Disturbances of motor unit rate modulation are prevalent in muscles of spastic-paretic stroke survivors.

Stroke survivors often exhibit abnormally low motor unit firing rates during voluntary muscle activation. Our purpose was to assess the prevalence of saturation in motor unit firing rates in the spastic-paretic biceps brachii muscle of stroke survivors. To achieve this objective, we recorded the incidence and duration of impaired lower- and higher-threshold motor unit firing rate modulation in spastic-paretic, contralateral, and healthy control muscle during increases in isometric force generated by the elbow flexor muscles. Impaired firing was considered to have occurred when firing rate became constant (i.e., saturated), despite increasing force. The duration of impaired firing rate modulation in the lower-threshold unit was longer for spastic-paretic (3.9 ± 2.2 s) than for contralateral (1.4 ± 0.9 s; P < 0.001) and control (1.1 ± 1.0 s; P = 0.005) muscles. The duration of impaired firing rate modulation in the higher-threshold unit was also longer for the spastic-paretic (1.7 ± 1.6 s) than contralateral (0.3 ± 0.3 s; P = 0.007) and control (0.1 ± 0.2 s; P = 0.009) muscles. This impaired firing rate of the lower-threshold unit arose, despite an increase in the overall descending command, as shown by the recruitment of the higher-threshold unit during the time that the lower-threshold unit was saturating, and by the continuous increase in averages of the rectified EMG of the biceps brachii muscle throughout the rising phase of the contraction. These results suggest that impairments in firing rate modulation are prevalent in motor units of spastic-paretic muscle, even when the overall descending command to the muscle is increasing.

Black box revisited: a technique for estimating postsynaptic potentials in neurons.

Our understanding of the operation of the brain depends on knowledge of its wiring. Currently, the wiring of the human brain is estimated by counting the number of neuron discharges that occur at specific times following a stimulus. There is now strong evidence that this approach generates significant errors. Recently, the accuracy of this 'count' method has been compared directly with an alternative 'rate' method in rat brain slices. The results confirmed that the count method generates significant errors that are minimized by the rate method, because the rate of discharge of a neuron accurately displays its excitability at the time of discharge. Therefore, it is now crucial that the rate method be used to reassess previous estimates of the characteristics of wiring in the brain.

Contributions of the input signal and prior activation history to the discharge behaviour of rat motoneurones.

The principal computational operation of neurones is the transformation of synaptic inputs into spike train outputs. The probability of spike occurrence in neurones is determined by the time course and magnitude of the total current reaching the spike initiation zone. The features of this current that are most effective in evoking spikes can be determined by injecting a Gaussian current waveform into a neurone and using spike-triggered reverse correlation to calculate the average current trajectory (ACT) preceding spikes. The time course of this ACT (and the related first-order Wiener kernel) provides a general description of a neurone's response to dynamic stimuli. In many different neurones, the ACT is characterized by a shallow hyperpolarizing trough followed by a more rapid depolarizing peak immediately preceding the spike. The hyperpolarizing phase is thought to reflect an enhancement of excitability by partial removal of sodium inactivation. Alternatively, this feature could simply reflect the fact that interspike intervals that are longer than average can only occur when the current is lower than average toward the end of the interspike interval. Thus, the ACT calculated for the entire spike train displays an attenuated version of the hyperpolarizing trough associated with the long interspike intervals. This alternative explanation for the characteristic shape of the ACT implies that it depends upon the time since the previous spike, i.e. the ACT reflects both previous stimulus history and previous discharge history. The present study presents results based on recordings of noise-driven discharge in rat hypoglossal motoneurones that support this alternative explanation. First, we show that the hyperpolarizing trough is larger in ACTs calculated from spikes preceded by long interspike intervals, and minimal or absent in those based on short interspike intervals. Second, we show that the trough is present for ACTs calculated from the discharge of a threshold-crossing neurone model with a postspike afterhyperpolarization (AHP), but absent from those calculated from the discharge of a model without an AHP. We show that it is possible to represent noise-driven discharge using a two-component linear model that predicts discharge probability based on the sum of a feedback kernel and a stimulus kernel. The feedback kernel reflects the influence of prior discharge mediated by the AHP, and it increases in amplitude when AHP amplitude is increased by pharmacological manipulations. Finally, we show that the predictions of this model are virtually identical to those based on the first-order Wiener kernel. This suggests that the Wiener kernels derived from standard white-noise analysis of noise-driven discharge in neurones actually reflect the effects of both stimulus and discharge history.

