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Frogs produce two distinct yet highly coordinated ventilatory behaviors, buccal and lung. Lung ventilation occurs in short episodes, interspersed with periods of buccal ventilation. Recent data suggests that two brainstem oscillators are involved in generating these behaviors, one primarily responsible for buccal ventilation, the other for lung. Here we use a modeling approach to demonstrate that the episodic pattern of lung ventilation might be an emergent property of the coupling between the oscillators, and may not require a perturbing input from another, as yet unidentified but previously postulated, neuronal oscillator. © 2004 Elsevier B.V. All rights reserved.

Frogs produce two distinct yet highly coordinated ventilatory behaviors, buccal and lung. Lung ventilation occurs in short episodes, interspersed with periods of buccal ventilation. Recent data suggests that two brainstem oscillators are involved in generating these behaviors, one primarily responsible for buccal ventilation, the other for lung. Here we use a modeling approach to demonstrate that the episodic pattern of lung ventilation might be an emergent property of the coupling between the oscillators, and may not require a perturbing input from another, as yet unidentified but previously postulated, neuronal oscillator. © 2004 Elsevier B.V. All rights reserved.

Highlights • The in situ perfused brainstem preparation of guinea pig generates physiological cardio-respiratory activity patterns. • It preserves central network activity required for multi-synaptic sensory reflex integration. • First demonstration that mechanical stimulation of the trachea triggers an in situ expiration reflex. • This new method will help to advance the field of central control of airway defense. Abstract The perfused working heart brainstem preparation of rodents has become a widely used tool to study brainstem function. Here, we adapt this experimental technique for newborn guinea pigs (postnatal day 7–14) to develop a tool that enables investigation of airway defense mechanisms not observed in other rodents. The perfused guinea pig brainstem preparation generates a stable eupnea-like motor pattern recorded from the phrenic, recurrent laryngeal and intercostal nerves and basic cardio-respiratory reflexes, including the arterial chemoreceptor, the baroreceptor reflex. In addition a fictive laryngeal cough reflex can be reliably elicited after mechanical stimulation of the trachea. Single unit recordings within the ponto-medullary respiratory column show robust central respiratory neuronal activity. Additionally, as in other species ponto-medullary transection of the brainstem produces apneusis. The latter suggests that the preparation fully preserves ponto-medullary synaptic connectivity that is required for eupnea-like respiratory rhythm and pattern formation and the mediation of various cardio-respiratory reflexes. We conclude that this novel research tool provides an alternative to established rat and mouse preparations and may become a experimental tool for the investigation of central mechanisms that mediate laryngeal cough. [ABSTRACT FROM AUTHOR]

The neuropeptide somatostatin is involved in many functions in the central nervous system as well as in the periphery. When it is centrally injected, an irreversible apnea is often developed. In the present review, we discuss the effects of somatostatin as the result of its actions at three levels of the respiratory neural network: a) by modulating the output of cranial or spinal motoneurons; b) by altering the genesis of the respiratory rhythm in the brainstem; and c) by regulating the chemosensory drive input into the respiratory pattern generator

Abstract: Surf1 gene mutations were detected as a main cause for Leigh syndrome (LS), also known as infantile subacute necrotizing encephalomyelopathy. This syndrome which is commonly associated with systemic cytochrome c oxidase (COX) deficiency manifests in early childhood and has an invariable poor prognosis. Progressive disturbances of the respiratory function, for which both the metabolic condition and necrotizing brainstem lesions contribute, belong to the major symptoms of LS. A constitutive knockout (KO) mouse for Surf1 enables invasive investigations of distinct aspects of LS. In the present study the respiratory function was analyzed applying an arterially perfused brainstem preparation. Compared to wild type (WT) preparations Surf1 KO preparations had a higher baseline respiratory frequency and abnormal responses to hypoxia and hypercapnia that involved both respiratory frequency and motor nerve discharge pattern. These data suggest that COX deficiency impairs peripheral and/or central chemoreceptor function. [Copyright &y& Elsevier]

