Biomedical subjects
Publications and source records attributed to G J Stuart.
Recent studies show that the precise timing of presynaptic inputs and postsynaptic action potentials influences the strength and sign of synaptic plasticity. In this issue of Neuron, Sjöström and colleagues (2001) determine how this so-called spike timing-dependent plasticity depends on the frequency and strength of the presynaptic inputs.
Neurons encode information and communicate via action potentials, which are generated following the summation of synaptic events. It is commonly assumed that action potentials reset the membrane potential completely, allowing another round of synaptic integration to begin. We show here that the conductances underlying the action potential act instead as a variable reset of synaptic integration. The strength of this reset is cell type-specific and depends on the kinetics, location, and timing of the synaptic input. As a consequence, distal synapses, as well as inputs mediated by N-methyl-d-aspartate receptor activation, can contribute disproportionately to synaptic integration during action potential firing.
We describe a mechanism for coincidence detection mediated by the interaction between backpropagating action potentials and EPSPs in neocortical pyramidal neurons. At distal dendritic locations, appropriately timed EPSPs or oscillations could increase the amplitude of backpropagating action potentials by three- to fourfold. This amplification was greatest when action potentials occurred at the peak of EPSPs or dendritic oscillations and could lead to somatic burst firing. The increase in amplitude required sodium channel activation but not potassium channel inactivation. The temporal characteristics of this amplification are similar to those required for changes in synaptic strength, suggesting that this mechanism may be involved in the induction of synaptic plasticity.
In vivo neocortical neurons fire apparently random trains of action potentials in response to sensory stimuli. Does this randomness represent a signal or noise around a mean firing rate? Here we use the timing of action potential trains recorded in vivo to explore the dendritic consequences of physiological patterns of action potential firing in neocortical pyramidal neurons in vitro. We find that action potentials evoked by physiological patterns of firing backpropagate threefold to fourfold more effectively into the distal apical dendrites (>600 microm from the soma) than action potential trains reflecting their mean firing rate. This amplification of backpropagation was maximal during high-frequency components of physiological spike trains (80-300 Hz). The disparity between backpropagation during physiological and mean firing patterns was dramatically reduced by dendritic hyperpolarization. Consistent with this voltage dependence, dendritic depolarization amplified single action potentials by fourfold to sevenfold, with a spatial profile strikingly similar to the amplification of physiological spike trains. Local blockade of distal dendritic sodium channels substantially reduced amplification of physiological spike trains, but did not significantly alter action potential trains reflecting their mean firing rate. Dendritic electrogenesis during physiological spike trains was also reduced by the blockade of calcium channels. We conclude that amplification of backpropagating action potentials during physiological spike trains is mediated by frequency-dependent supralinear temporal summation, generated by the recruitment of distal dendritic sodium and calcium channels. Together these data indicate that the temporal nature of physiological patterns of action potential firing contains a signal that is transmitted effectively throughout the dendritic tree.
Communication between neurons in the brain occurs primarily through synapses made onto elaborate treelike structures called dendrites. New electrical and optical recording techniques have led to tremendous advances in our understanding of how dendrites contribute to neuronal computation in the mammalian brain. The varied morphology and electrical and chemical properties of dendrites enable a spectrum of local and long-range signaling, defining the input-output relationship of neurons and the rules for induction of synaptic plasticity. In this way, diversity in dendritic signaling allows individual neurons to carry out specialized functions within their respective networks.
Thalamocortical (TC) neurons of the dorsal thalamus integrate sensory inputs in an attentionally relevant manner during wakefulness and exhibit complex network-driven and intrinsic oscillatory activity during sleep. Despite these complex intrinsic and network functions, little is known about the dendritic distribution of ion channels in TC neurons or the role such channel distributions may play in synaptic integration. Here we demonstrate with simultaneous somatic and dendritic recordings from TC neurons in brain slices that action potentials evoked by sensory or cortical excitatory postsynaptic potentials are initiated near the soma and backpropagate into the dendrites of TC neurons. Cell-attached recordings demonstrated that TC neuron dendrites contain a nonuniform distribution of sodium but a roughly uniform density of potassium channels across the somatodendritic area examined that corresponds to approximately half the average path length of TC neuron dendrites. Dendritic action potential backpropagation was found to be active, but compromised by dendritic branching, such that action potentials may fail to invade relatively distal dendrites. We have also observed that calcium channels are nonuniformly distributed in the dendrites of TC neurons. Low-threshold calcium channels were found to be concentrated at proximal dendritic locations, sites known to receive excitatory synaptic connections from primary afferents, suggesting that they play a key role in the amplification of sensory inputs to TC neurons.
