The review surveys various aspects of the plasticity of nerve fibres, in particular the prolonged increase in their excitability evoked by polarization, focusing on a long-lasting increase in the excitability of myelinated afferent fibres traversing the dorsal columns of the spinal cord. We review the evidence that increased axonal excitability (i) follows epidurally applied direct current as well as relatively short (5 or 10 ms) current pulses and synaptically evoked intrinsic field potentials; (ii) critically depends on the polarization of branching regions of afferent fibres at the sites where they bifurcate and give off axon collaterals entering the spinal grey matter in conjunction with actions of extrasynaptic GABAA membrane receptors; and (iii) shares the feature of being activity-independent with the short-lasting effects of polarization of peripheral nerve fibres. A comparison between the polarization evoked sustained increase in the excitability of dorsal column fibres and spinal motoneurons (plateau potentials) indicates the possibility that they are mediated by partly similar membrane channels (including non-inactivating type L Cav++ 1.3 but not Na+ channels) and partly different mechanisms. We finally consider under which conditions trans-spinally applied DC (tsDCS) might reproduce the effects of epidural polarization on dorsal column fibres and the possible advantages of increased excitability of afferent fibres for the rehabilitation of motor and sensory functions after spinal cord injuries.

To investigate the effects on evoked thalamic neuronal activity of application of notochordal cells and chondrocyte-like cells derived from nucleus pulposus (NP) onto a dorsal root ganglion (DRG) and to compare these effects with a previously reported increased thalamic activity induced by NP.

Spinocerebellar tract neurons are inhibited by various sources of input via pathways activated by descending tracts as well as peripheral afferents. Inhibition may be used to modulate transmission of excitatory information forwarded to the cerebellum. However it may also provide information on the degree of inhibition of motoneurons and on the operation of inhibitory premotor neurons. Our aim was to extend previous comparisons of morphological substrates of excitation of spinocerebellar neurons to inhibitory input. Contacts formed by inhibitory axon terminals were characterised as either GABAergic, glycinergic or both GABAergic/glycinergic by using antibodies against vesicular GABA transporter, glutamic acid decarboxylase and gephyrin. Quantitative analysis revealed the presence of much higher proportions of inhibitory contacts when compared with excitatory contacts on spinal border (SB) neurons. However similar proportions of inhibitory and excitatory contacts were associated with ventral spinocerebellar tract (VSCT) and dorsal spinocerebellar tract neurons located in Clarke's column (ccDSCT) and the dorsal horn (dhDSCT). In all of the cells, the majority of inhibitory terminals were glycinergic. The density of contacts was higher on somata and proximal versus distal dendrites of SB and VSCT neurons but more evenly distributed in ccDSCT and dhDSCT neurons. Variations in the density and distribution of inhibitory contacts found in this study may reflect differences in information on inhibitory processes forwarded by subtypes of spinocerebellar tract neurons to the cerebellum.

Non‐technical summary For the correct execution of centrally initiated movements, it is vital that the cerebellum receives continuous feedback from the spinal cord. We recently demonstrated that a population of spinocerebellar neurones provides the cerebellum with feedback on the likely outcome of descending commands relayed via reticulospinal neurones. We now demonstrate that the same spinocerebellar neurones provide information on the likely outcome of commands from the corticospinal tract (pyramidal tract) neurones as well as from the mesencephalic locomotor region. The results indicate that both voluntary motor actions and those related to locomotion are relayed by reticulospinal neurones and are monitored by the same population of spinocerebellar neurons, which may thereby provide the brain with information necessary for avoiding errors in issuing movements.

Non‐technical summary Limb movements are initiated and controlled by nerve cells in several brain regions. Of these, neurones in the red nucleus supplement actions of corticospinal neurones and may even substitute them after injuries of the motor cortex. We have investigated how commands sent from the red nucleus to spinal neurones, and via them to limb muscles, are monitored by a population of spinal neurones providing the cerebellum with feedback information on operation of spinal neuronal networks. The results show that actions expected to be evoked by neurones in the red nucleus on motoneurones may be monitored by the cerebellum, as actions of corticospinal neurones are, although they are monitored by spinal rather than reticulospinal neurones. These results may provide us with a better understanding of mechanisms contributing to the recovery of motor functions following brain injuries.

