Neural Signals in Red Nucleus during Reactive and Proactive Adjustments in Behavior.

The ability to adjust behavior is an essential component of cognitive control. Much is known about frontal and striatal processes that support cognitive control, but few studies have investigated how motor signals change during reactive and proactive adjustments in motor output. To address this, we characterized neural signals in red nucleus (RN), a brain region linked to motor control, as male and female rats performed a novel variant of the stop-signal task. We found that activity in RN represented the direction of movement and was strongly correlated with movement speed. Additionally, we found that directional movement signals were amplified on STOP trials before completion of the response and that the strength of RN signals was modulated when rats exhibited cognitive control. These results provide the first evidence that neural signals in RN integrate cognitive control signals to reshape motor outcomes reactively within trials and proactivity across them.SIGNIFICANCE STATEMENT Healthy human behavior requires the suppression or inhibition of errant or maladaptive motor responses, often called cognitive control. While much is known about how frontal brain regions facilitate cognitive control, less is known about how motor regions respond to rapid and unexpected changes in action selection. To address this, we recorded from neurons in the red nucleus, a motor region thought to be important for initiating movement in rats performing a cognitive control task. We show that red nucleus tracks motor plans and that selectivity was modulated on trials that required shifting from one motor response to another. Collectively, these findings suggest that red nucleus contributes to modulating motor behavior during cognitive control.

Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats.

Reorganization of residual descending motor circuits underlies poststroke recovery. We previously clarified a causal relationship between the cortico-rubral tract and intensive limb use-induced functional recovery after internal capsule hemorrhage (ICH). However, other descending tracts, such as the cortico-reticular tract, might also be involved in rehabilitation-induced compensation. To investigate whether rehabilitation-induced recovery after ICH involves a shift in the compensatory circuit from the cortico-rubral tract to the cortico-reticular tract, we established loss of function of the cortico-rubral tract or/and cortico-reticular tract using two sets of viral vectors comprising the Tet-on system and designer receptors exclusively activated by the designer drug system. We used an ICH model that destroyed almost 60% of the corticofugal fibers. Anterograde tracing in rehabilitated rats revealed abundant sprouting of axons from the motor cortex in the red nucleus but not in the medullary reticular formation during the early phase of recovery. This primary contribution of the cortico-rubral tract was demonstrated by its selective blockade, whereas selective cortico-reticular tract silencing had little effect. Interestingly, cortico-rubral tract blockade from the start of rehabilitation induced an obvious increase of axon sprouting in the reticular formation with substantial functional recovery. Additional cortico-reticular tract silencing under the cortico-rubral tract blockade significantly worsened the recovered forelimb function. Furthermore, the alternative recruitment of the cortico-reticular tract was gradually induced by intensive limb use under cortico-rubral tract blockade, in which cortico-reticular tract silencing caused an apparent motor deficit. These findings indicate that individual cortico-brainstem pathways have dynamic compensatory potency to support rehabilitative functional recovery after ICH.SIGNIFICANCE STATEMENT This study aimed to clarify the interaction between the cortico-rubral and the cortico-reticular tract during intensive rehabilitation and functional recovery after capsular stroke. Pathway-selective disturbance by two sets of viral vectors revealed that the cortico-rubral tract was involved in rehabilitation-induced recovery of forelimb function from an early phase after internal capsule hemorrhage, but that the cortico-reticular tract was not. The sequential disturbance of both tracts revealed that the cortico-reticular tract was recruited and involved in rehabilitation-induced recovery when the cortico-rubral tract failed to function. Our data demonstrate a dynamic compensatory action of individual cortico-brainstem pathways for recovery through poststroke rehabilitation.

Collaboration of Cerebello-Rubral and Cerebello-Striatal Loops in a Motor Preparation Task.

In this study, we used fMRI to identify brain regions associated with concentration (sustained attention) during a motor preparation task. In comparison with a non-concentration task, increased activities were observed (P < 0.05, FWE-corrected P values) in cerebellar lobules VI and VII, motor cortex, pre-supplementary motor area (pre-SMA), thalamus, red nucleus (RN), and caudate nucleus (CN). Moreover, analysis of effective connectivity inter-areal (psychophysiological interactions) showed that during preparation, concentration-related brain activity increase was dependent on Cerebello-thalamo-pre-SMA-RN and Pre-SMA-CN-thalamo-M1 loops. We postulate that, while pre-SMA common to both loops is specifically involved in the movement preparation and readiness for voluntary movement through the striatum, the cerebellar lobule VI in conjunction with RN, likely through a cerebellar-rubro-olivary-cerebellar loop, might be implicated in concentration-related optimization of upcoming motor performances.

Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus as an Independent Processor of Corollary Discharge Information in Mice.

Understanding cerebellar contributions to motor coordination requires deeper insight into how the output structures of the cerebellum, the cerebellar nuclei, integrate their inputs and influence downstream motor pathways. The magnocellular red nucleus (RNm), a brainstem premotor structure, is a major target of the interposed nucleus (IN), and has also been described in previous studies to send feedback collaterals to the cerebellum. Because such a pathway is in a key position to provide motor efferent information to the cerebellum, satisfying predictions about the use of corollary discharge in cerebellar computations, we studied it in mice of both sexes. Using anterograde viral tracing, we show that innervation of cerebellum by rubrospinal neuron collaterals is remarkably selective for the IN compared with the cerebellar cortex. Optogenetic activation of the pathway in acute mouse brain slices drove IN activity despite small amplitude synaptic currents, suggesting an active role in IN information processing. Monosynaptic transsynaptic rabies tracing indicated the pathway contacts multiple cell types within the IN. By contrast, IN inputs to the RNm targeted a region that lacked inhibitory neurons. Optogenetic drive of IN inputs to the RNm revealed strong, direct excitation but no inhibition of RNm neurons. Together, these data indicate that the cerebellar nuclei are under afferent control independent of the cerebellar cortex, potentially diversifying its roles in motor control.SIGNIFICANCE STATEMENT The common assumption that all cerebellar mossy fibers uniformly collateralize to the cerebellar nuclei and cortex underlies classic models of convergent Purkinje influence on cerebellar output. Specifically, mossy fibers are thought to both directly excite nuclear neurons and drive polysynaptic feedforward inhibition via Purkinje neurons, setting up a fundamental computational unit. Here we present data that challenge this rule. A dedicated cerebellar nuclear afferent comprised of feedback collaterals from premotor rubrospinal neurons can directly modulate IN output independent of Purkinje cell modulation. In contrast to the IN-RNm pathway, the RNm-IN feedback pathway targets multiple cell types, potentially influencing both motor output pathways and nucleo-olivary feedback.

Structural and functional connectivity of the nondecussating dentato-rubro-thalamic tract.

The dentato-rubro-thalamic tract (DRTT) regulates motor control, connecting the cerebellum to the thalamus. This tract is modulated by deep-brain stimulation in the surgical treatment of medically refractory tremor, especially in essential tremor, where high-frequency stimulation of the thalamus can improve symptoms. The DRTT is classically described as a decussating pathway, ascending to the contralateral thalamus. However, the existence of a nondecussating (i.e. ipsilateral) DRTT in humans was recently demonstrated, and these tracts are arranged in distinct regions of the superior cerebellar peduncle. We hypothesized that the ipsilateral DRTT is connected to specific thalamic nuclei and therefore may have unique functional relevance. The goals of this study were to confirm the presence of the decussating and nondecussating DRTT pathways, identify thalamic termination zones of each tract, and compare whether structural connectivity findings agree with functional connectivity. Diffusion-weighted imaging was used to perform probabilistic tractography of the decussating and nondecussating DRTT in young healthy subjects from the Human Connectome Project (n = 91) scanned using multi-shell diffusion-weighted imaging (270 directions; TR/TE = 5500/89 ms; spatial resolution = 1.25 mm isotropic). To define thalamic anatomical landmarks, a segmentation procedure based on the Morel Atlas was employed, and DRTT targeting was quantified based on the proportion of streamlines arriving at each nucleus. In parallel, functional connectivity analysis was performed using resting-state functional MRI (TR/TE = 720/33 ms; spatial resolution = 2 mm isotropic). It was found that the decussating and nondecussating DRTTs have significantly different thalamic endpoints, with the former preferentially targeting relatively anterior and lateral thalamic nuclei, and the latter connected to more posterior and medial nuclei (p < 0.001). Functional and structural connectivity measures were found to be significantly correlated (r = 0.45, p = 0.031). These findings provide new insight into pathways through which unilateral cerebellum can exert bilateral influence on movement and raise questions about the functional implications of ipsilateral cerebellar efferents.

Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke.

Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of-function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH. SIGNIFICANCE STATEMENT: The research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use.

Sensorimotor processing in the newborn rat red nucleus during active sleep.

Sensory feedback from sleep-related myoclonic twitches is thought to drive activity-dependent development in spinal cord and brain. However, little is known about the neural pathways involved in the generation of twitches early in development. The red nucleus (RN), source of the rubrospinal tract, has been implicated in the production of phasic motor activity during active sleep in adults. Here we hypothesized that the RN is also a major source of motor output for twitching in early infancy, a period when twitching is an especially abundant motor behavior. We recorded extracellular neural activity in the RN during sleep and wakefulness in 1-week-old unanesthetized rats. Neurons in the RN fired phasically before twitching and wake movements of the contralateral forelimb. A subpopulation of neurons in the RN exhibited a significant peak of activity after forelimb movement onset, suggesting reafferent sensory processing. Consistent with this observation, manual stimulation of the forelimb evoked RN responses. Unilateral inactivation of the RN using a mixture comprising GABAA, GABAB, and glycine receptor agonists caused an immediate and temporary increase in motor activity followed by a marked and prolonged decrease in twitching and wake movements. Altogether, these data support a causal role for the RN in infant motor behavior. Furthermore, they indicate that twitching, which is characterized by discrete motor output and reafferent input, provides an opportunity for sensorimotor integration and activity-dependent development of topography within the newborn RN.

Motor Cortex Activity Organizes the Developing Rubrospinal System.

The corticospinal and rubrospinal systems function in skilled movement control. A key question is how do these systems develop the capacity to coordinate their motor functions and, in turn, if the red nucleus/rubrospinal tract (RN/RST) compensates for developmental corticospinal injury? We used the cat to investigate whether the developing rubrospinal system is shaped by activity-dependent interactions with the developing corticospinal system. We unilaterally inactivated M1 by muscimol microinfusion between postnatal weeks 5 and 7 to examine activity-dependent interactions and whether the RN/RST compensates for corticospinal tract (CST) developmental motor impairments and CST misprojections after M1 inactivation. We examined the RN motor map and RST cervical projections at 7 weeks of age, while the corticospinal system was inactivated, and at 14 weeks, after activity returned. During M1 inactivation, the RN on the same side showed normal RST projections and reduced motor thresholds, suggestive of precocious development. By contrast, the RN on the untreated/active M1 side showed sparse RST projections and an immature motor map. After M1 activity returned later in adolescent cat development, RN on the active M1/CST side continued to show a substantial loss of spinal terminations and an impaired motor map. RN/RST on the inactivated side regressed to a smaller map and fewer axons. Our findings suggest that the developing rubrospinal system is under activity-dependent regulation by the corticospinal system for establishing mature RST connections and RN motor map. The lack of RS compensation on the non-inactivated side can be explained by development of ipsilateral misprojections from the active M1 that outcompete the RST. Significance statement: Skilled movements reflect the activity of multiple descending motor systems and their interactions with spinal motor circuits. Currently, there is little insight into whether motor systems interact during development to coordinate their emerging functions and, if so, the mechanisms underlying this process. This study examined activity-dependent interactions between the developing corticospinal and rubrospinal systems, two key systems for skilled limb movements. We show that the developing rubrospinal system competes with the corticospinal system in establishing the red nucleus motor map and rubrospinal tract connections. This is the first demonstration of one motor system steering development, and ultimately function, of another. Knowledge of activity-dependent competition between these two systems helps predict the response of the rubrospinal system following corticospinal system developmental injury.

Spontaneous activity and functional connectivity in the developing cerebellorubral system.

