Red nucleus structure and function: from anatomy to clinical neurosciences.

The red nucleus (RN) is a large subcortical structure located in the ventral midbrain. Although it originated as a primitive relay between the cerebellum and the spinal cord, during its phylogenesis the RN shows a progressive segregation between a magnocellular part, involved in the rubrospinal system, and a parvocellular part, involved in the olivocerebellar system. Despite exhibiting distinct evolutionary trajectories, these two regions are strictly tied together and play a prominent role in motor and non-motor behavior in different animal species. However, little is known about their function in the human brain. This lack of knowledge may have been conditioned both by the notable differences between human and non-human RN and by inherent difficulties in studying this structure directly in the human brain, leading to a general decrease of interest in the last decades. In the present review, we identify the crucial issues in the current knowledge and summarize the results of several decades of research about the RN, ranging from animal models to human diseases. Connecting the dots between morphology, experimental physiology and neuroimaging, we try to draw a comprehensive overview on RN functional anatomy and bridge the gap between basic and translational research.

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.

Impaired hippocampal and thalamic acetylcholine release in P301L tau-transgenic mice.

We evaluated acetylcholine release by microdialysis in 10 month old control and JNPL3 mice which carry a mutant tau gene (P301 L). Three brain regions were compared: hippocampus and thalamus which receive cholinergic input from the basal forebrain, and the red nucleus which receives cholinergic projections from brain stem nuclei. Cognitive and motor functions of the mice were largely normal. In microdialysis experiments, we found significant reductions in basal ACh levels in hippocampus and thalamus, but not in the red nucleus. ACh release was impaired most strongly (by 50%) when a physiological stimulus was applied, i.e. exploration of a novel environment, whereas most mice responded adequately with an increase of ACh release upon infusion of scopolamine. A strong reduction of scopolamine-mediated ACh release was seen after amyloid Aß42 peptide was administered into the hippocampus of tau-transgenic mice. Choline acetyltransferase activities were unchanged in tau-transgenic mice but acetylcholinesterase activities were increased in thalamus. Lactate and choline levels were increased in tau-transgenic mice but high-affinity choline uptake was slightly reduced. Our data suggest that even mild to moderate tau pathology in JNPL3 mice is able to depress cholinergic transmission in brain regions that receive input from the basal forebrain via long projection neurons. This impairment may be reinforced by amyloid peptide formation.

Excitatory rubral cells encode the acquisition of novel complex motor tasks.

The red nucleus (RN) is required for limb control, specifically fine motor coordination. There is some evidence for a role of the RN in reaching and grasping, mainly from lesion studies, but results so far have been inconsistent. In addition, the role of RN neurons in such learned motor functions at the level of synaptic transmission has been largely neglected. Here, we show that Vglut2-expressing RN neurons undergo plastic events and encode the optimization of fine movements. RN light-ablation severely impairs reaching and grasping functions while sparing general locomotion. We identify a neuronal population co-expressing Vglut2, PV and C1QL2, which specifically undergoes training-dependent plasticity. Selective chemo-genetic inhibition of these neurons perturbs reaching and grasping skills. Our study highlights the role of the Vglut2-positive rubral population in complex fine motor tasks, with its related plasticity representing an important starting point for the investigation of mechanistic substrates of fine motor coordination training.

Involvement of the Red Nucleus in the Compensation of Parkinsonism may Explain why Primates can develop Stable Parkinson's Disease.

Neurological compensatory mechanisms help our brain to adjust to neurodegeneration as in Parkinson's disease. It is suggested that the compensation of the damaged striato-thalamo-cortical circuit is focused on the intact thalamo-rubro-cerebellar pathway as seen during presymptomatic Parkinson, paradoxical movement and sensorimotor rhythm (SMR). Indeed, the size of the red nucleus, connecting the cerebellum with the cerebral cortex, is larger in Parkinson's disease patients suggesting an increased activation of this brain area. Therefore, the red nucleus was examined in MPTP-induced parkinsonian marmoset monkeys during the presymptomatic stage and after SMR activation by neurofeedback training. We found a reverse significant correlation between the early expression of parkinsonian signs and the size of the parvocellular part of the red nucleus, which is predominantly present in human and non-human primates. In quadrupedal animals it consists mainly of the magnocellular part. Furthermore, SMR activation, that mitigated parkinsonian signs, further increased the size of the red nucleus in the marmoset monkey. This plasticity of the brain helps to compensate for dysfunctional movement control and can be a promising target for compensatory treatment with neurofeedback technology, vibrotactile stimulation or DBS in order to improve the quality of life for Parkinson's disease patients.

