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D R McCrimmon

Publications and source records attributed to D R McCrimmon.

At least 19 recordsLinked to original sources
PubMed2003

Defining ventral medullary respiratory compartments with a glutamate receptor agonist in the rat.

The regional organization of the ventral respiratory group (VRG) was examined with respect to generation of respiratory rhythm (breathing frequency) versus control of the respiratory motor pattern on individual nerves. In urethane-anaesthetized, neuromuscularly blocked and vagotomized Sprague-Dawley rats, arterial blood pressure (ABP) and respiratory motor outputs (phrenic, pharyngeal branch of the vagus, or superior laryngeal nerves) were recorded. The VRG organization was mapped systematically using injections of the excitatory amino acid DL-homocysteic acid (DLH; 5-20 mM, 2-6 nl) from single- or double-barrel pipettes at 100-200 microm intervals between the facial nucleus and the calamus scriptorius. Recording of respiratory neurons through the injection pipette ensured that the pipette was located within the VRG. At the end of each experiment, the injection pipette was used to make an electrical lesion, thereby marking the electrode position for subsequent histological reconstruction of injection sites. Four rostrocaudal regions were identified: (1) a rostral bradypnoea area, at the level of the Bötzinger complex, in which respiratory rhythm slowed and ABP increased, (2) a tachypnoea/dysrhythmia area, at the level of the preBötzinger complex, in which breathing rate either increased or became irregular, with little or no change in ABP, (3) a caudal bradypnoea area at the level of the anterior part of the rostral VRG in which ABP decreased and (4) a caudal 'no effect' region in the posterior part of the rostral VRG. The peak amplitude of phrenic nerve activity decreased with injections into all three rostral regions. Changes in respiratory rhythm were associated with opposite changes in inspiratory (TI) and expiratory (TE) durations after injections into either the Bötzinger complex or anterior rostral VRG, while both TI and TE decreased after injections into the preBötzinger complex. Effects on selected cranial nerves were similar to those on the phrenic nerve except that tonic activity was elicited on the superior larygneal nerve ipsilateral to injections in the Bötzinger complex and on the pharyngeal branch of the vagus ipsilateral to injections in the preBötzinger complex. These data reinforce the subdivision of the VRG into functionally distinct compartments and suggest that a further subdivision of the rostral VRG is warranted. They also suggest that region-specific influences, especially on the pattern of cranial motor discharge, can be used to assist the identification of recording sites within the VRG. However, the postulated clear functional separation of rhythm- versus pattern-generating regions was not supported.

Animals↗
PubMed2003

Differential processing of excitation by GABAergic gain modulation in canine caudal ventral respiratory group neurons.

The discharge frequency (F(n)) patterns of medullary respiratory premotor neurons are subject to potent tonic GABAergic gain modulation. Studies in other neuron types suggest that the synaptic input for tonic inhibition is located on the soma where it can affect total neuronal output. However, our preliminary data suggested that excitatory responses elicited by highly local application of glutamate receptor agonists are not gain modulated. In addition, modulation of the amplitude of spike afterhyperpolarizations can gain modulate neuronal output, and this mechanism is located near the spike initiation zone and/or soma. The purpose of this study was to determine if these two gain-modulating mechanisms have different functional locations on the somatodendritic membrane of bulbospinal inspiratory and expiratory neurons. Four-barrel micropipettes were used for extracellular single-neuron recording and pressure ejection of drugs in decerebrate, paralyzed, ventilated dogs. The net increases in F(n) due to repeated short-duration picoejections of the glutamate receptor agonist, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), was quantified before and during locally induced antagonism of GABA(A) receptors by bicuculline or small-conductance, calcium-activated potassium channels by apamin. The AMPA-induced net increases in F(n) were not significantly altered by BIC, although it produced large increases in the respiratory-related activity. However, the AMPA-induced net responses were amplified in accordance with the gain increase of the respiratory-related activity by apamin. These findings suggest that GABAergic gain modulation may be functionally isolated from the soma/spike initiation zone, e.g., located on a dendritic shaft. This could allow other behavioral signals requiring strong neuronal activation (e.g., coughing, sneezing, vomiting) to utilize the same neuron without being attenuated by the GABAergic modulation.

