Biomedical subjects

Ronald L Calabrese

Publications and source records attributed to Ronald L Calabrese.

At least 19 recordsLinked to original sources

PubMed2006

Hybrid systems analysis of the control of burst duration by low-voltage-activated calcium current in leech heart interneurons.

The leech heartbeat CPG is paced by the alternating bursting of pairs of mutually inhibitory heart interneurons that form elemental half-center oscillators. We explore the control of burst duration in heart interneurons using a hybrid system, where a living, pharmacologically isolated, heart interneuron is connected with artificial synapses to a model heart interneuron running in real-time, by focusing on a low-voltage-activated (LVA) calcium current I(CaS). The transition from silence to bursting in this half-center oscillator occurs when the spike frequency of the bursting interneuron declines to a critical level, f(Final), at which the inhibited interneuron escapes owing to a build-up of the hyperpolarization-activated cation current, I(h). We varied I(CaS) inactivation time constant either in the living heart interneuron or in the model heart interneuron. In both cases, varying I(CaS) inactivation time constant did not affect f(Final) of either interneuron, but in the varied interneuron, the time constant of decline of spike frequency during bursts to f(Final) and thus the burst duration varied directly and nearly linearly with I(CaS) inactivation time constant. Bursts of the opposite, nonvaried interneuron did not change. We show also that control of burst duration by I(CaS) inactivation does not require synaptic interaction by reconstituting autonomous bursting in synaptically isolated living interneurons with injected I(CaS). Therefore inactivation of LVA calcium current is critically important for setting burst duration and thus period in a heart interneuron half-center oscillator and is potentially a general intrinsic mechanism for regulating burst duration in neurons.

Algorithms↗

PubMed2006

Endogenous and half-center bursting in morphologically inspired models of leech heart interneurons.

Based on a detailed morphology "Full Model" of a leech heart interneuron, we previously developed a computationally efficient, morphologically inspired "Reduced Model" to expedite tuning the model to produce endogenous bursting and alternating bursting when configured as a half-center oscillator (paired with reciprocally inhibitory synapses). To find conductance density distributions that produce endogenous bursting, we implemented a genetic algorithm automated parameter search. With multiple searches, we found eight parameter sets that produced endogenous bursting in the Reduced Model. When these parameter sets were applied to the Full Model, all produced endogenous bursting, although when the simulation time was extended from 80 to 300 s, only four parameter sets produced sustained bursting in the Reduced Models. All parameter sets produced alternating half-center bursting in the Reduced and Full Models throughout the entire 300 s. When conductance amplitudes were systematically varied for each of the four sustained burster sets, the effects on bursting activity differed, both for the same parameter set in the Reduced and Full Models and for different parameter sets with the same level of morphological detail. This implies that morphological detail can affect burst activity and that these parameter sets may represent different mechanisms for burst generation and/or regulation. We also tested the models with parameter variations that correspond to experimental manipulations. We conclude that, whereas similar output can be achieved with multiple different parameter sets, perturbations such as conductance variations can highlight differences. Additionally, this work demonstrates both the utility and limitations of using simplified models to represent more morphologically accurate models.

Action Potentials↗

PubMed2006

Creation and reduction of a morphologically detailed model of a leech heart interneuron.

Conductance-based neuron models aid in understanding the role intrinsic and synaptic currents play in producing neuronal activity. Incorporating morphological detail into a model allows for additional analysis of nonhomogeneous distributions of active and synaptic conductances, as well as spatial segregation of electrical events. We developed a morphologically detailed "Full Model" of a leech heart interneuron that replicates reasonably well intracellular recordings from these interneurons. However, it constitutes hundreds of compartments, each increasing parameter space and simulation time. To reduce the number of compartments of the Full Model, while preserving conductance densities and distributions, its compartments were grouped into functional groups that each share identical conductance densities. Each functional group was sequentially reduced to one or two compartments, preserving surface area, conductance densities, and its contribution to input resistance. As a result, the input resistance and membrane time constant were preserved. The axial resistances of several compartments were rescaled to match the amplitude of synaptic currents and low-threshold calcium currents and the shape of action potentials to those in the Full Model. This reduced model, with intrinsic conductances, matched the activity of the Full Model for a variety of simulated current-clamp and voltage-clamp data. Because surface area and conductance distribution of the functional groups of the Full Model were maintained, parameter changes introduced into the reduced model can be directly translated to the Full Model. Thus our computationally efficient reduced morphology model can be used as a tool for exploring the parameter space of the Full Model and in network simulations.

Action Potentials↗

PubMed2006

Graded inhibitory synaptic transmission between leech interneurons: assessing the roles of two kinetically distinct low-threshold Ca currents.

