PubMed Health⌕ Search

Biomedical subjects

John A White

Publications and source records attributed to John A White.

At least 19 recordsLinked to original sources
PubMed2007

Contributions of Ih to feature selectivity in layer II stellate cells of the entorhinal cortex.

Abstract Stellate cells (SCs) of the entorhinal cortex generate prominent subthreshold oscillations that are believed to be important contributors to the hippocampal theta rhythm. The slow inward rectifier Ih is expressed prominently in SCs and has been suggested to be a dominant factor in their integrative properties. We studied the input-output relationships in stellate cells (SCs) of the entorhinal cortex, both in control conditions and in the presence of the Ih antagonist ZD7288. Our results show that Ih is responsible for SCs' subthreshold resonance, and contributes to enhanced spiking reliability to theta-rich stimuli. However, SCs still exhibit other traits of rhythmicity, such as subthreshold oscillations, under Ih blockade. To clarify the effects of Ih on SC spiking, we used a generalized form of principal component analysis to show that SCs select particular features with relevant temporal signatures from stimuli. The spike-selected mix of those features varies with the frequency content of the stimulus, emphasizing the inherent nonlinearity of SC responses. A number of controls confirmed that this selectivity represents a stimulus-induced change in the cellular input-output relationship rather than an artifact of the analysis technique. Sensitivity to slow features remained statistically significant in ZD7288. However, with Ih blocked, slow stimulus features were less predictive of spikes and spikes conveyed less information about the stimulus over long time scales. Together, these results suggest that Ih is an important contributor to the input-output relationships expressed by SCs, but that other factors in SCs also contribute to subthreshold oscillations and nonlinear selectivity to slow features.

Action Potentials↗
PubMed2006

Simple models show the general advantages of dendrites in coincidence detection.

Dendrites can influence and improve information processing in single neurons. Here, simple models are used to elucidate mechanisms underlying the dendritic enhancement of coincidence detection. We focus on coincidence-detecting cells in the auditory system, which have bipolar dendrites and show acute sensitivity to interaural time difference (ITD), a critical cue for spatial hearing. A three-compartment model consisting of a single-compartment soma and two single-compartment dendrites is primarily used, although multiple-compartment dendrites are also tested. Two varieties of somata, with and without active ion channels, are studied. Using constant conductance inputs, we show analytically that the somatic response to balanced bilateral inputs is largest, whereas the response monotonically decreases as the input distribution becomes increasingly monolateral. This enhancement is a consequence of the sublinear saturating dendritic voltage response to conductance input and occurs when dendrites are composed of a single compartment or either a finite number or an infinite number (i.e., a cable) of compartments. Longer, thinner dendrites or greater numbers of compartments increase the enhancement of the somatic response to bilateral input. The time-independent dendritic enhancement, moreover, underlies improved coincidence detection of time-varying input. Coincidence sensitivity to a pair of conductance pulses and rate-ITD modulation to low-frequency (400-Hz) periodic inputs increases with dendritic length. These findings are related to the length gradient in the avian system, where low characteristic frequency (CF) cells have long dendrites and high CF cells have short dendrites. We conclude that dendrites fundamentally improve coincidence detection, increasing the computational power of many neurons in the nervous system.

Action Potentials↗
PubMed2006

The dynamic structure underlying subthreshold oscillatory activity and the onset of spikes in a model of medial entorhinal cortex stellate cells.

Medial entorhinal cortex layer II stellate cells display subthreshold oscillations (STOs). We study a single compartment biophysical model of such cells which qualitatively reproduces these STOs. We argue that in the subthreshold interval (STI) the seven-dimensional model can be reduced to a three-dimensional system of equations with well differentiated times scales. Using dynamical systems arguments we provide a mechanism for generations of STOs. This mechanism is based on the "canard structure," in which relevant trajectories stay close to repelling manifolds for a significant interval of time. We also show that the transition from subthreshold oscillatory activity to spiking ("canard explosion") is controlled in the STI by the same structure. A similar mechanism is invoked to explain why noise increases the robustness of the STO regime. Taking advantage of the reduction of the dimensionality of the full stellate cell system, we propose a nonlinear artificially spiking (NAS) model in which the STI reduced system is supplemented with a threshold for spiking and a reset voltage. We show that the synchronization properties in networks made up of the NAS cells are similar to those of networks using the full stellate cell models.

Action Potentials↗
PubMed2006

Synaptic input statistics tune the variability and reproducibility of neuronal responses.

