Lumbar V3 interneurons provide direct excitatory synaptic input onto thoracic sympathetic preganglionic neurons, linking locomotor, and autonomic spinal systems.

Although sympathetic autonomic systems are activated in parallel with locomotion, the neural mechanisms mediating this coordination are incompletely understood. Sympathetic preganglionic neurons (SPNs), primarily located in the intermediate laminae of thoracic and upper lumbar segments (T1-L2), increase activation of tissues and organs that provide homeostatic and metabolic support during movement and exercise. Recent evidence suggests integration between locomotor and autonomic nuclei occurs within the brainstem, initiating both descending locomotor and sympathetic activation commands. However, both locomotor and sympathetic autonomic spinal systems can be activated independent of supraspinal input, in part due to a distributed network involving propriospinal neurons. Whether an intraspinal mechanism exists to coordinate activation of these systems is unknown. We hypothesized that ascending spinal neurons located in the lumbar region provide synaptic input to thoracic SPNs. Here, we demonstrate that synaptic contacts from locomotor-related V3 interneurons (INs) are present in all thoracic laminae. Injection of an anterograde tracer into lumbar segments demonstrated that 8-20% of glutamatergic input onto SPNs originated from lumbar V3 INs and displayed a somatotopographical organization of synaptic input. Whole cell patch clamp recording in SPNs demonstrated prolonged depolarizations or action potentials in response to optical activation of either lumbar V3 INs in spinal cord preparations or in response to optical activation of V3 terminals in thoracic slice preparations. This work demonstrates a direct intraspinal connection between lumbar locomotor and thoracic sympathetic networks and suggests communication between motor and autonomic systems may be a general function of the spinal cord.

Spinal control of locomotion before and after spinal cord injury.

Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.

A fresh look at propriospinal interneurons plasticity and intraspinal circuits remodeling after spinal cord injury.

Spinal cord injury (SCI) disrupts communication between the brain-derived descending commands and the intraspinal circuits, the central pattern generator (CPG), that execute movements. Dynamic changes in the interaction of the brain-spinal cord as well as in structure-function relationships play a vital role in the determination of neurological function restoration. These changes also have important clinical implications for the treatment of patients with SCI. After SCI, at both brain and spinal cord levels, detour circuits formation and neuronal plasticity have been linked to functional improvement under the condition of spontaneous recovery as well as electrical stimulation- and rehabilitative training-assisted recovery. The principles governing neural circuit remodeling and the neuronal subtypes specifically involved during the recovery from SCI are largely unknown. In the present review, we focus on how multi-level neural circuits are reconstructed after SCI. We highlight some new studies using rodent and zebrafish SCI models that describe how the intraspinal detour circuits are reconstructed and the important roles of spinal excitatory interneurons.

Corticospinal circuit neuroplasticity may involve silent synapses: Implications for functional recovery facilitated by neuromodulation after spinal cord injury.

Spinal cord injury (SCI) leads to devastating physical consequences, such as severe sensorimotor dysfunction even lifetime disability, by damaging the corticospinal system. The conventional opinion that SCI is intractable due to the poor regeneration of neurons in the adult central nervous system (CNS) needs to be revisited as the CNS is capable of considerable plasticity, which underlie recovery from neural injury. Substantial spontaneous neuroplasticity has been demonstrated in the corticospinal motor circuitry following SCI. Some of these plastic changes appear to be beneficial while others are detrimental toward locomotor function recovery after SCI. The beneficial corticospinal plasticity in the spared corticospinal circuits can be harnessed therapeutically by multiple contemporary neuromodulatory approaches, especially the electrical stimulation-based modalities, in an activity-dependent manner to improve functional outcomes in post-SCI rehabilitation. Silent synapse generation and unsilencing contribute to profound neuroplasticity that is implicated in a variety of neurological disorders, thus they may be involved in the corticospinal motor circuit neuroplasticity following SCI. Exploring the underlying mechanisms of silent synapse-mediated neuroplasticity in the corticospinal motor circuitry that may be exploited by neuromodulation will inform a novel direction for optimizing therapeutic repair strategies and rehabilitative interventions in SCI patients.

The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice.

