Biomedical subjects

Gordon S Mitchell

Publications and source records attributed to Gordon S Mitchell.

24 records · Page 2Linked to original sources

PubMed2003

Neuroplasticity in respiratory motor control.

Although recent evidence demonstrates considerable neuroplasticity in the respiratory control system, a comprehensive conceptual framework is lacking. Our goals in this review are to define plasticity (and related neural properties) as it pertains to respiratory control and to discuss potential sites, mechanisms, and known categories of respiratory plasticity. Respiratory plasticity is defined as a persistent change in the neural control system based on prior experience. Plasticity may involve structural and/or functional alterations (most commonly both) and can arise from multiple cellular/synaptic mechanisms at different sites in the respiratory control system. Respiratory neuroplasticity is critically dependent on the establishment of necessary preconditions, the stimulus paradigm, the balance between opposing modulatory systems, age, gender, and genetics. Respiratory plasticity can be induced by hypoxia, hypercapnia, exercise, injury, stress, and pharmacological interventions or conditioning and occurs during development as well as in adults. Developmental plasticity is induced by experiences (e.g., altered respiratory gases) during sensitive developmental periods, thereby altering mature respiratory control. The same experience later in life has little or no effect. In adults, neuromodulation plays a prominent role in several forms of respiratory plasticity. For example, serotonergic modulation is thought to initiate and/or maintain respiratory plasticity following intermittent hypoxia, repeated hypercapnic exercise, spinal sensory denervation, spinal cord injury, and at least some conditioned reflexes. Considerable work is necessary before we fully appreciate the biological significance of respiratory plasticity, its underlying cellular/molecular and network mechanisms, and the potential to harness respiratory plasticity as a therapeutic tool.

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PubMed2002

Role of synaptic inhibition in turtle respiratory rhythm generation.

In vitro brainstem and brainstem-spinal cord preparations were used to determine the role of synaptic inhibition in respiratory rhythm generation in adult turtles. Bath application of bicuculline (a GABA(A) receptor antagonist) to brainstems increased hypoglossal burst frequency and amplitude, with peak discharge shifted towards the burst onset. Strychnine (a glycine receptor antagonist) increased amplitude and frequency, and decreased burst duration, but only at relatively high concentrations (10-100 microM). Rhythmic activity persisted during combined bicuculline and strychnine application (50 microM each) with increased amplitude and frequency, decreased burst duration, and a rapid onset-decrementing burst pattern. The bicuculline-strychnine rhythm frequency decreased during mu-opioid receptor activation or decreased bath P(C)(O(2)). Synaptic inhibition blockade in the brainstem of brainstem-spinal cord preparations increased burst amplitude in spinal expiratory (pectoralis) nerves and nearly abolished spinal inspiratory activity (serratus nerves), suggesting that medullary expiratory motoneurons were mainly active. Under conditions of synaptic inhibition blockade in vitro, the turtle respiratory network was able to produce a rhythm that was sensitive to characteristic respiratory stimuli, perhaps via an expiratory (rather than inspiratory) pacemaker-driven mechanism. Thus, these data indicate that the adult turtle respiratory rhythm generator has the potential to operate in a pacemaker-driven manner.

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PubMed2002

Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis.

Respiratory long-term facilitation (LTF) is a form of serotonin-dependent plasticity induced by intermittent hypoxia. LTF is manifested as a long-lasting increase in respiratory amplitude (and frequency) after the hypoxic episodes have ended. We tested the hypotheses that LTF of phrenic amplitude requires spinal serotonin receptor activation and spinal protein synthesis. A broad-spectrum serotonin receptor antagonist (methysergide) or protein synthesis inhibitors (emetine or cycloheximide) were injected intrathecally in the cervical spinal cord of anesthetized rats. Control rats, injected with vehicle (artificial CSF), exhibited an augmented phrenic burst amplitude after three 5 min episodes of hypoxia (78 +/- 15% above baseline, 60 min after hypoxia; p < 0.05), indicating LTF. Pretreatment with methysergide, emetine, or cycloheximide attenuated or abolished phrenic LTF (20 +/- 4, 0.2 +/- 11, and 20 +/- 2%, respectively; all p > 0.05). With protein synthesis inhibitors, phrenic LTF differed from control by 15 min after intermittent hypoxia. As an internal control against unintended drug distribution, we measured respiratory LTF in hypoglossal (XII) motor output. At 60 min after intermittent hypoxia, all treatment groups exhibited similar XII LTF (artificial CSF, 44 +/- 10%; methysergide, 40 +/- 5%; emetine, 35 +/- 9%; and cycloheximide, 57 +/- 29%; all p < 0.05), suggesting that drugs were restricted at effective doses to the spinal cord. We conclude that phrenic LTF requires spinal serotonin receptor activation and protein synthesis. Serotonin receptors on phrenic motoneuron dendrites may induce new protein synthesis, thereby giving rise to phrenic LTF.