Action Potentials↗
PubMed2002

Short-term plasticity of descending synaptic input to phrenic motoneurons in rats.

Respiratory afferent stimulation can elicit increases in respiratory motor output that outlast the period of stimulation by seconds to minutes [short-term potentiation (STP)]. This study examined the potential contribution of spinal mechanisms to STP in anesthetized, vagotomized, paralyzed rats. After C(1) spinal cord transection, stimulus trains (100 Hz, 5-60 s) of the C(1)-C(2) lateral funiculus elicited STP of phrenic nerve activity that peaked several seconds poststimulation. Intracellular recording revealed that individual phrenic motoneurons exhibited one of three different responses to stimulation: 1) depolarization that peaked several seconds poststimulation, 2) depolarization during stimulation and then exponential repolarization after stimulation, and 3) bistable behavior in which motoneurons depolarized to a new, relatively stable level that was maintained after stimulus termination. During the STP, excitatory postsynaptic potentials elicited by single-stimulus pulses were larger and longer. In conclusion, repetitive activation of the descending inputs to phrenic motoneurons causes a short-lasting depolarization of phrenic motoneurons, and augmentation of excitatory postsynaptic potentials, consistent with a contribution to STP.

Animals↗
PubMed2001

Respiratory rhythm generation: preBötzinger neuron discharge patterns and persistent sodium current.

Considerable evidence from several laboratories (c.f., Rekling and Feldman, Ramirez et al.) is consistent with the concept that the pBc contains the kernel of the central rhythm generating network for breathing. The work summarized in this manuscript is also generally consistent with this notion. Of particular note is the observation that pre-I neurons and E-Dec neurons maintain a consistent phase relationship with phrenic nerve activity and maintain a similar peak discharge rate despite marked changes in the phrenic nerve rhythm and pattern. Other categories of respiratory neurons failed to maintain this relationship. Hence, the findings are consistent with pBc pre-I and E-Dec neurons having a key role in rhythm generation. A persistent sodium current has been postulated to underlie the rhythm generating mechanism of pacemaker neurons within the pBc. In the present study, a substantial persistent sodium current was documented in many neurons from the pBc and adjacent respiratory regions. This finding is not inconsistent with the postulated role in rhythm generation. However, it does suggest that other neuronal properties must act in concert with the persistent current to define a unique population of pacemaker neurons.

Animals↗
PubMed2001

Normal breathing requires preBötzinger complex neurokinin-1 receptor-expressing neurons.

The normal breathing rhythm in mammals is hypothesized to be generated by neurokinin-1 receptor (NK1R)-expressing neurons in the preBötzinger complex (preBötC), a medullary region proposed to contain the kernel of the circuits generating respiration. If this hypothesis is correct, then complete destruction of preBötC NK1R neurons should severely perturb and perhaps even fatally arrest breathing. Here we show that specific and near complete bilateral (but not unilateral) destruction of preBötC NK1R neurons results in both an ataxic breathing pattern with markedly altered blood gases and pH, and pathological responses to challenges such as hyperoxia, hypoxia and anesthesia. Thus, these approximately 600 neurons seem necessary for the generation of normal breathing in rats.

Animals↗
PubMed2001

Differential modulation of respiratory neuronal discharge patterns by GABA(A) receptor and apamin-sensitive K(+) channel antagonism.