The specific membrane capacitance (C(m)) of a neuron influences synaptic efficacy and determines the speed with which electrical signals propagate along dendrites and unmyelinated axons. The value of this important parameter remains controversial. In this study, C(m) was estimated for the somatic membrane of cortical pyramidal neurons, spinal cord neurons, and hippocampal neurons. A nucleated patch was pulled and a voltage-clamp step was applied. The exponential decay of the capacitative charging current was analyzed to give the total membrane capacitance, which was then divided by the observed surface area of the patch. C(m) was 0.9 microF/cm(2) for each class of neuron. To test the possibility that membrane proteins may alter C(m), embryonic kidney cells (HEK-293) were studied before and after transfection with a plasmid coding for glycine receptor/channels. The value of C(m) was indistinguishable in untransfected cells and in transfected cells expressing a high level of glycine channels, indicating that differences in transmembrane protein content do not significantly affect C(m). Thus, to a first approximation, C(m) may be treated as a "biological constant" across many classes of neuron.
Neocortical layer 5 pyramidal neurons possess long apical dendrites that receive a significant portion of the neurons excitatory synaptic input. Passive neuronal models indicate that the time course of excitatory postsynaptic potentials (EPSPs) generated in the apical dendrite will be prolonged as they propagate toward the soma. EPSP propagation may, however, be influenced by the recruitment of dendritic voltage-activated channels. Here we investigate the properties and distribution of I(h) channels in the axon, soma, and apical dendrites of neocortical layer 5 pyramidal neurons, and their effect on EPSP time course. We find a linear increase (9 pA/100 microm) in the density of dendritic I(h) channels with distance from soma. This nonuniform distribution of I(h) channels generates site independence of EPSP time course, such that the half-width at the soma of distally generated EPSPs (up to 435 microm from soma) was similar to somatically generated EPSPs. As a corollary, a normalization of temporal summation of EPSPs was observed. The site independence of somatic EPSP time course was found to collapse after pharmacological blockade of I(h) channels, revealing pronounced temporal summation of distally generated EPSPs, which could be further enhanced by TTX-sensitive sodium channels. These data indicate that an increasing density of apical dendritic I(h) channels mitigates the influence of cable filtering on somatic EPSP time course and temporal summation in neocortical layer 5 pyramidal neurons.
1. Electrophysiological recordings and pharmacological manipulations were used to investigate the mechanisms underlying the generation of action potential burst firing and its postsynaptic consequences in visually identified rat layer 5 pyramidal neurons in vitro. 2. Based upon repetitive firing properties and subthreshold membrane characteristics, layer 5 pyramidal neurons were separated into three classes: regular firing and weak and strong intrinsically burst firing. 3. High frequency (330 +/- 10 Hz) action potential burst firing was abolished or greatly weakened by the removal of Ca2+ (n = 5) from, or by the addition of the Ca2+ channel antagonist Ni2+ (250-500 microm; n = 8) to, the perfusion medium. 4. The blockade of apical dendritic sodium channels by the local dendritic application of TTX (100 nM; n = 5) abolished or greatly weakened action potential burst firing, as did the local apical dendritic application of Ni2+ (1 mM; n = 5). 5. Apical dendritic depolarisation resulted in low frequency (157 +/- 26 Hz; n = 6) action potential burst firing in regular firing neurons, as classified by somatic current injection. The intensity of action potential burst discharges in intrinsically burst firing neurons was facilitated by dendritic depolarisation (n = 11). 6. Action potential amplitude decreased throughout a burst when recorded somatically, suggesting that later action potentials may fail to propagate axonally. Axonal recordings demonstrated that each action potential in a burst is axonally initiated and that no decrement in action potential amplitude is apparent in the axon > 30 microm from the soma. 7. Paired recordings (n = 16) from synaptically coupled neurons indicated that each action potential in a burst could cause transmitter release. EPSPs or EPSCs evoked by a presynaptic burst of action potentials showed use-dependent synaptic depression. 8. A postsynaptic, TTX-sensitive voltage-dependent amplification process ensured that later EPSPs in a burst were amplified when generated from membrane potentials positive to -60 mV, providing a postsynaptic mechanism that counteracts use-dependent depression at synapses between layer 5 pyramidal neurons.
