Reticulospinal Fibers Research Articles

Electrical stimulation of the cuneiform nucleus enhances the effects of rehabilitative training on locomotor recovery after incomplete spinal cord injury.

Most human spinal cord injuries are anatomically incomplete, leaving some fibers still connecting the brain with the sublesional spinal cord. Spared descending fibers of the brainstem motor control system can be activated by deep brain stimulation (DBS) of the cuneiform nucleus (CnF), a subnucleus of the mesencephalic locomotor region (MLR). The MLR is an evolutionarily highly conserved structure which initiates and controls locomotion in all vertebrates. Acute electrical stimulation experiments in female adult rats with incomplete spinal cord injury conducted in our lab showed that CnF-DBS was able to re-establish a high degree of locomotion five weeks after injury, even in animals with initially very severe functional deficits and white matter lesions up to 80-95%. Here, we analyzed whether CnF-DBS can be used to support medium-intensity locomotor training and long-term recovery in rats with large but incomplete spinal cord injuries. Rats underwent rehabilitative training sessions three times per week in an enriched environment, either with or without CnF-DBS supported hindlimb stepping. After 4 weeks, animals that trained under CnF-DBS showed a higher level of locomotor performance than rats that trained comparable distances under non-stimulated conditions. The MLR does not project to the spinal cord directly; one of its main output targets is the gigantocellular reticular nucleus in the medulla oblongata. Long-term electrical stimulation of spared reticulospinal fibers after incomplete spinal cord injury via the CnF could enhance reticulospinal anatomical rearrangement and in this way lead to persistent improvement of motor function. By analyzing the spared, BDA-labeled giganto-spinal fibers we found that their gray matter arborization density after discontinuation of CnF-DBS enhanced training was lower in the lumbar L2 and L5 spinal cord in stimulated as compared to unstimulated animals, suggesting improved pruning with stimulation-enhanced training. An on-going clinical study in chronic paraplegic patients investigates the effects of CnF-DBS on locomotor capacity.

From retina to motoneurons: A substrate for visuomotor transformation in salamanders.

The transformation of visual input into motor output is essential to approach a target or avoid a predator. In salamanders, visually guided orientation behaviors have been extensively studied during prey capture. However, the neural circuitry involved is not resolved. Using salamander brain preparations, calcium imaging and tracing experiments, we describe a neural substrate through which retinal input is transformed into spinal motor output. We found that retina stimulation evoked responses in reticulospinal neurons of the middle reticular nucleus, known to control steering movements in salamanders. Microinjection of glutamatergic antagonists in the optic tectum (superior colliculus in mammals) decreased the reticulospinal responses. Using tracing, we found that retina projected to the dorsal layers of the contralateral tectum, where the dendrites of neurons projecting to the middle reticular nucleus were located. In slices, stimulation of the tectal dorsal layers evoked glutamatergic responses in deep tectal neurons retrogradely labeled from the middle reticular nucleus. We then examined how tectum activation translated into spinal motor output. Tectum stimulation evoked motoneuronal responses, which were decreased by microinjections of glutamatergic antagonists in the contralateral middle reticular nucleus. Reticulospinal fibers anterogradely labeled from tracer injection in the middle reticular nucleus were preferentially distributed in proximity with the dendrites of ipsilateral motoneurons. Our work establishes a neural substrate linking visual and motor centers in salamanders. This retino‐tecto‐reticulo‐spinal circuitry is well positioned to control orienting behaviors. Our study bridges the gap between the behavioral studies and the neural mechanisms involved in the transformation of visual input into motor output in salamanders.

Focus on Functional Delayed Central Sleep Apnea Following Cervical Laminectomy. An Example of Respiratory Dysfunction in Restorative Neurosurgical Procedures.