Abstract: Recently developed transversal newborn rat brainstem slices with “calibrated” rostrocaudal margins unraveled novel features of rhythmogenic inspiratory active pre-Bötzinger complex (preBötC) neural networks (). For example, slice rhythm in physiological (3mM) superfusate K+ is depressed by modestly raised Ca2+ and restored by raised K+. Correspondingly, we generated here calibrated preBötC slices from commonly used newborn C57BL/6 mice in which rostrocaudal extents of respiratory marker structures, e.g., the inferior olive, turned out to be smaller than in newborn rats. Slices of 400–600μm thickness with likely centered preBötC kernel (“m-preBötC slices”) generated rhythm in 3mM K+ and 1mM Ca2+ for several hours although its rate decreased to <5bursts/min after >1h. Rhythm was stable at 8–12bursts/min in 6–7mM K+, depressed by 2mM Ca2+, and restored by 9mM K+. Our findings provide the basis for future structure–function analyses of the mouse preBötC, whose activity depends critically on a “Ca+/K+ antagonism” as in rats. [Copyright &y& Elsevier]

Inspiratory activity on the left and right sides must be coordinated to be effective. We used cross-correlation to examine the hypothesis that the coordination of left and right medullary inspiratory neurones is produced by excitation from common sources and by midline-crossing excitatory connections among these neurones. In adult rats, a total of 185 contralateral pairs of inspiratory neurones (n=370) were recorded extracellularly, and classified, according to their firing pattern, as augmenting (n=262), constant (n=82) or decrementing (n=26). Of the 262 augmenting inspiratory neurones, 98 were classified as phrenic premotor neurones by cross-correlation with phrenic nerve discharge. The 185 cross-correlograms showed little evidence of common activation, or midline-crossing excitatory connections. Of the 45 cross-correlograms for pairs of augmenting neurones, only 4 (≅9%) indicated a common activation, and only one a monosynaptic connection. Of the 45 for pairs of augmenting and phrenic premotor neurones, only 9 (20%) showed a common activation, and only 2 a monosynaptic excitatory connection. Of the 19 pairs of phrenic premotor neurones, 5 from the same rat showed high-frequency oscillations, and 1 a monosynaptic excitatory connection. Cross-correlograms for pair combinations of other types of neurones also exhibited few features. We suggest that, in the adult rat, although both common activation and excitatory cross-connections exist as a means for coordinating left and right ventral group inspiratory neurones to the same respiratory rhythm, they are insufficient to account for it. [ABSTRACT FROM AUTHOR]

The synchronisation of the discharges recorded from left and right phrenic nerves in the adult rat is produced in part by shared excitation from a common premotor neurone population. However, such synchronisation has not been examined for hypoglossal motoneurones in adult rats, or for phrenic and hypoglossal motoneurons in neonatal in vitro preparations. In adult rats, cross-correlograms computed between the inspiratory discharges of the left and right phrenic nerves, and the left and right hypoglossal nerves displayed central peaks with half-amplitude widths of 1.4±0.1 and 1.7±0.1 ms (mean±SE), respectively. We interpret these as evidence for common excitation. However, such central peaks were absent in the same cross-correlograms computed for neonatal in vitro preparations, although central peaks were observed in cross-correlograms computed between the discharges recorded from adjacent phrenic nerve rootlets. We conclude that, in the adult rat, left and right hypoglossal nerve discharges are synchronised by excitation from a common premotor neurone population, as for the phrenic nerves, but this type of synchronisation is undetectable in neonatal in vitro preparations. We speculate that the differences between the adult and neonatal preparations are due to developmental changes in respiratory drive transmission pathways. [ABSTRACT FROM AUTHOR]