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. The V3 neurons are known to be involved in interlimb coordination. We previously modeled the locomotor spinal circuitry controlling interlimb coordination (Danner et al., 2017). This model included the local V3 neurons that mediate mutual excitation between left and right rhythm generators (RGs). Here, our focus was on V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used a lateral-sequence walk. To reproduce this data and understand the functional roles of V3 aLPNs, we extended our previous model by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The extended model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left-right interactions within lumbar and cervical cords, promote left-right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.

Double viral vector intersectional approaches for pathway-selective manipulation of motor functions and compensatory mechanisms.

Selective manipulation of particular subcomponent of neural circuits is crucial for understanding the functional architecture of neural systems and for development of the future therapeutic strategies against neurological disorders. In this article, I review how the intersectional approaches with double viral vector technique was introduced for the pathway-selective manipulation of spinal circuits. In this technique, a retrograde gene transfer vector is injected into the terminal area of the targeted neurons and an anterograde vector is injected at the location of their somata. Either by using the Tet-transactivator or Cre-loxP system, the experimenter can chemogenetically or optogenetically manipulate the transmission of the target pathway originated from the double-infected neurons. This technique was first developed for manipulation of spinal cord interneurons in the macaque monkeys by selective expression of tetanus neurotoxin and successfully affected the dexterous hand movements. Currently, this technique is widely used on a variety of neural pathways both in rodents and primates in combination with a variety of retrograde vectors and a variety of optogenetic and chemogenetic tools. The advantage of this technique is that it is not necessary to generate transgenic animals. Knowledge of the cell-type specific promotors is not needed. Manipulation is achieved primarily by injection of two viral vectors based on the anatomical knowledge and it is applicable in a variety of animal species including primates. The pros, cons and future direction of this technique are discussed.

Silencing long ascending propriospinal neurons after spinal cord injury improves hindlimb stepping in the adult rat.

Long ascending propriospinal neurons (LAPNs) are a subpopulation of spinal cord interneurons that directly connect the lumbar and cervical enlargements. Previously we showed, in uninjured animals, that conditionally silencing LAPNs disrupted left-right coordination of the hindlimbs and forelimbs in a context-dependent manner, demonstrating that LAPNs secure alternation of the fore- and hindlimb pairs during overground stepping. Given the ventrolateral location of LAPN axons in the spinal cord white matter, many likely remain intact following incomplete, contusive, thoracic spinal cord injury (SCI), suggesting a potential role in the recovery of stepping. Thus, we hypothesized that silencing LAPNs after SCI would disrupt recovered locomotion. Instead, we found that silencing spared LAPNs post-SCI improved locomotor function, including paw placement order and timing, and a decrease in the number of dorsal steps. Silencing also restored left-right hindlimb coordination and normalized spatiotemporal features of gait such as stance and swing time. However, hindlimb-forelimb coordination was not restored. These data indicate that the temporal information carried between the spinal enlargements by the spared LAPNs post-SCI is detrimental to recovered hindlimb locomotor function. These findings are an illustration of a post-SCI neuroanatomical-functional paradox and have implications for the development of neuronal- and axonal-protective therapeutic strategies and the clinical study/implementation of neuromodulation strategies.

Long ascending propriospinal neurons provide flexible, context-specific control of interlimb coordination.

Within the cervical and lumbar spinal enlargements, central pattern generator (CPG) circuitry produces the rhythmic output necessary for limb coordination during locomotion. Long propriospinal neurons that inter-connect these CPGs are thought to secure hindlimb-forelimb coordination, ensuring that diagonal limb pairs move synchronously while the ipsilateral limb pairs move out-of-phase during stepping. Here, we show that silencing long ascending propriospinal neurons (LAPNs) that inter-connect the lumbar and cervical CPGs disrupts left-right limb coupling of each limb pair in the adult rat during overground locomotion on a high-friction surface. These perturbations occurred independent of the locomotor rhythm, intralimb coordination, and speed-dependent (or any other) principal features of locomotion. Strikingly, the functional consequences of silencing LAPNs are highly context-dependent; the phenotype was not expressed during swimming, treadmill stepping, exploratory locomotion, or walking on an uncoated, slick surface. These data reveal surprising flexibility and context-dependence in the control of interlimb coordination during locomotion.

