Hypoxia evokes a sequence of raphe-pontomedullary network operations for inspiratory drive amplification and gasping.

Hypoxia can trigger a sequence of breathing-related behaviors, from tachypnea to apneusis to apnea and gasping, an autoresuscitative behavior that, via large tidal volumes and altered intrathoracic pressure, can enhance coronary perfusion, carotid blood flow, and sympathetic activity, and thereby coordinate cardiac and respiratory functions. We tested the hypothesis that hypoxia-evoked gasps are amplified through a disinhibitory microcircuit within the inspiratory neuron chain and a distributed efference copy mechanism that generates coordinated gasp-like discharges concurrently in other circuits of the raphe-pontomedullary respiratory network. Data were obtained from 6 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated adult cats.

Initiating daily acute intermittent hypoxia (dAIH) therapy at 1-week after contusion spinal cord injury (SCI) improves lower urinary tract function in rat.

Spinal cord injury (SCI) above the level of the lumbosacral spinal cord produces lower urinary tract (LUT) dysfunction, resulting in impairment of urine storage and elimination (voiding). While spontaneous functional recovery occurs due to remodeling of spinal reflex micturition pathways, it is incomplete, indicating that additional strategies to further augment neural plasticity following SCI are essential. To this end, acute intermittent hypoxia (AIH) exposure has been proposed as a therapeutic strategy for improving recovery of respiratory and other somatic motor function following SCI; however, the impact of AIH as a therapeutic intervention to improve LUT dysfunction remains to be determined.

Intermittent hypoxia-induced respiratory long-term facilitation is dominated by enhanced burst frequency, not amplitude, in spontaneously breathing urethane-anesthetized neonatal rats.

Acute intermittent hypoxia (AIH) triggers a form of respiratory plasticity known as long-term facilitation (LTF), which is manifested as a progressive increase in respiratory motor activity that lasts for minutes to hours after the hypoxic stimulus is removed. Respiratory LTF has been reported in numerous animal models, but it appears to be influenced by a variety of factors (e.g.

Using a computational model to analyze the effects of firing frequency on synchrony of a network of gap junction-coupled hypoglossal motoneurons.

Hypoglossal motoneurons (HMs) are located in the brainstem and play an important role in the maintenance of upper airway patency. HMs are known to be coupled to one another via gap junctions and exhibit synchronous firing behavior when driven by premotor inputs. In the current study, we used a computational model to analyze the influence of firing frequency on synchronous firing behavior of a network of gap junction-coupled HMs.

Effects of calcium (Ca(2+)) extrusion mechanisms on electrophysiological properties in a hypoglossal motoneuron: insight from a mathematical model.

Spike-frequency dynamics and spike shape can provide insight into the types of ion channels present in any given neuron and give a sense for the precise response any neuron may have to a given input stimulus. Motoneuron firing frequency over time is especially important due to its direct effect on motor output. Of particular interest is intracellular Ca(2+), which exerts a powerful influence on both firing properties over time and spike shape.

Analyzing the effects of gap junction blockade on neural synchrony via a motoneuron network computational model.

In specific regions of the central nervous system (CNS), gap junctions have been shown to participate in neuronal synchrony. Amongst the CNS regions identified, some populations of brainstem motoneurons are known to be coupled by gap junctions. The application of various gap junction blockers to these motoneuron populations, however, has led to mixed results regarding their synchronous firing behavior, with some studies reporting a decrease in synchrony while others surprisingly find an increase in synchrony.

Emergent central pattern generator behavior in gap-junction-coupled Hodgkin-Huxley style neuron model.

Most models of central pattern generators (CPGs) involve two distinct nuclei mutually inhibiting one another via synapses. Here, we present a single-nucleus model of biologically realistic Hodgkin-Huxley neurons with random gap junction coupling. Despite no explicit division of neurons into two groups, we observe a spontaneous division of neurons into two distinct firing groups.

Application of a "staggered walk" algorithm for generating large-scale morphological neuronal networks.