Voluntary limb movements are initiated in the brain but the neurones responsible for activating the muscles (motoneurones and interneurones) are located in the spinal cord. The spinal cord also contains neurones that provide the brain, and especially the cerebellum, with continuous information on effects of the descending commands. We show that one population of such neurones provide the cerebellum with information on how likely the brain's commands (mediated by descending reticulospinal neurones) are to be executed as planned, depending on the degree of inhibition of motoneurones. They may therefore play an important role in preventing errors in activation of motoneurones and thereby help the brain to correct its signals to the spinal cord before such errors have been committed.

Strong evidence that premotor interneurons provide ventral spinocerebellar tract (VSCT) neurons with feedback information on their actions on motoneurons was previously found for Ia inhibitory interneurons and Renshaw cells, while indications for similar actions of other premotor interneurons were weaker and indirect. Therefore the aim of the present study was to reexamine this possibility with respect to interneurons relaying actions of group Ib afferents from tendon organs and group II afferents from muscle spindles. In all, 133 VSCT neurons in the L3-L5 segments (including 41 spinal border neurons) were recorded from intracellularly in deeply anesthetized cats to verify that stimuli applied in motor nuclei evoked monosynaptic inhibitory postsynaptic potentials (IPSPs) attributable to stimulation of axon collaterals of premotor interneurons. IPSPs were found in over two thirds of the investigated neurons. When intraspinal stimuli were preceded by stimuli applied to a muscle nerve at critical intervals, IPSPs evoked from motor nuclei were considerably reduced, indicating a collision of nerve volleys in axons of interneurons activated by group I and group II afferents. In individual VSCT neurons monosynaptic IPSPs were evoked from both biceps-semitendinosus and gastrocnemius-soleus motor nuclei, in parallel with disynaptic IPSPs from group Ib and group II as well as group Ia afferents. These observations indicate that individual VSCT neurons may monitor the degree of inhibition of both flexor and extensor motoneurons by premotor interneurons in inhibitory pathways from group Ib and group II afferents to motoneurons. They may thus be providing the cerebellum with feedback information on actions of these premotor interneurons on motoneurons.

The aim of the present study was to compare properties of excitatory and inhibitory spinal intermediate zone interneurons in pathways from group I and II muscle afferents in the cat. Interneurons were labelled intracellularly and their transmitter phenotypes were defined by using immunocytochemistry. In total 14 glutamatergic, 22 glycinergic and 2 GABAergic/glycinergic interneurons were retrieved. All interneurons were located in laminae V-VII of the L3-L7 segments. No consistent differences were found in the location, the soma sizes or the extent of the dendritic trees of excitatory and inhibitory interneurons. However, major differences were found in their axonal projections; excitatory interneurons projected either ipsilaterally, bilaterally or contralaterally, while inhibitory interneurons projected exclusively ipsilaterally. Terminal projections of glycinergic and glutamatergic cells were found within motor nuclei as well as other regions of the grey matter which include the intermediate region, laminae VII and VIII. Cells containing GABA/glycine had more restricted projections, principally within the intermediate zone where they formed appositions with glutamatergic axon terminals and unidentified cells and therefore are likely to be involved in presynaptic as well as postsynaptic inhibition. The majority of excitatory and inhibitory interneurons were found to be coexcited by group I and II afferents (monosynaptically) and by reticulospinal neurons (mono- or disynaptically) and to integrate information from several muscles. Taken together the morphological and electrophysiological data show that individual excitatory and inhibitory intermediate zone interneurons may operate in a highly differentiated way and thereby contribute to a variety of motor synergies.

The aim of this study was to analyse neurotransmitter content, projection areas and target cells of commissural interneurons with input from group I and/or II muscle afferents in lumbar segments in the cat. Axonal projections of 15 intracellularly labelled commissural interneurons were reconstructed. Ten interneurons (nine located in laminae VI–VII, one in lamina VIII) were glutamatergic; only one interneuron (located in lamina VIII) was glycinergic. Contralateral terminal projections were found both in motor nuclei and within laminae VI–VIII. In order to identify target cells of commissural interneurons, effects of stimulation of contralateral group I and II muscle afferents were investigated on interneurons within these laminae. Three tests were used: intracellular records from individual interneurons, modulation of probability of activation of extracellularly recorded interneurons and modulation of their actions on motoneurons using disynaptic PSPs evoked in motoneurons as a measure. All these tests revealed much more frequent and/or stronger excitatory actions of contralateral afferents. The results indicate that commissural interneurons with input from contralateral group I and II afferents target premotor interneurons in disynaptic pathways from ipsilateral group I and II afferents and that excitatory disynaptic actions of contralateral afferents on these interneurons are mediated primarily by intermediate zone commissural interneurons. A second group of commissural interneurons activated by reticulospinal neurons, previously described, frequently had similar, but occasionally opposing, actions to the cells described here, thus indicating that these two subpopulations may act on the same premotor interneurons and either mutually enhance or counteract each other's actions.