EphA4 Is Required for Neural Circuits Controlling Skilled Reaching.

Skilled forelimb movements are initiated by feedforward motor commands conveyed by supraspinal motor pathways. The accuracy of reaching and grasping relies on internal feedback pathways that update ongoing motor commands. In mice lacking the axon guidance molecule EphA4, axonal misrouting of the corticospinal tract and spinal interneurons is manifested, leading to a hopping gait in hindlimbs. Moreover, mice with a conditional forebrain deletion of EphA4, display forelimb hopping in adaptive locomotion and exploratory reaching movements. However, it remains unclear how loss of EphA4 signaling disrupts function of forelimb motor circuit and skilled reaching and grasping movements. Here we investigated how neural circuits controlling skilled reaching were affected by the loss of EphA4. Both male and female C57BL/6 wild-type, heterozygous EphA4+/-, and homozygous EphA4-/- mice were used in behavioral and in vivo electrophysiological investigations. We found that EphA4 knock-out (-/-) mice displayed impaired goal-directed reaching movements. In vivo intracellular recordings from forelimb motor neurons demonstrated increased corticoreticulospinal excitation, decreased direct reticulospinal excitation, and reduced direct propriospinal excitation in EphA4 knock-out mice. Cerebellar surface recordings showed a functional perturbation of the lateral reticular nucleus-cerebellum internal feedback pathway in EphA4 knock-out mice. Together, our findings provide in vivo evidence at the circuit level that loss of EphA4 disrupts the function of both feedforward and feedback motor pathways, resulting in deficits in skilled reaching.SIGNIFICANCE STATEMENT The central advances of this study are the demonstration that null mutation in the axon guidance molecule EphA4 gene impairs the ability of mice to perform skilled reaching, and identification of how these behavioral deficits correlates with discrete neurophysiological changes in central motor pathways involved in the control of reaching. Our findings provide in vivo evidence at the circuit level that loss of EphA4 disrupts both feedforward and feedback motor pathways, resulting in deficits in skilled reaching. This analysis of motor circuit function may help to understand the pathophysiological mechanisms underlying movement disorders in humans.

Music Restores Propriospinal Excitation During Stroke Locomotion.

Music-based therapy for rehabilitation induces neuromodulation at the brain level and improves the functional recovery. In line with this, musical rhythmicity improves post-stroke gait. Moreover, an external distractor also helps stroke patients to improve locomotion. We raised the question whether music with irregular tempo (arrhythmic music), and its possible influence on attention would induce neuromodulation and improve the post-stroke gait. We tested music-induced neuromodulation at the level of a propriospinal reflex, known to be particularly involved in the control of stabilized locomotion; after stroke, the reflex is enhanced on the hemiparetic side. The study was conducted in 12 post-stroke patients and 12 controls. Quadriceps EMG was conditioned by electrical stimulation of the common peroneal nerve, which produces a biphasic facilitation on EMG, reflecting the level of activity of the propriospinal reflex between ankle dorsiflexors and quadriceps (CPQ reflex). The CPQ reflex was tested during treadmill locomotion at the preferred speed of each individual, in 3 conditions randomly alternated: without music vs. 2 arrhythmic music tracks, including a pleasant melody and unpleasant aleatory electronic sounds (AES); biomechanical and physiological parameters were also investigated. The CPQ reflex was significantly larger in patients during walking without sound, compared to controls. During walking with music, irrespective of the theme, there was no more difference between groups. In controls, music had no influence on the size of CPQ reflex. In patients, CPQ reflex was significantly larger during walking without sound than when listening to the melody or AES. No significant differences have been revealed concerning the biomechanical and the physiological parameters in both groups. Arrhythmic music listening modulates the spinal excitability during post-stroke walking, restoring the CPQ reflex activity to normality. The plasticity was not accompanied by any clear improvement of gait parameters, but the patients reported to prefer walking with music than without. The role of music as external focus of attention is discussed. This study has shown that music can modulate propriospinal neural network particularly involved in the gait control during the first training session. It is speculated that repetition may help to consolidate plasticity and would contribute to gait recovery after stroke.

Propriospinal Neurons: Essential Elements of Locomotor Control in the Intact and Possibly the Injured Spinal Cord.