In leeches, two pairs of reciprocally inhibitory heart interneurons that form the core oscillators of the pattern-generating network for heartbeat possess both high- and low-threshold (HVA and LVA) Ca channels. LVA Ca current has two kinetically distinct components (one rapidly activating/inactivating, ICaF, and another slowly activating/inactivating, ICaS) that mediate graded transmission, generate plateau potentials driving burst formation, and modulate spike-mediated transmission between heart interneurons. Here we used different stimulating protocols and inorganic Ca channel blockers to separate the effects of ICaF and ICaS on graded synaptic transmission and determine their interaction and relative efficacy. Ca2+ entering by ICaF channels is more efficacious in mediating release than that entering by ICaS channels. The rate of Ca2+ entry by LVA Ca channels appears to be as critical as the amount of delivered Ca2+ for synaptic transmission. LVA Ca currents and associated graded transmission were selectively blocked by 1 mM Ni2+, leaving spike-mediated transmission unaffected. Nevertheless, 1 mM Ni2+ affected homosynaptic enhancement of spike-mediated transmission that depends on background Ca2+ provided by LVA Ca channels. Ca2+ provided by both ICaF and ICaS depletes a common pool of readily releasable synaptic vesicles. The balance between availability of vesicles and Ca2+ concentration and its time course determine the strength of inhibitory transmission between heart interneurons. We argue that Ca2+ from multichannel domains arising from ICaF channels, clustered near but not directly associated with the release trigger, and Ca2+ radially diffusing from generally distributed ICaS channels interact at common release sites to mediate graded transmission.

Action Potentials↗

PubMed2006

Spike-mediated and graded inhibitory synaptic transmission between leech interneurons: evidence for shared release sites.

Inhibitory synaptic transmission between leech heart interneurons consist of two components: graded, gated by Ca2+ entering by low-threshold [low-voltage-activated (LVA)] Ca channels and spike-mediated, gated by Ca2+ entering by high-threshold [high-voltage-activated (HVA)] Ca channels. Changes in presynaptic background Ca2+ produced by Ca2+ influx through LVA channels modulate spike-mediated transmission, suggesting LVA channels have access to release sites controlled by HVA channels. Here we explore whether spike-mediated and graded transmission can use the same release sites and thus how Ca2+ influx by HVA and LVA Ca channels might interact to evoke neurotransmitter release. We recorded pre- and postsynaptic currents from voltage-clamped heart interneurons bathed in 0 mM Na+/5 mM Ca2+ saline. Using different stimulating paradigms and inorganic Ca channel blockers, we show that strong graded synaptic transmission can occlude high-threshold/spike-mediated synaptic transmission when evoked simultaneously. Suppression of LVA Ca currents diminishes graded release and concomitantly increases the ability of Ca2+ entering by HVA channels to release transmitter. Uncaging of Ca chelator corroborates that graded release occludes spike-mediated transmission. Our results indicate that both graded and spike-mediated synaptic transmission depend on the same readily releasable pool of synaptic vesicles. Thus Ca2+, entering cells through different Ca channels (LVA and HVA), acts to gate release of the same synaptic vesicles. The data argue for a closer location of HVA Ca channels to release sites than LVA Ca channels. The results are summarized in a conceptual model of a heart interneuron release site.

Action Potentials↗

PubMed2006

A central pattern generator producing alternative outputs: temporal pattern of premotor activity.

The central pattern generator for heartbeat in medicinal leeches constitutes seven identified pairs of segmental heart interneurons. Four identified pairs of heart interneurons make a staggered pattern of inhibitory synaptic connections with segmental heart motor neurons. Using extracellular recording from multiple interneurons in the network in 56 isolated nerve cords, we show that this pattern generator produces a side-to-side asymmetric pattern of intersegmental coordination among ipsilateral premotor interneurons. This pattern corresponds to a similarly asymmetric fictive motor pattern in heart motor neurons and asymmetric constriction pattern of the two tubular hearts, synchronous and peristaltic. We provide a quantitative description of the firing pattern of all the premotor interneurons, including phase, duty cycle, and intraburst frequency of this premotor activity pattern. This analysis identifies two stereotypical coordination modes corresponding to synchronous and peristaltic, which show phase constancy over a broad range of periods as do the fictive motor pattern and the heart constriction pattern. Coordination mode is controlled through one segmental pair of heart interneurons (switch interneurons). Side-to-side switches in coordination mode are a regular feature of this pattern generator and occur with changes in activity state of these switch interneurons. Associated with synchronous coordination of premotor interneurons, the ipsilateral switch interneuron is in an active state, during which it produces rhythmic bursts, whereas associated with peristaltic coordination, the ipsilateral switch interneuron is largely silent. We argue that timing and pattern elaboration are separate functions produced by overlapping subnetworks in the heartbeat central pattern generator.

