The impact of neuromodulators on active dendritic conductances was investigated by the use of intracellular recording techniques in spinal motoneurons in the adult cat. The well known lack of voltage control of dendritic regions during voltage clamp applied at the soma was used to estimate dendritic amplification of a steady monosynaptic input generated by muscle spindle Ia afferents. In preparations deeply anesthetized with pentobarbital, Ia current either decreased with depolarization or underwent a modest increase at membrane potentials above Ϫ40 mV. In unanesthetized decerebrate preparations (which have tonic activity in axons originating in the brainstem and releasing serotonin or norepinephrine), active dendritic currents caused strong amplification of Ia input. In the range of Ϫ50 to Ϫ40 mV, peak Ia current was over four times as large as that in the pentobarbital-anesthetized preparations. Exogenous administration of a noradrenergic agonist in addition to the tonic activity further enhanced amplification (sixfold increase). Amplification was not seen in preparations with spinal transections. Overall, the dendritic amplification with moderate or strong neuromodulatory drive was estimated to be large enough to allow the motoneurons innervating slow muscle fibers to be driven to their maximum force levels by remarkably small synaptic inputs. In these cells, the main role of synaptic input may be to control the activation of a highly excitable dendritic tree. The neuromodulatory control of synaptic amplification provides motor commands with the potential to adjust the level of amplification to suit the demands of different motor tasks. Key words: motoneuron; spinal cord; neuromodulation; electrophysiology; serotonin; norepinephrine; plateau potential; bistable; dendritic amplificationVoltage-sensitive conductances within the dendritic tree of the postsynaptic neuron play a major role in synaptic integration (Johnston et al., 1996;Yuste and Tank, 1996). Many types of voltage-sensitive conductances are under the control of neuromodulatory inputs acting via second messenger systems. Thus, the potential exists for the neuromodulatory inputs to control synaptic integration by altering the activation of voltage-sensitive currents in the dendrites of neurons.The spinal motoneuron is subject to potent neuromodulatory control by axons that originate in the brainstem and release either serotonin (5-HT) or norepinephrine (NE) (Hounsgaard et al., 1988;Takahashi and Berger, 1990;Wang and Dun, 1990;White et al., 1991;Binder et al., 1996). In the presence of these neuromodulators, motoneurons exhibit a persistent inward current (Hounsgaard and Kiehn, 1989;Svirskis and Hounsgaard, 1998;Lee and Heckman, 1999a). The composition of this current may vary in different types of motoneurons (Hounsgaard and Kiehn, 1989;Hsiao and Chandler, 1995;Zhang et al., 1995;Lee and Heckman, 1998b). In spinal motoneurons in the adult cat, the total persistent inward current (I PIC ) is exceedingly large Heckman, 1998a, 1999a). Activation of I...

Synaptic integration in vivo often involves activation of many afferent inputs whose firing patterns modulate over time. In spinal motoneurons, sustained excitatory inputs undergo enormous enhancement due to persistent inward currents (PICs) that are generated primarily in the dendrites and are dependent on monoaminergic neuromodulatory input from the brain stem to the spinal cord. We measured the interaction between dendritic PICs and inhibition generated by tonic electrical stimulation of nerves to antagonist muscles during voltage clamp in motoneurons in the lumbar spinal cord of the cat. Separate samples of cells were obtained for two different states of monoaminergic input: standard (provided by the decerebrate preparation, which has tonic activity in monoaminergic axons) and minimal (the chloralose anesthetized preparation, which lacks tonic monoaminergic input). In the standard state, steady inhibition that increased the input conductance of the motoneurons by an average of 38% reduced the PIC by 69%. The range of this reduction, from <10% to >100%, was proportional to the magnitude of the applied inhibition. Thus nearly linear integration of synaptic inhibition may occur in these highly active dendrites. In the minimal state, PICs were much smaller, being approximately equal to inhibition-suppressed PICs in the standard state. Inhibition did not further reduce these already small PICs. Overall, these results demonstrate that inhibition from local spinal circuits can oppose the facilitation of dendritic PICs by descending monoaminergic inputs. As a result, local inhibition may also suppress active dendritic integration of excitatory inputs.