In sleep-related breathing disorders, sleep apnea is a clinical symptom that can be categorized as obstructive sleep apnea (OSA) or mixed apnea by analysis using polysomnography. The occurrence of delayed central sleep apnea (CSA) is an extremely rare complication of cervical laminectomy for spondylotic myelopathy. So far only three studies concerning such an event have been reported in the literature. Naim-ur-Rahman, in 1994, reported a case of postoperative CSA following C3-C6 laminectomy, and Visocchi and colleagues, in 2014, in two studies, stressed the lack of association with any other neurological sign of spinal cord damage. No definitive mechanism has been recognized so far for delayed CSA after cervical laminectomy. A transient dysfunction of the reticulo-spinal fibers directed to the nucleus of the phrenic nerve can be speculated, although neither emi-diaphragm paralysis, nor any prominent nocturnal sleep-related disorders are associated with this delayed CSA.

Terminations of reticulospinal fibers originating from the gigantocellular reticular formation in the mouse spinal cord.

The present study investigated the projections of the gigantocellular reticular nucleus (Gi) and its neighbors--the dorsal paragigantocellular reticular nucleus (DPGi), the alpha/ventral part of the gigantocellular reticular nucleus (GiA/V), and the lateral paragigantocellular reticular nucleus (LPGi)--to the mouse spinal cord by injecting the anterograde tracer biotinylated dextran amine (BDA) into the Gi, DPGi, GiA/GiV, and LPGi. The Gi projected to the entire spinal cord bilaterally with an ipsilateral predominance. Its fibers traveled in both the ventral and lateral funiculi with a greater presence in the ventral funiculus. As the fibers descended in the spinal cord, their density in the lateral funiculus increased. The terminals were present mainly in laminae 7-10 with a dorsolateral expansion caudally. In the lumbar and sacral cord, a considerable number of terminals were also present in laminae 5 and 6. Contralateral fibers shared a similar pattern to their ipsilateral counterparts and some fibers were seen to cross the midline. Fibers arising from the DPGi were similarly distributed in the spinal cord except that there was no dorsolateral expansion in the lumbar and sacral segments and there were fewer fiber terminals. Fibers arising from GiA/V predominantly traveled in the ventral and lateral funiculi ipsilaterally. Ipsilaterally, the density of fibers in the ventral funiculus decreased along the rostrocaudal axis, whereas the density of fibers in the lateral funiculus increased. They terminate mainly in the medial ventral horn and lamina 10 with a smaller number of fibers in the dorsal horn. Fibers arising from the LPGi traveled in both the ventral and lateral funiculi and the density of these fibers in the ventral and lateral funiculi decreased dramatically in the lumbar and sacral segments. Their terminals were present in the ventral horn with a large portion of them terminating in the motor neuron columns. The present study is the first demonstration of the termination pattern of fibers arising from the Gi, DPGi, GiA/GiV, and LPGi in the mouse spinal cord. It provides an anatomical foundation for those who are conducting spinal cord injury and locomotion related research.

Reorganization of spinal neural circuitry and functional recovery after spinal cord injury

Reorganization of spinal neural circuitry and functional recovery after spinal cord injury

Bridging the gap: a reticulo-propriospinal detour bypassing an incomplete spinal cord injury.

Anatomically incomplete spinal cord injuries are often followed by considerable functional recovery in patients and animal models, largely because of processes of neuronal plasticity. In contrast to the corticospinal system, where sprouting of fibers and rearrangements of circuits in response to lesions have been well studied, structural adaptations within descending brainstem pathways and intraspinal networks are poorly investigated, despite the recognized physiological significance of these systems across species. In the present study, spontaneous neuroanatomical plasticity of severed bulbospinal systems and propriospinal neurons was investigated following unilateral C4 spinal hemisection in adult rats. Injection of retrograde tracer into the ipsilesional segments C3-C4 revealed a specific increase in the projection from the ipsilesional gigantocellular reticular nucleus in response to the injury. Substantial regenerative fiber sprouting of reticulospinal axons above the injury site was demonstrated by anterograde tracing. Regrowing reticulospinal fibers exhibited excitatory, vGLUT2-positive varicosities, indicating their synaptic integration into spinal networks. Reticulospinal fibers formed close appositions onto descending, double-midline crossing C3-C4 propriospinal neurons, which crossed the lesion site in the intact half of the spinal cord and recrossed to the denervated cervical hemicord below the injury. These propriospinal projections around the lesion were significantly enhanced after injury. Our results suggest that severed reticulospinal fibers, which are part of the phylogenetically oldest motor command system, spontaneously arborize and form contacts onto a plastic propriospinal relay, thereby bypassing the lesion. These rearrangements were accompanied by substantial locomotor recovery, implying a potential physiological relevance of the detour in restoration of motor function after spinal injury.

