Biomedical subjects

Douglas A Baxter

Publications and source records attributed to Douglas A Baxter.

At least 19 recordsLinked to original sources

PubMed2006

Role of A-type K+ channels in spike broadening observed in soma and axon of Hermissenda type-B photoreceptors: a simulation study.

In Hermissenda type-B photoreceptors, the spike is generated in the axon and back-propagated to the soma, resulting in smaller somatic spikes. Experimentally, blocking the A-type K+ current (IK,A) results in broadening of somatic spikes. Similarly, in a compartmental model of the photoreceptor, reducing the maximum A-type K+ conductance (gK,Amax) results in broadening of somatic spikes. However, simulations predict that little or no broadening of axonal spikes occurs when gK,Amax is reduced. The results can be explained by the voltage-dependent properties of IK,A and the different potential ranges that the somatic and axonal spike traverse. Because of the steeper I-V curve and faster activation of the K+ channels at higher potentials, the recruitment of additional K+ channels in the axon is able to compensate for the decrease in K+ conductance, yielding less spike broadening. These results also support the idea that spike duration in the axon may not be reliably inferred based upon recordings collected from the soma.

Action Potentials↗

PubMed2006

Bifurcation and singularity analysis of a molecular network for the induction of long-term memory.

Withdrawal reflexes of the mollusk Aplysia exhibit sensitization, a simple form of long-term memory (LTM). Sensitization is due, in part, to long-term facilitation (LTF) of sensorimotor neuron synapses. LTF is induced by the modulatory actions of serotonin (5-HT). Pettigrew et al. developed a computational model of the nonlinear intracellular signaling and gene network that underlies the induction of 5-HT-induced LTF. The model simulated empirical observations that repeated applications of 5-HT induce persistent activation of protein kinase A (PKA) and that this persistent activation requires a suprathreshold exposure of 5-HT. This study extends the analysis of the Pettigrew model by applying bifurcation analysis, singularity theory, and numerical simulation. Using singularity theory, classification diagrams of parameter space were constructed, identifying regions with qualitatively different steady-state behaviors. The graphical representation of these regions illustrates the robustness of these regions to changes in model parameters. Because persistent protein kinase A (PKA) activity correlates with Aplysia LTM, the analysis focuses on a positive feedback loop in the model that tends to maintain PKA activity. In this loop, PKA phosphorylates a transcription factor (TF-1), thereby increasing the expression of an ubiquitin hydrolase (Ap-Uch). Ap-Uch then acts to increase PKA activity, closing the loop. This positive feedback loop manifests multiple, coexisting steady states, or multiplicity, which provides a mechanism for a bistable switch in PKA activity. After the removal of 5-HT, the PKA activity either returns to its basal level (reversible switch) or remains at a high level (irreversible switch). Such an irreversible switch might be a mechanism that contributes to the persistence of LTM. The classification diagrams also identify parameters and processes that might be manipulated, perhaps pharmacologically, to enhance the induction of memory. Rational drug design, to affect complex processes such as memory formation, can benefit from this type of analysis.

Algorithms↗

PubMed2006

A model of the roles of essential kinases in the induction and expression of late long-term potentiation.

The induction of late long-term potentiation (L-LTP) involves complex interactions among second-messenger cascades. To gain insights into these interactions, a mathematical model was developed for L-LTP induction in the CA1 region of the hippocampus. The differential equation-based model represents actions of protein kinase A (PKA), MAP kinase (MAPK), and CaM kinase II (CAMKII) in the vicinity of the synapse, and activation of transcription by CaM kinase IV (CAMKIV) and MAPK. L-LTP is represented by increases in a synaptic weight. Simulations suggest that steep, supralinear stimulus-response relationships between stimuli (e.g., elevations in [Ca(2+)]) and kinase activation are essential for translating brief stimuli into long-lasting gene activation and synaptic weight increases. Convergence of multiple kinase activities to induce L-LTP helps to generate a threshold whereby the amount of L-LTP varies steeply with the number of brief (tetanic) electrical stimuli. The model simulates tetanic, -burst, pairing-induced, and chemical L-LTP, as well as L-LTP due to synaptic tagging. The model also simulates inhibition of L-LTP by inhibition of MAPK, CAMKII, PKA, or CAMKIV. The model predicts results of experiments to delineate mechanisms underlying L-LTP induction and expression. For example, the cAMP antagonist RpcAMPs, which inhibits L-LTP induction, is predicted to inhibit ERK activation. The model also appears useful to clarify similarities and differences between hippocampal L-LTP and long-term synaptic strengthening in other systems.

