Steven P. Lieske

Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps

Are different forms of breathing derived from one or multiple neural networks? We demonstrate that brainstem slices containing the pre-Bötzinger complex generated two rhythms when normally oxygenated, with striking similarities to eupneic (‘normal’) respiration and sighs. Sighs were triggered by eupneic bursts under control conditions, but not in the presence of strychnine (1 μM). Although all neurons received synaptic inputs during both activities, the calcium channel blocker cadmium (4 μM) selectively abolished sighs. In anoxia, sighs ceased, and eupneic activity was reconfigured into gasping, which like eupnea was insensitive to 4 μM cadmium. This reconfiguration was accompanied by suppression of synaptic inhibition. We conclude that a single medullary network underlies multiple breathing patterns.

Autonomic Nervous System Dysregulation: Breathing and Heart Rate Perturbation During Wakefulness in Young Girls with Rett Syndrome

This study characterizes cardiorespiratory dysregulation in young girls with MECP2 mutation–confirmed Rett syndrome (RS). Respiratory inductance plethysmography of chest/abdomen and ECG was obtained during daytime wakefulness in 47 girls with MECP2 mutation–confirmed RS and 47 age-, gender-, and ethnicity-matched controls (ages 2–7 y). An in-home breath-to-breath and beat-to-beat characterization was conducted and revealed that breathing was more irregular, with an increased breathing frequency, mean airflow, and heart rate in RS versus controls. There was a decreased correlation between normal breathing and heart rate variability, and an exaggerated increase in heart rate response to breathholds in RS versus controls. We conclude that girls with RS have cardiorespiratory dysregulation during breathholds as well as during “normal” breaths and during breaths before and subsequent to breathholds. This dysregulation may offer insight into the mechanisms that render girls with RS more vulnerable to sudden death.

Differential modulation of neural network and pacemaker activity underlying eupnea and sigh-breathing activities

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.

Autonomic dysregulation in young girls with Rett Syndrome during nighttime in‐home recordings

This study was designed to specifically characterize the autonomic phenotype of cardiorespiratory dysregulation during the nighttime in young girls with MECP2 mutation-confirmed Rett Syndrome (RS), studied in their home environment. Computerized breath-to-breath and beat-to-beat characterization of at-home continuously recorded respiratory inductance plethysmography of chest/abdomen and ECG (VivoMetrics, Inc.) was obtained during overnight recordings in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicity-matched screened controls (ages 2-7 years). We determined that although the breathing and heart rate appear more regular during the night compared to the day, young girls with RS demonstrate apparent nocturnal irregularities. Comparing daytime versus nighttime, breathing was more irregular, with an increased breathing frequency (and irregularity), mean amplitude of respiratory inductance plethysmography sum (AMP)/T(I), and heart rate and decreased AMP in girls with RS. Comparing girls with RS versus controls during nighttime recording, breathing was more irregular, with an increased breathing frequency (and irregularity), mean AMP/T(I), and heart rate. An increased uncoupling between measures of breathing and heart rate control indicates malregulation in the autonomic nervous system, and is apparent during the day as well as the night. This uncoupling may represent a mechanism that renders the girls with RS more vulnerable to sudden death.

The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration.

Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R1 and R2 receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake. Using an operant self-administration paradigm, we demonstrate that systemic administration of almorexant decreased operant self-administration of both 20% ethanol and 5% sucrose. We further demonstrate that intra-ventral tegmental area (VTA) infusions, but not intra-substantia nigra infusions, of almorexant reduced ethanol self-administration. Extracellular recordings performed in VTA neurons revealed that orexin-A increased firing and this enhancement of firing was blocked by almorexant. The results demonstrate that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors.

Respiratory rhythm generation: converging concepts from in vitro and in vivo approaches?

The timing and activation pattern of breathing movements are determined by the respiratory network. This network is amenable to a variety of in vivo and in vitro approaches, which offers a unique opportunity to investigate multiple organizational levels. It is only recently, however, that concepts obtained under in vivo and in vitro conditions are being integrated into a coherent model of breathing behavior. For example, the pre-Bötzinger complex as an essential site for rhythm generation was first identified in vitro, but has since been verified in vivo. Conversely, timing signals provided by other central and peripheral neuronal areas have so far been investigated in vivo, but it is now possible to address these issues with more complex in vitro preparations. Several key issues remain unresolved. For example, to what extent is the respiratory pattern controlled independently of the underlying rhythm? Answers to this and other questions require a dissection of mechanisms that is only possible through a complementary combination of experimental approaches.

Commentary on the definition of eupnea and gasping.

Despite clear qualitative differences, it has proven difficult to identify criteria that reliably differentiate eupnea and gasping--particularly when multiple species or experimental preparations are considered. From a motor control perspective, this is unsurprising. Three organizational rules are common to nearly all rhythmic activities: (1) the basic rhythm is produced by a small network of cells, (2) the activity of this network in isolation often differs dramatically from the behavior of the whole animal, and (3) the rhythmogenic networks responsible for related behaviors are not fixed and independent but dynamically modifiable and overlapping. In this context, it becomes clear that the definition of a particular pattern and the investigation of the mechanisms underlying its production are inseparable. Rather than attempting to rigidly apply criteria developed using any one experimental preparation, the classification of respiratory patterns must evolve alongside our understanding of how each pattern is produced-a process that is only aided by investigations using a variety of experimental preparations.

Reconfiguration of the Central Respiratory Network Under Normoxic and Hypdxic Conditions

Apart from the obvious medical interest in understanding breathing, the respiratory rhythm is ideally suited for the study of state dependence and modifiability in central pattern generators (CPGs) in general. The list of variables with dramatic effects on breathing is impressive, including temperature, sleep/wake state, 02 and CO2 concentrations, airway irritation, conscious control, and a variety of pathological conditions. The ongoing breathing rhythm can be interrupted by coughing, sneezing, hiccoughing, swallowing, or vomiting; it can also be suspended in the post-inspiratory phase by vocalization. The pattern of breathing itself can take on several qualitatively distinct patterns, including eupneic (“normal”) breathing, panting, sighing, periodic breathing (during sleep), and gasping (in hypoxia).