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The release of endogenous gamma-aminobutyric acid (GABA) from the cat red nucleus was studied in a slice preparation. Potassium-induced depolarization caused a release of GABA in a calcium-dependent manner. The release of GABA was also induced by veratrine and blocked by tetrodotoxin. The demonstration of release satisfies one of the important criteria for identification of GABA as the inhibitory neurotransmitter.
The intrinsic organization of the red nucleus (RN) was studied in the mouse using the rapid Golgi method. Cytoarchitecturally, the RN was divided into the magnocellular (RNmc) and parvocellular parts (RNpc). The former occupied the caudal one-third and the latter formed the rostral two-thirds of the RN. Based primarily on the size of somata, the RN neurons were classified into four types: giant, large, medium-sized and small neurons. Of these, the former two types of neurons were distributed mainly in the RNmc, while the latter two types of neurons were seen mainly in the RNpc. Axons of the RN neurons, at least those of the former three types of neurons, ran medially or caudomedially. Some axons ran across the mesencephalic raphe region to be lost in the medial region of the contralateral tegmentum. Two groups of afferent fibers to the RN were distinguished. Group I afferents were fibers composing the superior cerebellar peduncle. After crossing in the decussation of the superior cerebellar peduncle, these fibers entered the RN from the caudomedial aspect, ran rostrally in the nucleus emitting numerous collaterals. Group II afferents reached the RN from the ventrolateral aspect and traveled mediodorsally to be distributed totally within this nucleus.
The magnocellular red nucleus (RNm) becomes highly active when a monkey reaches to grasp an object. However, the only spike-triggered averaging studies of the RNm to date have been restricted to a simple wrist tracking paradigm and electromyographic (EMG) measurements of muscles of the forearm. We have now measured EMG signals from a large number of muscles throughout the shoulder, arm, forearm, and hand during a variety of tasks, including unconstrained reaching and grasping movements. Relations between these EMG signals and single-unit activity were assessed by on-line spike-triggered averaging and revealed significant post-spike effects among muscles of the shoulder and proximal arm, as well as intrinsic hand muscles. Although there remained a strong bias toward the extensor muscles of the forearm, as has been shown earlier, these results reinforce the importance of the RNm in the control of coordinated, whole-limb reaching movements.
Single cells were recorded in the magnocellular red nucleus (RNm) of two cynomolgus monkeys using tungsten microelectrodes. The first monkey was trained to press finger switches and to operate a push-pull device. Comparison of responses while operating the two devices demonstrated a strong distal bias. The finger device elicited large modulations in discharge (greater than or equal to 50 impulses/s) in 75% of the sampled neurons. Most cells fired optimally during thumb switch operation, but also fired vigorously in association with other switch operations. The left motor cortex was removed from the second monkey 18 months prior to microelectrode recording. Cells in the cortically denervated RNm discharged vigorously in association with grouped finger movements that opened and closed the affected right hand. These results coupled with our previous findings suggest that the RNm is preferentially linked to distal limb muscles, and the primary role of the forelimb zone may be to control coordinated hand function including grouped movements of the fingers.
The maturing large neurons of the rat red nucleus in animals ranging in age from 1 to 21 days of postnatal life were studied ultrastructurally. Days 1--6 were characterized by rapid morphologic maturation occurring concomitantly with the onset of synaptogenesis. Morphogenesis was confined to the soma, while the first synaptic contacts were also formed in relationship to the soma. Days 6--9 demonstrated continued somal morphogenesis exemplified by cytoplasmic expansion and by the conspicuous presence of perisomatic and growth cone processes. Proximal dendritic morphogenesis was initiated, and synaptogenesis became complex with synaptic sites occurring in relation to the neuronal soma, the perisomatic processes and proximal dendrites. Days 9--15 were characterized by the completion of somal and proximal dendritic morphogenesis and by a massive degree of synaptogenic activity. During this interval, the soma lost perisomatic and growth cone processes, while somatic spines appeared. By the end of this period the neuronal soma and the proximal dendrites appeared mature in terms of both morphology and synaptic input. Complete neuronal maturation was ultimately attained by day 21 of postnatal life.
Unilateral transection of the rubrospinal tract before lesion of the red nucleus or the ventrolateral thalamic nucleus has been shown to facilitate recovery of operantly conditioned reflexes and compensatory processes in rats. Such strengthening of the recovery plasticity and operantly conditioned was found when transection of the bulbar pyramide performed before ablation of the sensorimotor cortex. These influences are explained by activation of the rubroolivary projection, which is switching of descending cortico-rubrospinal system on the corticospinal system, and on the contrary. The general property of this phenomenon is that preliminary lesion of the peripheral part of the descending spinal projection to acquire a signal forestalling significance for mibilization of compensatory brain capacity in order to recovery the deficit of central link of the system.