Propriospinal interneurons (INs) communicate information over short and long distances within the spinal cord. They act to coordinate different parts of the body by linking motor circuits that control muscles across the forelimbs, trunk, and hindlimbs. Their role in coordinating locomotor circuits near and far may be invaluable to the recovery of locomotor function lost due to injury to the spinal cord where the flow of motor commands from the brain and brainstem to spinal motor circuits is disrupted. The formation and activation of circuits established by spared propriospinal INs may promote the re-emergence of locomotion. In light of progress made in animal models of spinal cord injury (SCI) and in human patients, we discuss the role of propriospinal INs in the intact spinal cord and describe recent studies investigating the assembly and/or activation of propriospinal circuits to promote recovery of locomotion following SCI.

Dexterous Hand Movements and Their Recovery After Central Nervous System Injury.

Hand dexterity has uniquely developed in higher primates and is thought to rely on the direct corticomotoneuronal (CM) pathway. Recent studies have shown that rodents and carnivores lack the direct CM pathway but can control certain levels of dexterous hand movements through various indirect CM pathways. Some homologous pathways also exist in higher primates, and among them, propriospinal (PrS) neurons in the mid-cervical segments (C3-C4) are significantly involved in hand dexterity. When the direct CM pathway was lesioned caudal to the PrS and transmission of cortical commands to hand motoneurons via the PrS neurons remained intact, dexterous hand movements could be significantly recovered. This recovery model was intensively studied, and it was found that, in addition to the compensation by the PrS neurons, a large-scale reorganization in the bilateral cortical motor-related areas and mesolimbic structures contributed to recovery. Future therapeutic strategies should target these multihierarchical areas.

Effect of lesion proximity on the regenerative response of long descending propriospinal neurons after spinal transection injury.

BACKGROUND: The spinal cord is limited in its capacity to repair after damage caused by injury or disease. However, propriospinal (PS) neurons in the spinal cord have demonstrated a propensity for axonal regeneration after spinal cord injury. They can regrow and extend axonal projections to re-establish connections across a spinal lesion. We have previously reported differential reactions of two distinct PS neuronal populations-short thoracic propriospinal (TPS) and long descending propriospinal tract (LDPT) neurons-following a low thoracic (T10) spinal cord injury in a rat model. Immediately after injury, TPS neurons undergo a strong initial regenerative response, defined by the upregulation of transcripts to several growth factor receptors, and growth associated proteins. Many also initiate a strong apoptotic response, leading to cell death. LDPT neurons, on the other hand, show neither a regenerative nor an apoptotic response. They show either a lowered expression or no change in genes for a variety of growth associated proteins, and these neurons survive for at least 2 months post-axotomy. There are several potential explanations for this lack of cellular response for LDPT neurons, one of which is the distance of the LDPT cell body from the T10 lesion. In this study, we examined the molecular response of LDPT neurons to axotomy caused by a proximal spinal cord lesion. RESULTS: Utilizing laser capture microdissection and RNA quantification with branched DNA technology, we analyzed the change in gene expression in LDPT neurons following axotomy near their cell body. Expression patterns of 34 genes selected for their robust responses in TPS neurons were analyzed 3 days following a T2 spinal lesion. Our results show that after axonal injury nearer their cell bodies, there was a differential response of the same set of genes evaluated previously in TPS neurons after proximal axotomy, and LDPT neurons after distal axotomy (T10 spinal transection). The genetic response was much less robust than for TPS neurons after proximal axotomy, included both increased and decreased expression of certain genes, and did not suggest either a major regenerative or apoptotic response within the population of genes examined. CONCLUSIONS: The data collectively demonstrate that the location of axotomy in relation to the soma of a neuron has a major effect on its ability to mount a regenerative response. However, the data also suggest that there are endogenous differences in the LDPT and TPS neuronal populations that affect their response to axotomy. These phenotypic differences may indicate that different or multiple therapies may be needed following spinal cord injury to stimulate maximal regeneration of all PS axons.

An attempt to explain the Vojta therapy mechanism of action using the surface polyelectromyography in healthy subjects: A pilot study.