Action Potentials↗

PubMed2005

Neuronal control of leech behavior.

The medicinal leech has served as an important experimental preparation for neuroscience research since the late 19th century. Initial anatomical and developmental studies dating back more than 100 years ago were followed by behavioral and electrophysiological investigations in the first half of the 20th century. More recently, intense studies of the neuronal mechanisms underlying leech movements have resulted in detailed descriptions of six behaviors described in this review; namely, heartbeat, local bending, shortening, swimming, crawling, and feeding. Neuroethological studies in leeches are particularly tractable because the CNS is distributed and metameric, with only 400 identifiable, mostly paired neurons in segmental ganglia. An interesting, yet limited, set of discrete movements allows students of leech behavior not only to describe the underlying neuronal circuits, but also interactions among circuits and behaviors. This review provides descriptions of six behaviors including their origins within neuronal circuits, their modification by feedback loops and neuromodulators, and interactions between circuits underlying with these behaviors.

Animals↗

PubMed2005

Myomodulin increases Ih and inhibits the NA/K pump to modulate bursting in leech heart interneurons.

In the medicinal leech, a rhythmically active 14-interneuron network composes the central pattern generator for heartbeat. In two segmental ganglia, bilateral pairs of reciprocally inhibitory heart interneurons (oscillator interneurons) produce a rhythm of alternating bursts of action potentials that paces activity in the pattern-generating network. The neuropeptide myomodulin decreases the period of this bursting and increases the intraburst spike frequency when applied to isolated ganglia containing these oscillator interneurons. Myomodulin also decreases period, increases spike frequency, and increases the robustness of endogenous bursting in synaptically isolated (with bicuculline) oscillator interneurons. In voltage-clamp experiments using hyperpolarizing ramps, we identify an increase in membrane conductance elicited by myomodulin with the properties of a hyperpolarization-activated current. Voltage steps confirm that myomodulin indeed increases the maximum conductance of the hyperpolarization-activated current I(h). In similar experiments using Cs(+) to block I(h), we demonstrate that myomodulin also causes a steady offset in the ramp current that is not associated with an increase in conductance. This current offset is blocked by ouabain, indicating that myomodulin inhibits the Na/K pump. In current-clamp experiments, when I(h) is blocked with Cs(+), myomodulin decreases period and increases spike frequency of alternating bursting in synaptically connected oscillator interneurons, suggesting that inhibiting the Na/K pump modulates these burst characteristics. These observations indicate that myomodulin decreases period and increases spike frequency of endogenous bursting in synaptically isolated oscillator heart interneurons and alternating bursting of reciprocally inhibitory pairs of interneurons, at least in part, by increasing I(h) and by decreasing the Na/K pump.

Action Potentials↗

PubMed2005

Mechanism of bistability: tonic spiking and bursting in a neuron model.

Neurons can demonstrate various types of activity; tonically spiking, bursting as well as silent neurons are frequently observed in electrophysiological experiments. The methods of qualitative theory of slow-fast systems applied to biophysically realistic neuron models can describe basic scenarios of how these regimes of activity can be generated and transitions between them can be made. Here we demonstrate that a bifurcation of a codimension one can explain a transition between tonic spiking behavior and bursting behavior. Namely, we argue that the Lukyanov-Shilnikov bifurcation of a saddle-node periodic orbit with noncentral homoclinics may initiate a bistability observed in a model of a leech heart interneuron under defined pharmacological conditions. This model can exhibit two coexisting types of oscillations: tonic spiking and bursting, depending on the initial state of the neuron model. Moreover, the neuron model also generates weakly chaotic bursts when a control parameter is close to the bifurcation values that correspond to homoclinic bifurcations of a saddle or a saddle-node periodic orbit.

Animals↗

PubMed2004

Using a hybrid neural system to reveal regulation of neuronal network activity by an intrinsic current.