Chasing central nervous system plasticity: the brainstem's contribution to locomotor recovery in rats with spinal cord injury.

Anatomical plasticity such as fibre growth and the formation of new connections in the cortex and spinal cord is one known mechanism mediating functional recovery after damage to the central nervous system. Little is known about anatomical plasticity in the brainstem, which contains key locomotor regions. We compared changes of the spinal projection pattern of the major descending systems following a cervical unilateral spinal cord hemisection in adult rats. As in humans (Brown-Séquard syndrome), this type of injury resulted in a permanent loss of fine motor control of the ipsilesional fore- and hindlimb, but for basic locomotor functions substantial recovery was observed. Antero- and retrograde tracings revealed spontaneous changes in spinal projections originating from the reticular formation, in particular from the contralesional gigantocellular reticular nucleus: more reticulospinal fibres from the intact hemicord crossed the spinal midline at cervical and lumbar levels. The intact-side rubrospinal tract showed a statistically not significant tendency towards an increased number of midline crossings after injury. In contrast, the corticospinal and the vestibulospinal tract, as well as serotonergic projections, showed little or no side-switching in this lesion paradigm. Spinal adaptations were accompanied by modifications at higher levels of control including side-switching of the input to the gigantocellular reticular nuclei from the mesencephalic locomotor region. Electrolytic microlesioning of one or both gigantocellular reticular nuclei in behaviourally recovered rats led to the reappearance of the impairments observed acutely after the initial injury showing that anatomical plasticity in defined brainstem motor networks contributes significantly to functional recovery after injury of the central nervous system.

Evidence for long‐lasting subcortical facilitation by transcranial direct current stimulation in the cat

The main aim of the study was to examine the effects of transcranial polarization on neurons in two descending motor systems, rubro- and reticulospinal. Anodal DC current was applied through an electrode in contact with the skull over the contralateral sensori-motor cortex, against an electrode placed between the skull and the ipsilateral temporal muscles in deeply anaesthetized cats. Its effects were estimated from changes in descending volleys evoked by electrical stimuli applied in the red nucleus (RN), medial longitudinal fascicle (MLF; to reticulospinal fibres) and the pyramidal tract (PT; to corticospinal or corticoreticular fibres). The descending volleys were recorded from the surface of the spinal cord at a cervical level. Rubrospinal neurones were activated either directly or indirectly, via interpositorubral fibres. Reticulospinal neurons were likewise activated directly and indirectly, via other reticulospinal or corticospinal fibres. Transcranial polarization facilitated transsynaptic activation of both rubrospinal and reticulospinal neurons, shortening the latency of the indirect descending volleys and/or increasing them, Direct activation of descending axons was much less affected. The facilitation of all subcortical neurons examined was potentiated by repeated applications of transcranial direct current stimulation (tDCS) and outlasted the polarization by at least 1-2 h, replicating tDCS effects on indirect activation of cortical neurons. The results indicate that the beneficial effects of tDCS on motor performance in humans may be due to more efficient activation of not only cortical but also subcortical neuronal systems. Combined actions of tDCS on cortical and subcortical neurones might thus further improve recovery of motor functions during rehabilitation after central injuries. 249/250.

A Revised Clinical Assessment of Motor and Memory Disturbances

For clinical assessment of motor disturbances, the motor system is better classified into the voluntary versus automatic motor systems than into the pyramidal versus extrapyramidal motor systems. The voluntary motor system is related to externally guided movements initiated by the premotor area while the automatic motor system is related to memory guided automatic movements initiated by the supplementary motor area and supported by an appropriate posture and associated movements. Among the pyramidal tract signs, muscle weakness alone is related to involvement of the corticospinal fibers of Betz cell origin while hyperreflexia and spasticity is related to involvement of the reticulospinal fibers running medial to the corticospinal fibers in the spinal cord. The earliest clinical manifestation of cervical myelopathy due to cervical spondylosis is always hyperreflexia and spasticity without any muscle weakness. The memory depends upon the 3 processes of encoding, retention, and recall, and must be classified into the immediate memory or recall lasting for only several seconds tested by the digit span test, the intermediate memory lasting for up to 2 years at maximum at the hippocampus whose disturbance can best be tested by the digit learning test, and the long-term memory which can last as long as one lives which can be tested by asking one's experience before more than 2 years. The classical dichotic concept of recent (short-term) versus remote (long-term) memories must be abandoned.