The development of the cerebellar system depends in part on the emergence of functional connectivity in its input and output pathways. Characterization of spontaneous activity within these pathways provides insight into their functional status in early development. In the present study we recorded extracellular activity from the interpositus nucleus (IP) and its primary downstream target, the red nucleus (RN), in unanesthetized rats at postnatal days 8 (P8) and P12, a period of dramatic change in cerebellar circuitry. The two structures exhibited state-dependent activity patterns and age-related changes in rhythmicity and overall firing rate. Importantly, sensory feedback (i.e., reafference) from myoclonic twitches (spontaneous, self-generated movements that are produced exclusively during active sleep) drove neural activity in the IP and RN at both ages. Additionally, anatomic tracing confirmed the presence of cerebellorubral connections as early as P8. Finally, inactivation of the IP and adjacent nuclei using the GABAA receptor agonist muscimol caused a substantial decrease in neural activity in the contralateral RN at both ages, as well as the disappearance of rhythmicity; twitch-related activity in the RN, however, was preserved after IP inactivation, indicating that twitch-related reafference activates the two structures in parallel. Overall, the present findings point to the contributions of sleep-related spontaneous activity to the development of cerebellar networks.

Nucleus Ruber of Actinopterygians.

Nucleus ruber is known as an important supraspinal center that controls forelimb movements in tetrapods, and the rubral homologue may serve similar functions in fishes (motor control of pectoral fin). However, two apparently different structures have been identified as 'nucleus ruber' in actinopterygians. One is nucleus ruber of Goldstein (1905) (NRg), and the other nucleus ruber of Nieuwenhuys and Pouwels (1983) (NRnp). It remains unclear whether one of these nuclei (or perhaps both) is homologous to tetrapod nucleus ruber. To resolve this issue from a phylogenetic point of view, we have investigated the distribution of tegmental neurons retrogradely labeled from the spinal cord in eight actinopterygian species. We also investigated the presence/absence of the two nuclei with Nissl- or Bodian-stained brain section series of an additional 28 actinopterygian species by comparing the morphological features of candidate rubral neurons with those of neurons revealed by the tracer studies. Based on these analyses, the NRg was identified in all actinopterygians investigated in the present study, while the NRnp appears to be absent in basal actinopterygians. The phylogenetic distribution pattern indicates that the NRg is the more likely homologue of nucleus ruber, and the NRnp may be a derived nucleus that emerged during the course of actinopterygian evolution.

Postnatal maturation of the red nucleus motor map depends on rubrospinal connections with forelimb motor pools.

The red nucleus (RN) and rubrospinal tract (RST) are important for forelimb motor control. Although the RST is present postnatally in cats, nothing is known about when rubrospinal projections could support motor functions or the relation between the development of the motor functions of the rubrospinal system and the corticospinal system, the other major system for limb control. Our hypothesis is that the RN motor map is present earlier in development than the motor cortex (M1) map, to support early forelimb control. We investigated RN motor map maturation with microstimulation and RST cervical enlargement projections using anterograde tracers between postnatal week 3 (PW3) and PW16. Microstimulation and tracer injection sites were verified histologically to be located within the RN. Microstimulation at PW4 evoked contralateral wrist, elbow, and shoulder movements. The number of sites producing limb movement increased and response thresholds decreased progressively through PW16. From the outset, all forelimb joints were represented. At PW3, RST projections were present within the cervical intermediate zone, with a mature density of putative synapses. In contrast, beginning at PW5 there was delayed and age-dependent development of forelimb motor pool projections and putative rubromotoneuronal synapses. The RN has a more complete forelimb map early in development than previous studies showed for M1, supporting our hypothesis of preferential rubrospinal rather than corticospinal control for early movements. Remarkably, development of the motor pool, not intermediate zone, RST projections paralleled RN motor map development. The RST may be critical for establishing the rudiments of motor skills that subsequently become refined with further CST development.

Can the period of postnatal codevelopment of the rubrospinal and corticospinal systems provide new insights into refinement of limb movement?

The corticospinal and the rubrospinal tracts are thought to synergistically contribute to the limb control during motor development. Williams et al. (J Neurosci 34: 4432-4441, 2014) demonstrate that the postnatal maturation of red nucleus motor map and the rubrospinal tract develops earlier than the corticospinal tract, to support early forelimb control. They have two distinct phases of maturation; a "precorticospinal" phase characterized by development of the rubrospinal system, and a "cocorticospinal" phase where they overlap with corticospinal development.