Objective.-Noninvasive estimation of motoneuron excitability in human motoneurons is achieved through a paired motor unit analysis (ΔF) that quantifies hysteresis in the instantaneous firing rates at motor unit recruitment and de-recruitment. The ΔF technique provides insight into the magnitude of neuromodulatory synaptic input and persistent inward currents (PICs). While the ΔF technique is commonly used for estimating motoneuron excitability during voluntary contractions, computational parameters used for the technique vary across studies. A systematic investigation into the relationship between these parameters and ΔF values is necessary.Approach.-We assessed the sensitivity of the ΔF technique with several criteria commonly used in selecting motor unit pairs for analysis and methods used for smoothing the instantaneous motor 10

Spinal motoneurons can exhibit bistable behavior, which consists of stable self-sustained firing that is initiated by a brief excitatory input and terminated by brief inhibitory input. This bistable behavior is generated by a persistent inward current (I(PIC)). In cat motoneurons with low input conductances and slow axonal conduction velocities, I(PIC) exhibits little decay with time and thus self-sustained firing is long-lasting. In contrast, in cells that have high input conductances and fast conduction velocities, I(PIC) decays with time, and these cells cannot maintain long duration self-sustained firing. An alternative way to measure bistable behavior is to assess plateau potentials after the action potential has been blocked by intracellular injection of QX-314 to block sodium (Na(+)) currents. However, QX-314 also blocks calcium (Ca(2+)) currents and, because I(PIC) may be generated by a mixture of Ca(2+) and Na(+) currents, a reduction in amplitude of I(PIC) was expected. We therefore systematically compared the properties of I(PIC) in a sample of cells recorded with QX-314 to a control sample of cells without QX-314, which was obtained in a previous study. Single-electrode voltage-clamp techniques were applied in spinal motoneurons in the decerebrate cat preparation following administration of a standardized dose of the noradrenergic alpha1 agonist methoxamine. In the sample with QX-314, the average value of I(PIC) was only about half that in the control sample. However, the reduction of I(PIC) was much greater in cells with slow as compared with fast conduction velocities. Because a substantial portion of I(PIC) originates in dendritic regions and because conduction velocity covaries with the extent of the dendritic tree, this result suggests that QX-314 may fail to diffuse very far into the dendrites of the largest motoneurons. The analysis of the decay of I(PIC) and plateau potentials in cells with QX-314 also produced an unexpected result: QX-314 virtually eliminated time-dependent decay in both I(PIC) and plateau potentials. Consequently, I(PIC) became equally persistent in high and low input conductance cells. Therefore the decay in I(PIC) in high input conductance cells in the absence of QX-314 is not due to an intrinsic tendency of the underlying inward current to decay. Instead it is possible that the decay may result from activation of a slow outward current. Overall, these results show that QX-314 has a profound effect on I(PIC) and thus plateau potentials obtained using QX-314 do not accurately reflect the properties of I(PIC) in normal cells without QX-314.

We investigated changes in motor unit (MU) behaviour and vasti-muscle contractile properties during sustained submaximal fatiguing contractions with a new time-domain tracking technique in order to understand the mechanisms responsible for task failure. Sixteen participants performed a non-fatiguing 15s isometric knee-extension at 50% of the maximum voluntary torque (MVC), followed by a 30% MVC sustained contraction until exhaustion. Two grids of 64 surface electromyography electrodes were placed over vastus medialis and lateralis. Signals were decomposed into MU discharge-times and the MUs from the 30% MVC sustained contraction were followed until task failure by overlapping decomposition intervals. These MUs were then tracked between 50% and 30% MVC. During the sustained fatiguing contraction, MUs of the two muscles decreased their discharge rate until ~40% of the endurance time, referred to as the reversal time, and then increased their discharge rate until task failure. This reversal in firing behaviour predicted total endurance time and was matched by opposite changes in twitch force (increase followed by a decrease). Despite the later increase in MU firing rates, peak discharge rates at task failure did not reach the frequency attained during a non-fatiguing 50% MVC contraction. These results show that changes in MU firing properties are influenced by adjustments in contractile properties during the course of the contraction, allowing the identification of two phases. Nevertheless, the contraction cannot be sustained possibly due to progressive motoneuron inhibition/decreased excitability, as the later increase in firing rate saturates at a much lower frequency compared to a higher-force non-fatiguing contraction.