Animals↗

PubMed2005

Classical and operant conditioning differentially modify the intrinsic properties of an identified neuron.

A long-standing debate in neuroscience is whether classical and operant conditioning are mechanistically similar or distinct. The feeding behavior of Aplysia provides a model system suitable for addressing this question. Here we report that classical and operant conditioning of feeding behavior differentially modify the intrinsic excitability of neuron B51, a critical element for the expression of the feeding response, thus revealing that these two forms of associative learning differ at the cellular level.

Animals↗

PubMed2004

Extending in vitro conditioning in Aplysia to analyze operant and classical processes in the same preparation.

Operant and classical conditioning are major processes shaping behavioral responses in all animals. Although the understanding of the mechanisms of classical conditioning has expanded significantly, the understanding of the mechanisms of operant conditioning is more limited. Recent developments in Aplysia are helping to narrow the gap in the level of understanding between operant and classical conditioning, and have raised the possibility of studying the neuronal processes underlying the interaction of operant and classical components in a relatively complex learning task. In the present study, we describe a first step toward realizing this goal, by developing a single in vitro preparation in which both operant and classical conditioning can be studied concurrently. The new paradigm reproduced previously published results, even under more conservative and homogenous selection criteria and tonic stimulation regime. Moreover, the observed learning was resistant to delay, shortening, and signaling of reinforcement.

Analysis of Variance↗

PubMed2004

Current- and voltage-clamp recordings and computer simulations of Kenyon cells in the honeybee.

The mushroom body of the insect brain is an important locus for olfactory information processing and associative learning. The present study investigated the biophysical properties of Kenyon cells, which form the mushroom body. Current- and voltage-clamp analyses were performed on cultured Kenyon cells from honeybees. Current-clamp analyses indicated that Kenyon cells did not spike spontaneously in vitro. However, spikes could be elicited by current injection in approximately 85% of the cells. Of the cells that produced spikes during a 1-s depolarizing current pulse, approximately 60% exhibited repetitive spiking, whereas the remaining approximately 40% fired a single spike. Cells that spiked repetitively showed little frequency adaptation. However, spikes consistently became broader and smaller during repetitive activity. Voltage-clamp analyses characterized a fast transient Na+ current (INa), a delayed rectifier K+ current (IK,V), and a fast transient K+ current (IK,A). Using the neurosimulator SNNAP, a Hodgkin-Huxley-type model was developed and used to investigate the roles of the different currents during spiking. The model led to the prediction of a slow transient outward current (IK,ST) that was subsequently identified by reevaluating the voltage-clamp data. Simulations indicated that the primary currents that underlie spiking are INa and IK,V, whereas IK,A and IK,ST primarily determined the responsiveness of the model to stimuli such as constant or oscillatory injections of current.

Algorithms↗

PubMed2004

Simulation of Drosophila circadian oscillations, mutations, and light responses by a model with VRI, PDP-1, and CLK.

A model of Drosophila circadian rhythm generation was developed to represent feedback loops based on transcriptional regulation of per, Clk (dclock), Pdp-1, and vri (vrille). The model postulates that histone acetylation kinetics make transcriptional activation a nonlinear function of [CLK]. Such a nonlinearity is essential to simulate robust circadian oscillations of transcription in our model and in previous models. Simulations suggest that two positive feedback loops involving Clk are not essential for oscillations, because oscillations of [PER] were preserved when Clk, vri, or Pdp-1 expression was fixed. However, eliminating positive feedback by fixing vri expression altered the oscillation period. Eliminating the negative feedback loop in which PER represses per expression abolished oscillations. Simulations of per or Clk null mutations, of per overexpression, and of vri, Clk, or Pdp-1 heterozygous null mutations altered model behavior in ways similar to experimental data. The model simulated a photic phase-response curve resembling experimental curves, and oscillations entrained to simulated light-dark cycles. Temperature compensation of oscillation period could be simulated if temperature elevation slowed PER nuclear entry or PER phosphorylation. The model makes experimental predictions, some of which could be tested in transgenic Drosophila.

Acetylation↗

PubMed2004

Multimodal behavior in a four neuron ring circuit: mode switching.

