Recurrent inhibition of human firing motoneurons (experimental and modeling study)

Recurrent inhibition between tonically activated single human motoneurons was studied experimentally and by means of a computer simulation. Motor unit activity was recorded during weak isometric constant-force muscle contractions of brachial biceps (BB) and soleus (SOL) muscles. Three techniques (cross correlogram, frequencygram, and interspike interval analysis) were used to gauge the relations between single motor unit potential trains. Pure inhibition was detected in 5.6% of 54 BB motoneuron pairs and in 5.2% of 43 SOL motoneuron pairs. In 27.8% (BB) and 23.7% (SOL) presumed inhibition symptoms were accompanied by a synchrony peak; 37% (BB) and 48.8% (SOL) exhibited synchrony alone. The demonstrated inhibition was very weak, at the edge of detectability. Computer simulations were based on the threshold-crossing model of a tonically firing motoneuron. The model included synaptic noise as well as threshold and postsynaptic potential (PSP) amplitude change within interspike interval. Inhibition efficiency of the model neurons increased with IPSP amplitude and duration, and with increasing source firing rate. The efficiency depended on target motoneuron interspike interval in a manner similar to standard deviation of ISI. The minimum detectable amplitude estimated in the simulations was about 50V, which, compared with the experimental results, suggests that amplitudes of detectable recurrent IPSPs in human motoneurons during weak muscle contractions do not exceed this magnitude. Since recurrent inhibition is known to be progressively depressed with an increase in the force of voluntary contraction, it is concluded that the recurrent inhibition hardly plays any important role in the isometric muscle contractions of constant force.     

Detection and analysis of recurrent inhibition of firing motoneurons in man

During regular firing of "small" motor units, activated during weak voluntary contraction of the human soleus muscle, thick efferent fibers of n. tibialis were stimulated (a small M response was evoked, in which the small units did not participate). Peristimulus histograms of potentials of single motor units were constructed and the effect of stimulation on interspike interval duration was analyzed. The firing rate of the motor units was 4.5–7.6 spikes/sec. Stimulation of the nerve led to a sharp decrease in probability of their discharge or even complete temporary cessation of firing, i.e., it had a well marked inhibitory effect (lasting 10–20 msec). The latent period of inhibition (35–40 msec) was only a little longer than the latent period of the monosynaptic reflex of the soleus muscle. The effect of an inhibitory volley on duration of the interspike interval of the motor units depended on the time when the volley arrived during the interval. Lengthening of the interval was observed only if the inhibitory volley arrived in the second half or at the end of the interval. It is concluded that inhibition of firing of small motor units is due to Renshaw cells, activated on stimulation of axons of large motoneurons. The efficiency of a short (compared with the duration of the interspike interval) inhibitory volley reaching a motoneuron firing at low frequency characteristic of its adequate activation, is discussed.Institute for Problems of Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 16, No. 1, pp. 88–96, January–February, 1984.     

Testing excitability in human firing motoneurons during the interspike interval

Monosynaptic testing of excitability in firing triceps surae muscle motoneurons activated during volitional contraction was performed using a technique for recording potentials from single motor units and by producing H-reflex. Motoneuronal excitability was assessed according to level of firing index. Motoneuronal firing index decreased during transition from a low background rhythmic firing rate of less than 6 spikes/sec to one of 6–8 spikes/sec. It hardly changed with a further rise in rate to 12 spikes/sec. The dependence between firing index and spike rate are put down to changes occurring in motoneuronal excitability during the interspike interval. Findings indicate that in the low frequency range of motoneuronal firing characteristic of natural muscle contraction, discharge rate may be considered one of the factors determining excitability in the motoneuron and hence its transmission qualities.Institute of Problems in Information Transmission, Academy of Sciences of the USSR. Translated from Neirofiziologiya, Vol. 19, No. 2, pp. 210–216, March–April, 1987.     