Estimation of postsynaptic potentials in rat hypoglossal motoneurones: insights for human work.

Classical techniques for estimating postsynaptic potentials in motoneurones include spike-triggered averages of rectified surface and multiunit electromyographic recordings (SEMG and MU-EMG), as well as the compilation of peristimulus time histograms (PSTH) based on the discharge of single motor units (SMU). These techniques rely on the probability of spike occurrence in relation to the stimulus and can be contaminated by count- and synchronization-related errors, arising from post-spike refractoriness and the discharge statistics of motoneurones. On the other hand, since these probability-based techniques are easy to use and require only inexpensive equipment, it is very likely that they will continue to be used in clinical and laboratory settings for the foreseeable future. One aim of the present study was to develop a modification of these probability-based analyses in order to provide a better estimate of the initial phase of postsynaptic potentials. An additional aim was to combine probability-based analyses with frequency-based analyses to provide a more reliable estimate of later phases of postsynaptic potentials. To achieve these aims, we have injected simple as well as complex current transients into regularly discharging hypoglossal motoneurones recorded in vitro from rat brainstem slices. We examined the discharge output of these cells using both probability- and frequency-based analyses to identify which of the two represented the profile of the postsynaptic potential more closely. This protocol was designed to obtain PSTHs of the responses of single motor units to repeated application of the same afferent input. We have also simulated multiunit responses to afferent input by replacing the times of spike occurrence in individual trials with a representation of either an intramuscular or surface-recording single motor unit waveform and summing many of these trials to obtain either a simulated SEMG or MU-EMG. We found that in a regularly discharging motoneurone, the rising phase of an EPSP moves the occurrence of spikes forward and hence induces a substantial peak in all probability-based records. This peak is followed immediately by a period of reduced activity ('silent period') due to the phase advancement of spikes that were to occur at this period. Similarly, the falling phase of an IPSP delays spikes so that they occur during the rising phase of the IPSP. During the delay, the probability-based analyses display gaps and during the occurrence of the delayed spikes they generate peaks. We found that all the probability-based analyses (SEMG, MU-EMG and PSTH) can be made useful for illustrating the underlying initial PSP by a special use of the cumulative sum (CUSUM) calculation. We have illustrated that, in most cases, the CUSUM of probability-based analyses can overcome the delay- or advance-related (i.e. the count-related) errors of the classical methods associated with the first PSP only. The probability-based records also induce secondary and tertiary peaks and troughs due to synchronization of the spikes in relation to the stimulus (i.e. the synchronization-related errors) by the first PSP to occur at fixed times from the stimulus. Special CUSUM analyses cannot overcome these synchronization-related errors. Frequency-based analysis (PSFreq) of individual and summed trials gave comparable and often better indications of the underlying PSPs than the probability-based analyses. When used in combination, these analyses compliment each other so that a more accurate estimation of the underlying PSP is possible. Since the correct identification of the connections in the central nervous system is of utmost importance in order to understand the operation of the system, we suggest that as well as the using the special CUSUM approach on probability-based records, researchers should seriously consider the use of frequency-based analyses in their indirect estimation of stimulus-induced compound synaptic potentials in human motoneurones.

The effects of common input characteristics and discharge rate on synchronization in rat hypoglossal motoneurones.