We study a four-neuron ring circuit comprised of oscillating burst-type neurons unidirectionally coupled via inhibitory synapses. Simple circuits of this type have been used previously to study gait patterns. The ring circuit itself is a variant of the basic reciprocal inhibition network, and it exhibits the property of multistability (multiple stable modes of behavior). That is, different gait modes can be achieved via appropriate initialization of and parameterization of this self-excited oscillatory network. We demonstrate three common gait modes with this circuit: the walk, the bound, and a slightly rotated trot mode. Attention is focused mainly on the mechanisms of rapidly and effectively switching between these modes. Our simulations suggest that neuron membrane dynamics, as well as synaptic junctional properties, strongly influence phase sensitivity in the network; each synapse is a combination of both and can be characterized by a transient phase response curve (PRC). We use the same bursting neuron model to characterize all network neurons, and shape different transient PRCs by using different synaptic properties. The characteristics of these PRCs determine the gait modes sustained in any network configuration, as well as, the ability to switch between modes. The mechanisms explored in this simple circuit, may find application in the switching of more complicated gait pattern networks, as well as, in the design of neuromorphic gait pattern circuits.

Action Potentials↗

PubMed2003

Modeling interactions between electrical activity and second-messenger cascades in Aplysia neuron R15.

The biophysical properties of neuron R15 in Aplysia endow it with the ability to express multiple modes of oscillatory electrical activity, such as beating and bursting. Previous modeling studies examined the ways in which membrane conductances contribute to the electrical activity of R15 and the ways in which extrinsic modulatory inputs alter the membrane conductances by biochemical cascades and influence the electrical activity. The goals of the present study were to examine the ways in which electrical activity influences the biochemical cascades and what dynamical properties emerge from the ongoing interactions between electrical activity and these cascades. The model proposed by Butera et al. in 1995 was extended to include equations for the binding of Ca(2+) to calmodulin (CaM) and the actions of Ca(2+)/CaM on both adenylyl cyclase and phosphodiesterase. Simulations indicated that levels of cAMP oscillated during bursting and that these oscillations were approximately antiphasic to the oscillations of Ca(2+). In the presence of cAMP oscillations, brief perturbations could switch the electrical activity between bursting and beating (bistability). Compared with a constant-cAMP model, oscillations of cAMP substantially expanded the range of bistability. Moreover, the integrated electrical/biochemical model simulated some early experimental results such as activity-dependent inactivation of the anomalous rectifier. The results of the present study suggest that the endogenous activity of R15 depends, in part, on interactions between electrical activity and biochemical cascades.

Adenylyl Cyclases↗

PubMed2003

Burst-induced synaptic depression and its modulation contribute to information transfer at Aplysia sensorimotor synapses: empirical and computational analyses.

The Aplysia sensorimotor synapse is a key site of plasticity for several simple forms of learning. Plasticity of this synapse has been extensively studied, albeit primarily with individual action potentials elicited at low frequencies. Yet, the mechanosensory neurons fire high-frequency bursts in response to even moderate tactile stimuli delivered to the skin. In the present study, we extend this analysis to show that sensory neurons also fire bursts in the range of 1-60 Hz in response to electrical stimuli similar to those used in behavioral studies of sensitization. Intracellular stimulation of sensory neurons to fire a burst of action potentials at 10 Hz for 1 sec led to significant homosynaptic depression of postsynaptic responses. The depression was transient and fully recovered within 10 min. During the burst, the steady-state depressed phase of the postsynaptic response, which was only 20% of the initial EPSP of the burst, still contributed to firing the motor neuron. To explore the functional contribution of transient homosynaptic depression to the response of the motor neuron, computer simulations of the sensorimotor synapse with and without depression were compared. Depression allowed the motor neuron to produce graded responses over a wide range of presynaptic input strength. In addition, enhancement of synaptic transmission throughout a burst increased motor neuron output substantially more than did preferential enhancement of the initial phase of a burst. Thus, synaptic depression increased the dynamic range of the sensorimotor synapse and can, in principle, have a profound effect on information processing.

Action Potentials↗

PubMed2003

Spontaneous activity of dopaminergic retinal neurons.

Dopaminergic local circuit neurons in the retina (DA cells) show robust, spontaneous, tetrodotoxin-sensitive pacemaking. To investigate the mechanism underlying this behavior, we characterized the sodium current and a subset of the potassium currents in the cells in voltage-clamp experiments. We found that there is a persistent component of the sodium current in DA cells which activates at more depolarized potentials than the transient component of the current. The transient component was completely inactivated at -50 mV, but DA cells remained able to fire spontaneous action potentials when potassium channels were partially blocked and the membrane potential remained above -40 mV. Based on these electrophysiological data, we developed a reduced computer model that reproduced the major features of DA cells. In simulations at the physiological resting potential, the persistent component of the sodium current was both necessary and sufficient to account for spontaneous activity, and the major contribution of the transient component of the sodium current was to initiate the depolarization of the model cell during the interspike interval. When tonic inhibition was simulated by lowering the input impedance of the model cell, the transient component played a larger role.