The discharge patterns of respiratory neurons of the caudal ventral respiratory group (cVRG) appear to be subject to potent GABAergic gain modulation. Local application of the GABA(A) receptor antagonist bicuculline methochloride amplifies the underlying discharge frequency (F(n)) patterns mediated by endogenous excitatory and inhibitory synaptic inputs. Gain modulation can also be produced by alterations in the amplitude of spike afterhyperpolarizations (AHPs) mediated by apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels. Since methyl derivatives of bicuculline (BICm) also have been shown to reduce the amplitude of AHPs, in vitro, it is possible that the BICm-induced gain modulation is due to a block of SK channels. The purpose of these studies was to determine the mechanisms by which BICm produces gain modulation and to characterize the influence of SK channels in the control of respiratory neuron discharge. Six protocols were used in this in vivo study of cVRG inspiratory (I) and expiratory (E) neurons in decerebrate, paralyzed, ventilated dogs. The protocols included characterizations of the neuronal responses to 1) BICm and apamin on the same neuron, 2) BICm during maximum apamin-induced block of AHPs, 3) apamin during maximum BICm-induced gain modulatory responses, 4) the specific GABA(A) receptor antagonist, (+)beta-hydrastine, 5) the specific GABA(A) receptor agonist, muscimol, and 6) the GABA uptake inhibitor, nipecotic acid. For protocols 3, 5, and 6, only E neurons were studied. Four-barrel micropipettes were used for extracellular single neuron recording and pressure ejection of drugs. Cycle-triggered histograms were used to quantify the F(n) patterns and to determine the drug-induced changes in the gain (slope) and offset of the F(n) patterns. Compared to apamin at maximum effective dose rates, BICm produced a 2.1-fold greater increase in peak F(n) and a 3.1-fold greater increase in average F(n). BICm and apamin produced similar increases in gain, but the offsets due to apamin were more negative. The responses to hydrastine were similar to BICm. During maximum apamin block, BICm produced an additional 112 +/- 22% increase in peak F(n). Conversely, apamin produced an additional 176 +/- 74% increase in peak F(n) during the maximum BICm-induced response. Muscimol and nipecotic acid both decreased the gain and offset of the discharge patterns. Taken together, these results suggest that the gain modulatory effect of BICm is due to a reduction of GABA(A)-ergic shunting inhibition rather than a reduction in AHPs by block of SK channels in canine cVRG neurons.

Alkaloids↗
PubMed2000

Unraveling the mechanism for respiratory rhythm generation.

Breathing is generated by a neuronal network located within the caudal brainstem. One area of particular significance for respiratory rhythm generation is the pre-Bötzinger (preBotC) complex in the ventrolateral medulla. An important step towards understanding the cellular and network basis by which neurons within this region generate the respiratory rhythm was made in a recent study by Koshiya and Smith.(1) Using simultaneous image analysis and electrophysiological techniques these authors identified a discrete population of synaptically-coupled pacemaker neurons within the preBotC. They postulated that these neurons constitute the minimal essential network component (kernel) for generating the respiratory rhythm. BioEssays 22:6-9, 2000.

Animals↗
PubMed2000

Medical and veterinary students' structural knowledge of pulmonary physiology concepts.

PURPOSE: The goal of this study was to assess quantitatively medical and veterinary students' knowledge structures of 12 pulmonary physiology concepts before and after receiving a focused instructional block. The "goodness of fit" and internal consistency reliability of the students' knowledge structures were evaluated. Indexes of the students' structural knowledge were correlated with customary measures of student learning of the same concepts. METHOD: Knowledge structures were assessed using a questionnaire that requested similarity judgments about all possible pairs of the concepts: n(n - 1)/2 = 66 pairs. The similarity judgment data were analyzed using the individual differences (INDSCAL) model of multidimensional scaling (MDS). Dimension weights for individual students were then correlated with their final examination scores. RESULTS: A four-dimensional MDS solution provided the best structural fit to the pairwise concept-similarity data. Dimension 1 ranges from control of breathing to lung gas exchange. Dimension 2 ranges from control of breathing to respiratory mechanics. Dimension 3 separates perfusion from diffusion. Dimension 4 addresses ventilatory control. Hierarchical concept clusters are located within this framework. However, indexes of structural learning did not correlate with other measures of knowledge about the same concepts. CONCLUSION: The study outcomes, in contrast to research in other fields, suggest that structural knowledge in this domain differs from knowledge assessed by standard examinations. Further research involving other basic science or clinical concept sets is needed to verify or refute this finding.