Synchronous discharges between a pair of concurrently active motoneurones are thought to arise from the spike-triggering effects of synaptic inputs shared by the pair. Although there are a number of quantitative indices that have been developed to estimate the strength of this common input, there is still some debate as to whether motoneurone discharge rate affects the values of these indices. The aim of the present study was to test the effects of motoneurone discharge rate on these synchronization indices using known common inputs. To achieve this aim we elicited repetitive discharge in rat hypoglossal motoneurones by combining a suprathreshold injected current step with superimposed noise to mimic the synaptic drive likely to occur during physiological activation. The amplitude of the current step was varied in different trials to achieve discharge rates from 5 to 22 Hz. We first examined the effect of discharge rate on the spike-triggering efficacy of individual EPSPs. Motoneurones were more responsive to large EPSPs delivered at a low rate when their background discharge rate was relatively low and the probability of the EPSPs evoking an extra spike decreased with increasing discharge rate. However, the opposite dependence was found for small, high-frequency EPSPs. We then compared the discharge records obtained in several trials in which the same EPSP train was applied repeatedly to the same cell firing at different background discharge rates. The effect of this 'common input' on motoneurone discharge probability was determined by compiling cross-correlation histograms (CCHists) between the discharges of the same cell at different times. The common inputs induced synchronous discharge that gave rise to large central peaks in the CCHists. The relationship between the discharge rate and the level of synchronization changed depending on the synchronization indices used and the amplitude of the common EPSPs. When large EPSPs were used as the common input, the normalized probability of synchronous spikes declined as the discharge rate increased, regardless of the method of normalization used. In contrast, when the common input was composed of a large number of small EPSPs, similar to that likely to occur during physiological activation of motoneurones, different synchronization indices exhibited a positive, a negative or no dependence on the background discharge rate. Indices based on normalizing the number of synchronous spikes by either the number of discharges in the lower frequency train (E), or by the total number of discharges in both trains (S) showed no dependence on background discharge rate and therefore may be the most suitable for quantifying motoneurone synchrony over a range of background discharge rates.

Effects of common excitatory and inhibitory inputs on motoneuron synchronization.

We compared the effects of common excitatory and inhibitory inputs on motoneuron synchronization by simulating synaptic inputs with injected current transients. We elicited repetitive discharge in hypoglossal motoneurons recorded in slices of rat brain stem using a combination of a suprathreshold injected current step with superimposed noise to mimic the synaptic drive likely to occur during physiological activation. The effects of common inputs to motoneurons were simulated by the addition of a waveform composed of from 6 to 300 trains of current transients designed to mimic excitatory and/or inhibitory synaptic currents. We compared the discharge records obtained in several trials in which the same "common input" waveform was applied repeatedly in the presence of different background noise waveforms. The effects of the common input on motoneuron discharge probability and discharge rate were determined by compiling a cross-correlation histogram (CCHist) and a perispike frequencygram (PSFreq) between the discharges of the same cell at different times. Both excitatory and inhibitory common inputs induced synchronous discharge that was evident by a large central peak in the CCHist. The CCHists produced by common excitatory inputs were characterized by larger and narrower central peaks than those generated by common inhibitory inputs. The PSFreqs produced by common excitatory inputs indicated an increase in the discharge rate of motoneurons around time 0 that coincided with the narrow and large central peak in the CCHist. On the other hand, inhibitory inputs often generated very little, if any, change in the discharge rate around time 0 corresponding with the small and wide central peak in the CCHist. These results suggest that the CCHist indicates the effective strength of the net common input but not its sign. Although correlated changes in discharge rate are often quite different for net excitatory and inhibitory common input, except in some restricted conditions, the PSFreq analysis also cannot be used to unambiguously distinguish net excitation from net inhibition.

Relationship between simulated common synaptic input and discharge synchrony in cat spinal motoneurons.

Synchronized discharge of individual motor units is commonly observed in the muscles of human subjects performing voluntary contractions. The amount of this synchronization is thought to reflect the extent to which motoneurons in the same and related pools share common synaptic input. However, the relationship between the proportion of shared synaptic input and the strength of synchronization has never been measured directly. In this study, we simulated common shared synaptic input to cat spinal motoneurons by driving their discharge with noisy, injected current waveforms. Each motoneuron was stimulated with a number of different injected current waveforms, and a given pair of waveforms were either completely different or else shared a variable percentage of common elements. Cross-correlation histograms were then compiled between the discharge of motoneurons stimulated with noise waveforms with variable degrees of similarity. The strength of synchronization increased with the amount of simulated "common" input in a nonlinear fashion. Moreover, even when motoneurons had >90% of their simulated synaptic inputs in common, only approximately 25-45% of their spikes were synchronized. We used a simple neuron model to explore how variations in neuron properties during repetitive discharge may lead to the low levels of synchronization we observed experimentally. We found that small variations in spike threshold and firing rate during repetitive discharge lead to large decreases in synchrony, particularly when neurons have a high degree of common input. Our results may aid in the interpretation of studies of motor unit synchrony in human hand muscles during voluntary contractions.

Input-output functions of mammalian motoneurons.

