defensive behaviors are controlled by a recruited behavioral control assembly system that is organized in a fashion that allows for precise coordination of the expression of these behaviors to maintain airway protection.

Serotonergic neurons in the nucleus raphe obscurus contribute to interaction between central and peripheral ventilatory responses to hypercapnia

Serotonergic (5-HT) neurons in the nucleus raphe obscurus (ROb) are involved in the respiratory control network. However, it is not known whether ROb 5-HT neurons play a role in the functional interdependence between central and peripheral chemoreceptors. Therefore, we investigated the role of ROb 5-HT neurons in the ventilatory responses to CO₂ and their putative involvement in the central-peripheral CO₂ chemoreceptor interaction in unanaesthetised rats. We used a chemical lesion specific for 5-HT neurons (anti-SERT-SAP) of the ROb in animals with the carotid body (CB) intact or removed (CBR). Pulmonary ventilation (V (E)), body temperature and the arterial blood gases were measured before, during and after a hypercapnic challenge (7% CO₂). The lesion of ROb 5-HT neurons alone (CB intact) or the lesion of 5-HT neurons of ROb+CBR did not affect baseline V (E) during normocapnic condition. Killing ROb 5-HT neurons (CB intact) significantly decreased the ventilatory response to hypercapnia (p < 0.05). The reduction in CO₂ sensitivity was approximately 15%. When ROb 5-HT neurons lesion was combined with CBR (anti-SERT-SAP+CBR), the V (E) response to hypercapnia was further decreased (-31.2%) compared to the control group. The attenuation of CO₂ sensitivity was approximately 30%, and it was more pronounced than the sum of the individual effects of central (ROb lesion; -12.3%) or peripheral (CBR; -5.5%) treatments. Our data indicate that ROb 5-HT neurons play an important role in the CO₂ drive to breathing and may act as an important element in the central-peripheral chemoreception interaction to CO₂ responsiveness.

Theory of gastric CO2 ventilation and its control during respiratory acidosis: Implications for central chemosensitivity, pH regulation, and diseases causing chronic CO2 retention

The theory of gastric CO(2) ventilation describes a previously unrecognized reflex mechanism controlled by neurons in the caudal solitary complex (cSC) for non-alveolar elimination of systemic CO(2) during respiratory acidosis. Neurons in the cSC, which is a site of CO(2) chemosensitivity for cardiorespiratory control, also control various gastroesophageal reflexes that remove CO(2) from blood. CO(2) is consumed in the production of gastric acid and bicarbonate in the gastric epithelium and then reconstituted as CO(2) in the stomach lumen from the reaction between H(+) and HCO(3)(-). Respiratory acidosis and gastric CO(2) distension induce cSC/vagovagal mediated transient relaxations of the lower esophageal sphincter to vent gastric CO(2) upwards by bulk flow along an abdominal-to-esophageal (=intrapleural) pressure gradient the magnitude of which increases during abdominal (gastric) compression caused by increased contractions of respiratory muscles. Esophageal distension induces cSC/nucleus ambiguus/vagovagal reflex relaxation of the upper esophageal sphincter and CO(2) is vented into the pharynx and mixed with pulmonary gas during expiration or, alternatively, during eructation. It is proposed that gastric CO(2) ventilation provides explanations for (1) the postprandial increase in expired CO(2) and (2) the negative P(blood - expired)CO₂difference that occurs with increased inspired CO(2). Furthermore, it is postulated that gastric CO(2) ventilation and alveolar CO(2) ventilation are coordinated under dual control by CO(2) chemosensitive neurons in the cSC. This new theory, therefore, presupposes a level of neural control and coordination between two previously presumed dissimilar organ systems and supports the notion that different sites of CO(2) chemosensitivity address different aspects of whole body pH regulation. Consequently, not all sites of central chemosensitivity are equal regarding the mechanism(s) activated for CO(2) elimination. A distributed CO(2) chemosensitive network-at least nine different areas in the CNS, including the cSC, have been reported to date-may reflect the complexity and dynamic nature of the fundamental neural circuitry required to achieve CO(2)/pH regulation across multiple organ systems under various states of arousal, oxygenation, pH status, and redox state. Moreover, coordination of respiratory and digestive control networks through the cSC could also account for the frequent co-expression of pulmonary diseases that cause chronic respiratory acidosis (and overstimulation of cSC neurons) with peptic ulcer disease or gastroesophageal reflux disease.