Education, Medical↗
PubMed2000

Quantitative concept mapping in pulmonary physiology: comparison of student and faculty knowledge structures.

Quantitative concept mapping, in contrast with qualitative approaches, is rigorous scientifically and permits statistical analyses of data about concept learning. This study extends past quantitative research on the structure of student concept learning in pulmonary physiology. Pathfinder scaling is used to derive concept maps for medical and veterinary students and their physiology instructors at Northwestern University and the University of Wisconsin, respectively. The concept maps are evaluated for coherence (internal consistency), student-instructor similarity, and correlation of similarity with final examination scores. Results show that student and instructor concept maps are coherent and that student concept maps become increasingly similar to instructors' concept maps from pre- to postinstruction, but that student-instructor concept map similarity does not correlate with examination performance. Research outcomes are discussed concerning possible sources of variation in student and faculty knowledge structures.

Data Collection↗
PubMed2000

Relative magnitude of tonic and phasic synaptic excitation of medullary inspiratory neurons in dogs.

The relative contribution of phasic and tonic excitatory synaptic drives to the augmenting discharge patterns of inspiratory (I) neurons within the ventral respiratory group (VRG) was studied in anesthetized, ventilated, paralyzed, and vagotomized dogs. Multibarrel micropipettes were used to record simultaneously single-unit neuronal activity and pressure microejected antagonists of GABAergic, glycinergic, N-methyl-D-aspartate (NMDA) and non-NMDA glutamatergic, and cholinergic receptors. The discharge patterns were quantified via cycle-trigger histograms. The findings suggest that two-thirds of the excitatory drive to caudal VRG I neurons is tonic and mediated by NMDA receptors and the other third is ramp-like phasic and mediated by non-NMDA receptors. Cholinergic receptors do not appear to be involved. The silent expiratory phase is produced by phasic inhibition of the tonic activity, and approximately 80% of this inhibition is mediated by gamma-aminobutyric acid receptors (GABA(A)) and approximately 20% by glycine receptors. Phasic I inhibition by the I decrementing neurons does not appear to contribute to the predominantly step-ramp patterns of these I neurons. However, this decrementing inhibition may be very prominent in controlling the rate of augmentation in late-onset I neurons and those with ramp patterns lacking the step component.

2-Amino-5-phosphonovalerate↗
PubMed1999

Differential roles of ionotropic glutamate receptors in canine medullary inspiratory neurons of the ventral respiratory group.

The relative roles of ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in supplying excitatory drive to inspiratory (I) augmenting pattern neurons of the ventral respiratory group were studied in anesthetized, ventilated, paralyzed, and vagotomized dogs. Multibarrel micropipettes were used to record simultaneously single-unit neuronal activity and pressure microeject the NMDA antagonist, 2-amino-5-phosphonovalerate (AP5; 2 mM), the non-NMDA antagonist 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX; 0.25 mM), and an artificial cerebrospinal fluid vehicle. Ejected volume-rates were measured directly via meniscus level changes. The moving time average of phrenic nerve activity was used to determine respiratory phase durations and to synchronize cycle-triggered histograms of the discharge patterns. Both AP5 and NBQX produced dose-dependent reductions in peak spontaneous I neuronal discharge frequency (Fn). The average (+/- SE) maximum reduction in peak Fn produced by AP5 was 69.1 +/- 4.2% and by NBQX was 47.1 +/- 3.3%. Blockade of both glutamate receptor subtypes nearly silenced these neurons, suggesting that their activity is highly dependent on excitatory synaptic drive mediated by ionotropic glutamate receptors. Differential effects were found for the two glutamatergic antagonists. AP5 produced downward, parallel shifts in the augmenting pattern of discharge, whereas NBQX reduced the slope of the augmenting discharge pattern. These results suggest that time-varying excitatory input patterns to the canine I bulbospinal neurons are mediated by non-NMDA glutamate receptors and that constant or tonic input patterns to these neurons are mediated by NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1998

Differential effects of GABAA receptor antagonists in the control of respiratory neuronal discharge patterns.