Synaptic waveforms, constructed from excitatory and inhibitory presynaptic Poisson trains, are presented to living and computational neurons. We review how the average output of a neuron (e.g., the firing rate) is set by the difference between excitatory and inhibitory event rates while neuronal variability is set by their sum. We distinguish neuronal variability from reproducibility. Variability quantifies how much an output measure is expected to vary; for example, the interspike interval coefficient of variation quantifies the typical range of interspike intervals. Reproducibility quantifies the similarity of neuronal outputs in response to repeated presentations of identical stimuli. Although variability and reproducibility are conceptually distinct, we show that, for ideal current source synapses, reproducibility is defined entirely by variability. For physiologically realistic conductance-based synapses, however, reproducibility is distinct from variability and average output, set by the Poisson rate and the degree of synchrony within the synaptic waveform.

Action Potentials↗
PubMed2006

Low-dimensional maps encoding dynamics in entorhinal cortex and hippocampus.

Cells that produce intrinsic theta oscillations often contain the hyperpolarization-activated current I(h). In this article, we use models and dynamic clamp experiments to investigate the synchronization properties of two such cells (stellate cells of the entorhinal cortex and O-LM cells of the hippocampus) in networks with fast-spiking (FS) interneurons. The model we use for stellate cells and O-LM cells is the same, but the stellate cells are excitatory and the O-LM cells are inhibitory, with inhibitory postsynaptic potential considerably longer than those from FS interneurons. We use spike time response curve methods (STRC), expanding that technique to three-cell networks and giving two different ways in which the analysis of the three-cell network reduces to that of a two-cell network. We show that adding FS cells to a network of stellate cells can desynchronize the stellate cells, while adding them to a network of O-LM cells can synchronize the O-LM cells. These synchronization and desynchronization properties critically depend on I(h). The analysis of the deterministic system allows us to understand some effects of noise on the phase relationships in the stellate networks. The dynamic clamp experiments use biophysical stellate cells and in silico FS cells, with connections that mimic excitation or inhibition, the latter with decay times associated with FS cells or O-LM cells. The results obtained in the dynamic clamp experiments are in a good agreement with the analytical framework.

Action Potentials↗
PubMed2005

Increasing Ca2+ transients by broadening postsynaptic action potentials enhances timing-dependent synaptic depression.

Repeated induction of pre- and postsynaptic action potentials (APs) at a fixed time difference leads to long-term potentiation (LTP) or long-term depression (LTD) of the synapse, depending on the temporal order of pre- and postsynaptic activity. This phenomenon of spike-timing-dependent plasticity (STDP) is believed to arise by nonlinear processes that lead to larger calcium transients (and thus LTP) when presynaptic APs precede postsynaptic APs and smaller calcium transients (and thus LTD) when postsynaptic APs precede presynaptic APs. In contrast to predictions from such calcium-peak-detector models, we show that constitutively or artificially broadened APs in layer II/III pyramidal cells of entorhinal cortex (EC) lead to an increase in the dendritic calcium transient and shift the balance of STDP toward LTD. STDP in entorhinal pyramidal cells is NMDA-receptor-dependent and modulated by the Ca(V)1Ca(2+) channel-blocker nifedipine. Results are consistent with an elaboration of the calcium-peak-detector model in which downstream signals from voltage-dependent Ca(2+) channels suppress LTP relative to LTD. Our results suggest that modulation of AP width is a potent way to adjust the rules of synaptic plasticity in the EC.

Action Potentials↗
PubMed2005

Channel noise is essential for perithreshold oscillations in entorhinal stellate neurons.

Previous experimental and computational work (for review, see White et al., 2000) has suggested that channel noise, generated by the stochastic flicker of voltage-gated ion channels, can be a major contributor to electrical membrane noise in neurons. In spiny stellate neurons of the entorhinal cortex, we remove the primary source of channel noise by pharmacologically blocking the native persistent Na+ conductance. Via the dynamic-clamp technique (Robinson and Kawai, 1993; Sharp et al., 1993), we then introduce virtual persistent Na+ channels into the membranes of the stellate neurons. By altering the mathematical properties of these virtual "knock-ins," we demonstrate that stochastic flicker of persistent Na+ channels is necessary for the existence of slow perithreshold oscillations that characterize stellate neurons. Channel noise also alters the ability of stellate neurons to phase lock to weak sinusoidal stimuli. These results provide the first direct demonstration that physiological levels of channel noise can produce qualitative changes in the integrative properties of neurons.