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.

Buyang huanwu decoction combined with BMSCs transplantation promotes recovery after spinal cord injury by rescuing axotomized red nucleus neurons.

ETHNOPHARMACOLOGICAL RELEVANCE: Buyang huanwu decoction (BYHWD) is a classic recipe in traditional Chinese medicine (TCM) to supplement Qi and activate blood. It has been used to recover the neural function after the injury of central nervous system for hundreds of years in China. AIM OF THE STUDY: This study investigated whether Buyang huanwu decoction (BYHWD) combined with bone marrow mesenchymal stem cells (BMSCs) transplantation had synergistic effect on neuroprotection of red nucleus neurons after spinal cord injury (SCI). MATERIALS AND METHODS: Rubrospinal tract (RST) transection model was established and BMSCs were collected. The forelimb locomotor function was recorded using inclined plate test and spontaneous vertical exploration. cAMP level in red nucleus was detected with Enzyme-linked immunosorbent assay (ELISA). Morphology and number of red nucleus neurons was observed using Nissl's staining. Expression of cAMP-response element binding protein (CREB), ras homolog gene family member A (RhoA) and nerve growth factor (NGF) in red nucleus was detected using immunohistochemistry, qRT-PCR and Western-blotting. RESULTS: The combination of BYHWD and BMSCs transplantation could improve the forelimb locomotor function significantly and give the red nucleus somas a better protection. Meanwhile, cAMP level, CREB and NGF increased, while RhoA decreased remarkably in the BYHWD+BMSCs group. CONCLUSIONS: BYHWD combined with BMSCs transplantation had synergistic effect on neuroprotection of red nucleus neurons after SCI; the mechanism may be related to up-regulating cAMP level, activating the cAMP/CREB/RhoA signaling pathway, and promoting expression of NGF.

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.

Rat motor neurons caudal to a rubrospinal tract (RST) transection remain viable.

In the rat, the rubrospinal tract (RST) is a descending motor pathway involved in the production of skilled reaching movement. The RST originates in the red nucleus in the midbrain and runs down the spinal cord in the lateral most aspect of the dorsolateral funiculus (DLF). The RST makes monosynaptic contact with interneurons within the intermediate laminae of the cord, however a contingent of RST axons constitutes direct supraspinal input for spinal cord motor neurons. The current study investigated the effects of unilateral RST transection at cervical levels C3-4 on the population of motor neurons in both spinal segments C5-6 and L2-3. The total number of large, medium and small motor neurons in these segments was estimated with stereological techniques in both ventral horns at 1, 3, 7 and 14days post-injury. In both spinal cord segments under investigation, no change was detected in mean number of motor neurons over time, in either ventral horn. That the loss of direct supraspinal input resulting from the RST transection does not affect the viability of motor neurons caudal to the injury indicates that these neurons have the potential to be re-innervated, should the RST injury be repaired.

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.

Neuronal Correlates of Functional Coupling between Reach- and Grasp-Related Components of Muscle Activity.

Coordinated reach-to-grasp movements require precise spatiotemporal synchrony between proximal forelimb muscles (shoulder, elbow) that transport the hand toward a target during reach, and distal muscles (wrist, digit) that simultaneously preshape and orient the hand for grasp. The precise mechanisms through which the redundant neuromuscular circuitry coordinates reach with grasp, however, remain unclear. Recently, Geed and Van Kan (2016) demonstrated, using exploratory factor analysis (EFA), that limited numbers of global, template-like transport/preshape- and grasp-related muscle components underlie the complexity and variability of intramuscular electromyograms (EMGs) of up to 21 distal and proximal muscles recorded while monkeys performed reach-to-grasp tasks. Importantly, transport/preshape- and grasp-related muscle components showed invariant spatiotemporal coupling, which provides a potential mechanism for coordinating forelimb muscles during reach-to-grasp movements. In the present study, we tested whether ensemble discharges of forelimb neurons in the cerebellar nucleus interpositus (NI) and its target, the magnocellular red nucleus (RNm), a source of rubrospinal fibers, function as neuronal correlates of the transport/preshape- and grasp-related muscle components we identified. EFA applied to single-unit discharges of populations of NI and RNm neurons recorded while the same monkeys that were used previously performed the same reach-to-grasp tasks, revealed neuronal components in the ensemble discharges of both NI and RNm neuronal populations with characteristics broadly similar to muscle components. Subsets of NI and RNm neuronal components were strongly and significantly crosscorrelated with subsets of muscle components, suggesting that similar functional units of reach-to-grasp behavior are expressed by NI and RNm neuronal populations and forelimb muscles. Importantly, like transport/preshape- and grasp-related muscle components, their NI and RNm neuronal correlates showed invariant spatiotemporal coupling. Clinical and lesion studies have reported disruption of coupling between reach and grasp following cerebellar damage; the present results expand on those studies by identifying a neuronal mechanism that may underlie cerebellar contributions to spatiotemporal coordination of distal and proximal limb muscles during reaching to grasp. We conclude that finding similar functional units of behavior expressed at multiple levels of information processing along interposito-rubrospinal pathways and forelimb muscles supports the hypothesis that functionally related populations of NI and RNm neurons act synergistically in the control of complex coordinated motor behaviors.