To ascertain the role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in shaping and controlling the phasic discharge patterns of medullary respiratory premotor neurons, localized pressure applications of the competitive GABAA receptor antagonist bicuculline (BIC) and the noncompetitive GABAA receptor antagonist picrotoxin (PIC) were studied. Multibarrel micropipettes were used in halothane anesthetized, paralyzed, ventilated, vagotomized dogs to record single unit activity from inspiratory and expiratory neurons in the caudal ventral respiratory group and to picoeject GABAA receptor antagonists. The moving time average of phrenic nerve activity was used to determine respiratory phase durations and to synchronize cycle-triggered histograms of discharge patterns. Picoejection of BIC and PIC had qualitatively different effects on the discharge patterns of respiratory neurons. BIC caused an increase in the discharge rate during the neuron's active phase without inducing activity during the neuron's normally silent phase. The resulting discharge patterns were amplified replicas (x2-3) of the underlying preejection phasic patterns. In contrast, picoejection of PIC did not increase the peak discharge rate during the neuron's active phase but induced a tonic level of activity during the neuron's normally silent phase. The maximum effective BIC dose (15 +/- 1.8 pmol/min) was considerably smaller than that for PIC (280 +/- 53 pmol/min). These findings suggest that GABAA receptors with differential pharmacology mediate distinct functions within the same neuron, 1) gain modulation that is BIC sensitive but PIC insensitive and 2) silent-phase inhibition blocked by PIC. These studies also suggest that the choice of an antagonist is an important consideration in the determination of GABA receptor function within the respiratory motor control system.

Animals↗
PubMed1997

Modulation of the synaptic drive to respiratory premotor and motor neurons.

The characteristics of GABAergic inhibitory modulation of respiratory bulbospinal neuronal activity and short-term potentiation (STP) of phrenic motoneuronal activity were studied. Extracellular unit recording and picoejection techniques in anesthetized dogs showed that both the spontaneous rhythmic and reflexly induced discharge patterns of inspiratory (I) and expiratory (E) premotor neurons were proportionately amplified by the localized application of picomole amounts of bicuculline (Bic), a competitive GABAA antagonist. Intracellular recording and paired-pulse stimulation techniques in anesthetized rats demonstrated an STP of phrenic motor output that appears to be mediated by NMDA receptors and is associated with facilitation of EPSPs and prolonged depolarization of individual phrenic motoneurons. We speculate that both GABAergic gain modulation of premotor neuronal activity and NMDA-mediated STP of phrenic activity may be neural substrates which are involved with the optimization of respiratory and non-respiratory behaviors, via adaptive and/or differential control of breathing.

Action Potentials↗
PubMed1996

Respiratory neurons mediating the Breuer-Hering reflex prolongation of expiration in rat.

Afferent input from pulmonary stretch receptors is important in the control of the timing of inspiratory and expiratory phases of the respiratory cycle. The current study was undertaken to identify neurons within a column of respiratory neurons in the ventrolateral medulla (termed the ventral respiratory group, VRG) that, when activated by lung inflation, produce the Breuer-Hering (BH) reflex in which lung inflation causes inspiratory termination and expiratory prolongation. Intracellular recordings of VRG neurons revealed three groups of inspiratory (I) and two groups of expiratory (E) neurons similar to previous descriptions: I-augmenting (I-Aug), I-decrementing (I-Dec), I-plateau (I-All), E-augmenting (E-Aug), and E-decrementing (E-Dec) neurons. Low-intensity, low-frequency stimulation of a vagus nerve elicited paucisynaptic EPSPs in E-Dec, I-Aug, and I-All neurons that could be divided into two groups on the basis of latency (2.8 +/- 0.1 msec, n = 10; 4.0 +/- 0.1 msec, n = 17). IPSPs were elicited in I-Aug and I-All neurons (4.8 +/- 0.1 msec, n = 12). However, only E-Dec neurons were depolarized when the BH reflex was activated by lung inflation (7.5 cm H2O) or mimicked by vagus nerve stimulation (50 Hz). All other neurons were hyperpolarized and ceased firing during BH reflex-mediated expiratory prolongation. A subset of E-Dec neurons (termed E-Decearly) discharged before inspiratory termination and could contribute to inspiratory termination. The findings are consistent with the hypothesis that a group of E-Dec neurons receives a paucisynaptic (probably disynaptic) input from pulmonary afferents and, in turn, inhibits inspiratory neurons, thereby lengthening expiration.