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PubMed2002

Intermittent hypoxia induces phrenic long-term facilitation in carotid-denervated rats.

Episodic hypoxia elicits a long-lasting augmentation of phrenic inspiratory activity known as long-term facilitation (LTF). We investigated the respective contributions of carotid chemoafferent neuron activation and hypoxia to the expression of LTF in urethane-anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats. One hour after three 5-min isocapnic hypoxic episodes [arterial Po(2) (Pa(O(2))) = 40 +/- 5 Torr], integrated phrenic burst amplitude was greater than baseline in both carotid-denervated (n = 8) and sham-operated (n = 7) rats (P < 0.05), indicating LTF. LTF was reduced in carotid-denervated rats relative to sham (P < 0.05). In this and previous studies, rats were ventilated with hyperoxic gas mixtures (inspired oxygen fraction = 0.5) under baseline conditions. To determine whether episodic hyperoxia induces LTF, phrenic activity was recorded under normoxic (Pa(O(2)) = 90-100 Torr) conditions before and after three 5-min episodes of isocapnic hypoxia (Pa(O(2)) = 40 +/- 5 Torr; n = 6) or hyperoxia (Pa(O(2)) > 470 Torr; n = 6). Phrenic burst amplitude was greater than baseline 1 h after episodic hypoxia (P < 0.05), but episodic hyperoxia had no detectable effect. These data suggest that hypoxia per se initiates LTF independently from carotid chemoafferent neuron activation, perhaps through direct central nervous system effects.

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PubMed2002

Chronic cervical spinal sensory denervation reveals ineffective spinal pathways to phrenic motoneurons in the rat.

We hypothesized that pretreatment with chronic cervical dorsal rhizotomy (CDR; C(3)-C(6)) would reveal ineffective crossed spinal pathways to phrenic motoneurons. Anesthetized CDR (1 week post-rhizotomy) and control rats were spinally hemisected at C(2), and phrenic potentials were evoked by stimulating the ventrolateral funiculus contralateral and rostral to hemisection. Phrenic potentials contralateral to the stimulating electrode were evoked at lower stimulus currents (CDR=640 +/- 46 microA; control=900 +/- 50 microA; P<0.05) and potential amplitude was significantly greater in CDR versus control rats (P<0.05). The serotonin receptor antagonist methysergide (4 mg/kg, i.v.) had no effect on the crossed phrenic potential amplitude (91+/-17% of control at 800 microA; P>0.05). Thus, CDR enhances crossed phrenic pathways but serotonin receptor activation is not necessary to maintain this effect.

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PubMed2002

Activity-dependent plasticity in descending synaptic inputs to respiratory spinal motoneurons.

This review focuses on recent evidence for short- and long-term activity-dependent plasticity in descending synaptic inputs to respiratory spinal motoneurons. In anesthetized rats, application of high frequency (100 Hz) conditioning stimulation to descending inputs to phrenic motoneurons elicits short-term potentiation of spontaneous inspiratory bursts. In turtle brainstem-spinal cords in vitro, 10-100 Hz conditioning stimulation elicits short-term potentiation in descending inputs to inspiratory-related serratus motoneurons; 100 Hz stimulation also elicits long-term potentiation in some preparations. In contrast, 1-10 Hz stimulation of descending synaptic inputs to expiratory-related pectoralis motoneurons elicits depression during conditioning stimulation (temporal depression), and long-term depression following stimulation. We hypothesize that inspiratory descending pathways to spinal motoneurons express short-term potentiation, with little evidence for long-term activity-dependent plasticity; other forms of long-lasting plasticity (e.g. serotonin-dependent long-term facilitation) may predominate in these pathways. In contrast, expiratory descending pathways appear biased towards activity-dependent depression possibly to conserve resources during passive expiration.

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