Dorsal horn interneurons with input from group II muscle spindle afferents are components of networks involved in motor control. Thirteen dorsal horn interneurons with monosynaptic group II input were characterized electrophysiologically and labeled intracellularly with Neurobiotin. Their axonal projections were traced, and neurotransmitter content was established by using immunocytochemistry. Two subpopulations were identified: five interneurons had axons that contained vesicular glutamate transporter 2 and hence were glutamatergic and excitatory. Terminals of the remaining eight interneurons were immunoreactive for the glycine transporter 2 or were apposed to gephyrin but did not contain the GABA-synthesizing enzyme glutamic acid decarboxylase and were therefore glycinergic and inhibitory. Excitatory cells were located mainly in the central region of lamina IV and had relatively small somata and restricted dendritic trees. In contrast, inhibitory interneurons were located more ventrally, in lamina V and had relatively larger somata and more extensive dendritic trees. Axonal projections of the two subpopulations differed considerably. Excitatory interneurons predominantly projected ipsilaterally, whereas most inhibitory interneurons projected both ipsilaterally and contralaterally. Three inhibitory axons formed contacts with large cholinergic cells in motor nuclei, thus revealing a novel direct coupling between inhibitory dorsal horn interneurons and motoneurons. The organization of the excitatory interneurons is consistent with current knowledge of reflex pathways to motoneurons, but the existence and connections of the inhibitory subpopulation could not be predicted from previous data. Our results indicate that these latter interneurons exercise widespread inhibitory control over a variety of cell types located on both sides of the spinal cord.

Interneurones interconnecting the two sides of the spinal cord (commissural interneurones) are critically important for interlimb coordination, but little is known about their organization. We have examined the inputs to commissural interneurones located in the midlumbar segments with projections to contralateral motor nuclei, aiming to determine whether they form distinct subpopulations. Based on intracellular records from 78 interneurones, two major non-overlapping subpopulations were identified: one monosynaptically excited by group II muscle afferents (n=10), the other monosynaptically excited by reticulospinal neurones (n=52). Monosynaptic input from group I muscle afferents and/or from vestibulospinal tract neurones was found in those with monosynaptic reticulospinal, but not group II input, and in a few other neurones (n=6). Only disynaptic input from these sources was found in the remaining 10 interneurones. Disynaptic excitatory input from ipsilateral and contralateral muscle afferents and from descending tracts was distributed less selectively and might mediate coexcitation of interneurones with monosynaptic afferent or descending input. The dominant disynaptic and polysynaptic input was, however, inhibitory. IPSPs were evoked from the descending tracts in a high proportion of the commissural interneurones that were monosynaptically excited by group II afferents (55%) and from group II afferents in a high proportion of the commissural interneurones that were monosynaptically excited by reticulospinal fibres (78%). This distribution suggests that the two subpopulations are activated differentially, rather than being coactivated, in either centrally initiated movements or reflex adjustments. This would be consistent with the previous demonstration that noradrenaline differentially affects commissural neurones of the two subpopulations.

Modulatory actions of monoamines were investigated on spinal commissural interneurons which coordinate left-right hindlimb muscle activity through direct projections to the contralateral motor nuclei. Commissural interneurons located in Rexed lamina VIII, with identified projections to the contralateral gastrocnemius-soleus motor nuclei, were investigated in deeply anaesthetized cats. Most interneurons had dominant input from either the reticular formation or from group II muscle afferents; a small proportion of neurons had input from both. Actions of ionophoretically applied serotonin and noradrenaline were examined on extracellularly recorded spikes evoked monosynaptically by group II muscle afferents or reticulospinal tract fibres. Activation by reticulospinal fibres was facilitated by both serotonin and noradrenaline. Activation by group II afferents was also facilitated by serotonin but was strongly depressed by noradrenaline. To investigate the possible morphological substrates of this differential modulation, seven representative commissural interneurons were labelled intracellularly with tetramethylrhodamine-dextran and neurobiotin. Contacts from noradrenergic and serotoninergic fibres were revealed by immunohistochemistry and analysed with confocal microscopy. There were no major differences in the numbers and distributions of contacts among the interneurons studied. The findings suggest that differences in modulatory actions of monoamines, and subsequent changes in the recruitment of subpopulations of commissural interneurons in various behavioural situations, depend on intrinsic interneuron properties rather than on the patterns of innervation by monoaminergic fibres. The different actions of noradrenaline on different populations of interneurons might permit reconfiguration of the actions of the commissural neurons according to behavioural context.