Animals↗
PubMed2005

Ion-channel noise places limits on the miniaturization of the brain's wiring.

The action potential (AP) is transmitted by the concerted action of voltage-gated ion channels. Thermodynamic fluctuations in channel proteins produce probabilistic gating behavior, causing channel noise. Miniaturizing signaling systems increases susceptibility to noise, and with many cortical, cerebellar, and peripheral axons <0.5 mum diameter [1, 2 and 3], channel noise could be significant [4 and 5]. Using biophysical theory and stochastic simulations, we investigated channel-noise limits in unmyelinated axons. Axons of diameter below 0.1 microm become inoperable because single, spontaneously opening Na channels generate spontaneous AP at rates that disrupt communication. This limiting diameter is relatively insensitive to variations in biophysical parameters (e.g., channel properties and density, membrane conductance and leak) and will apply to most spiking axons. We demonstrate that the essential molecular machinery can, in theory, fit into 0.06 microm diameter axons. However, a comprehensive survey of anatomical data shows a lower limit for AP-conducting axons of 0.08-0.1 microm diameter. Thus, molecular fluctuations constrain the wiring density of brains. Fluctuations have implications for epilepsy and neuropathic pain because changes in channel kinetics or axonal properties can change the rate at which channel noise generates spontaneous activity.

Animals↗
PubMed2005

Slow and fast inhibition and an H-current interact to create a theta rhythm in a model of CA1 interneuron network.

The oriens-lacunosum moleculare (O-LM) subtype of interneuron is a key component in the formation of the theta rhythm (8-12 Hz) in the hippocampus. It is known that the CA1 region of the hippocampus can produce theta rhythms in vitro with all ionotropic excitation blocked, but the mechanisms by which this rhythmicity happens were previously unknown. Here we present a model suggesting that individual O-LM cells, by themselves, are capable of producing a single-cell theta-frequency firing, but coupled O-LM cells are not capable of producing a coherent population theta. By including in the model fast-spiking (FS) interneurons, which give rise to IPSPs that decay faster than those of the O-LM cells, coherent theta rhythms are produced. The inhibition to O-LM cells from the FS cells synchronizes the O-LM cells, but only when the FS cells themselves fire at a theta frequency. Reciprocal connections from the O-LM cells to the FS cells serve to parse the FS cell firing into theta bursts, which can then synchronize the O-LM cells. A component of the model O-LM cell critical to the synchronization mechanism is the hyperpolarization-activated h-current. The model can robustly reproduce relative phases of theta frequency activity in O-LM and FS cells.

Animals↗
PubMed2005

Effects of inhibitory feedback in a network model of avian brain stem.

The avian auditory brain stem consists of a network of specialized nuclei, including nucleus laminaris (NL) and superior olivary nucleus (SON). NL cells show sensitivity to interaural time difference (ITD), a critical cue that underlies spatial hearing. SON cells provide inhibitory feedback to the rest of the network. Empirical data suggest that feedback inhibition from SON could increase the ITD sensitivity of NL across sound level. Using a bilateral network model, we assess the effects of SON feedback inhibition. Individual cells are specified as modified leaky-integrate-and-fire neurons with time constants and thresholds that vary with inhibitory input. Acoustic sound level is reflected in the discharge rates of the model auditory-nerve fibers, which innervate the network. Simulations show that with SON inhibitory feedback, ITD sensitivity is maintained in model NL cells over a threefold range in auditory-nerve discharge rate. In contrast, without SON feedback inhibition, ITD sensitivity is significantly reduced as input rates are increased. Feedback inhibition is most beneficial in maintaining ITD sensitivity at high-input rates (simulating high sound levels). With SON inhibition, ITD sensitivity is maintained for both interaurally balanced inputs (simulating an on-center sound source) and interaurally imbalanced inputs (simulating a lateralized source). Further, the empirically observed temporal build-up of SON inhibition and the presence of reciprocal inhibitory connections between the ipsi- and contralateral SON both improve ITD sensitivity. In sum, our network model shows that inhibitory feedback can substantially increase the sensitivity and dynamic range of ITD coding in the avian auditory brain stem.

Action Potentials↗
PubMed2005

Beyond two-cell networks: experimental measurement of neuronal responses to multiple synaptic inputs.