Our intent in this review was to consider the relationship between the biophysical properties of motoneurons and the mechanisms by which they transduce the synaptic inputs they receive into changes in their firing rates. Our emphasis has been on experimental results obtained over the past twenty years, which have shown that motoneurons are just as complex and interesting as other central neurons. This work has shown that motoneurons are endowed with a rich complement of active dendritic conductances, and flexible control of both somatic and dendritic channels by endogenous neuromodulators. Although this new information requires some revision of the simple view of motoneuron input-output properties that was prevalent in the early 1980's (see sections 2.3 and 2.10), the basic aspects of synaptic transduction by motoneurons can still be captured by a relatively simple input-output model (see section 2.3, equations 1-3). It remains valid to describe motoneuron recruitment as a product of the total synaptic current delivered to the soma, the effective input resistance of the motoneuron and the somatic voltage threshold for spike initiation (equations 1 and 2). However, because of the presence of active channels activated in the subthreshold range, both the delivery of synaptic current and the effective input resistance depend upon membrane potential. In addition, activation of metabotropic receptors by achetylcholine, glutamate, noradrenaline, serotonin, substance P and thyrotropin releasing factor (TRH) can alter the properties of various voltage- and calcium-sensitive channels and thereby affect synaptic current delivery and input resistance. Once motoneurons are activated, their steady-state rate of repetitive discharge is linearly related to the amount of injected or synaptic current reaching the soma (equation 3). However, the slope of this relation, the minimum discharge rate and the threshold current for repetitive discharge are all subject to neuromodulatory control. There are still a number of unresolved issues concerning the control of motoneuron discharge by synaptic inputs. Under dynamic conditions, when synaptic input is rapidly changing, time- and activity-dependent changes in the state of ionic channels will alter both synaptic current delivery to the spike-generating conductances and the relation between synaptic current and discharge rate. There is at present no general quantitative expression for motoneuron input-output properties under dynamic conditions. Even under steady-state conditions, the biophysical mechanisms underlying the transfer of synaptic current from the dendrites to the soma are not well understood, due to the paucity of direct recordings from motoneuron dendrites. It seems likely that resolving these important issues will keep motoneuron afficiandoes well occupied during the next twenty years.

Amplification and linear summation of synaptic effects on motoneuron firing rate.

The aim of this study was to measure the effects of synaptic input on motoneuron firing rate in an unanesthetized cat preparation, where activation of voltage-sensitive dendritic conductances may influence synaptic integration and repetitive firing. In anesthetized cats, the change in firing rate produced by a steady synaptic input is approximately equal to the product of the effective synaptic current measured at the resting potential (I(N)) and the slope of the linear relation between somatically injected current and motoneuron discharge rate (f-I slope). However, previous studies in the unanesthetized decerebrate cat indicate that firing rate modulation may be strongly influenced by voltage-dependent dendritic conductances. To quantify the effects of these conductances on motoneuron firing behavior, we injected suprathreshold current steps into medial gastrocnemius motoneurons of decerebrate cats and measured the changes in firing rate produced by superimposed excitatory synaptic input. In the same cells, we measured I(N) and the f-I slope to determine the predicted change in firing rate (Delta F = I(N) * f-I slope). In contrast to previous results in anesthetized cats, synaptically induced changes in motoneuron firing rate were greater-than-predicted. This enhanced effect indicates that additional inward current was present during repetitive firing. This additional inward current amplified the effective synaptic currents produced by two different excitatory sources, group Ia muscle spindle afferents and caudal cutaneous sural nerve afferents. There was a trend toward more prevalent amplification of the Ia input (14/16 cells) than the sural input (11/16 cells). However, in those cells where both inputs were amplified (10/16 cells), amplification was similar in magnitude for each source. When these two synaptic inputs were simultaneously activated, their combined effect was generally very close to the linear sum of their amplified individual effects. Linear summation is also observed in medial gastrocnemius motoneurons of anesthetized cats, where amplification is not present. This similarity suggests that amplification does not disturb the processes of synaptic integration. Linear summation of amplified input was evident for the two segmental inputs studied here. If these phenomena also hold for other synaptic sources, then the presence of active dendritic conductances underlying amplification might enable motoneurons to integrate multiple synaptic inputs and drive motoneuron firing rates throughout the entire physiological range in a relatively simple fashion.

Relationship between the time course of the afterhyperpolarization and discharge variability in cat spinal motoneurones.