Contralateral pyramidal tract (PT) neurons arising in the primary motor cortex are the major route through which volitional limb movements are controlled. However, the contralateral hemiparesis that follows PT neuron injury on one side may be counteracted by ipsilateral of actions of PT neurons from the undamaged side. To investigate the spinal relays through which PT neurons may influence ipsilateral motoneurons, we analyzed the synaptic actions evoked by stimulation of the ipsilateral pyramid on hindlimb motoneurons after transecting the descending fibers of the contralateral PT at a low thoracic level. The results show that ipsilateral PT neurons can affect limb motoneurons trisynaptically by activating contralaterally descending reticulospinal neurons, which in turn activate spinal commissural interneurons that project back across to motoneurons ipsilateral to the stimulated pyramidal tract. Stimulation of the pyramids alone did not evoke synaptic actions in motoneurons but potently facilitated disynaptic EPSPs and IPSPs evoked by stimulation of reticulospinal tract fibers in the medial longitudinal fascicle. In parallel with this double-crossed pathway, corticospinal neurons could also evoke ipsilateral actions via ipsilateral descending reticulospinal tract fibers, acting through ipsilaterally located spinal interneurons. Because the actions mediated by commissural interneurons were found to be stronger than those of ipsilateral premotor interneurons, the study leads to the conclusion that ipsilateral actions of corticospinal neurons via commissural interneurons may provide a better opportunity for recovery of function in hemiparesis produced by corticospinal tract injury.

Previous studies have demonstrated that group II muscle afferents exert powerful actions on contralateral motoneurones and that these actions are mediated primarily via lamina VIII commissural interneurones. We examined whether dorsal horn interneurones also contribute to these actions, as they have been shown to contribute to the actions of group II afferents on ipsilateral motoneurones. We tested the susceptibility of IPSPs and EPSPs evoked from group II afferents in contralateral motoneurones to presynaptic inhibition as an indicator of the relative contribution of dorsal horn interneurones to these PSPs, since the monosynaptic activation of dorsal horn interneurones is more weakly and more briefly depressed by presynaptic inhibition than is the monosynaptic activation of lamina VIII and other intermediate zone and ventral horn interneurones. While the earliest components of IPSPs and EPSPs evoked by group II afferents were abolished by conditioning stimulation of group II afferents, consistent with them being evoked disynaptically by commissural interneurones, trisynaptic components of these PSPs were only partly reduced and are therefore attributed to dorsal horn interneurones. The same conditioning stimuli depressed the disynaptic excitation of lamina VIII commissural interneurones by group II afferents much less effectively than they depressed monosynaptic excitation, indicating that dorsal horn interneurones contribute to this disynaptic excitation. On the basis of these observations we conclude that that dorsal horn interneurones contribute to the late actions of group II muscle afferents on contralateral motoneurones through their disynaptic actions on commissural interneurones.

Previous studies have shown that monoamines may modulate operation of spinal neuronal networks by depressing or facilitating responses of the involved neurons. Recently, activation of interneurons mediating reciprocal inhibition from muscle spindle (Ia) afferents and nonreciprocal inhibition from muscle spindle and tendon organ (Ia/Ib) afferents in the cat was found to be facilitated by noradrenaline (NA). However, which subclass membrane receptors are involved in mediating this facilitation was not established; the aim of the present experiments was to investigate this. Individual Ia- and Ia/Ib-inhibitory interneurons were identified in the cat lumbar spinal cord, and NA agonists were applied close to these neurons by ionophoresis. The agonists included the alpha1-receptor agonist phenylephrine, the alpha2-receptor agonists clonidine and tizanidine, and the beta-receptor agonist isoproterenol. Effects were measured by comparing changes in the number of extracellularly recorded spike potentials evoked by electrical stimulation of muscle nerves and changes in the latency of these potentials before, during, and after application of the tested compounds. Results show that the facilitatory effect of phenylephrine is as strong as that of NA, whereas the facilitatory effect of isoproterenol is weaker. Clonidine depressed activity of both Ia- and Ia/Ib-inhibitory interneurons, whereas tizanidine had no effect. These findings lead to the conclusion that beneficial antispastic effects of clonidine and tizanidine in humans are unlikely to be associated with an enhancement of the actions of Ia- and Ia/Ib-inhibitory interneurons, and the findings also support previous proposals that these compounds exert their antispastic actions via effects on other neuronal populations.