Action Potentials↗

PubMed2003

Reduced models of the circadian oscillators in Neurospora crassa and Drosophila melanogaster illustrate mechanistic similarities.

We have developed a reduced model representing feedback loops of transcriptional regulation underlying circadian rhythms in Neurospora crassa. The model contains two delay differential equations that describe the dynamics of two core gene products, FRQ and WCC. In a negative feedback loop, FRQ protein represses frq transcription by binding the white-collar complex (WCC), which consists of the WC-1 and WC-2 proteins. In a positive feedback loop, WCC indirectly enhances its own formation. The model simulates circadian oscillations, light entrainment, and a phase-response curve (PRC) similar to experimental PRCs. The Neurospora model is virtually identical to a model describing Drosophila circadian rhythm generation, illustrating that rhythm generation in these divergent organisms shares important mechanistic elements. Significant dynamic differences were found when the parameter spaces of both models were explored to analyze changes in oscillations and bifurcations to steady states. Stochastic fluctuations in molecule numbers were simulated with the Gillespie algorithm. Circadian oscillations and entrainment to light were simulated with <80 molecules of FRQ and WCC present on average. Simulations suggest that in both Neurospora and Drosophila, only the negative feedback loop is essential for circadian oscillations. Similar models may aid understanding of circadian mechanisms in mammals and other organisms.

Animals↗

PubMed2002

Correlation between activity in neuron B52 and two features of fictive feeding in Aplysia.

The present study examined the correlation between the level of activity neuron B52 and the transition from protraction to retraction phases of buccal motor patterns (BMPs) and the termination of the BMPs. The level of activity in B52 during the protraction phase was positively correlated with the duration of that phase. A second burst of activity in B52 was associated with the termination of the retraction phase. An apparent monosynaptic inhibitory connection from B52 to B64, may mediate the effects of B52. The first burst of activity in B52 delays the onset of activity in B64, thereby prolonging the protraction phase, and the second burst inhibits activity in B64, thereby terminating the retraction phase. These results suggest that activity in B52 may contribute to switching between ingestion-like and rejection-like BMPs by regulating both phase transition and termination of BMPs.

Action Potentials↗

PubMed2002

Operant reward learning in Aplysia: neuronal correlates and mechanisms.

Operant conditioning is a form of associative learning through which an animal learns about the consequences of its behavior. Here, we report an appetitive operant conditioning procedure in Aplysia that induces long-term memory. Biophysical changes that accompanied the memory were found in an identified neuron (cell B51) that is considered critical for the expression of behavior that was rewarded. Similar cellular changes in B51 were produced by contingent reinforcement of B51 with dopamine in a single-cell analog of the operant procedure. These findings allow for the detailed analysis of the cellular and molecular processes underlying operant conditioning.

Animals↗

PubMed2002

A reduced model clarifies the role of feedback loops and time delays in the Drosophila circadian oscillator.

Although several detailed models of molecular processes essential for circadian oscillations have been developed, their complexity makes intuitive understanding of the oscillation mechanism difficult. The goal of the present study was to reduce a previously developed, detailed model to a minimal representation of the transcriptional regulation essential for circadian rhythmicity in Drosophila. The reduced model contains only two differential equations, each with time delays. A negative feedback loop is included, in which PER protein represses per transcription by binding the dCLOCK transcription factor. A positive feedback loop is also included, in which dCLOCK indirectly enhances its own formation. The model simulated circadian oscillations, light entrainment, and a phase-response curve with qualitative similarities to experiment. Time delays were found to be essential for simulation of circadian oscillations with this model. To examine the robustness of the simplified model to fluctuations in molecule numbers, a stochastic variant was constructed. Robust circadian oscillations and entrainment to light pulses were simulated with fewer than 80 molecules of each gene product present on average. Circadian oscillations persisted when the positive feedback loop was removed. Moreover, elimination of positive feedback did not decrease the robustness of oscillations to stochastic fluctuations or to variations in parameter values. Such reduced models can aid understanding of the oscillation mechanisms in Drosophila and in other organisms in which feedback regulation of transcription may play an important role.