Large-scale models of neuronal structures are needed to explore emergent properties of mammalian brains. Because these models have trillions of synapses, a major problem in their creation is synapse placement. Here we present a novel method for exploiting consistent fiber orientation in a neural tissue to perform a highly efficient modified plane-sweep algorithm, which identifies all regions of 3D overlaps between dendritic and axonal projection fields.

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.

Influence of extracellular [K+]o on inspiratory network complexity of phrenic and hypoglossal nerve discharge in arterially-perfused adult rat.

Many in vitro mammalian preparations are used to study multiple aspects of central respiratory control. In these preparations, recordings of respiratory-related outputs that range from individual and population neuronal activities to hypoglossal (XII) nerve output to phrenic (PHR) nerve discharge commonly are used. These reduced preparations typically are supplied with an artificial cerebral spinal fluid (aCSF) containing an extracellular potassium level ([K(+)](o)) elevated above physiological levels in order to increase excitability and maintain a stable respiratory output.

Upper airway and abdominal motor output during sneezing: is the in vivo decererate rat an adequate model?

While numerous studies have focused on identifying and characterizing the neural mechanisms mediating upper airway defense reflexes in the anesthetized or decerebrate adult cat, little is known about these behaviors in in vivo rodent models. The current study was undertaken to investigate whether the in vivo decelerate adult rat might serve as an acceptable model for studying these behaviors. To begin to address this possibility, we examined multiple respiratory motor activities in response to mechanical stimulation of the anterior nasal cavity (sufficient to elicit fictive sneezing) in in vivo decerebrate adult rats.

Influence of 5-HT2A receptor blockade on phrenic nerve discharge at three levels of extracellular K+ in arterially-perfused adult rat.

Recent observations from in vitro rodent preparations suggest an important role for the serotonin-2A (5-HT(2A)) receptor in eupneic (basal) and gasping respiratory activities, although the precise role appears to be different in different preparations. Since these in vitro preparations are typically supplied with elevated (and different) levels of K(+) to increase neuronal excitability, the role of endogenous activation of 5-HT(2A) receptors in these respiratory behaviors under "normal" levels of extracellular K(+) ([K(+)](o)) requires clarification. The current study sought to evaluate the influence of [K(+)](o) on the 5-HT(2A) receptor-mediated effects on basal respiratory activity and the phases of the hypoxic ventilatory response (HVR), including ischemia-induced gasping in an arterially-perfused adult rat preparation.

Geometrical analysis of bursting pacemaker neurons generated by computational models: comparison to in vitro pre-Bötzinger complex bursting neurons.

Despite an incredible amount of progress toward understanding respiratory rhythm generation through the use of reduced mathematical models, controversy exists concerning the role of various ionic conductances in generating bursting behavior. Moreover, the dynamical behavior of these model neurons has not been examined. Here, we have used two well described pre-Bötzinger complex (pre-BötC) pacemaker neuron models to investigate their dynamical features.

Effects of aerobic and anaerobic metabolic inhibitors on avian intrapulmonary chemoreceptors.

Birds have rapidly responding respiratory chemoreceptors [intrapulmonary chemoreceptors (IPC)] that provide vagal sensory feedback about breathing pattern. IPC are exquisitely sensitive to CO(2) but are unaffected by hypoxia. IPC continue to respond to CO(2) during hypoxic and even anoxic conditions, suggesting that they may generate ATP needed for signal transduction anaerobically.

Pontine-ventral respiratory column interactions through raphe circuits detected using multi-array spike train recordings.

Recently, Segers et al. identified functional connectivity between the ventrolateral respiratory column (VRC) and the pontine respiratory group (PRG). The apparent sparseness of detected paucisynaptic interactions motivated consideration of other potential functional pathways between these two regions.

Functional connectivity in the pontomedullary respiratory network.

Current models propose that a neuronal network in the ventrolateral medulla generates the basic respiratory rhythm and that this ventrolateral respiratory column (VRC) is profoundly influenced by the neurons of the pontine respiratory group (PRG). However, functional connectivity among PRG and VRC neurons is poorly understood. This study addressed four model-based hypotheses: 1) the respiratory modulation of PRG neuron populations reflects paucisynaptic actions of multiple VRC populations; 2) functional connections among PRG neurons shape and coordinate their respiratory-modulated activities; 3) the PRG acts on multiple VRC populations, contributing to phase-switching; and 4) neurons with no respiratory modulation located in close proximity to the VRC and PRG have widely distributed actions on respiratory-modulated cells.