Reciprocal inhibition studied in discharging human motor units

The effect of excitation of group Ia afferents, evoked by stimulation of a mixed nerve, on the firing pattern of voluntarily activated single motor units of an antagonist muscle (biceps femoris, triceps surae, and tibialis anterior muscles) was studied. Poststimulus histograms were constructed for rhythmic sequences of motor unit potentials recorded by needle electrodes and the duration of interspike intervals was analyzed. Reciprocal inhibition and other effects accompanying nerve stimulation were discovered in the motoneurons of all three muscles. Distinguishing features of the manifestation of reciprocal inhibition in a discharging motoneuron were investigated; the effect was shown to depend on the time of occurrence of the inhibitory action in the interspike interval.Institute for Problems in Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 10, No. 6, pp. 626–636, November–December, 1978.     

Effect of brief inhibitory volley upon human firing motoneurons (experiment and model)

We investigated the effect of reciprocal inhibition upon single firing motoneurons of the human soleus and ex. carpus uln. A computer simulation of the effect of an inhibitory volley upon motoneuron impulse activity was carried out on the basis of our own data and data in the literature [3, 4]. It was shown that the duration of the silent period (SP), i.e., the period of complete cessation of firing as revealed on the peristimulus histogram (PSH), can be altered under the influence of the following factors: mean frequency of background firing (inverse dependence); variance of interspike intervals (ISIs) of background firing (inverse dependence); duration of that portion of an ISI of motoneuron activity during which an inhibitory volley causes a prolongation of the ISI (d); the maximum prolongation of the ISI (x_max). If _maxmax for the briefest ISI within the range of variability in background firing. If x_max>d, the duration of the SP is similar to the duration d of the briefest ISI. To a significant degree, the parameters of the peristimulus histogram thus determine the frequency and variance of ISIs in the background firing and possibly also the individual tendency of the motoneuron to respond to an inhibitory volley by prolongation of the ISI.L. A. Orbeli Institute of Biocybernetics and Biomedical Engineering PAS, Warsaw (Republic of Poland), Institute for Problems of Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 23, No. 4, pp. 463–471, July–August, 1991.     

Coerulospinal enhancement of repetitive firing with correlative changes in postspike afterhyperpolarization of cat spinal motoneurons

The present study was aimed at determining if inputs from the locus coeruleus (LC) have any effect on repetitive firing of ventral horn motoneurons in cats. In hindlimb flexor and extensor motoneurons stimulated intrasomatically with current below the threshold for repetitive discharges, added LC-evoked excitatory post-synaptic potentials (EPSPs) were consistently found to produce repetitive firing, suggesting a lowering in the repetitive firing threshold attributable to excitatory LC inputs. With those extensor motoneurons showing episodic, self-sustained firing, LC-EPSPs introduced during the quiescent period were capable of starting a continuous discharge with rhythmic frequencies higher than the spontaneous activity. In some of these cells, intracellularly applied hyperpolarizing current was able to stop the spontaneous discharges. Subsequently, LC stimuli were found to reinitiate repetitive discharges, thus counteracting the ongoing suppression of the motoneurons. Quantitative analysis of the single-spike afterhyperpolarization (AHP) indicated a consistent reduction in its amplitude and time course (duration, time-to-peak, half-decay time) for flexor and extensor motoneurons in response to LC conditioning stimuli. Present results suggest an excitatory LC action on the repetitive discharges of cat motoneurons accompanied by a concurrent decrease in the amplitude and time course of the single-spike AHPs.     

Reduction in maximal firing rate of motoneurons after 1-week immobilization of finger muscle in human subjects.