Since the rubro-olivary projection has not been demonstrated in the rat, unlike the monkey and cat (refs. in text). HRP or highly-concentrated wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected into the inferior olivary nucleus using a ventral approach. After processing with a modified technique, sections were examined under high power. Three rats injected with WGA-HRP showed labelling in the red nucleus. In one of those rats with a well-confined injection, 583 neurons contained grains of HRP reaction product consistent with light retrograde labeling. This observation lends support to the existence of a rubro-olivary projection in the rat.
Intracellular records were obtained from neurons in the region of the red nucleus (RN) of cat brain slices. Both EPSPs and IPSPs were recorded in response to local electrical stimulation and these resembled similar electrophysiological responses observed in experiments conducted in vivo. Monosynaptic and polysynaptic IPSPs were observed, suggesting the existence of inhibitory interneurons near or within the RN region. When added to the bathing solution, L-glutamate and L-aspartate depolarized RN neurons with a decrease in input resistance. gamma-Aminobutyric acid (GABA) and glycine hyperpolarized the cells with a decrease in input resistance. GABA also elicited a depolarizing response. These amino acid actions had direct postsynaptic effects, since the experiments were conducted in a low Ca2+/high Mg2+ medium which blocked synaptic transmission.
In a previous study, we have shown that electrical and chemical stimulation of the red nucleus (RN) facilitates the jaw-opening reflex (JOR). The RN sends projection fibers bilaterally, with contralateral dominance, to the part of the parvicellular reticular formation (RFp) containing premotor neurons projecting to the trigeminal motor nucleus. This implies that RN-induced facilitation of the JOR might be mediated via last-order neurons in the RFp. Here, we address this issue by investigating whether microinjection of lidocaine or l-glutamate into the RFp affects RN-induced modulation of the JOR. Experiments were performed on rats anesthetized with urethane-chloralose. The JOR was evoked by electrical stimulation of the inferior alveolar (IA) nerve and was recorded as an electromyographic response from the anterior belly of the digastric muscle. Conditioning stimulation was delivered unilaterally to the RN 12 ms before the IA test stimulation. We found that local injections of 2% lidocaine (0.5 microl) into the RFp, contralateral to the RN, significantly (P < 0.05) reduce RN-induced facilitation of the JOR, whereas corresponding injections of 0.1 mM l-glutamate (0.5 microl) significantly (P < 0.05) increase it. These results suggest that the facilitatory effect of RN stimulation on the JOR is mediated partly by a relay in the RFp.
The effects of 5-hydroxytryptamine (5-HT) on the responses of red nucleus (RN) neurones to glutamate (glu) and its agonists were studied using a microiontophoretic technique in anaesthetised rats. Extracellular unitary recordings of RN neuronal activity showed that 5-HT application induced a significant and reversible depression of glu-evoked excitations in 85% of the RN units tested. This effect was independent of the action of the amine on background firing, which appeared enhanced in the majority of cases but was either depressed or uninfluenced in other cases. Microiontophoretic 5-HT also depressed the excitatory responses evoked in RN neurones by electrical stimulation of sensorimotor cortex. Methysergide application, which prevented the enhancing effects of 5-HT on the background firing, was scarcely effective in antagonising the depression of glu responses. In contrast, the serotonergic effects on the glu responses were reduced by the iontophoretically applied antagonist of 5-HT1A receptors, NAN-190. Microiontophoretic 5-HT was also able to influence the neuronal responses evoked by glu agonists quisqualate (quis) and N-methyl-D-aspartate (NMDA), acting on non-NMDA and NMDA receptors respectively. In fact 5-HT depressed quis-evoked excitations and induced mixed effects on NMDA responses, which were reduced in 45%, enhanced in 34% and unmodified in 21% of the units tested. These results suggest that 5-HT is able to modulate the motor glutamatergic input to RN by acting mostly on non-NMDA receptors. The modulation of non-NMDA and NMDA receptors by 5-HT in the RN appears significant and its functional meaning is discussed.