Pathways through which reticulospinal neurons can influence contralateral limb movements were investigated by recording from motoneurons innervating hindlimb muscles. Reticulospinal tract fibers were stimulated within the brainstem or in the lateral funiculus of the thoracic spinal cord contralateral to the motoneurons. Effects evoked by ipsilaterally descending reticulospinal tract fibers were eliminated by a spinal hemisection at an upper lumbar level. Stimuli applied in the brainstem evoked EPSPs, IPSPs, or both at latencies of 1.42 +/- 0.03 and 1.53 +/- 0.04 msec, respectively, from the first components of the descending volleys and with properties indicating a disynaptic linkage, in most contralateral motoneurons: EPSPs in 76% and IPSPs in 26%. EPSPs with characteristics of monosynaptically evoked responses, attributable to direct actions of crossed axon collaterals of reticulospinal fibers, were found in a small proportion of the motoneurons, whether evoked from the brainstem (9%) or from the thoracic cord (12.5%). Commissural neurons, which might mediate the crossed disynaptic actions (i.e., were antidromically activated from contralateral motor nuclei and monosynaptically excited from the ipsilateral reticular formation), were found in Rexed's lamina VIII in the midlumbar segments (L3-L5). The results reveal that although direct actions of reticulospinal fibers are much more potent on ipsilateral motoneurons, interneuronally mediated actions are as potent contralaterally as ipsilaterally, and midlumbar commissural neurons are likely to contribute to them. They indicate a close coupling between the spinal interneuronal systems used by the reticulospinal neurons to coordinate muscle contractions ipsilaterally and contralaterally.

Axonal projections and neurotransmitters used by commissural interneurons mediating crossed actions of reticulospinal neurons were investigated in adult cats. Eighteen interneurons, located in or close to lamina VIII in midlumbar segments, that were monosynaptically excited by reticulospinal tract fibres and projected to contralateral motor nuclei were labelled by intracellular injection of tetramethylrhodamine-dextran and Neurobiotin. The nine most completely labelled interneurons were analysed with combined confocal and light microscopy. None of the stem axons gave off ipsilateral axon collaterals. Seven cells had axon collaterals that arborized in the contralateral grey matter in the ventral horn of the same segments. Transmitters were identified by using antibodies raised against vesicular glutamate transporters 1 and 2, glutamic acid decarboxylase and the glycine transporter 2. The axons of two cells were immunoreactive for the glycine transporter 2 and hence were glycinergic. Three cells were immunoreactive for the vesicular glutamate transporter 2 and hence were glutamatergic. None of the axons displayed immunoreactivity for glutamic acid decarboxylase. Electron microscopy of two cells revealed direct synaptic connections with motoneurons and other neurons. Axonal swellings of one neuron formed synapses with profiles in motor nuclei whereas those of the other formed synapses with other structures, including cell bodies in lamina VII. The results show that this population of commissural interneurons includes both excitatory and inhibitory cells that may excite or inhibit contralateral motoneurons directly. They may also influence the activity of motoneurons indirectly by acting through interneurons located outside motor nuclei in the contralateral grey matter but are unlikely to have direct actions on interneurons in the ipsilateral grey matter.

Ventral spinocerebellar tract neurons located in laminae V-VII of cat lumbar spinal cord were tested for the effects of ionophoretically applied monoamines and receptor selective agonists. Extracellularly recorded responses, monosynaptically evoked by group I afferents in a muscle nerve, were compared before, during, and after ionophoresis. They were analyzed with respect to changes in the number of evoked spikes and in the latency, Both serotonin (5-HT) and noradrenaline (NA) were found to facilitate responses of all neurons tested. Ionophoresis of three serotonin subtype receptor agonists (5-carboxamidotryptamine maleate, 5 methoxytryptamine HCl, and alpha-methyl 5-hydroxytryptamine) and of two NA receptor agonists (phenylephrine and isoproterenol) likewise had a facilitatory effect. However, three other 5-HT receptor agonists (8-hydroxy-dipropylaminotetraline hydrobromide), 2-methyl 5-hydroxytryptamine, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl and two NA receptor agonists (tizanidine and clonidine) had the opposite effect because they depressed responses of the tested neurons. These results show that information forwarded by means of the ventral spinocerebellar tract may be modulated by monoamines and that several receptor subtypes, located pre- or postsynaptically, may be involved. The results also demonstrate that transmission by means of group I muscle afferents may not only be facilitated by monoamines but also depressed by selective receptor subtype activation. J. Comp.Neurol. 443:298-309,2002. (C) 2002 Wiley-Liss, Inc.