We investigated the effects of immobilization on the maximal motoneuronal firing rate recorded from the first dorsal interosseous (FDI) during voluntary isometric contraction. In five human subjects, the middle finger, index finger, and thumb were immobilized for 1 week in a fiber-glass cast, which kept FDI in a shortened position. During a maximal voluntary contraction, single muscle-fiber action potentials were recorded using a tungsten microelectrode, and mean firing rate was calculated for each action-potential train. Three recording sessions were held: before immobilization (pre), after immobilization (post), and after a 1-week recovery period (recovery). The mean firing rate of FDI motoneurons during maximal voluntary contraction was decreased immediately after the 1-week immobilization (pre: 39.0+/-3.2 Hz, number of detected spike trains (n)=353; post: 33.1+/-1.5 Hz, n=285; p<0.05), and there was a return to control after the recovery period (40.2+/-3.4 Hz, n=236). This suggests that the maximal motoneuronal firing rate achieved during maximal voluntary contraction is reduced after short-term immobilization. The functional implications and the contribution of this phenomenon to the immobilization-induced reduction in maximal voluntary force are discussed.     

Reciprocal inhibition and slow calcium decay in perigeniculate interneurons explain changes of spontaneous firing of thalamic cells caused by cortical inactivation

The role of cortical feedback in the thalamocortical processing loop has been extensively investigated over the last decades. With an exception of several cases, these searches focused on the cortical feedback exerted onto thalamo-cortical relay (TC) cells of the dorsal lateral geniculate nucleus (LGN). In a previous, physiological study, we showed in the cat visual system that cessation of cortical input, despite decrease of spontaneous activity of TC cells, increased spontaneous firing of their recurrent inhibitory interneurons located in the perigeniculate nucleus (PGN). To identify mechanisms underlying such functional changes we conducted a modeling study in NEURON on several networks of point neurons with varied model parameters, such as membrane properties, synaptic weights and axonal delays. We considered six network topologies of the retino-geniculo-cortical system. All models were robust against changes of axonal delays except for the delay between the LGN feed-forward interneuron and the TC cell. The best representation of physiological results was obtained with models containing reciprocally connected PGN cells driven by the cortex and with relatively slow decay of intracellular calcium. This strongly indicates that the thalamic reticular nucleus plays an essential role in the cortical influence over thalamo-cortical relay cells while the thalamic feed-forward interneurons are not essential in this process. Further, we suggest that the dependence of the activity of PGN cells on the rate of calcium removal can be one of the key factors determining individual cell response to elimination of cortical input.     

Estimation of the individual firing frequencies of two neurons recorded with a single electrode

When monitoring neurons with a single extracellular electrode, it is common to record action potentials from different neurons. A recurring problem with such recordings is to identify which neuron is active. Sorting spikes into separate classes is possible if each neuron discharge spikes differing by their shapes and sizes. However, this approach is not applicable when the spikes are indistinguishable. In this paper, we develop a method for estimating the respective firing frequencies of two neurons, producing indistinguishable spikes. It is based on the fact that, when a neuron fires a spike, there is an interval of time during which the probability of generating a second spike is very low. If a spike occurs during this 'silent period', it is likely to be generated from another neuron and the number of occurrences of such 'doublets' can be used to estimate the respective frequencies of two spike trains. We demonstrate here that a simple relation holds between the frequency of doublets d, the respective frequencies of the two neurons A and B, fA and fB, and a chosen value Delta shorter than the silent period, d=2fAfBDelta. This relation holds for a wide class of firing processes. We used this method to analyze responses from Drosophila taste sensilla. We first checked if the method was consistent with results obtained with stimuli that elicit responses of two taste neurons firing distinguishable spikes. We then applied this method to the study of a pair of taste neurons involved in the coding for salt taste in Drosophila melanogaster.     

When inhibition not excitation synchronizes neural firing

Excitatory and inhibitory synaptic coupling can have counter-intuitive effects on the synchronization of neuronal firing. While it might appear that excitatory coupling would lead to synchronization, we show that frequently inhibition rather than excitation synchronizes firing. We study two identical neurons described by integrate-and-fire models, general phase-coupled models or the Hodgkin-Huxley model with mutual, non-instantaneous excitatory or inhibitory synapses between them. We find that if the rise time of the synapse is longer than the duration of an action potential, inhibition not excitation leads to synchronized firing.     