Deep brain stimulation for essential tremor: targeting the dentato-rubro-thalamic tract?

OBJECTIVE: The aim of our study was to evaluate the influence of the stimulation site relative to the dentato-rubro-thalamic tract (DRTT) on the alleviation of tremor in deep brain stimulation. METHODS: Ten DRTTs in five patients were investigated using preoperative diffusion tensor imaging (DTI). Regions of interest for fiber tracking were located in the cerebellar dentate nucleus, the superior cerebellar peduncle and the contralateral red nucleus. The position and distance of all intraoperative stimulation sites to the DRTT were measured and correlated to the amount of tremor reduction. RESULTS: Nine of 10 DRTTs could be identified using DTI-based fiber tracking. Better tremor reduction was achieved in locations in or posterior and lateral to the DRTT than in medial and anterior positions (p = 0.001). Stimulation sites inferior to and in the DRTT achieved better results than locations superior to the DRTT (p < 0.05). The vicinity of the stimulation site to the DRTT did not correlate with tremor alleviation. DISCUSSION: In deep brain stimulation targeting for thalamic stimulation sites is limited to statistical, atlas-based coordinates. Diffusion tensor imaging and fiber tracking was used to visualize the dentato-rubro-thalamic tract as a potential, individualized target structure. However, we could not demonstrate that contacts closer to the DRTT provided better clinical effects than distant contacts, in any given direction. DTI sequences with a higher number of read-out directions, probabilistic fiber tracking and three Tesla MRI scanners may lead to different results in the depiction of the chosen fiber tract and may provide a better correlation with stimulation effects. CONCLUSIONS: The results do not provide sufficient evidence to define the DRTT as a new DBS-target for tremor. Further investigations on different fiber tracts, DTI sequences, and fiber tracking algorithms are mandatory.

Presynaptic actions of transcranial and local direct current stimulation in the red nucleus.

The main aim of the present study was to examine to what extent long-lasting subcortical actions of transcranial direct current stimulation (tDCS) may be related to its presynaptic actions. This was investigated in the red nucleus, where tDCS was recently demonstrated to facilitate transmission between interpositorubral and rubrospinal neurons. Changes in the excitability of preterminal axonal branches of interpositorubral neurons close to rubrospinal neurons were investigated during and after tDCS (0.2 mA) applied over the sensorimotor cortical area in deeply anaesthetized rats and cats. As a measure of the excitability, we used the probability of antidromic activation of individual interpositorubral neurons by electrical stimuli applied in the red nucleus. Our second aim was to compare effects of weak (≤1 µA) direct current applied within the red nucleus with effects of tDCS to allow the use of local depolarization in a further analysis of mechanisms of tDCS instead of widespread and more difficult to control depolarization evoked by distant electrodes. Local cathodal polarization was found to replicate all effects of cathodal tDCS hitherto demonstrated in the rat, including long-lasting facilitation of trans-synaptically evoked descending volleys and trisynaptically evoked EMG responses in neck muscles. It also replicated all effects of anodal tDCS in the cat. In both species, it increased the excitability of preterminal axonal branches of interpositorubral neurons up to 1 h post-tDCS. Local anodal polarization evoked opposite effects. We thus show that presynaptic actions of polarizing direct current may contribute to both immediate and prolonged effects of tDCS.

Red nucleus neurons actively contribute to the acquisition of classically conditioned eyelid responses in rabbits.

The red nucleus (RN) is a midbrain premotor center that has been suggested as being involved in the acquisition and/or performance of classically conditioned nictitating membrane/eyelid responses. We recorded in rabbits the activity of RN and pararubral neurons during classical eyeblink conditioning using a delay paradigm. Neurons were identified by their antidromic activation from contralateral facial and accessory abducens nuclei and by their synaptic activation from the ipsilateral motor cortex (MC) and the contralateral cerebellar interpositus (IP) nucleus. For conditioning, we used a tone as a conditioned stimulus (CS) followed 250 ms later by a 100 ms air puff as an unconditioned stimulus (US) coterminating with it. Conditioned responses (CRs) were determined from the evoked changes in the electromyographic activity of the orbicularis oculi (OO) muscle. Recorded neurons were classified by their antidromic activation and by their changes in firing rate during the CS-US interval. Identified neurons increased their firing rates in relation to the successive conditioning sessions, but their discharge rates were related more to the EMG activity of the OO muscle than to the learning curves. Reversible inactivation of the IP nucleus with lidocaine during conditioning evoked a complete disappearance of both conditioned and unconditioned eyelid responses, and a progressive decrease in CR-related activity of RN neurons. In contrast, MC inactivation evoked a decrease in the acquisition process and an initial disfacilitation of neuronal firing (which was later recovered), together with the late appearance of CRs. Thus, RN neurons presented learning-dependent changes in activity following MC inactivation.