1. We elicited repetitive discharges in cat spinal motoneurones by injecting noisy current waveforms through a microelectrode to study the relationship between the time course of the motoneurone's afterhyperpolarization (AHP) and the variability in its spike discharge. Interspike interval histograms were used to estimate the interval death rate, which is a measure of the instantaneous probability of spike occurrence as a function of the time since the preceding spike. It had been previously proposed that the death rate can be used to estimate the AHP trajectory. We tested the accuracy of this estimate by comparing the AHP trajectory predicted from discharge statistics to the measured AHP trajectory of the motoneurone. 2. The discharge statistics of noise-driven cat motoneurones shared a number of features with those previously reported for voluntarily activated human motoneurones. At low discharge rates, the interspike interval histograms were often positively skewed with an exponential tail. The standard deviation of the interspike intervals increased with the mean interval, and the plots of standard deviation versus the mean interspike interval generally showed an upward bend, the onset of which was related to the motoneurone's AHP duration. 3. The AHP trajectories predicted from the interval death rates were generally smaller in amplitude (i.e. less hyperpolarized) than the measured AHP trajectories. This discrepancy may result from the fact that spike threshold varies during the interspike interval, so that the distance to threshold at a given time depends upon both the membrane trajectory and the spike threshold trajectory. Nonetheless, since the interval death rate is likely to reflect the instantaneous distance to threshold during the interspike interval, it provides a functionally relevant measure of fluctuations in motoneurone excitability during repetitive discharge.

Summation of effective synaptic currents and firing rate modulation in cat spinal motoneurons.

The aim of this study was to examine how cat spinal motoneurons integrate the synaptic currents generated by the concurrent activation of large groups of presynaptic neurons. We obtained intracellular recordings from cat triceps surae motoneurons and measured the effects of repetitive activity in different sets of presynaptic neurons produced by electrical stimulation of descending fibers or peripheral nerves and by longitudinal vibration of the triceps surae muscles (to activate primary muscle spindle Ia afferent fibers). We combined synaptic activation with subthreshold injected currents to obtain estimates of effective synaptic currents at the resting potential (I(Nrest)) and at the threshold for repetitive discharge (I(Nthresh)). We then superimposed synaptic activation on suprathreshold injected current steps to measure the synaptically evoked change in firing rate. We studied eight different pairs of synaptic inputs. When any two synaptic inputs were activated concurrently, both the effective synaptic currents (I(Nrest)) and the synaptically evoked changes in firing rate generally were equal to or slightly less than the linear sum of the effects produced by activating each input alone. However, there were several instances in which the summation was substantially less than linear. In some motoneurons, we induced a partial blockade of potassium channels by adding tetraethylammonium (TEA) or cesium to the electrolyte solution in the intracellular pipette. In these cells, persistent inward currents were evoked by depolarization that led to instances of substantially greater-than linear summation of injected and synaptic currents. Overall our results indicate that the spatial distribution of synaptic boutons on motoneurons acts to minimize electrical interactions between synaptic sites permitting near linear summation of synaptic currents. However, modulation of voltage-gated conductances on the soma and dendrites of the motoneuron can lead to marked nonlinearities in synaptic integration.

Effects of large excitatory and inhibitory inputs on motoneuron discharge rate and probability.

We elicited repetitive discharge in hypoglossal motoneurons recorded in slices of rat brain stem using a combination of a suprathreshold injected current step with superimposed noise to mimic the synaptic drive likely to occur during physiological activation. The effects of repetitive en mass stimulation of afferent nerves were simulated by the further addition of trains of injected current transients of varying shapes and sizes. The effects of a given current transient on motoneuron discharge timing and discharge rate were measured by calculating a peristimulus time histogram (PSTH) and a peristimulus frequencygram (PSF). The amplitude and time course of the simulated postsynaptic potentials (PSPs) produced by the current transients were calculated by convolving the current transient with an estimate of the passive impulse response of the motoneuron. We then compared the shape of the injected current transient and the simulated PSP to the profiles of the PSTH and the PSF records. The PSTHs produced by excitatory PSPs (EPSPs) were characterized by a large, short-latency increase in firing probability that lasted slightly longer than the rising phase of the EPSP, followed by a reduced discharge probability during the falling phase of the EPSP. In contrast, the PSF analysis revealed a proportionate increase in discharge rate over the entire profile of the EPSP, even though relatively few spikes occurred during the falling phase. The PSTHs associated with inhibitory PSPs (IPSPs) indicated a reduction in discharge probability during the initial, hyperpolarizing phase of the IPSP, followed by an increase in the discharge probability during its subsequent repolarizing phase. Using the PSF analysis, the initial phase of the IPSP appeared as a large hole in the record where a very small number or no discharges occurred. The subsequent phase of the IPSP was associated with frequency values that were lower than the background values. The primary features of both PSTHs and PSFs can be used to estimate the relative amplitudes of the underlying EPSPs and IPSPs. However, PSTHs contain secondary peaks and troughs that are not directly related to the underlying PSP but instead reflect the regular recurrence of spikes following those affected by the PSP. The PSF analysis is more useful for indicating the total duration and the profile of the underlying PSP. The shape of the underlying PSP can be obtained directly from the PSF records because the discharge frequency of the spikes follow the PSPs very closely, especially for EPSPs.

