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.

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.

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.

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.

Experimental evaluation of input-output models of motoneuron discharge.

1. We measured the modulation of the background firing rate of cat spinal motoneurons produced by simulated, repetitive excitatory postsynaptic potentials (EPSPs) to test the accuracy of several proposed motoneuron input-output functions. Rhythmic discharge was elicited in the motoneurons by injecting suprathreshold current steps 1-1.5 s in duration. On alternate trials, trains of short (0.5-5 ms) current pulses were superimposed on the current steps to stimulate the effects of trains of individual EPSPs. The increase in firing rate (delta F) due to the addition of the pulses was calculated as the difference in motoneuron discharge rate between trials with and without the superimposed pulse trains. 2. In the same motoneurons, we were able to study the effects of changes in pulse frequency, duration, and amplitude, as well as changes in the background discharge rate. A sublinear relationship between pulse rate and delta F was observed, with delta F rising relatively steeply with increasing pulse frequency at low pulse rates and saturating at high pulse rates. A similarly shaped relation was observed between delta F and pulse duration. In contrast, delta F generally increased in a greater than linear fashion with increasing pulse amplitude. 3. In previous studies we demonstrated that when a relatively constant synaptic input is produced by high-frequency synaptic activity, delta F is approximately equal to the product of the net synaptic current reaching the soma and the slope of the motoneuron's steady-state frequency-current (f-I) relation. In the present study, this input-output function consistently underestimated the observed delta F, particularly for low input rates, indicating that the transient current pulses are more effective in modulating motoneuron discharge than an equivalent amount of constant current. 4. Other investigators have proposed input-output functions derived from the relation between synaptic potential amplitude and the magnitude of the peak of a cross correlogram compiled from the discharge of the pre- and postsynaptic neurons. These functions consistently overestimated the observed delta F, particularly for high pulse rates. This overestimation may result in part from the fact that the effects of a synaptic potential (or current pulse) on postsynaptic discharge probability also include a period of decreased firing probability. Moreover, the cross correlation function may depend on the arrival rate of synaptic potentials (or current pulses). 5. Another proposed input-output function based on a simple threshold-crossing model of the motoneuron with a fixed spike threshold predicts firing rates that were often close to the observed delta F. However, the model did not reproduce the observed relations between delta F and input pulse rate or pulse duration. 6. The deficiencies of the basic threshold-crossing model may arise from the fact that it does not incorporate variations in membrane conductance and firing threshold that occur in real motoneurons. A more complete motoneuron model that incorporates both of these features was able to replicate the observed delta Fs associated with changes in input pulse frequency and duration.

Effective synaptic current and motoneuron firing rate modulation.

1. We used a modified voltage-clamp technique to measure the steady-state effective synaptic currents (I(N)) produced by activating four different input systems to cat hindlimb motoneurons: Ia afferent fibers, Ia-inhibitory interneurons, Renshaw interneurons, and contralateral rubrospinal neurons. In the same motoneurons, we measured the slope of the firing rate-injected current (f-I) relation in the primary range. We then reactivated these synaptic inputs during steady, repetitive firing to assess their effects on motoneuron discharge rate. 2. Our measurements of I(N) were derived from recordings made near the resting membrane potential, whereas the effects of the synaptic inputs on repetitive discharge were evaluated at more depolarized membrane potentials. Thus we adjusted the I(N) values for these changes in driving force based on estimates of the synaptic reversal potential and the mean membrane potential during repetitive discharge. 3. We found that changes in the steady-state discharge rate of a motoneuron produced by these synaptic inputs could be reasonably well predicted by the product of the estimated value of I(N) during repetitive firing and the slope of the motoneuron's f-I relation. Although there was a high correlation between predicted and observed changes in firing rate for our entire sample of motoneurons (r = 0.93; P < 0.001), the slope of the relation between predicted and observed firing rate modulation was significantly greater than 1. 4. The systematic difference between predicted and observed firing rate modulation observed in the overall sample was primarily due to the fact that our predictions underestimated the changes in firing rate produced by Ia excitation and Ia inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Spike frequency adaptation studied in hypoglossal motoneurons of the rat.