Subcortical effects of transcranial direct current stimulation in the rat.

Transcranial direct current stimulation (tDCS) affects neurons at both cortical and subcortical levels. The subcortical effects involve several descending motor systems but appeared to be relatively weak, as only small increases in the amplitude of subcortically initiated descending volleys and a minute shortening of latencies of these volleys were found. The aim of the present study was therefore to evaluate the consequences of facilitation of these volleys on the ensuing muscle activation. The experiments were carried out on deeply anaesthetized rats without neuromuscular blockade. Effects of tDCS were tested on EMG potentials recorded from neck muscles evoked by weak (20-60 µA) single, double or triple stimuli applied in the medial longitudinal fascicle (MLF) or in the red nucleus (RN). Short latencies of these potentials were compatible with monosynaptic or disynaptic actions of reticulospinal and disynaptic or trisynaptic actions of rubrospinal neurons on neck motoneurons. Despite only weak effects on indirect descending volleys, the EMG responses from both the MLF and the RN were potently facilitated by cathodal tDCS and depressed by anodal tDCS. Both the facilitation and the depression developed relatively rapidly (within the first minute) but both outlasted tDCS and were present for up to 1 h after tDCS. The study thus demonstrates long-lasting effects of tDCS on subcortical neurons in the rat, albeit evoked by an opposite polarity of tDCS to that found to be effective on subcortical neurons in the cat investigated in the preceding study, or for cortical neurons in the humans.

[Study of resting state functional connectivity of the red nucleus and substantia nigra were in normal adult].

OBJECTIVE: To detect the functional networks of the red nucleus and substantia nigra during the resting state in normal subjects with functional magnetic resonance imaging (fMRI). METHODS: Sixteen normal subjects were performed resting state fMRI scanning and susceptibility weighted imaging. The function connectivity networks base on seed regions of the red nucleus and substantia nigra were extracted from low frequency fluctuation signal in fMRI data by using a temporal correlation method. Individual functional maps were entered two-tailed one-sample t test to determine brain regions with significant positive correlation to the seeds. The statistic threshold was set at P < 0.001, cluster size>42 (336 mm(3)), cluster connectivity criterion 5 min with Alphasim correction. RESULTS: Brain regions involved in the functional connectivity network of the red nucleus include: dorsal anterior cingutate, supramarginal gyrus, the ventrolateral and the ventromedial nucleus of the thalamus, globus pallidus, dorsal thalamus, hippocampus, substantia nigra, red nucleus, pons, dentate nucleus, vermis; Brain regions involved in the functional connectivity network of the substantia nigra include: anterior cingutate, supramarginal gyrus, globus pallidus, dorsal thalamus, hippocampus, lobus insularis, substantia nigra, red nucleus, pons, dentate nucleus. The distribution of the networks of the red nucleus and substantia nigra presented symmetrical. Although the functional networks of the red nucleus and substantia nigra over lapped largely with each other, the rubral network was slightly different with the nigral network, witch showed strong correlations with more wide-spread striatum and thalamus areas. CONCLUSION: The functional networks of the red nucleus and substantia nigra reflected strong interplay within the extrapyramidal subcortical system, as well as correlations between some limited cerebral cortices; Functional magnetic resonance imaging is a potential powerful tool to explore the extrapyramidal system.

Chondroitinase ABC promotes recovery of adaptive limb movements and enhances axonal growth caudal to a spinal hemisection.