Phasic or Transient? Comment on the Terminology of the AASM Manual for the Scoring of Sleep and Associated Events

In the recently published American Academy of Sleep Medicine (AASM) scoring manual for sleep stages,1 the term phasic was replaced throughout by transient. Recommendations for changes in terminology should be made with great care, especially when terminology is a core topic, as indicated by the subtitle of the AASM manual, “Rules, Terminology, and Technical Specifications.” The decision by the Visual Task Force was substantiated in an accompanying paper.2 The recommendation was based on the following reasoning, “Dictionary definitions of phase do not include short-lived transient activity and the term is used in physics for a particular appearance or state in a regularly cycle of changes.”2p129 This argument is misleading, since the term phasic in the context of rapid eye movement (REM) sleep was derived from physiology not physics. Physiologists discriminate between phasic and tonic muscle fibers according to the discharge pattern (see, e.g.3). This also becomes clear by the following quotation from Hobson and Scheibel.4 “Orlovsky (1970) has shown that, complementing these slowly conducting systems, fast reticulospinal fibers are activated in phase with mainly the flexors of one of the limbs in each step and Shimamura and Kuruge (1977) have demonstrated that the reticulospinal neurons thought to be part of the spinal-bulbar-spinal reflex are also phasically activated. Phasic rhythmic activity may also be recorded in vestibulo-spinal and rubrospinal pathways during locomotion (Orlovsky, 1972a,b).”4p62 In his book Neuronal Substrates of Sleep and Epilepsy, Steriade devoted a whole chapter to phasic events.5p187–98

Differential modulation by monoamine membrane receptor agonists of reticulospinal input to lamina VIII feline spinal commissural interneurons

Noradrenaline and serotonin have previously been demonstrated to facilitate the transmission between descending reticulospinal tracts fibres and commissural interneurons coordinating left-right hindlimb muscle activity. The aim of the present study was to investigate the contribution of subclasses of monoaminergic membrane receptors to this facilitation. The neurons were located in Rexed lamina VIII in midlumbar segments and identified by their projections to the contralateral gastrocnemius-soleus motor nuclei and by lack of projections rostral to the lumbosacral enlargement. The effects of ionophoretically applied membrane receptor agonists [phenylephrine (noradrenergic alpha(1)), clonidine (noradrenergic alpha(2)), 8-OH-DPAT (5-HT(1A), 5-HT(7)), 2-me-5-HT (5-HT(3)), 5-me-5-HT (5-HT(2)) and alpha-me-5-HT (5-HT(2))] were examined on extracellularly recorded spikes evoked monosynaptically by electric stimulation of descending reticulospinal fibres in the medial longitudinal fascicle. Application of alpha(1) and 5-HT(2) agonists resulted in a facilitation of responses in all investigated neurons while application of alpha(2), 5-HT(1A/7) and 5-HT(3) agonists resulted in a depression. These opposite modulatory effects of different agonists suggest that the facilitatory actions of noradrenaline and serotonin on responses of commissural interneurons reported previously following ionophoretic application are the net outcome of the activation of different subclasses of monoaminergic membrane receptors. As these receptors may be distributed predominantly, or even selectively, at either pre- or postsynaptic sites their differential modulatory actions could be compatible with a presynaptically induced depression and a postsynaptically evoked enhancement of synaptic transmission between reticulospinal neurons and commissural interneurons.