In this study of adult and neonatal rats, we used cross-correlation analysis to detect synchronous neuronal events in hypoglossal and phrenic nerves to infer synaptic connections. We found evidence for the common excitation of medial and lateral hypoglossal motoneurones in 12 anaesthetized adult rats but not in 6 in vitro brainstem-spinal cord preparations. We did not find evidence for the common activation of phrenic and hypoglossal motoneurones in 23 adult and 10 neonatal rat preparations. We confirmed this negative result by demonstrating that 26 medullary inspiratory neurones activating phrenic motoneurones did not activate hypoglossal motoneurones in 23 adult decerebrate rats (except in one case). We also found that 15 Bötzinger expiratory neurones inhibiting phrenic motoneurones did not inhibit hypoglossal motoneurones. We conclude that: (1) motoneurones of the medial and lateral hypoglossal nerve branches receive inspiratory drive from a common premotor population in adult rats, but in neonatal rats adjacent nerve rootlets do not; (2) in both adult and neonatal rats phrenic premotor neurones do not monosynaptically excite hypoglossal motoneurones; (3) Bötzinger expiratory neurones that inhibit phrenic motoneurones do not inhibit hypoglossal motoneurones. We therefore suggest that the respiratory control of hypoglossal motoneurones is separate from that of phrenic motoneurones. [ABSTRACT FROM AUTHOR]

Intracellular calcium signals are critical for modulation of neuronal function, and also for pathophysiological states during human neurodegenerative disease, such as Morbus Alzheimer and amyotrophic lateral sclerosis (ALS). We investigated intracellular calcium signals in motoneurones of the nucleus hypoglossus from the mouse, which were maintained in a functionally intact state of rhythmic, respiratory-related activity. Simultaneous patch-clamp recordings and calcium imaging demonstrated that rhythmic inspiratory-related clusters of action potential (AP) discharges are paralleled by calcium oscillations both in somatic and dendritic compartments. Calcium oscillations resulted primarily from the AP-induced opening of voltage-dependent calcium channels in the soma and dendrites. Dendritic calcium transients differed from somatic responses in their kinetics, amplitude, voltage dependence and regulation of basal calcium levels. Based on a combination of infrared differential interference contrast optics, microfluorimetric calcium imaging and electrophysiological patch-clamp recordings, our results demonstrate that the brainstem slice preparation is an attractive model system to study the integration and superposition of calcium signals in a functionally intact neuronal net. [ABSTRACT FROM AUTHOR]

Abstract In vitro, the respiratory activity in rodents is characterized by: (i) the rapidly peaking, slowly decrementing pattern of spontaneous and rhythmic active phases recorded from the motor rootlets, and (ii) the specific location of their rhythmic generator in the ventrolateral medulla. The aim of the present study was to assess whether the trigeminal and facial motor rootlets still exhibit respiratory activity in the absence of peripheral and higher cerebral structures, and to compare the onset of their active phases with that of other respiratory rootlets, using the in vitro isolated brainstem–spinal cord preparation of the newborn mouse and rat. Spontaneous rhythmic activity was recorded from the trigeminal and facial rootlets. It was regular and synchronized bilaterally and ipsilaterally with the hypoglossal or cervical C1–C6 rootlets. Brainstem transection experiments demonstrated that for both the trigeminal and facial rootlets, the spontaneous rhythmic activity originates from the medulla, in a region consistent with the pre-Bötzinger complex and the rostral ventrolateral medulla. The pattern of the respiratory motor activity recorded from the trigeminal and facial rootlets was identical to the pattern recorded from the hypoglossal and cervical C1–C6 rootlets with rapidly peaking, slowly decrementing characteristics. The duration of the ascending part and the total duration of their active phases were similar. The onset of the active phases of the phrenic rootlets was delayed compared with that of the trigeminal, facial and hypoglossal rootlets. However, no difference in the onsets of the active phases of the cranial rootlets could be observed. Removal of the rostral pons suppressed the delay in onset of the active phases of the phrenic rootlets. Our findings show that: (i) rhythmic activities of the trigeminal and facial rootlets are preserved in absence of control by peripheral or high cerebral structures; (ii) the pattern and the location of the rhythmic generator for these activities are of the respiratory type; and (iii) the rostral pons is responsible for a delay in the onset of the active phases of the phrenic rootlets compared with that of the trigeminal, facial and hypoglossal rootlets. [ABSTRACT FROM AUTHOR]