Synaptic integration in spinal motoneurones.

Spinal motoneurones receive thousands of presynaptic excitatory and inhibitory synaptic contacts distributed throughout their dendritic trees. Despite this extensive convergence, there have been very few studies of how synaptic inputs interact in mammalian motoneurones when they are activated concurrently. In the experiments reported here, we measured the effective synaptic currents and the changes in firing rate evoked in cat spinal motoneurones by concurrent repetitive activation of two separate sets of presynaptic neurons. We compared these effects to those predicted by a linear sum of the effects produced by activating each set of presynaptic neurons separately. We generally found that when two inputs were activated concurrently, both the effective synaptic currents and the synaptically-evoked changes in firing rate they produced in motoneurones were generally linear, or slightly less than the linear sum of the effects produced by activating each input alone. The results suggest that the spatial distribution synaptic terminals on the dendritic trees of motoneurones may help isolate synapses from one another, minimizing non-linear interactions.

Functional identification of the input-output transforms of mammalian motoneurones.

We studied the responses of rat hypoglossal and cat lumbar motoneurones to a variety of excitatory and inhibitory injected current transients during repetitive discharge. The amplitudes and time courses of the transients were comparable to those of the synaptic currents underlying postsynaptic potentials (PSPs) recorded in these cells. Poisson trains of these current transients were combined with an additional independent, high frequency random waveform to approximate band-limited white noise. The composite, white noise waveform was then superimposed on long duration suprathreshold current steps. We used the responses of the motoneurones to the white noise stimulus to derive zero-, first- and second-order Wiener kernels, which provide a quantitative description of the relation between injected current and discharge probability. The convolution integral computed for an injected current waveform and the first-order Wiener kernel provides the best linear prediction of the associated peristimulus time histogram (PSTH). This linear model provided good matches to most of the PSTHs compiled between the times of occurrence of individual current transients and motoneurone discharges. However, for the largest amplitude current transients, a significant improvement in the PSTH match was often achieved by expanding the model to include the convolution of the second-order Wiener kernel with the input. The overall transformation of current inputs into firing rate could be approximated by a second-order Wiener Model, i.e., a cascade of a dynamic, linear filter followed by a static non-linearity. At a given mean firing rate, the non-linear component of the motoneurone's response could be described by the square of the linear component multiplied by a constant coefficient. The amplitude of the response of the linear component increased with the average firing rate, whereas the value of the multiplicative coefficient in the nonlinear component decreased. As a result, the overall transform could be predicted from the mean firing rate and the linear impulse response, yielding a relatively simple, general description of the motoneurone's input-output function.

Multiple mechanisms of spike-frequency adaptation in motoneurones.

Spike-frequency adaptation is the continuous decline in discharge rate in response to a constant stimulus. We have described three distinct phases of adaptation in rat hypoglossal motoneurones: initial, early and late. The initial phase of adaptation is over in one or two intervals, and is primarily due to summation of the calcium-activated potassium conductance underlying the medium duration afterhyperpolarization (mAHP). The biophysical mechanisms underlying the later phases of adaptation are not well understood. Two of the previously-proposed mechanisms for adaptation are an increase in outward current flowing through calcium-activated potassium channels and increasing outward current produced by the electrogenic sodium-potassium pump. We found that neither of these mechanisms are necessary for the expression of the early and late phases of adaptation. The magnitude of the initial phase of adaptation was reduced when the calcium in the external solution was replaced with manganese, but the magnitudes of the early and late phases were consistently increased under these conditions. Partial blockade of the sodium-potassium pump with ouabain had no significant effect on any of the three phases of adaptation. Our current working hypothesis is that the magnitude of late adaptation depends upon the interplay between slow inactivation of sodium currents, that tends to decrease discharge rate, and the slow activation or facilitation of a calcium current that tends to increase discharge rate. Adaptation is often associated with a progressive decrease in the peak amplitude and rate of rise of action potentials, and a computer model that incorporated slow inactivation of sodium channels reproduced this phenomenon. However, the time course of adaptation does not always parallel changes in spike shape, indicating that the progressive activation of another inward current might oppose the decline in frequency caused by slow sodium inactivation.