Neuronal relays in double crossed pathways between feline motor cortex and ipsilateral hindlimb motoneurones

Coupling between pyramidal tract (PT) neurones and ipsilateral hindlimb motoneurones was investigated by recording from commissural interneurones interposed between them. Near maximal stimulation of either the left or right PT induced short latency EPSPs in more than 80% of 20 commissural interneurones that were monosynaptically excited by reticulospinal tract fibres in the medial longitudinal fascicle (MLF). The EPSPs were evoked at latencies that were only 1-2 ms longer than those of EPSPs evoked from the MLF, compatible with a disynaptic coupling between PT fibres and these commissural interneurones. EPSPs evoked by PT stimulation were frequently associated with IPSPs which either followed or preceded the EPSPs. The latencies of the IPSPs (on average about 1 ms longer than latencies of the earliest EPSPs) indicated that they were mediated via single additional inhibitory interneurones. Records from a sample of nine commissural interneurones from a different population (with monosynaptic input from group I and/or II muscle afferents, and disynaptically excited from the MLF) suggest that actions of PT fibres on such interneurones are weaker because only four of them were excited by PT stimuli and at longer latencies. By demonstrating disynaptic coupling between PT neurones and commissural interneurones via reticulospinal fibres, the results provide a direct demonstration of trisynaptic coupling in the most direct pathways between PT neurones and ipsilateral motoneurones, and thereby strengthen the proposal that the double crossed pathways between PT neurones and ipsilateral motoneurones might be used to replace crossed actions of damaged PT neurones.

Spontaneous locomotor recovery in spinal cord injured rats is accompanied by anatomical plasticity of reticulospinal fibers

Although injured axons in mammalian spinal cords do not regenerate, some recovery of locomotor function following incomplete injury can be observed in patients and animal models. Following a lateral hemisection injury of the thoracic spinal cord, rats spontaneously recover weight-bearing stepping in the hind limb ipsilateral to the injury. The mechanisms behind this recovery are not completely understood. Plasticity in the reticulospinal tract (RtST), the tract responsible for the initiation of walking, has not been studied. In this study, rats received lateral thoracic hemisection of the spinal cord, and RtST projections were compared in two groups of rats, one early in recovery (7 days) and the other at a time point when weight-bearing stepping was fully regained (42 days). We found that this recovery occurs in parallel with increased numbers of collaterals of spared RtST fibers entering the intermediate lamina below the injury at L2. Sprouting of injured RtST fibers above the lesion was not found. In conclusion, our study suggests that sprouting of spared RtST fibers might be involved in the recovery of locomotion following incomplete spinal cord injury.

Functional differentiation and organization of feline midlumbar commissural interneurones

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.

Immediate plasticity in the motor pathways after spinal cord hemisection: implications for transcranial magnetic motor-evoked potentials

The present study evaluates motor functional recovery after C2 spinal cord hemisection with or without contralateral brachial root transection, which causes a condition that is similar to the crossed phrenic phenomenon on rats. Descending motor pathways, including the reticulospinal extrapyramidal tract and corticospinal pyramidal tracts, were evaluated by transcranial magnetic motor-evoked potentials (mMEPs) and direct cortical electrical motor-evoked potentials (eMEP), respectively. All MEPs recorded from the left forelimb were abolished immediately after the left C2 hemisection. Left mMEPs recovered dramatically immediately after contralateral right brachial root transection. Corticospinal eMEPs never recovered, regardless of transection. The facilitation of mMEPs in animals that had undergone combined contralateral root transection was well correlated with open-field behavioral motor performance. Both electrophysiological and neurological facilitations were significantly attenuated by the selective serotonin synthesis inhibitor para-chlorophenylalanine ( p-CPA). These results suggest that serotonergic reticulospinal fibers located contralateral to hemisection contribute to the behavioral and electrophysiological improvement that immediately follows spinal cord injury (SCI).

The actions of monoamines and distribution of noradrenergic and serotoninergic contacts on different subpopulations of commissural interneurons in the cat spinal cord.

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.

Are Crossed Actions of Reticulospinal and Vestibulospinal Neurons on Feline Motoneurons Mediated by the Same or Separate Commissural Neurons?