1. We studied spike frequency adaptation of motoneuron discharge in the rat hypoglossal nucleus using a brain stem slice preparation. The characteristics of adaptation in response to long (60 s) injected current steps were qualitatively similar to those observed previously in cat hindlimb motoneurons. The discharge rate typically exhibited a rapid initial decline, characterized by a linear frequency-time relation, followed by a gradual exponential decline that continued for the duration of current injection. However, a more systematic, quantitative analysis of the data revealed that there were often three distinct phases of the adaptation rather than two. 2. The three phases of adaptation (initial, early, and late) were present in at least one 60-s trial of repetitive firing in all but a small number of motoneurons. Initial adaptation was limited to the first few spikes except in a few trials (7%) in which there was no initial adaptation. The time course of the subsequent decline in rate could be adequately described by a single-exponential function in about half of the trials (48%). In the remaining trials this subsequent decline in frequency was better described as the sum of two exponential functions: an early phase, lasting < 2 s, and a late phase, which lasted for the duration of the discharge period. 3. The magnitude of initial adaptation was correlated with the initial firing frequency (i.e., the reciprocal of the 1st interspike interval). The magnitudes of the early and late phases of adaptation were correlated with the firing frequency reached at the end of initial adaptation. Neither the magnitudes nor the time courses of the three phases were correlated with other membrane properties such as input resistance, rheobase, or repetitive firing threshold. 4. The slope of the frequency-current (f-I) curve was steeper in the initial phase (first 2-5 spikes) than in either the early (< 2 s) or late (> 2 s) phases of adaptation as previously reported by other investigators. In the absence of early adaptation, a steady state for the f-I slope was reached by 0.7-1 s, the time typically reported in studies of repetitive discharge. However, when early adaptation was present (50% of the trials), a steady-state value for the f-I slope was not reached until the cell had discharged for > 1 s. 5. To characterize the time course of firing rate recovery from the adaptive processes, the current was turned off for periods of < or = 10 s during the course of a 60-s trial.(ABSTRACT TRUNCATED AT 400 WORDS)

Intrinsic properties of motoneurons. Implications for muscle fatigue.

The following is a brief review of the intrinsic properties of motoneurons that contribute to their recruitment and rate modulation. Our emphasis is on properties that may either accelerate or delay the onset of muscular fatigue. In general, intrinsic motoneuron properties are regulated in a way that minimizes energy expenditure. The correlation of recruitment threshold with motoneuron type ensures that the most fatigable motor units are reserved for the most forceful contractions. The variation in minimum firing rates arising from variations in AHP characteristics ensures that motoneurons begin to fire at rates that are matched to the force producing characteristics of their muscle units. Further, it is possible that spike-frequency adaptation contributes to optimization of the tension (force)-firing frequency (T-f) transform of individual motor units.

Distribution of vestibulospinal synaptic input to cat triceps surae motoneurons.

We applied supramaximal, repetitive stimulation to the lateral vestibular nucleus (Deiters' nucleus, DN) at 200 Hz to evoke stead-state synaptic potentials in ipsilateral triceps surae motoneurons of the cat. The effective synaptic currents underlying these potentials were measured using a modified voltage-clamp technique. The steady-state effective synaptic currents evoked by activating DN were generally small and depolarizing (mean 2.5 +/- 2.6 nA). DN stimulation generated hyperpolarizing synaptic currents in 2 of the 34 triceps motoneurons studied. The effective synaptic currents from DN tended to be larger in putative type F motoneurons than in putative type S cells (type F mean 3.0 +/- 3.1 nA; type S mean 1.8 +/- 1.0 nA). There was a statistically significant difference between the inputs to putative type FF and putative type S motoneurons (mean difference 2.8 nA, t = 2.87, P < 0.01). The synaptic input from DN to medial gastrocnemius motoneurons had approximately the same amplitude as that from homonymous Ia afferent fibers. However, the distribution of DN input with respect to putative motor unit type was the opposite of that previously reported for Ia afferent input. Thus, the synaptic input from DN might act to compress the range of recruitment thresholds within the motoneuron pool and thereby increase the gain of its input-output function.

Overexpression of the Grb2 gene in human breast cancer cell lines.

A receptor blotting technique was used to detect SH2 domain containing epidermal growth factor receptor (EGFR) substrates that exhibited differential expression either between normal breast epithelial cells and breast cancer cells or between different human breast cancer cell lines. This identified a 25 kD protein, subsequently identified as Grb2, which was markedly overexpressed in three breast cancer cell lines (MCF-7, MDA-MB-361 and -453) relative to both normal breast epithelial cells and the majority of breast cancer cell lines. Northern blot analysis revealed that 7/19 breast cancer cell lines exhibited more than twofold overexpression of Grb2 mRNA, with overexpression correlating with high expression of erbB receptors. In MCF-7, MDA-MB-361 and -453 cells the overexpression of Grb2 mRNA and protein was accompanied by a small amplification of the Grb2 gene locus. Overexpression of Grb2 correlated with increased complex formation between Grb2 and the hSos-1 Ras GDP-GTP exchange protein. This upregulation of the Ras signalling pathway might modulate the growth factor sensitivity of human breast cancer cells and therefore play a role in tumour progression.

How different afferent inputs control motoneuron discharge and the output of the motoneuron pool.

In theory, there are at least two distinct mechanisms by which afferent inputs could alter motoneuron discharge and shape the output of a motoneuron pool: either by delivering synaptic current to the motoneurons' somata ('classic' synaptic transduction); or by altering the motoneurons' voltage-sensitive conductances (neuromodulation). Recent work has confirmed the operation of both of these mechanisms. It has been shown that the effect of a 'classic' synaptic input on motoneuron firing rate is predicted by the product of the effective synaptic current and the slope of the motoneuron's frequency-current relation. It has also been shown that neuromodulators can alter both the slope of a motoneuron's frequency-current relation and its threshold for repetitive firing. It is argued here, however, that when two or more sources of synaptic input are activated concurrently, the distinction between these two mechanisms is blurred. Computer simulations of motoneuron and motor pool behavior have proved extremely useful in understanding these processes.