Automatic selection of the threshold value R for approximate entropy.

Calculation of approximate entropy (ApEn) requires a priori determination of two unknown parameters, m and r. While the recommended values of r, in the range of 0.1-0.

Glutamatergic neurotransmission is not essential for, but plays a modulatory role in, the production of gasping in arterially-perfused adult rat.

Glutamatergic neurotransmission appears to be essential for generation of the eupneic pattern of inspiratory motor discharge as well as the expression of inspiratory-phase synchronization. The role of glutamatergic neurotransmission in the generation of gasping, including its accompanying modulation of spectral activity, is less well understood. The current investigation was, therefore, undertaken to investigate the effects of blockade of ionotropic glutamate receptors on (1) the generation and expression of gasping and (2) the magnitude and timing of spectral activity during gasping using an arterially-perfused decerebrate adult rat preparation.

Burst-to-Burst variability in respiratory timing, inspiratory-phase spectral activity, and inspiratory neural network complexity in urethane-anesthetized C57BL/6 mice in vivo.

Recent work from our laboratory has focused on identifying burst-to-burst variability in temporal and spectral characteristics for 5-minute time series segments of basal inspiratory motor discharges from urethane-anesthetized adult C57BL/6 mice. The current investigation, as the continuation of our previous studies, examined short- and long-term burst-to-burst variability in temporal and spectral components as well as in complexity, which reflects the central respiratory network dynamics. All measures were assessed by quantitative poincaré plot analyses and the determination of the coefficient of variation.

Fast oscillatory rhythms in inspiratory motor discharge: a mathematical model.

In this paper, a mathematic model is applied to characterize spectral activity associated with fast oscillatory rhythms inherent in inspiratory discharges. Based on the estimated parameters, features are extracted to allow the model to discriminate between changes in the location, magnitude, and shape of spectral activities under basal conditions and during pharmacological blockade of gap junctions.

Respiratory network complexity in neonatal rat in vivo and in vitro.

Numerous experimental preparations from neonatal rodents have been developed to study mechanisms responsible for respiratory rhythm generation. Amongst them, the in vivo anesthetized neonatal rat preparation and the in vitro medullary slice preparation from neonatal rat are commonly used. These two preparations not only contain a different extent of the neuroanatomical axis associated with central respiratory control, but they are also studied under markedly different conditions, all of which may affect the complex dynamics underlying the central inspiratory neural network.

A mathematical model of pH(i) regulation in central CO2- chemoreception.

In CO2 chemosensitive neurons, an increase in CO2 (hypercapnia) leads to a maintained reduction in intracellular pH (pH(i)) while in non-chemosensitive neurons pH(i) recovery is observed. The precise mechanisms for the differential regulation of pH(i) recovery between these cell populations remain to be identified; however, studies have begun to explore the role of Na+/H+ exchange (NHE). Here, we compare the results of two different formulations of a mathematical model to begin to explore pH(i) regulation in central CO2 chemoreception.

Differences in pHi recovery in CO2-chemosensitive and non-chemosensitive cells: predictions from a mathematical model.

In this paper, we present a mathematic model designed to identify potential mechanisms responsible for the observed differences in pHi recovery in CO(2)-chemosensitive versus non-chemosensitive cells. The model suggests that differences in pHi regulation may be dependent upon differences in the activation set-point of the internal modifier site of the Na(+)/H(+) exchanger (NHE).

Fast oscillatory rhythms in inspiratory motor discharge: a mathematical model.

In this paper, a mathematic model is applied to characterize spectral activity associated with fast oscillatory rhythms inherent in inspiratory discharges. Based on the estimated parameters, features are extracted to allow the model to discriminate between changes in the location, magnitude, and shape of spectral activities under basal conditions and during pharmacological blockade of gap junctions.