Ex vivo gene therapy, utilizing modified fibroblasts that deliver BDNF or NT-3 to the acutely injured spinal cord, has been shown to elicit regeneration and recovery of function in the adult rat. Delayed grafting into the injured spinal cord is of great clinical interest as a model for treatment of chronic injury but may pose additional obstacles that are not present after acute injury, such as the need to remove an established scar, increased retrograde cell loss and/or atrophy, and diminished capacity for regeneration by neurons which may be doubly injured. The purpose of the present study was to determine if delayed grafting of neurotrophin secreting fibroblasts would have anatomical effects similar to those seen in acute grafting models. We grafted a mixture of BDNF and NT-3 producing fibroblasts or control fibroblasts into a complete unilateral cervical hemisection after a 6-week delay. Fourteen weeks after delayed grafting we found that both the neurotrophin secreting fibroblasts and control fibroblasts survived, but that only the neurotrophin secreting grafts provided a permissive environment for host axon growth, as indicated by immunostaining for RT-97, a marker for axonal neurofilaments, GAP-43, a marker for elongating axons, CGRP, a marker for dorsal root axons, and 5-HT, a marker for raphe spinal axons, within the graft. Anterograde tracing of the uninjured vestibulospinal tract showed growth into neurotrophin producing transplants but not into control grafts, while anterograde tracing of the axotomized rubrospinal tract showed a small number of regenerating axons within the genetically modified grafts, but none in control grafts. The neurotrophin expressing grafts, but not the control grafts, significantly reduced retrograde degeneration and atrophy in the injured red nucleus. Grafts of BDNF + NT-3 expressing fibroblasts delayed 6 weeks after injury therefore elicit growth from intact segmental and descending spinal tracts, stimulate modest regenerative growth by rubrospinal axons, and partially rescue axotomized supraspinal neurons and protect them from atrophy. The regeneration of rubrospinal axons into delayed transplants was much less than has been observed when similar transplants were placed acutely into a lateral funiculus or, after a 4-week delay, into a hemisection lesion. This suggests that the regenerative capacity of chronically injured red nucleus neurons was markedly diminished. The increased GAP43 reactivity in the corticospinal tracts ipsilaterally and contralaterally to the combination grafts suggests that these axons remain responsive to the neurotrophins, that the neurotrophins may stimulate both regenerative and sprouting responses, and that the grafted cells continue to secrete the neurotrophins.
In anesthetized and immobilized cats, dichotic stimulation revealed a high sensitivity of red nucleus (RN) neurons to interaural difference in time (83% of neurons) and intensity (82% of neurons) of stimulation. Percentage of the NR neurons (71%) altering their their activity in response to signals simulating movements of the sound source in horizontal plane, was higher than in centers of the auditory system. Utilization of the acoustic information by the NR neurons for organization of movement elements of the localization behaviour, is discussed.
The experiments were performed on cats under pentobarbital anesthesia. The following results were obtained. (1) Most of the neurons in the rostral part of the red nucleus (RN) were activated by stimulation of the parietal association cortex (P) and the lateral cerebellar nucleus (CN). A number of the neurons were regarded as rubro-olivary since they responded antidromically to inferior olive (IO) stimulation. (2) Stimulation of the P as well as the frontal motor cortex activated IO neurons. A longer and more variable latency in P-induced responses indicated the existence of an indirect connection from the P to the IO. The recording sites for P-induced responses were located in the rostral region of the IO, giving off projection fibers to the cerebellar hemispheral part. After horseradish peroxidase (HRP) injection through recording microelectrodes into the IO where P-induced responses were recorded, small cells labeled retrogradely with HRP were found distributed in the rostral part of the RN. (3) Effects of stimulus to or lesion of the rostral part of the RN revealed that the climbing fiber responses to P stimulation were conveyed through the rubro-olivary pathway originating in the rostral part of the RN. (4) Following HRP injection through recording electrodes into the rostral part of the RN where P-induced responses were recorded, retrogradely labeled cells were seen and located in the P and CN. From these findings, the rostral part of the RN investigated in this study could be regarded as the rubral parvocellular part. The present study suggests that the latero (dentato-)-rubro-olivo-cerebellar circuit forms an internal feedback loop and the P acts on this loop.
OBJECTIVE: To analyze the morphology, cytoarchitecture, and lumbosacral spinal cord projections of the red nucleus (RN) in cattle. ANIMALS: 8 healthy Friesian male calves. PROCEDURES: Anesthetized calves underwent a dorsal laminectomy at L5. Eight bilateral injections (lateral to the midline) of the neuronal retrograde fluorescent tracer fast blue (FB) were administered into the exposed lumbosacral portion of the spinal cord. A postsurgical calf survival time of 38 to 55 days was used. Following euthanasia, the midbrain and the L5-S2 spinal cord segments were removed. Nissl's method of staining was applied on paraffin-embedded and frozen sections of the midbrain. RESULTS: The mean length of the RN from the caudal to cranial end ranged from 6,680 to 8,640 microm. The magnocellular and parvicellular components of the RN were intermixed throughout the nucleus, but the former predominate at the caudal portion of the nucleus and the latter at the cranial portion with a gradual transitional zone. The FB-labeled neurons were found along the entire craniocaudal extension of the nucleus, mainly in its ventrolateral part. The number of FB-labeled neurons was determined in 4 calves, ranging from 191 to 1,469 (mean, 465). The mean cross-sectional area of the FB-labeled neurons was approximately 1,680 microm2. CONCLUSIONS AND CLINICAL RELEVANCE: In cattle, small, medium, and large RN neurons, located along the entire craniocaudal extension of the RN, contribute to the rubrospinal tract reaching the L6-S1 spinal cord segments. Thus, in cattle, as has been shown in cats, the RN parvicellular population also projects to the spinal cord.