A number of studies have shown that chondroitinase ABC (Ch'ase ABC) digestion of inhibitory chondroitin sulfate glycosaminoglycans significantly enhances axonal growth and recovery in rodents following spinal cord injury (SCI). Further, our group has shown improved recovery following SCI in the larger cat model. The purpose of the current study was to determine whether intraspinal delivery of Ch'ase ABC, following T10 hemisections in adult cats, enhances adaptive movement features during a skilled locomotor task and/or promotes plasticity of spinal and supraspinal circuitry. Here, we show that Ch'ase ABC enhanced crossing of a peg walkway post-SCI and significantly improved ipsilateral hindlimb trajectories and integration into a functional forelimb-hindlimb coordination pattern. Recovery of these complex movements was associated with significant increases in neurofilament immunoreactivity immediately below the SCI in the ipsilateral white (p = 0.033) and contralateral gray matter (p = 0.003). Further, the rubrospinal tract is critical in the normal cat during skilled movements that require accurate paw placements and trajectories like those seen during peg walkway crossing. Rubrospinal connections were assessed following Fluoro-Gold injections, caudal to the hemisection. Significantly more retrogradely labeled right (axotomized) red nucleus (RN) neurons were seen in Ch'ase ABC-treated (23%) compared with control-treated cats (8%; p = 0.032) indicating that a larger number of RN neurons in Ch'ase ABC-treated cats had axons below the lesion level. Thus, following SCI, Ch'ase ABC may facilitate axonal growth at the spinal level, enhance adaptive features of locomotion, and affect plasticity of rubrospinal circuitry known to support adaptive behaviors in the normal cat.

Activity of red nucleus neurons in the cat during postural corrections.

The dorsal-side-up body posture in standing quadrupeds is maintained by the postural system, which includes spinal and supraspinal mechanisms driven by somatosensory inputs from the limbs. A number of descending tracts can transmit supraspinal commands for postural corrections. The first aim of this study was to understand whether the rubrospinal tract participates in their transmission. We recorded activity of red nucleus neurons (RNNs) in the cat maintaining balance on the periodically tilting platform. Most neurons were identified as rubrospinal ones. It was found that many RNNs were profoundly modulated by tilts, suggesting that they transmit postural commands. The second aim of this study was to examine the contribution of sensory inputs from individual limbs to posture-related RNN modulation. Each RNN was recorded during standing on all four limbs, as well as when two or three limbs were lifted from the platform and could not signal platform displacements. By comparing RNN responses in different tests, we found that the amplitude and phase of responses in the majority of RNNs were determined primarily by sensory input from the corresponding (fore or hind) contralateral limb, whereas inputs from other limbs made a much smaller contribution to RNN modulation. These findings suggest that the rubrospinal system is primarily involved in the intralimb postural coordination, i.e., in the feedback control of the corresponding limb and, to a lesser extent, in the interlimb coordination. This study provides a new insight into the formation of supraspinal motor commands for postural corrections.

Do spinocerebellar neurones forward information on spinal actions of neurones in the feline red nucleus?

We recently demonstrated that feline ventral spinocerebellar tract (VSCT) neurones monitor descending commands for voluntary movements initiated by pyramidal tract (PT) neurones as well as locomotor movements relayed by reticulospinal (RS) neurones. The aim of the present study was to examine whether VSCT neurones likewise monitor descending commands from the red nucleus (RN). Extracellular records from the spinal border (SB) subpopulation of VSCT neurons revealed that a third (31%) of SB neurones may be discharged by trains of stimuli applied in the RN. Moreover, when RN stimuli failed to discharge SB neurones they facilitated activation of some of these neurones by RS and/or PT neurones, while activation of other SB neurones was depressed. We propose that the facilitation and depression of actions of RS neurones by RN neurones might serve to reflect a higher or lower excitability of motoneurones and therefore a likely higher or lower efficacy of the RS descending commands, prompting the cerebellum to adjust the activation of reticulospinal neurones. Activation of SB neurones by RN stimuli alone would also allow monitoring and adjusting the RN descending commands. Intracellular records from SB neurones revealed both monosynaptic and disynaptic EPSPs and disynaptic IPSPs evoked by RN stimuli. The disynaptic actions remained following transection of axons of reticulospinal neurones within the medullary longitudinal fascicle (MLF) and were therefore taken to be relayed primarily by spinal neurones, in contrast to EPSPs and IPSPs evoked by PT stimuli found to be relayed by reticulospinal rather than spinal neurones.