Afferent Pathways↗
PubMed1996

Respiratory motor responses to cranial nerve afferent stimulation in rats.

It was hypothesized that, because rats appear to lack a prominent disynaptic projection from the dorsal respiratory group to phrenic motoneurons (Phr), they would lack the short-latency excitation of Phr output seen in cats in response to stimulation of some cranial nerve afferents. Single-pulse superior laryngeal nerve (SLN) stimulation elicited a short-latency bilateral excitation of glossopharyngeal (IX) and hypoglossal (XII) nerves and an ipsilateral excitation of pharyngeal branch of vagus (PhX) in 67% of rats, but no excitation of Phr. Vagus (X) stimulation elicited a bilateral excitation of Phr and a predominantly ipsilateral excitation of IX and PhX. Single-pulse stimulation of SLN or X also elicited longer-latency, bilateral decreases in activity of all recorded nerves. Repetitive stimulation (50 Hz) of SLN or X suppressed inspiratory activity and prolonged expiration. Lung inflation (7.5 cmH2O) inhibited Phr and PhX activity; X stimulation inhibited Phr but prolonged PhX activity. In conclusion, rats predictably lack the SLN-induced short latency Phr excitation but exhibit other short latency reflexes for which the underlying circuitry is not clear.

Afferent Pathways↗
PubMed1995

NMDA receptor-mediated transmission of carotid body chemoreceptor input to expiratory bulbospinal neurones in dogs.

1. This study tested the hypothesis that excitatory amino acid receptors mediate the excitatory response of expiratory bulbospinal neurones to carotid body chemoreceptor inputs. 2. Studies were carried out in thiopental sodium anaesthetized, paralysed, ventilated, vagotomized dogs. 3. Brisk, short-duration chemoreceptor activation was produced by bilateral bolus injections of CO2-saturated saline (PCO2 > 700 mmHg) into the autoperfused carotid arteries. A pressurized-reservoir-solenoid valve system was used to deliver the CO2 bolus injections just prior to the onset of the neural expiratory phase, as determined from the phrenic neurogram, about once per minute. 4. Multibarrelled micropipettes were used to record neuronal unit activity and deliver neurotransmitter agents. Net responses of expiratory bulbospinal neurones to peripheral chemoreceptor activation were determined by subtracting the mean discharge frequencies (Fn) during three control expiratory cycles from the Fn during administration of a CO2 test bolus. The role of excitatory amino acid receptors in mediating this response was determined by comparing the baseline and bolus expiratory neuronal Fn before, during and after the pressure microejection of the NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP5) or the non-NMDA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl- benzo(f)quinoxaline (NBQX). Ejection rates of AP5 and NBQX were measured by monitoring the movement of the pipette meniscus. 5. AP5 reduced Fn during both the control and bolus cycles, as well as reducing the change in Fn between control and bolus cycles. NBQX had no effect on either baseline or bolus responses. 6. AP5 did not prevent excitation of expiratory bulbospinal neurones by AMPA. Coadministration of AMPA with AP5 prevented the AP5-mediated decrease in Fn but not the dose-dependent reduction in the CO2 bolus response. 7. Taken together, these data strongly suggest that the carotid chemoreceptor-mediated excitation of expiratory bulbospinal neurones is dependent on NMDA but not non-NMDA glutamate receptors.

2-Amino-5-phosphonovalerate↗