The effects of microiontophoretic 5-hydroxytryptamine (5-HT) on the firing rate of red nucleus (RN) neurons were studied in urethane-anesthetized rats. The background discharge rate of almost all the neurons tested (97%) was modified by 5-HT, and generally increased (89%). Responses were dose dependent. Twenty-three percent of the excitatory responses were preceded by a short inhibitory phase. No significant difference in the effect of 5-HT was found between those RN neurons that project to the spinal cord and those that do not The excitatory responses to 5-HT were blocked or greatly reduced by the 5-HT antagonists methysergide and ketanserin, and were even reversed in some cases. The 5-HT2/5-HT1A antagonist spiperone, in small doses, also blocked the transient inhibitory phases in addition to the excitatory effects. In RN neurons exhibiting a short-lasting inhibition in the response to 5-HT, the 5-HT1A agonist 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT) induced inhibitory effects. These results support the hypothesis that 5-HT exerts control throughout the RN, mostly by acting on 5-HT2 receptors. Furthermore, an influence of this amine on the electrical activity of small groups of RN neurons by 5-HT1A receptors, and eventually by different mechanisms, appears probable. The functional significance of serotoninergic control of RN neuronal activity is discussed.
The effects of benzodiazepine receptor agonists on the electrical activity of red nucleus (RN) and neocortex were studied in rabbits. Under basal conditions, 30-40 microV, 40-50 Hz waves were recorded in RN. An increase of the amplitude (Emax, 75-90 microV) was found after IV injection of flunitrazepam (ED50, 0.14 mg/kg), diazepam (ED50, 0.28 mg/kg), alpidem (ED50, 1.57 mg/kg) and zolpidem (ED50, 0.73 mg/kg). Clonazepam (ED50, 0.12 mg/kg) and Cl 218,872 (ED50, 0.63 mg/kg) were less effective. In contrast, 2-10-fold higher doses were required to induce a slight decrease of the frequency. At the level of the cortex all benzodiazepine agonists induced synchronization and spindles. The effects of diazepam (5 mg/kg IV) in both areas were antagonized by flumazenil (0.04 mg/kg IV) and bicuculline (0.2 mg/kg IV). Pentamethylentetrazole (10-30 mg/kg IV) selectively abated the effect at the level of the cortex, whereas both clonazepam (2 mg/kg IV) and beta-CCM (0.6 mg/kg IV) selectively suppressed only the effects on the RN. These results suggest that activation of benzodiazepine receptor mainly influences the RN waves amplitude. The efficacy in increasing the amplitude appears related to the reported relative efficacy of the compound in potentiating GABA responses. The possibility exists that these effects are dependent upon the partial or full agonist action of the drugs or upon their binding at distinct benzodiazepine receptor types.
The long-term effects of the inferior olive destruction on the red nucleus activity, were studied in the rat following injection of 3-acetylpyridine. As soon as the olivary activity was suppressed, the discharge of the rubral units drastically decreased. Then, they progressively recovered the control frequency during the first month, although a normal rubral activity was not restored up to 8 months. The hypothesis is advanced that the olivocerebellar system is essential to shape the activity of the rubrospinal pathway.
We studied the dynamical relationship between magnocellular red nucleus (RNm) discharge and electromyographic (EMG) activity of 10-15 limb muscles in two monkeys during voluntary limb movement. Recordings were made from 158 neurons during two different kinds of limb movement tasks. One was a tracking task in which the subjects were required to acquire targets displayed on an oscilloscope by rotating one of six different single degree of freedom manipulanda. During this task, we recorded the angular position of the manipulandum. The monkeys also were trained in several free-form food-retrieval tasks that were much less constrained mechanically. There was generally significantly greater neuronal discharge during the free-form tasks than during the tracking task. During both types of tasks, cross-correlation and impulse response functions calculated between RNm and EMG were predominantly pulse-shaped, indicating that the dynamics of the RNm discharge were very similar to those of the muscle activity. There was no evidence during either task for a substantial dynamical transformation (e.g., integration) between the two signals as had been previously suggested. In only 15% of the cases, did these correlations have step or pulse-step dynamics. There was a relatively broad, unimodal distribution of lag times between RNm and EMG, based on the time of occurrence of the peak correlation. During tracking, the mode of this distribution was approximately 50 ms, with 80% of the lags falling between -100 and 200 ms. During the free-form task, the mode was between 0 and 20 ms, with 65% of the lags between -100 and 200 ms. A positive lag indicates that RNm discharge preceded EMG. The shape and timing of both the cross-correlation and the impulse response functions were consistent with a model in which many RNm neurons contribute mutually correlated signals which are simply summed within the spinal cord to produce a muscle activation signal.