Differential Modulation of Neural Network and Pacemaker Activity Underlying Eupnea and Sigh-Breathing Activities

Medical College of Wisconsin, Department of Physiology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Journal of Neurophysiology (Impact Factor: 2.89). 06/2008; 99(5):2114-25. DOI: 10.1152/jn.01192.2007
Source: PubMed


Many networks generate distinct rhythms with multiple frequency and amplitude characteristics. The respiratory network in the pre-Bötzinger complex (pre-Böt) generates both the low-frequency, large-amplitude sigh rhythm and a faster, smaller-amplitude eupneic rhythm. Could the same set of pacemakers generate both rhythms? Here we used an in vitro respiratory brainslice preparation. We describe a subset of synaptically isolated pacemakers that spontaneously generate two distinct bursting patterns. These two patterns resemble network activity including sigh-like bursts that occur at low frequencies and have large amplitudes and eupneic-like bursts with higher frequency and smaller amplitudes. Cholinergic neuromodulation altered the network and pacemaker bursting: fictive sigh frequency is increased dramatically, whereas fictive eupneic frequency is drastically lowered. The data suggest that timing and amplitude characteristics of fictive eupneic and sigh rhythms are set by the same set of pacemakers that are tuned by changes in the neuromodulatory state.

Download full-text


Available from: Andrew K Tryba,
26 Reads
  • Source
    • "Therefore, distinguishing the separate cell populations responsible for the two inspiratory-related activities is rendered difficult, although such an extensive overlap could at least partially explain how two different burst types are apparently generated within a single network. It is interesting in this context that pacemaker inspiratory neurons that are capable of expressing both endogenous eupnoeic and sigh-like bursting properties have been identified in the newborn mouse (Tryba et al. 2008), although whether such bimodal pacemakers already exist and contribute to sigh generation at the prenatal stage remains to be determined. In any case, our present data indicate that while eupnoea and sigh activities arise mostly from the same neuronal population, there also exists a subset of inspiratory neurons that are probably endowed with membrane and synaptic properties specialized for promoting sigh burst production. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In mammals, eupneic breathing is periodically interrupted by spontaneous augmented breaths (sighs) that include a larger-amplitude inspiratory effort, typically followed by a post-sigh apnea. Previous in vitro studies in newborn rodents have demonstrated that the respiratory oscillator of the pre-Bötzinger complex (preBötC) can generate the distinct inspiratory motor patterns for both eupnea- and sigh-related behaviour. During mouse embryonic development, the preBötC begins to generate eupneic rhythmicity at embryonic day (E) 15.5, but the network's ability to also generate sigh-like activity remains unexplored at prenatal stages. Using transverse brainstem slice preparations we monitored the neuronal population activity of the preBötC at different embryonic ages. Spontaneous sigh-like rhythmicity was found to emerge progressively, being expressed in 0/32 slices at E15.5, 7/30 at E16.5, 9/22 at E17.5 and 23/26 at E18.5. Calcium imaging showed that the preBötC cell population that participates in eupneic-like discharge was also active during fictive sighs. However, patch-clamp recordings revealed the existence of an additional small subset of neurons that fired exclusively during sigh activity. Changes in glycinergic inhibitory synaptic signalling, either by pharmacological blockade, functional perturbation or natural maturation of the chloride co-transporters KCC2 or NKCC1 selectively, and in an age-dependent manner, altered the bi-phasic nature of sigh bursts and their coordination with eupneic bursting, leading to the generation of an atypical monophasic sigh-related event. Together our results demonstrate that the developmental emergence of a sigh generating capability occurs after the onset of eupneic rhythmogenesis and requires the proper maturation of chloride-mediated glycinergic synaptic transmission.
    The Journal of Physiology 03/2014; 592(10). DOI:10.1113/jphysiol.2013.268730 · 5.04 Impact Factor
  • Source