The generation of rhythmic patterns by neuronal networks is a complex phenomenon, relying on the interaction of numerous intrinsic and synaptic currents, as well as modulatory agents. To investigate the functional contribution of an individual ionic current to rhythmic pattern generation in a network, we constructed a hybrid system composed of a silicon model neuron and a heart interneuron from the heartbeat timing network of the medicinal leech. When the model neuron and a heart interneuron are connected by inhibitory synapses, they produce rhythmic activity similar to that observed in the heartbeat network. We focused our studies on investigating the functional role of the hyperpolarization-activated inward current (I(h)) on the rhythmic bursts produced by the network. By introducing changes in both the model and the heart interneuron, we showed that I(h) determines both the period of rhythmic bursts and the balance of activity between the two sides of the network, because the amount and the activation/deactivation time constant of I(h) determines the length of time that a neuron spends in the inhibited phase of its burst cycle. Moreover, we demonstrated that the model neuron is an effective replacement for a heart interneuron and that changes made in the model can accurately mimic similar changes made in the living system. Finally, we used a previously developed mathematical model (Hill et al. 2001) of two mutually inhibitory interneurons to corroborate these findings. Our results demonstrated that this hybrid system technique is advantageous for investigating neuronal properties that are inaccessible with traditional techniques.

Analysis of Variance↗

PubMed2004

Neuronal networks: dissection one channel at a time.

Researchers working on neuronal networks are increasingly taking advantage of the ability to overexpress particular molecular components such as channels. What hope do such studies hold for understanding neuronal phenotype and its role in network function?

Animals↗

PubMed2004

Bifurcation of synchronous oscillations into torus in a system of two reciprocally inhibitory silicon neurons: experimental observation and modeling.

Oscillatory activity in the central nervous system is associated with various functions, like motor control, memory formation, binding, and attention. Quasiperiodic oscillations are rarely discussed in the neurophysiological literature yet they may play a role in the nervous system both during normal function and disease. Here we use a physical system and a model to explore scenarios for how quasiperiodic oscillations might arise in neuronal networks. An oscillatory system of two mutually inhibitory neuronal units is a ubiquitous network module found in nervous systems and is called a half-center oscillator. Previously we created a half-center oscillator of two identical oscillatory silicon (analog Very Large Scale Integration) neurons and developed a mathematical model describing its dynamics. In the mathematical model, we have shown that an in-phase limit cycle becomes unstable through a subcritical torus bifurcation. However, the existence of this torus bifurcation in experimental silicon two-neuron system was not rigorously demonstrated or investigated. Here we demonstrate the torus predicted by the model for the silicon implementation of a half-center oscillator using complex time series analysis, including bifurcation diagrams, mapping techniques, correlation functions, amplitude spectra, and correlation dimensions, and we investigate how the properties of the quasiperiodic oscillations depend on the strengths of coupling between the silicon neurons. The potential advantages and disadvantages of quasiperiodic oscillations (torus) for biological neural systems and artificial neural networks are discussed.

Action Potentials↗

PubMed2004

A multiconductance silicon neuron with biologically matched dynamics.

We have designed, fabricated, and tested an analog integrated-circuit architecture to implement the conductance-based dynamics that model the electrical activity of neurons. The dynamics of this architecture are in accordance with the Hodgkin-Huxley formalism, a widely exploited, biophysically plausible model of the dynamics of living neurons. Furthermore the architecture is modular and compact in size so that we can implement networks of silicon neurons, each of desired complexity, on a single integrated circuit. We present in this paper a six-conductance silicon-neuron implementation, and characterize it in relation to the Hodgkin-Huxley formalism. This silicon neuron incorporates both fast and slow ionic conductances, which are required to model complex oscillatory behaviors (spiking, bursting, subthreshold oscillations).

Action Potentials↗

PubMed2003

Detailed model of intersegmental coordination in the timing network of the leech heartbeat central pattern generator.

To address the general problem of intersegmental coordination of oscillatory neuronal networks, we have studied the leech heartbeat central pattern generator. The core of this pattern generator is a timing network that consists of two segmental oscillators, each of which comprises two identified, reciprocally inhibitory oscillator interneurons. Intersegmental coordination between the segmental oscillators is mediated by synaptic interactions between the oscillator interneurons and identified coordinating interneurons. The small number of neurons (8) and the distributed structure of the timing network have made the experimental analysis of the segmental oscillators as discrete, independent units possible. On the basis of this experimental work, we have made conductance-based models to explore how intersegmental phase and cycle period are determined. We show that although a previous simple model, which ignored many details of the living system, replicated some essential features of the living system, the incorporation of specific cellular and network properties is necessary to capture the behavior of the system seen under different experimental conditions. For example, spike frequency adaptation in the coordinating interneurons and details of asymmetries in intersegmental connectivity are necessary for replicating driving experiments in which one segmental oscillator was injected with periodic current pulses to entrain the activity of the entire network. Nevertheless, the basic mechanisms of phase and period control demonstrated here appear to be very general and could be used by other networks that produce coordinated segmental motor outflow.

Action Potentials↗

PubMed2003

Heartbeat control in leeches. I. Constriction pattern and neural modulation of blood pressure in intact animals.