The dendrites of neurons in the mammalian central nervous system have been considered as electrically passive structures which funnel synaptic potentials to the soma and axon initial segment, the site of action potential initiation. More recent studies, however, have shown that the dendrites of many neurons are not passive, but contain active conductances. The role of these dendritic voltage-activated channels in the initiation of action potentials in neurons is largely unknown. To assess this directly, patch-clamp recordings were made from the dendrites of neocortical pyramidal cells in brain slices. Voltage-activated sodium currents were observed in dendritic outside-out patches, while action potentials could be evoked by depolarizing current pulses or by synaptic stimulation during dendritic whole-cell recordings. To determine the site of initiation of these action potentials, simultaneous whole-cell recordings were made from the soma and the apical dendrite or axon of the same cell. These experiments showed that action potentials are initiated first in the axon and then actively propagate back into the dendritic tree.
A description is given of the implementation of infrared differential interference contrast (IR-DIC) video microscopy to an upright compound microscope. Using the improved resolution offered by IR-DIC a procedure is described for making patch-pipette recordings from visually identified neuronal somata and dendrites in brain slices. As an example of the application of this technique to electrophysiological recordings from small neuronal processes in brain slices we describe whole-cell current-clamp and cell-attached and excised patch-clamp recordings from the apical dendrites of layer V pyramidal neurons in slices of rat neocortex.
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The Chemotherapy and Treatment Scheduling System provides integrated appointment and facility scheduling for very complex procedures. It is fully integrated with other scheduling systems at The Johns Hopkins Oncology Center and is supported by the Oncology Clinical Information System (OCIS). It provides a combined visual and textual environment for the scheduling of events that have multiple dimensions and dependencies on other scheduled events. It is also fully integrated with other clinical decision support and ancillary systems within OCIS. The system has resulted in better patient flow through the ambulatory care areas of the Center. Implementing the system required changes in behavior among physicians, staff, and patients. This system provides a working example of building a sophisticated rule-based scheduling system using a relatively simple paradigm. It also is an example of what can be achieved when there is total integration between the operational and clinical components of patient care automation.
1. The role of GABAA and GABAB receptors in presynaptic inhibition was studied by examining the effect of local application of antagonists by ionophoresis during intracellular recording of presynaptic inhibition of compound and unitary group Ia afferent excitatory postsynaptic potentials (EPSPs) in gastrocnemius motoneurones. 2. Ionophoresis of the GABAA antagonist bicuculline methochloride (BMC) was found to block presynaptic inhibition of both compound and unitary EPSPs by up to 85%. BMC also substantially reduced, and occasionally abolished, the late part of the inhibitory postsynaptic potential (IPSP) evoked in motoneurones by the conditioning stimulation. The early part of this IPSP was found to be sensitive to ionophoresis of strychnine hydrochloride. 3. Ionophoresis of 2-OH-saclofen caused a reduction in presynaptic inhibition of compound EPSPs by 5-25% but had no effect on the IPSP evoked in motoneurones by the conditioning stimulation. 4. Ionophoresis of the GABAB antagonist (-)-baclofen reduced the amplitude of unconditioned EPSPs; however it had little effect on presynaptic inhibition. 5. It was concluded that at the Ia afferent-motoneurone synapse presynaptic inhibition is mediated primarily through the activation of GABAA receptors. The activation of GABAB receptors appears to play only a minor role in presynaptic inhibition at this synapse. This contrasts with the relative ease with which (-)-baclofen can reduce transmitter release from Ia afferent terminals and suggests that the receptors activated by (-)-baclofen are predominantly extrasynaptic.