    • "Interestingly, a " post-sigh-like apnea " can be simulated centrally, by maximally stimulating isolated medullary respiratory pacemaker neurons. This purely central electrical stimulation is followed by a prolonged pause in the rhythmic bursting of these respiratory neurons (Tryba et al., 2008). The post-sigh apnea is an important manifestation of a central apnea (Eckert et al., 2007a; Radulovacki et al., 2001; Saponjic et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apnea, the cessation of breathing, is a common physiological and pathophysiological phenomenon with many basic scientific and clinical implications. Among the different forms of apnea, obstructive sleep apnea (OSA) is clinically the most prominent manifestation. OSA is characterized by repetitive airway occlusions that are typically associated with peripheral airway obstructions. However, it would be a gross oversimplification to conclude that OSA is caused by peripheral obstructions. OSA is the result of a dynamic interplay between chemo- and mechanosensory reflexes, neuromodulation, behavioral state and the differential activation of the central respiratory network and its motor outputs. This interplay has numerous neuronal and cardiovascular consequences that are initially adaptive but in the long-term become major contributors to the morbidity and mortality associated with OSA. However, not only OSA, but all forms of apnea have multiple, and partly overlapping mechanisms. In all cases the underlying mechanisms are neither "exclusively peripheral" nor "exclusively central" in origin. While the emphasis has long been on the role of peripheral reflex pathways in the case of OSA, and central mechanisms in the case of central apneas, we are learning that such a separation is inconsistent with the integration of these mechanisms in all cases of apneas. This review discusses the complex interplay of peripheral and central nervous components that characterizes the cessation of breathing.
    Respiratory Physiology & Neurobiology 06/2013; 189(2). DOI:10.1016/j.resp.2013.06.004 · 1.97 Impact Factor
  • Source
    • "The α 1a subunit colocalizes with cholinergic neurons (Plomp et al., 2000), and here we found a dramatic difference in the respiratory response to muscarine between KO and CT slices. While muscarine reduced the respiratory frequency in CT slices and augmented sighs (Zanella et al., 2007; Tryba et al., 2008), it completely abolished fictive eupnea in KO slices. Muscarine activates several receptors and can modulate both Ca v 2.2 and Ca v 2.1 (Endoh, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: P/Q-type voltage-gated calcium channels (Ca(v)2.1) play critical presynaptic and postsynaptic roles throughout the nervous system and have been implicated in a variety of neurological disorders. Here we report that mice with a genetic ablation of the Ca(v)2.1 pore-forming α(1A) subunit (α(1A)(-/-)) encoded by CACNA1a (Jun et al., 1999) suffer during postnatal development from increasing breathing disturbances that lead ultimately to death. Breathing abnormalities include decreased minute ventilation and a specific loss of sighs, which was associated with lung atelectasis. Similar respiratory alterations were preserved in the isolated in vitro brainstem slice preparation containing the pre-Bötzinger complex. The loss of Ca(v)2.1 was associated with an alteration in the functional dependency on N-type calcium channels (Ca(v)2.2). Blocking N-type calcium channels with conotoxin GVIA had only minor effects on respiratory activity in slices from control (CT) littermates, but abolished respiratory activity in all slices from α(1A)(-/-) mice. The amplitude of evoked EPSPs was smaller in inspiratory neurons from α(1A)(-/-) mice compared with CTs. Conotoxin GVIA abolished all EPSPs in inspiratory neurons from α(1A)(-/-) mice, while the EPSP amplitude was reduced by only 30% in CT mice. Moreover, neuromodulation was significantly altered as muscarine abolished respiratory network activity in α(1A)(-/-) mice but not in CT mice. We conclude that excitatory synaptic transmission dependent on N-type and P/Q-type calcium channels is required for stable breathing and sighing. In the absence of P/Q-type calcium channels, breathing, sighing, and neuromodulation are severely compromised, leading to early mortality.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2013; 33(8):3633-3645. DOI:10.1523/JNEUROSCI.6390-11.2013 · 6.34 Impact Factor
Show more