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Donald R McCrimmon

Publications and source records attributed to Donald R McCrimmon.

15 recordsLinked to original sources
PubMed2006

Central pathways of pulmonary and lower airway vagal afferents.

Lung sensory receptors with afferent fibers coursing in the vagus nerves are broadly divided into three groups: slowly (SAR) and rapidly (RAR) adapting stretch receptors and bronchopulmonary C fibers. Central terminations of each group are found in largely nonoverlapping regions of the caudal half of the nucleus of the solitary tract (NTS). Second order neurons in the pathways from these receptors innervate neurons located in respiratory-related regions of the medulla, pons, and spinal cord. The relative ease of selective activation of SARs, and to a lesser extent RARs, has allowed for more complete physiological and morphological characterization of the second and higher order neurons in these pathways than for C fibers. A subset of NTS neurons receiving afferent input from SARs (termed pump or P-cells) mediates the Breuer-Hering reflex and inhibits neurons receiving afferent input from RARs. P-cells and second order neurons in the RAR pathway also provide inputs to regions of the ventrolateral medulla involved in control of respiratory motor pattern, i.e., regions containing a predominance of bulbospinal premotor neurons, as well as regions containing respiratory rhythm-generating neurons. Axon collaterals from both P-cells and RAR interneurons, and likely from NTS interneurons in the C-fiber pathway, project to the parabrachial pontine region where they may contribute to plasticity in respiratory control and integration of respiratory control with other systems, including those that provide for voluntary control of breathing, sleep-wake behavior, and emotions.

Afferent Pathways↗
PubMed2005

Sodium currents in medullary neurons isolated from the pre-Bötzinger complex region.

The pre-Bötzinger complex (preBötC) in the ventrolateral medulla contains interneurons important for respiratory rhythm generation. Voltage-dependent sodium channels mediate transient current (I(NaT)), underlying action potentials, and persistent current (I(NaP)), contributing to repetitive firing, pacemaker properties, and the amplification of synaptic inputs. Voltage-clamp studies of the biophysical properties of these sodium currents were conducted on acutely dissociated preBötC region neurons. Reverse transcription-PCR demonstrated the presence of mRNA for Nav1.1, Nav1.2, and Nav1.6 alpha-subunits in individual neurons. A TTX-sensitive I(NaP) was evoked in all tested neurons by ramp depolarization from -80 to 0 mV. Including a constant in the Boltzmann equation for inactivation by estimating the steady-state fraction of Na+ channels available for inactivation allowed prediction of a window current that did not decay to 0 at voltages positive to -20 mV and closely matched the measured I(NaP). Riluzole (3 microM), a putative I(NaP) antagonist, reduced both I(NaP) and I(NaT) and produced a hyperpolarizing shift in the voltage dependence of steady-state inactivation. The latter decreased the predicted window current by an amount equivalent to the decrease in I(NaP). Riluzole also decreased the inactivation time constant at potentials in which the peak window/persistent currents are generated. Together, these findings imply that I(NaP) and I(NaT) arise from the same channels and that a simple modification of the Hodgkin-Huxley model can satisfactorily account for both currents. In the rostral ventral respiratory group (immediately caudal to preBötC), I(NaP) was also detected, but peak conductance, current density, and input resistance were smaller than in preBötC region cells.

Action Potentials↗
PubMed2004

Pontine influences on breathing: an overview.

Historical and contemporary views of the functional organization of the lateral pontine regions influencing breathing are reviewed. In vertebrates, the rhombencephalon generates a breathing rhythm and detailed motor pattern that persist throughout life. Key to this process is an essentially continuous column of neurons extending from the spino-medullary border through the ventrolateral medulla, continuing through the ventral pons and arcing into the dorsolateral medulla. Comparative neuroanatomy and physiology indicate this is a richly interconnected network divided into serial, functionally distinct compartments. Serial compartmentalization of pontomedullary structures related to breathing also reflects the developmental segmentation of the rhombencephalon. However, with migration of cell groups such as the facial nucleus from the pons to the medulla during ontogeny, the boundaries of the adult pons are sometimes difficult to precisely define. Accordingly, a working definition of rostral and caudal pontine boundaries for adult mammals is depicted.

Animals↗
PubMed2004

Parabrachial-lateral pontine neurons link nociception and breathing.

We investigated the role of the parabrachial complex in cutaneous nociceptor-induced respiratory stimulation in chloralose-urethane anesthetized, vagotomized rats. Noxious stimulation (mustard oil, MO) applied topically to a forelimb or hindlimb enhanced the peak amplitude of the integrated phrenic nerve discharge and, with forelimb application, increased phrenic nerve burst frequency. Bilateral inactivation of neural activity in the parabrachial complex with injection of the GABA agonist muscimol (3nl) markedly attenuated the response to MO application. Injection of the retrograde tracer FluoroGold within the medullary ventral respiratory column labeled neurons in dorsolateral pontine regions known to receive nociceptive inputs (i.e., Kolliker-Fuse, lateral crescent, and superior lateral subnuclei of the parabrachial complex). Extracellular recordings of 65 dorsolateral parabrachial neurons revealed about 15% responded to a noxious cutaneous pinch with either an increase or a decrease in discharge and approximately 40% of these exhibited a phasic respiratory-related component to their discharge. In conclusion, parabrachial pontine neurons contribute to cutaneous nociceptor-induced increases in breathing.

Action Potentials↗
PubMed2004

Resurgent Na currents in four classes of neurons of the cerebellum.