Two tubular hearts propel blood through the closed circulatory system of the medicinal leech. The hearts are myogenic but are driven by a centrally generated motor pattern that controls heart rate and intersegmental coordination. In two consecutive papers, we address the question of how the motor pattern is translated into the pattern of diastole and systole of leech hearts. We imaged the constriction patterns of the hearts in quiescent intact animals. In one heart, systole progresses rear-to-front (peristaltic coordination mode), whereas systole occurs nearly simultaneously in the other heart (synchronous coordination mode) with regular switches between these two coordination modes. Intersegmental phase relations between heart segments do not vary with changes in the heartbeat period. The peristaltic heart drives blood forward through itself and then rearward through the other longitudinal vessels. The synchronous heart does not seem to contribute to rearward flow along the body axis and may support segmental circulation instead. Simultaneous monitoring of heart motor neuron discharge and the constriction of the corresponding heart segment in innervated, reduced preparations enabled us later to meld the constriction pattern with the fictive motor pattern described in the following paper. Current injections into one heart modulatory neuron while monitoring intravascular pressure from the corresponding heart showed that these neurons can acutely change diastolic and systolic pressure. However, they do not determine the different systolic pressure profiles associated with the two coordination modes, which appear to result from the constriction pattern.

Action Potentials↗

PubMed2003

Heartbeat control in leeches. II. Fictive motor pattern.

The rhythmic beating of the tube-like hearts in the medicinal leech is driven and coordinated by rhythmic activity in segmental heart motor neurons. The motor neurons are controlled by rhythmic inhibitory input from a network of heart interneurons that compose the heartbeat central pattern generator. In the preceding paper, we described the constriction pattern of the hearts in quiescent intact animals and showed that one heart constricts in a rear-to-front wave (peristaltic coordination mode), while the other heart constricts in near unison over its length (synchronous coordination mode) and that they regularly switch coordination modes. Here we analyze intersegmental and side-to-side-coordination of the fictive motor pattern for heartbeat in denervated nerve cords. We show that the intersegmental phase relations among heart motor neurons in both coordination modes are independent of heartbeat period. This finding enables us to combine data from different experiments to form a detailed analysis of the relative phases, duty cycle, and intraburst spike frequency of the bursts of the segmental heart motor neurons. The fictive motor pattern and the constriction pattern seen in intact leeches closely match in their intersegmental and side-to-side coordination, indicating that sensory feedback is not necessary for properly phased intersegmental coordination. Moreover, the regular switches in coordination mode of the fictive motor pattern mimic those seen in intact animals indicating that these switches likely arise by a central mechanism.

Action Potentials↗

PubMed2003

Behavioral choices: how neuronal networks make decisions.

To survive, animals must constantly make behavioral choices. The analysis of simple, almost binary, behavioral choices in invertebrate animals with restricted nervous systems is beginning to yield insight into how neuronal networks make such decisions.

Animals↗

PubMed2003

Modulation of spike-mediated synaptic transmission by presynaptic background Ca2+ in leech heart interneurons.

At the core of the rhythmically active leech heartbeat central pattern generator are pairs of mutually inhibitory interneurons. Synaptic transmission between these interneurons consists of spike-mediated and graded components, both of which wax and wane on a cycle-by-cycle basis. Low-threshold Ca2+ currents gate the graded component. Ca imaging experiments indicate that these low-threshold currents are widespread in the neurons and that they contribute to neuron-wide changes in internal background Ca2+ concentration (Ivanov and Calabrese, 2000). During normal rhythmic activity, background Ca2+ concentration oscillates, and thus graded synaptic transmission waxes and wanes as the neurons move from the depolarized to the inhibited phases of their activity. Here we show that in addition to gating graded transmitter release, the background Ca2+ concentration changes evoked by low-threshold Ca2+ currents modulate spike-mediated synaptic transmission. We develop stimulation paradigms to simulate the changes in baseline membrane potential that accompany rhythmic bursting. Using Ca imaging and electrophysiological measurements, we show that the strength of spike-mediated synaptic transmission follows the changes in background Ca2+ concentration that these baseline potential changes evoke and that it does not depend on previous spike activity. Moreover, we show using internal EGTA and photo-release of caged Ca2+ and caged Ca2+ chelator that changes in internal Ca2+ concentration modulate spike-mediated synaptic transmission. Thus activity-dependent changes in background Ca2+, which have been implicated in homeostatic regulation of intrinsic membrane currents and synaptic strength, may also regulate synaptic transmission in an immediate way to modulate synaptic strength cycle by cycle in rhythmically active networks.

Action Potentials↗