Distribution of effective synaptic currents in cat triceps surae motoneurons. VI. Contralateral pyramidal tract.

We measured the effective synaptic currents (IN) produced by stimulating the contralateral pyramidal tract (PT) in triceps surae motoneurons of the cat. This is an oligosynaptic pathway in the cat that generates both excitation and inhibition in hindlimb motoneurons. We also determined the effect of the PT synaptic input on the discharge rate of some of the motoneurons by inducing repetitive firing with long, injected current pulses during which the PT stimulation was repeated. At resting potential, all but one triceps motoneuron received a net depolarizing effective synaptic current from the PT stimulation. The effective synaptic currents (IN) were much larger in putative type F motoneurons than in putative type S motoneurons [+4.6 +/- 2.9 (SD) nA for type F vs. 0.9 +/- 2.4 nA for putative type S]. When the values of IN at the threshold for repetitive firing were estimated, the distribution was markedly altered. More than 60% of the putative type S motoneurons received a net hyperpolarizing effective synaptic current from the pyramidal tract stimulation as did 33% of the putative type F motoneurons. This distribution pattern is very similar to that observed previously for the effective synaptic currents produced by stimulating the contralateral red nucleus. As would be expected from the wide range of IN values at threshold (-4.8 to +8.7 nA), the PT stimulation produced dramatically different effects on the discharge of different triceps motoneurons. The discharge rates of those motoneurons that received depolarizing effective synaptic currents at threshold were accelerated by PT stimulation (+1 to +8 imp/s), whereas the discharge rates of cells that received hyperpolarizing currents were retarded by the PT input (-2 to -7 imp/s). The change in firing rates produced by the PT stimulation was generally approximated by the product of the effective synaptic currents and the slopes of the motoneurons' frequency-current relations. Our findings indicate that the contralateral pyramidal tract may provide a powerful source of synaptic drive to some high-threshold motoneurons while concurrently inhibiting low-threshold cells. Thus this input system, like that from the contralateral red nucleus, can potentially alter the gain of the input-output function of the motoneuron pool as well as disrupt the normal hierarchy of recruitment thresholds.

Functional identification of the input-output transforms of motoneurones in the rat and cat.

1. We studied the responses of rat hypoglossal and cat lumbar motoneurones to a variety of excitatory and inhibitory injected current transients during repetitive discharge. The amplitudes and time courses of the transients were comparable to those of the synaptic currents underlying unitary and small compound postsynaptic potentials (PSPs) recorded in these cells. Poisson trains of ten of these excitatory and ten inhibitory current transients were combined with an additional independent, high-frequency random waveform to approximate band limited white noise. The white noise waveform was then superimposed on long duration (39 s) suprathreshold current steps. 2. We measured the effects of each of the current transients on motoneurone discharge by compiling peristimulus time histograms (PSTHs) between the times of occurrence of individual current transients and motoneurone discharges. We estimated the changes in membrane potential associated with each current transient by approximating the passive response of the motoneurone with a simple resistance-capacitance circuit. The relations between the features of these simulated PSPs and those of the PSTHs were similar to those reported previously for real PSPs: the short-latency PSTH peak (or trough) was generally longer than the initial phase of the PSP derivative, but shorter than the time course of the PSP itself. Linear models of the PSP to PSTH transform based on the PSP time course, the time derivative of the PSP, or a linear combination of the two parameters could not reproduce the full range of PSTH profiles observed. 3. We also used the responses of the motoneurones to the white noise stimulus to derive zero-, first- and second-order Wiener kernels, which provide a quantitative description of the relation between injected current and discharge probability. The convolution integral computed for an injected current waveform and the first-order Wiener kernel should provide the best linear prediction of the associated PSTH. This linear model provided good matches to the PSTHs associated with a wide range of current transients. However, for the largest amplitude current transients, a significant improvement in the PSTH match was often achieved by expanding the model to include the convolution of the second-order Wiener kernel with the input. 4. The overall transformation of current inputs into firing rate could be approximated by a second-order Wiener model, i.e. a cascade of a dynamic, linear filter followed by a static non-linearity. At a given mean firing rate, the non-linear component of the response of the motoneurone could be described by the square of the linear component multiplied by a constant coefficient. The amplitude of the response of the linear component increased with the average firing rate, whereas the value of the multiplicative coefficient in the non-linear component decreased. As a result, the overall transform could be predicted from the mean firing rate and the linear impulse response, yielding a relatively simple, general description of the motoneurone input-output function.