Neutralization of human papillomavirus with monoclonal antibodies reveals different mechanisms of inhibition

The mechanisms of human papillomavirus (HPV) neutralization by antibodies are incompletely understood. We have used HPV16 pseudovirus infection of HaCaT cells to analyze how several neutralizing monoclonal antibodies (MAbs) generated against HPV16 L1 interfere with the process of keratinocyte infection. HPV16 capsids normally bind to both the cell surface and extracellular matrix (ECM) of HaCaT cells. Surprisingly, two strongly neutralizing MAbs, V5 and E70, did not prevent attachment of capsids to the cell surface. However, they did block association with the ECM and prevented internalization of cell surface-bound capsids. In contrast, MAb U4 prevented binding to the cell surface but not to the ECM. The epitope recognized by U4 was inaccessible when virions were bound to the cell surface but became accessible after endocytosis, presumably coinciding with receptor detachment. Treatment of capsids with heparin, which is known to interfere with binding to cell surface heparan sulfate proteoglycans (HSPGs), also resulted in HPV16 localization to the ECM. These results suggest that the U4 epitope on the intercapsomeric C-terminal arm is likely to encompass the critical HSPG interaction residues for HPV16, while the V5 and E70 epitopes at the apex of the capsomer overlap the ECM-binding sites. We conclude that neutralizing antibodies can inhibit HPV infection by multiple distinct mechanisms, and understanding these mechanisms can add insight to the HPV entry processes.     

Substantial changes in synaptic firing frequencies induced by glial ATP hysteresis

Recent experimental studies strongly suggest the influence of glial purinergic transmission in the modulation of synaptic dynamics. By releasing adenosine triphosphate (ATP), which accumulates as adenosine, astrocytes tonically suppressed synaptic transmission. The delayed multi-step feedback of the glial ATP with the neuron suggests the existence of a discrete hysteresis phenomena. By integration of this hysteretic behavior into a delayed leaky integrate-and-fire model for the tripartite synapses, a significant sensitivity of the pre- and postsynaptic firing frequency patterns to the adenosine feedback-delays is observed that might be of importance for adenosine-related neurological deficits, such as sleep disorders.     

Functional interactions in hierarchically organized neural networks studied with spatiotemporal firing patterns and phase-coupling frequencies

A scalable hardware/software hybrid module--called Ubidule--endowed with bio-inspired ontogenetic and epigenetic features is configured to run a neural networks simulation with developmental and evolvable capabilities. We simulated the activity of hierarchically organized spiking neural networks characterized by an initial developmental phase featuring cell death followed by spike timing dependent synaptic plasticity in presence of background noise. An upstream 'sensory' network received a spatiotemporally organized external input and downstream networks were activated only via the upstream network. Precise firing sequences, formed by recurrent patterns of spikes intervals above chance levels, were observed in all recording conditions, thus suggesting the build-up of a connectivity able to sustain temporal information processing. The activity of a Ubinet--a network of Ubidules--is analyzed by means of virtual electrodes that recorded neural signals similar to EEG. The analysis of these signals was compared with a small set of human recordings and revealed common patterns of shift in quadratic phase coupling. The results suggest some interpretations of changes and plasticity of functional interactions between cortical areas driven by external stimuli and by learning/cognitive     

Double discharges in human motoneurons

Potentials of motor units from the trapezius and rectus femoris muscles were recorded with selective needle electrodes during weak and moderately strong voluntary isometric contraction. The sequence of interspike intervals was analyzed. Double discharges (interspike interval not exceeding 20 msec) were found most commonly during recruiting of the motor units, but also at its end. Intervals between double discharges arising while the motor units were firing at a mean rate of 10–18 spikes/sec were outside the limits of statistical scatter of the remaining intervals. Double discharges were recorded chiefly in high-threshold units. The mean interval between double discharges recorded from the trapezius muscle was significantly smaller and the double discharges appeared considerably more often than in the rectus femoris muscle. Comparison of the results of these experiments with those obtained by other workers showed correlation between the mean duration of the interval between the double discharges and the duration of delayed depolarization of the motoneuron; this fact probably plays an important role in the creation of double discharges.