Oscillations of large populations of neurons are thought to be important in the normal functioning of the brain. We have used phase response curve (PRC) methods to characterize the dynamics of single neurons and predict population dynamics. Our past experimental work was limited to special circumstances (e.g., 2-cell networks of periodically firing neurons). Here, we explore the feasibility of extending our methods to predict the synchronization properties of stellate cells (SCs) in the rat entorhinal cortex under broader conditions. In particular, we test the hypothesis that PRCs in SCs scale linearly with changes in synaptic amplitude, and measure how well responses to Poisson process-driven inputs can be predicted in terms of PRCs. Although we see nonlinear responses to excitatory and inhibitory inputs, we find that models based on weak coupling account for scaling and Poisson process-driven inputs reasonably accurately.

Animals↗
PubMed2004

Synchronization in hybrid neuronal networks of the hippocampal formation.

Understanding the mechanistic bases of neuronal synchronization is a current challenge in quantitative neuroscience. We studied this problem in two putative cellular pacemakers of the mammalian hippocampal theta rhythm: glutamatergic stellate cells (SCs) of the medial entorhinal cortex and GABAergic oriens-lacunosum-molecular (O-LM) interneurons of hippocampal region CA1. We used two experimental methods. First, we measured changes in spike timing induced by artificial synaptic inputs applied to individual neurons. We then measured responses of free-running hybrid neuronal networks, consisting of biological neurons coupled (via dynamic clamp) to biological or virtual counterparts. Results from the single-cell experiments predicted network behaviors well and are compatible with previous model-based predictions of how specific membrane mechanisms give rise to empirically measured synchronization behavior. Both cell types phase lock stably when connected via homogeneous excitatory-excitatory (E-E) or inhibitory-inhibitory (I-I) connections. Phase-locked firing is consistently synchronous for either cell type with E-E connections and nearly anti-synchronous with I-I connections. With heterogeneous connections (e.g., excitatory-inhibitory, as might be expected if members of a given population had heterogeneous connections involving intermediate interneurons), networks often settled into phase locking that was either stable or unstable, depending on the order of firing of the two cells in the hybrid network. Our results imply that excitatory SCs, but not inhibitory O-LM interneurons, are capable of synchronizing in phase via monosynaptic mutual connections of the biologically appropriate polarity. Results are largely independent of synaptic strength and synaptic kinetics, implying that our conclusions are robust and largely unaffected by synaptic plasticity.

Animals↗
PubMed2004

Epilepsy in small-world networks.

In hippocampal slice models of epilepsy, two behaviors are seen: short bursts of electrical activity lasting 100 msec and seizure-like electrical activity lasting seconds. The bursts originate from the CA3 region, where there is a high degree of recurrent excitatory connections. Seizures originate from the CA1, where there are fewer recurrent connections. In attempting to explain this behavior, we simulated model networks of excitatory neurons using several types of model neurons. The model neurons were connected in a ring containing predominantly local connections and some long-distance random connections, resulting in a small-world network connectivity pattern. By changing parameters such as the synaptic strengths, number of synapses per neuron, proportion of local versus long-distance connections, we induced "normal," "seizing," and "bursting" behaviors. Based on these simulations, we made a simple mathematical description of these networks under well-defined assumptions. This mathematical description explains how specific changes in the topology or synaptic strength in the model cause transitions from normal to seizing and then to bursting. These behaviors appear to be general properties of excitatory networks.

Cell Communication↗
PubMed2003

Cultivation in rotating bioreactors promotes maintenance of cardiac myocyte electrophysiology and molecular properties.

We tested the hypothesis that cardiomyocytes maintained their phenotype better if cultured as three-dimensional tissue constructs than if cultured as confluent monolayers. Neonatal rat cardiomyocytes were cultured on biomaterial scaffolds in rotating bioreactors for 1 week, and resulting tissue constructs were compared with confluent monolayers and slices of native ventricular tissue with respect to proteins involved in cell metabolism (creatine kinase isoform MM), contractile function (sarcomeric myosin heavy chain), and intercellular communication (connexin 43), as well as action potential characteristics (e.g., membrane resting potential, maximum depolarization slope, and action potential duration), and macroscopic electrophysiological properties (maximum capture rate). The molecular and electrophysiological properties of cardiomyocytes cultured in tissue constructs, although inferior to those of native neonatal ventricles, were superior to those of the same cells cultured as monolayers. Construct levels of creatine kinase, myosin heavy chain, and connexin 43 were 40-60% as high as ventricle levels, whereas monolayer levels of the same proteins were only 11-20% as high. Construct action potential durations were 1.8-fold higher than those in ventricles, whereas monolayer action potential durations were 2.4-fold higher. Pharmacological studies using 4-aminopyridine showed that prolonged action potential duration and reduced maximum capture rate in tissue constructs as compared with native ventricles could be explained by decreased transient outward potassium current.