Both reticulo- and vestibulospinal neurons coordinate the activity of ipsilateral and contralateral limb muscles. The aim of this study was to investigate whether their actions on contralateral motoneurons are mediated via common interneurons. Two series of experiments were made on deeply anesthetized cats. First, the effects of stimuli applied within the lateral vestibular nucleus and to reticulospinal tract fibers within or close to the medial longitudinal fascicle in the medulla were tested on midlumbar commissural interneurons that projected to contralateral motor nuclei. EPSPs of vestibular origin were found in 16 of 20 (80%) of the interneurons, all of which were excited monosynaptically by reticulospinal fibers. These EPSPs were evoked either monosynaptically or disynaptically. Second, the effects of stimuli applied at the same two locations were tested on contralateral motoneurons, selecting motoneurons in which large disynaptic EPSPs or IPSPs were evoked by reticulospinal fibers. When stimuli that were too weak to evoke any PSPs by themselves were applied together, similar EPSPs or IPSPs were evoked in all 26 motoneurons that were tested, indicating that spatial facilitation occurred premotoneuronally. Facilitation was strongest at those intervals optimal for summation of monosynaptic and/or disynaptic EPSPs evoked in commissural neurons by the earliest reticulospinal and vestibulospinal volleys. The same interneurons thus may be used by reticulospinal and vestibulospinal neurons to influence the activity of contralateral hindlimb muscles. Separate modulation of commands from these two descending neuronal systems may occur at the level of the interneurons that mediate disynaptic excitation of commissural neurons by reticulospinal and vestibulospinal neurons, thereby increasing their flexibility.

Expression of pro-inflammatory cytokine and caspase genes promotes neuronal apoptosis in pontine reticular formation after spinal cord transection

We identified apoptotic neurons in pontine reticular formation (PRF), the origin of pontine reticulospinal fibers, in adult Sprague–Dawley rats after complete spinal cord transection (SCT) at T8 level. SCT also increased the expression in PRF of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, caspase-1, or caspase-3 mRNA. This was followed by an augmented expression of activated caspase-3 protein, an increase in caspase-3 activity, and expression of a cleaved fragment of poly(ADP-ribose) polymerase (PARP), a proteolytic substrate of the activated caspase-3. Microinjection bilaterally into the PRF of an antiserum against TNF-α attenuated the expression of IL-6 mRNA and up-regulation of caspase-3 mRNA, and a caspase-3 inhibitor, DEVD-CHO, suppressed the augmentation in activated caspase-3 or cleaved PARP expression after SCT. Both treatments also reduced the number of SCT-induced apoptotic PRF neurons. We conclude that PRF neurons in adult mammalian brain may actively degrade themselves after SCT through apoptosis, via signaling processes that involve activation of proinflammatory cytokine genes and the intracellular caspase-3 pathway.

Neuronal Basis of Crossed Actions from the Reticular Formation on Feline Hindlimb Motoneurons

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.

Degeneration and Sprouting of Identified Descending Supraspinal Axons after Contusive Spinal Cord Injury in the Rat

Contusive spinal cord injury (SCI) results in the formation of a chronic lesion cavity surrounded by a rim of spared fibers. Tissue bridges containing axons extend from the spared rim into the cavity dividing it into chambers. Whether descending axons can grow into these trabeculae or whether fibers within the trabeculae are spared fibers remains unclear. The purposes of the present study were (1) to describe the initial axonal response to contusion injury in an identified axonal population, (2) to determine whether and when sprouts grow in the face of the expanding contusion cavity, and (3) in the long term, to see whether any of these sprouts might contribute to the axonal bundles that have been seen within the chronic contusion lesion cavity. The design of the experiment also allowed us to further characterize the development of the lesion cavity after injury. The corticospinal tract (CST) underwent extensive dieback after contusive SCI, with retraction bulbs present from 1 day to 8 months postinjury. CST sprouting occurred between 3 weeks and 3 months, with penetration of CST axons into the lesion matrix occurring over an even longer time course. Collateralization and penetration of reticulospinal fibers were observed at 3 months and were more extensive at later time points. This suggests that these two descending systems show a delayed regenerative response and do extend axons into the lesion cavity and that the endogenous repair can continue for a very long time after SCI.