Action potential firing rates are generally limited by the refractory period, which depends on the recovery from inactivation of voltage-gated Na channels. In cerebellar Purkinje neurons, the kinetics of Na channels appear specialized for rapid firing. Upon depolarization, an endogenous open-channel blocker rapidly terminates current flow but prevents binding of the "fast" inactivation gate. Upon repolarization, unbinding of the blocker produces "resurgent" Na current while allowing channels to recover rapidly. Because other cerebellar neurons, including granule cells, unipolar brush cells, and neurons of the cerebellar nuclei, also fire rapidly, we tested whether these cells might also express Na channels with resurgent kinetics. Neurons were acutely isolated from mice and rats, and TTX-sensitive Na currents were recorded under voltage clamp. Unlike Purkinje cells, the other cerebellar neurons produced only tiny resurgent currents in solutions optimized for voltage-clamping Na currents (50 mM Na+; Co2+ substitution for Ca2+). Under more physiological ionic conditions (155 mM Na+; 2 mM Ca2+ with 0.03 mM Cd2+), however, granule cells, unipolar brush cells, and cerebellar nuclear cells all produced robust resurgent currents. The increase in resurgent current, which was greater than predicted by the Goldman-Hodgkin-Katz equation, appeared to result from a combination of knock-off of open-channel blockers by permeating ions as well as relief of divalent block at negative potentials. These results indicate that resurgent current is typical of many cerebellar neurons and suggest that rapid open-channel block and unblock may be a widespread mechanism for restoration of Na channel availability in rapidly firing neurons.

Animals↗
PubMed2004

Intrinsic bursting activity in the pre-Bötzinger complex: role of persistent sodium and potassium currents.

Computational models of single pacemaker neuron and neural population in the pre-Bötzinger Complex (pBC) were developed based on the previous models by Butera et al. (1999a,b). Our modeling study focused on the conditions that could define endogenous bursting vs. tonic activity in single pacemaker neurons and population bursting vs. asynchronous firing in populations of pacemaker neurons. We show that both bursting activity in single pacemaker neurons and population bursting activity may be released or suppressed depending on the expression of persistent sodium ( I(Na) P) and delayed-rectifier potassium ( I(K)) currents. Specifically, a transition from asynchronous firing to population bursting could be induced by a reduction of I(K) via a direct suppression of the potassium conductance or through an elevation of extracellular potassium concentration. Similar population bursting activity could be triggered by an augmentation of I(Na) P. These findings are discussed in the context of the possible role of population bursting activity in the pBC in the respiratory rhythm generation in vivo vs. in vitro and during normal breathing in vivo vs. gasping.

Action Potentials↗
PubMed2004

Concept mapping in pulmonary physiology using pathfinder scaling.

This three-part article begins with a brief presentation of a framework that describes different approaches to conduct and report research on expert knowledge. The framework contrasts direct vs. indirect approaches and provides examples of each. Second, the article gives a detailed description of the methods and results of three concept mapping studies in pulmonary physiology that employ Pathfinder scaling, an indirect approach. The studies derive concepts maps for a variety of faculty experts individually and in groups. Two of the studies focus on changes in students' concept maps of the pulmonary physiology concepts as a result of instruction. Changes are gauged in terms of the degree to which students' concept maps approximate instructors' concept maps due to educational interventions. An index of student-instructor concept map similarity is also correlated with student performance on final examinations. The article concludes by articulating several "next steps" in the Feinberg Northwestern and Wisconsin program of health sciences education research on concept mapping using Pathfinder scaling.

Adult↗
PubMed2003

Sodium currents in neurons from the rostroventrolateral medulla of the rat.

Rapidly inactivating and persistent sodium currents have been characterized in acutely dissociated neurons from the area of rostroventrolateral medulla that included the pre-Bötzinger Complex. As demonstrated in many studies in vitro, this area can generate endogenous rhythmic bursting activity. Experiments were performed on neonate and young rats (P1-15). Neurons were investigated using the whole cell voltage-clamp technique. Standard activation and inactivation protocols were used to characterize the steady-state and kinetic properties of the rapidly inactivating sodium current. Slow depolarizing ramp protocols were used to characterize the noninactivating sodium current. The "window" component of the rapidly inactivating sodium current was calculated using mathematical modeling. The persistent sodium current was revealed by subtraction of the window current from the total noninactivating sodium current. Our results provide evidence of the presence of persistent sodium currents in neurons of the rat rostroventrolateral medulla and determine voltage-gated characteristics of activation and inactivation of rapidly inactivating and persistent sodium channels in these neurons.

Animals↗
PubMed2002

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.

Animals↗
PubMed2002

Gain modulation of respiratory neurons.

A possible mechanism underlying adaptive control of the respiratory system is gain modulation of the discharge frequency (F(n)) patterns of medullary respiratory neurons mediated by GABA(A) receptors. Antagonism of GABA(A) receptors with bicuculline results in an F(n) pattern that is an amplified replica of the underlying control pattern. The contours of F(n) patterns remain proportional to one another. Studies suggest that a tonic GABA(A)ergic input constrains the control- and reflexly-induced activities of these neurons to about 35-50% of the discharge rate without this inhibitory input. The pharmacology of this mechanism is unusual in that picrotoxin, a noncompetitive GABA(A) receptor antagonist, does not produce gain modulation, but is able to block the silent phase inhibition (e.g. E phase of an I neuron). Alterations in the amplitude of spike afterhyperpolarizations mediated by Ca(2+) activated K(+) channels also produces gain modulation. This mechanism modulates exogenously- and endogenously-induced neuronal activities, whereas the bicuculline-sensitive GABAergic mechanism modulates only the respiratory-related activities. Thus, these two forms of gain modulation, acting in cascade manner, may provide robust mechanisms for the optimal control of respiratory, as well as other behavioral functions (e.g. coughing, sneezing, vomiting) mediated by respiratory premotor neurons.

Adaptation, Physiological↗