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.

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.

Role of the vestibular nuclear complex in facilitating the jaw-opening reflex following stimulation of the red nucleus.

According to our previous studies, stimulation of the red nucleus (RN) facilitates the low-threshold afferent-evoked jaw-opening reflex (L-JOR). It has been reported that the RN projects to the superior (SVN), lateral (LVN) and inferior vestibular (IVN) nuclei. The SVN and the LVN have reciprocal intrinsic connections with the medial vestibular nucleus (MVN). Our previous study demonstrated that stimulation of the vestibular nuclear complex (VN) modulates the L-JOR. These facts suggest that RN-induced facilitation of the L-JOR is mediated via the VN. In the present work we investigated whether electrically induced lesions of the VN, or microinjection of muscimol into the VN, affects RN-induced facilitation of the L-JOR. The L-JOR was evoked by electrical stimulation of the inferior alveolar nerve. The stimulus intensity was 1.2 times the evocation threshold. Lesions of the MVN or the LVN or the SVN, and the muscimol injection into the MVN or the LVN or the SVN, reduced the RN-induced facilitation of the L-JOR. Conversely, lesions of the IVN, and the muscimol injection into the IVN, increased the RN-induced facilitation of the L-JOR. These results suggest that the RN-induced facilitation of the L-JOR is mediated by a relay in the VN.

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.

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.

Mapping the functional connectivity of the substantia nigra, red nucleus and dentate nucleus: A network analysis hypothesis associated with the extrapyramidal system.

This study aimed to examine the functional networks related to the extrapyramidal system using a temporal oscillation signal correlation analysis method based on critical nodes in the substantia nigra (SN), red nucleus (RN) and dentate nucleus (DN). Nineteen healthy subjects underwent resting-state fMRI and susceptibility weighted imaging (SWI). For the brain network analysis, the SN, RN and DN were positioned on susceptibility weighted images and used as seeds for temporal correlations analyzed via BOLD data. T-tests were performed for the correlation coefficients of each seed. We demonstrated that the SN, RN and DN were functionally connected to each other, and, in general, their connectivity maps overlapped in a series of subcortical extrapyramidal structures and regions of cerebral cortices. A Granger causality analysis indicated that the effective connectivity graphs within extrapyramidal structures mainly exhibited a spacial up-down pattern for the positive and negative influences, respectively. Our findings suggest that extensive regions involved in the extrapyramidal system constituted a relatively exclusive network via spatial-temporal correlation signals that analogously corresponded to the anatomical structures. The investigation of extrapyramidal system networks may have potential clinical implications.

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.

Noradrenergic modulation of glutamate-induced excitatory responses in single neurons of the red nucleus: an electrophysiological study.

The effect induced by noradrenaline (NA) on the spiking activity evoked by glutamate (Glu) on single neurons of the mesencephalic red nucleus (RN) of the rat was studied extracellularly. Long-lasting microiontophoretic applications of the amine induced a significant and reversible depression of the responsiveness of RN neurons to Glu. This effect was mediated by noradrenergic alpha2 receptors since it was mimicked by application of clonidine, an alpha2 adrenoceptor agonist, and blocked or at least reduced by application of yohimbine, an antagonist of NA for the same receptors. The effect appears homogeneously throughout the nucleus and is independent of the effect of NA on baseline firing rate. Application of isoproterenol, a beta adrenoceptor agonist, either enhanced or depressed neuronal responses to Glu in a high percentage (86%) of the tested neurons. Moreover, application of timolol, a beta adrenoceptor antagonist, was able to strengthen the depressive effects induced by NA application on neuronal responsiveness to Glu. Although these data suggest some involvement of beta adrenergic receptors in the modulation of neuronal responsiveness to Glu, the overall results indicate a short-term depressive action of NA, mediated by alpha2 receptors, on the responsiveness of RN neurons and suggest that stress initially leads to an attenuation of the relay function of the RN.