Action Potentials↗
PubMed2002

Comparison of algorithms for the simulation of action potentials with stochastic sodium channels.

This paper presents a comparison of computational algorithms to simulate action potentials using stochastic sodium channels. Four algorithms are compared in single-node models: Strassberg and DeFelice (1993) (SD), Rubinstein (1995) (R), Chow and White (1996) (CW), and Fox (1997) (F). Neural responses are simulated to a simple and a preconditioned monophasic current pulse. Three exact algorithms implementing Markov jumping processes (SD, R, CW) resulted in similar responses, while the approximation algorithm using Langevin's equation (F) showed quite different responses from those in the exact algorithms. The computational time was measured as well: 1(F), 7(CW), 32(SD), 39(R) relative to that of the F algorithm. Furthermore, it is shown that as the sampling step for integration of the transmembrane potential increases, neural responses in all algorithms tended to be different from those in dense sampling steps, however, the CW algorithm was robust even at a sparse sampling step. It is concluded that the most computationally efficient algorithm having appropriate properties of neural excitability is the CW algorithm.

Action Potentials↗
PubMed2002

Frequency selectivity of layer II stellate cells in the medial entorhinal cortex.

Electrophysiologically, stellate cells (SCs) from layer II of the medial entorhinal cortex (MEC) are distinguished by intrinsic 4- to 12-Hz subthreshold oscillations. These oscillations are thought to impose a pattern of slow periodic firing that may contribute to the parahippocampal theta rhythm in vivo. Using stimuli with systematically differing frequency content, we examined supra- and subthreshold responses in SCs with the goal of understanding how their distinctive characteristics shape these responses. In reaction to repeated presentations of identical, pseudo-random stimuli, the reliability (repeatability) of the spiking response in SCs depends critically on the frequency content of the stimulus. Reliability is optimal for stimuli with a greater proportion of power in the 4- to 12-Hz range. The simplest mechanistic explanation of these results is that rhythmogenic subthreshold membrane mechanisms resonate with inputs containing significant power in the 4- to 12-Hz band, leading to larger subthreshold excursions and thus enhanced reliability. However, close examination of responses rules out this explanation: SCs do show clear subthreshold resonance (i.e., selective amplification of inputs with particular frequency content) in response to sinusoidal stimuli, while simultaneously showing a lack of subthreshold resonance in response to the pseudo-random stimuli used in reliability experiments. Our results support a model with distinctive input-output relationships under subthreshold and suprathreshold conditions. For suprathreshold stimuli, SC spiking seems to best reflect the amount of input power in the theta (4-12 Hz) frequency band. For subthreshold stimuli, we hypothesize that the magnitude of subthreshold theta-range oscillations in SCs reflects the total power, across all frequencies, of the input.

Algorithms↗
PubMed2002

A pooled data analysis of injury incidence in rugby league football.

OBJECTIVE: The aim of this study was to summarise the injury rates in professional rugby league football. METHODS: Previously published studies were identified from database searches of the literature from Medline, Sports Discus and Web of Science. A total of 18 articles, which reported the prospective injury data collection for at least one playing season in professional rugby league worldwide, were included. The definition of injury adopted required an injured player to miss the subsequent game through injury. Ten studies satisfied the injury definition criteria for inclusion. A review of articles and extraction of relevant data were carried out independently by two authors. RESULTS: A total of 517 injuries were reported during 12819 hours of exposure (753 games), which resulted in an overall injury rate of 40.3 injuries per 1000 hours [95% confidence interval (CI) 36.9 to 43.8]. Most injuries were to the lower half of the body (20.7 per 1000 hours, 95% CI 17.7 to 24), with the trunk receiving the least (6.7 per 1000 hours, 95% CI 5 to 8.6). CONCLUSIONS: Injury rates in professional rugby league are higher than in some other contact sports, probably because of the large number of physical collisions that take place. This pooled data analysis provides more accurate estimates of injury incidence in the game of professional rugby league football.

Athletic Injuries↗