In today's medical care environment of cost containment and restricted reimbursement, it is important to maximize the use of expensive facility and personnel resources. Concurrently, it is important to provide superior and timely patient services in order to remain competitive in an extremely flexible market. There are many areas in today's larger hospital environments where such ideals can be easily achieved. One of the more obvious areas is the automation of appointment and resource scheduling for ambulatory care services. This article focuses on maximizing the use of available physical and personnel resources in the ambulatory care setting of large and specialty hospitals. The Johns Hopkins Oncology Center's integrated outpatient scheduling and resource management systems are used as examples of what can be achieved. It is hoped that the experiences of the Oncology Center in developing these integrated systems will help others in similar efforts.
An investigation was made of the effect of presynaptic inhibition on paired-pulse facilitation (PPF) of group Ia afferent excitatory postsynaptic potentials (EPSPs). The main finding from this study was that PPF was enhanced during presynaptic inhibition of compound Ia EPSPs. This increase in PPF is identical to that seen at other synapses when the probability of transmitter release is decreased by lowering the extracellular calcium or raising the extracellular magnesium concentration, providing unequivocal evidence that presynaptic inhibition is associated with a decrease in the probability of transmitter release. Further, by analogy with the effects of reduced calcium influx on PPF at other synapses, the results support the idea that presynaptic inhibition is associated with reduced calcium influx into nerve terminals.
1. Inhibitory postsynaptic currents (IPSCs) were recorded in voltage clamped posterior biceps or semitendinosus motoneurones of the cat during reciprocal inhibition. 2. Population IPSCs, recorded following stimulation of the whole quadriceps muscle nerve, had an average time-to-peak of 0.51 +/- 0.02 ms (+/- S.E.M., n = 22) and decayed exponentially, with an average time constant of 0.99 +/- 0.04 ms (at 37 degrees C) at resting membrane potentials. 3. Unitary IPSCs, recorded following spike-triggered averaging from an identified reciprocal inhibitory interneurone, had amplitudes of 120-220 pA with an average time-to-peak of 0.40 +/- 0.06 ms (n = 5). The decay of these unitary currents was exponential, with an average time constant of 0.82 +/- 0.07 ms (at 37 degrees C) at resting membrane potentials. 4. The time course of IPSCs was unaffected by either alpha-chloralose or pentobarbitone at concentrations necessary for deep anaesthesia. 5. The peak synaptic current varied linearly with the membrane potential over the range -90 to -30 mV, and had an average reversal potential of -80.7 +/- 1.5 mV (+/- S.E.M., n = 6) when measured using KCH3SO4-filled electrodes. 6. The reversal potential for the IPSC was used to calculate [Cl-]i. This was estimated to be 6.5 mM assuming that the inhibitory synaptic current was mediated purely by Cl- ions. 7. The rate at which synaptic currents decayed was exponentially dependent on the postsynaptic membrane potential, the decay time constant increasing e-fold for a 91 mV depolarization. This result was independent of [Cl-]i or of the magnitude of the synaptic conductance and was interpreted as a voltage dependence of the glycine channel open time. 8. The average unitary peak conductance was 9.1 +/- 1.7 nS (+/- S.E.M., n = 5), corresponding to the opening of approximately 200 glycine-activated postsynaptic channels following neurotransmitter release from a single Ia reciprocal interneurone.
The tonic vibration reflex evoked in the vibrated medial gastrocnemius muscle was compared with that induced simultaneously in an unvibrated close synergist, the lateral gastrocnemius muscle, in the unanesthetized decerebrated cat. The time course of the force rise and fall in the synergist muscle was found to be markedly different from that produced in the vibrated muscle. In addition the magnitude of force produced in the synergist was only weakly modulated with increasing vibration frequency, in that the synergist uniformly displayed much flatter force-frequency relations than the vibrated muscle, and even showed overt force saturation in several preparations. Comparable differences in reflex responses arose when the lateral gastrocnemius served as the unvibrated synergist. In a parallel series of experiments, low intensity electrical stimulation of the proximal end of the sectioned medial gastrocnemius muscle nerve at different frequencies weakly modulated the amount of reflex force induced in the lateral gastrocnemius muscle. High frequency electrical stimulation caused the synergist force to saturate in a similar way to that seen in the vibrated preparations. A variety of possible mechanisms are discussed, with particular emphasis on "bistable" properties of motoneurons and Ia excitatory interneuronal contributions.