Algorithms↗

PubMed2002

Mechanisms underlying fictive feeding in aplysia: coupling between a large neuron with plateau potentials activity and a spiking neuron.

The buccal ganglia of Aplysia contain a central pattern generator (CPG) that organizes the rhythmic movements of the radula and buccal mass during feeding. Many of the cellular and synaptic elements of this CPG have been identified and characterized. However, the roles that specific cellular and synaptic properties play in generating patterns of activity are not well understood. To examine these issues, the present study developed computational models of a portion of this CPG and used simulations to investigate processes underlying the initiation of patterned activity. Simulations were done with the SNNAP software package. The simulated network contained two neurons, B31/B32 and B63. The development of the model was guided and constrained by the available current-clamp data that describe the properties of these two protraction-phase interneurons B31/B32 and B63, which are coupled via electrical and chemical synapses. Several configurations of the model were examined. In one configuration, a fast excitatory postsynaptic potential (EPSP) from B63 to B31/B32 was implemented in combination with an endogenous plateau-like potential in B31/B32. In a second configuration, the excitatory synaptic connection from B63 to B31/B32 produced both fast and slow EPSPs in B31/B32 and the plateau-like potential was removed from B31/B32. Simulations indicated that the former configuration (i.e., electrical and fast chemical coupling in combination with a plateau-like potential) gave rise to a circuit that was robust to changes in parameter values and stochastic fluctuations, that closely mimicked empirical observations, and that was extremely sensitive to inputs controlling the onset of a burst. The coupling between the two simulated neurons served to amplify exogenous depolarizations via a positive feedback loop and the subthreshold activation of the plateau-like potential. Once a burst was initiated, the circuit produced the program in an all-or-none fashion. The slow kinetics of the simulated plateau-like potential played important roles in both initiating and maintaining the burst activity. Thus the present study identified cellular and network properties that contribute to the ability of the simulated network to integrate information over an extended period before a decision is made to initiate a burst of activity and suggests that similar mechanisms may operate in the buccal ganglia in initiating feeding movements.

Action Potentials↗

PubMedDate not supplied

Computational model of touch sensory cells (T Cells) of the leech: role of the afterhyperpolarization (AHP) in activity-dependent conduction failure.

Bursts of spikes in T cells produce an AHP, which results from activation of a Na+/K+ pump and a Ca2+-dependent K+ current. Activity-dependent increases in the AHP are believed to induce conduction block of spikes in several regions of the neuron, which in turn, may decrease presynaptic invasion of spikes and thereby decrease transmitter release. To explore this possibility, we used the neurosimulator SNNAP to develop a multi-compartmental model of the T cell. The model incorporated empirical data that describe the geometry of the cell and activity-dependent changes of the AHP. Simulations indicated that at some branching points, activity-dependent increases of the AHP reduced the number of spikes transmitted from the minor receptive fields to the soma and beyond. More importantly, simulations also suggest that the AHP could modulate, under some circumstances, transmission from the soma to the synaptic terminals, suggesting that the AHP can regulate spike conduction within the presynaptic arborizations of the cell and could in principle contribute to the synaptic depression that is correlated with increases in the AHP.

Action Potentials↗

PubMedDate not supplied

Dynamic properties of regulatory motifs associated with induction of three temporal domains of memory in aplysia.

A model was developed to examine dynamical properties of regulatory motifs correlated with different temporal domains of memory. The model represents short-, intermediate-, and long-term phases of protein kinase A (PKA) activation, which appear related to corresponding phases of facilitation of the Aplysia sensorimotor synapse. The model also represents phosphorylation of the transcription factor CREB1 by PKA and consequent induction of the immediate-early gene Aplysia ubiquitin hydrolase (Ap-uch), which is essential for long-term synaptic facilitation (LTF). Simulations suggest mechanisms responsible for differing profiles of synaptic facilitation following massed vs. spaced exposures to 5-HT, and suggest a novel regulatory motif (gated positive feedback) is important for LTF. Simulations suggest zero-order ultrasensitivity may underlie a requirement of a threshold number of exposures to 5-HT for LTF induction. The model makes predictions for the dynamics of PKA activation and Ap-uch induction when MAP kinase is activated, or when repression of Ap-uch is relieved by inhibiting the transcription factor CREB2. This model may therefore be useful for understanding processes underlying memory formation in Aplysia and other systems.

Amino Acid Motifs↗