Synchrony is altered in the respiratory pattern generator following acute hypoxic challenge

Arthur B. Otis stated in 1954 that the work of breathing accounts for a small fraction of basal metabolism and that inspiration, not expiration, consumes energy. In line with Otis’ findings, our hypothesis is that the respiratory control network uses synchrony, in addition to recruitment and firing rate changes, to generate an efficient respiratory pattern. We hypothesize that synchrony may have unique roles in respiration and that this property is malleable, adapting to maintain homeostasis. To test our hypotheses, we used the perfused in situ preparation of rat (SD/Harlan) and recorded (n=7) from the left phrenic nerve and ensembles of respiratory neurons (n=53) in the Bötzinger/pre‐Bötzinger region using a multielectrode array. Preparations were exposed to acute bouts (20–45s) of hypoxia and spike synchronization between neuronal pairs (n=240) was quantified during baseline and post‐hypoxic epochs (80s/epoch). Neuron pairs from populations which appeared homogenous with respect to firing pattern demonstrated consistent changes in coordinated firing after hypoxia with the exception of a subpopulation of expiratory neurons which showed both increasing and decreasing synchrony. We conclude that synchronization is malleable within populations of the respiratory pattern generator and may contribute to patterning changes during post hypoxic frequency decline. Funded by AHA SDG 0735037N and NIH HL090554

What to do about apnea of prematurity?

apnea of prematurity and resultant intermittent hypoxic episodes are universal in preterm infants. These events range from presumably benign “periodic” breathing to clinically significant events that may require mechanical ventilation. Persistence of these events is a major factor in prolonging

Spike synchronization is population specific in the respiratory pattern generator

Breathing accounts for only a small fraction of basalmetabolism and its motor pattern is highly efficientmechanically [1]. While this view is widely accepted, noone understands whether this property is malleable andwhether it can be utilized to attenuate respiratory failureas well as to facilitate weaning from artificial ventilation.Several factors influence muscle force including firing rateand recruitment of pre-motor and motoneurons (MNs),which increase energy consumption. Another factor is thesynchronization of spikes of MNs, which increases muscleforce in an energy efficient manner, preserving rather thanincreasing the firing frequency of active motor units. Inline with Otis's findings, we hypothesized that the respira-tory control network uses synchrony to generate an effi-cient inspiratory pattern, minimizing the work ofdiaphragm contraction, chest wall expansion and lunginflation.

Ethanol affects the respiratory control network through more than GABA receptors

Central nervous system networks that drive oscillatory activity rely on inhibitory amino acids like GABA for rhythm generation. Application of GABA to an intact but isolated ventilatory‐control network elicits an overall reduction in respiratory rhythm. In isolated bullfrog tadpole brainstem preparations the reduction in respiratory nerve output is both a decline in lung burst frequency and an abolition of gill‐associated neuroventilation. Ethanol is a GABA‐mimetic, and the ventilatory reduction exhibited during acute ethanol exposure has been associated with GABA‐meditated pathways. Chronic ethanol exposure has been found to attenuate responses to subsequent exposure to GABA and ethanol in the tadpole brainstem preparation. Despite these correlations between GABA and ethanol, preliminary experiments using acute ethanol application failed to reduce tadpole gill‐associated neuroventilation concomitant with a clear decrease in lung burst frequency. This suggests the effect of ethanol on respiratory rhythm generation is not exclusive to GABA‐mediated neurotransmission or, alternatively, that the role of GABA in the amphibian respiratory control network is more complex than previously speculated.