Contribution of outward currents to spike-frequency adaptation in hypoglossal motoneurons of the rat.

Contribution of outward currents to spike-frequency adaptation in hypoglossal motoneurons of the rat. J. Neurophysiol. 78: 2246-2253, 1997. Spike-frequency adaptation has been attributed to the actions of several different membrane currents. In this study, we assess the contributions of two of these currents: the net outward current generated by the electrogenic Na+-K+ pump and the outward current that flows through Ca2+-activated K+ channels. In recordings made from hypoglossal motoneurons in slices of rat brain stem, we found that bath application of a 4-20 microM ouabain solution produced a partial block of Na+-K+ pump activity as evidenced by a marked reduction in the postdischarge hyperpolarization that follows a period of sustained discharge. However, we observed no significant change in either the initial, early, or late phases of spike-frequency adaptation in the presence of ouabain. Adaptation also has been related to increases in the duration and magnitude of the medium-duration afterhyperpolarization (mAHP) mediated by Ca2+-activated K+ channels. When we replaced the 2 mM Ca2+ in the bathing solution with Mn2+, there was a significant decrease in the amplitude of the mAHP after a spike. The decrease in mAHP amplitude resulted in a decrease in the magnitude of the initial phase of spike-frequency adaptation as has been reported previously by others. However, quite unexpectedly we also found that reducing the mAHP resulted in a dramatic increase in the magnitude of both the early and late phases of adaptation. These changes could be reversed by restoring the normal Ca2+ concentration in the bath. Our results with ouabain indicate that the Na+-K+ pump plays little, if any, role in the three phases of adaptation in rat hypoglossal motoneurons. Our results with Ca2+ channel blockade support the hypothesis that initial adaptation is, in part, controlled by conductances underlying the mAHP. However, our failure to eliminate initial adaptation completely by blocking Ca2+ channels suggests that other membrane mechanisms also contribute. Finally, the increase in both the early and late phases of adaptation in the presence of Mn2+ block of Ca2+ channels lends further support to the hypothesis that the initial and later (i.e., early and late) phases of spike-frequency adaptation are mediated by different cellular mechanisms.

Effects of background noise on the response of rat and cat motoneurones to excitatory current transients.

1. We studied the responses of rat hypoglossal motoneurones to excitatory current transients (ECTs) using a brainstem slice preparation. Steady, repetitive discharge at rates of 12-25 impulses s-1 was elicited from the motoneurones by injecting long (40 s) steps of constant current. Poisson trains of the ECTs were superimposed on these steps. The effects of additional synaptic noise was simulated by adding a zero-mean random process to the stimuli. 2. We measured the effects of the ECTs on motoneurone discharge probability by compiling peristimulus time histograms (PSTHs) between the times of occurrence of the ECTs and the motoneurone spikes. The ECTs produced modulation of motoneurone discharge similar to that produced by excitatory postsynaptic currents. 3. The addition of noise altered the pattern of the motoneurone response to the current transients: both the amplitude and the area of the PSTH peaks decreased as the power of the superimposed noise was increased. Noise tended to reduce the efficacy of the ECTs, particularly when the motoneurones were firing at lower frequencies. Although noise also increased the firing frequency of the motoneurones slightly, the effects of noise on ECT efficacy did not simply result from noise-induced changes in mean firing rate. 4. A modified version of the experimental protocol was performed in lumbar motoneurones of intact, pentobarbitone-anaesthetized cats. These recordings yielded results similar to those obtained in rat hypoglossal motoneurones in vitro. 5. Our results suggest that the presence of concurrent synaptic inputs reduces the efficacy of any one input. The implications of this change in efficacy and the possible underlying mechanisms are discussed.