BACKGROUND: Rehabilitation according to Vojta is a neurophysiological method used to obtain reflex responses in muscles following stimulation of particular activation zones. OBJECTIVES: This study aims to objectively evaluate the muscular responses following stimulation according to Vojta's method. The possible routes of spinal transmission responsible for the phenomenon of muscle activation in upper and lower extremities are considered. METHODS: Polyelectromyographic (pEMG) recordings in the upper and lower extremities in healthy volunteers (N = 25; aged 24 ± 1 year) were performed to find out the possible routes of spinal transmission, responsible for muscle activation. The left acromion and right femoral epicondyle were stimulated by a Vojta therapist; pEMG recordings were made including the bilateral deltoid and rectus femoris muscles. RESULTS AND DISCUSSION: Following acromion stimulation, muscle activation was mostly expressed in the contralateral rectus femoris, rather than the contralateral deltoid and the ipsilateral rectus femoris muscles. After stimulation of the lower femoral epicondyle, the following order was observed: contra lateral deltoid, ipsilateral deltoid and the contra lateral rectus femoris muscle. One of the candidates responsible for the main crossed neural transmission involved in the Vojta therapy mechanism would be the long propriospinal tract neurons.

Corticospinal control from M1 and PMv areas on inhibitory cervical propriospinal neurons in humans.

Inhibitory propriospinal neurons with diffuse projections onto upper limb motoneurons have been revealed in humans using peripheral nerve stimulation. This system is supposed to mediate descending inhibition to motoneurons, to prevent unwilling muscle activity. However, the corticospinal control onto inhibitory propriospinal neurons has never been investigated so far in humans. We addressed the question whether inhibitory cervical propriospinal neurons receive corticospinal inputs from primary motor (M1) and ventral premotor areas (PMv) using spatial facilitation method. We have stimulated M1 or PMv using transcranial magnetic stimulation (TMS) and/or median nerve whose afferents are known to activate inhibitory propriospinal neurons. Potential input convergence was evaluated by studying the change in monosynaptic reflexes produced in wrist extensor electromyogram (EMG) after isolated and combined stimuli in 17 healthy subjects. Then, to determine whether PMv controlled propriospinal neurons directly or through PMv-M1 interaction, we tested the connectivity between PMv and propriospinal neurons after a functional disruption of M1 produced by paired continuous theta burst stimulation (cTBS). TMS over M1 or PMv produced reflex inhibition significantly stronger on combined stimulations, compared to the algebraic sum of effects induced by isolated stimuli. The extra-inhibition induced by PMv stimulation remained even after cTBS which depressed M1 excitability. The extra-inhibition suggests the existence of input convergence between peripheral afferents and corticospinal inputs onto inhibitory propriospinal neurons. Our results support the existence of direct descending influence from M1 and PMv onto inhibitory propriospinal neurons in humans, possibly though direct corticospinal or via reticulospinal inputs.

Computational modeling of spinal circuits controlling limb coordination and gaits in quadrupeds.

Interactions between cervical and lumbar spinal circuits are mediated by long propriospinal neurons (LPNs). Ablation of descending LPNs in mice disturbs left-right coordination at high speeds without affecting fore-hind alternation. We developed a computational model of spinal circuits consisting of four rhythm generators coupled by commissural interneurons (CINs), providing left-right interactions, and LPNs, mediating homolateral and diagonal interactions. The proposed CIN and diagonal LPN connections contribute to speed-dependent gait transition from walk, to trot, and then to gallop and bound; the homolateral LPN connections ensure fore-hind alternation in all gaits. The model reproduces speed-dependent gait expression in intact and genetically transformed mice and the disruption of hindlimb coordination following ablation of descending LPNs. Inputs to CINs and LPNs can affect interlimb coordination and change gait independent of speed. We suggest that these interneurons represent the main targets for supraspinal and sensory afferent signals adjusting gait.

Neural computational modeling reveals a major role of corticospinal gating of central oscillations in the generation of essential tremor.

Essential tremor, also referred to as familial tremor, is an autosomal dominant genetic disease and the most common movement disorder. It typically involves a postural and motor tremor of the hands, head or other part of the body. Essential tremor is driven by a central oscillation signal in the brain. However, the corticospinal mechanisms involved in the generation of essential tremor are unclear. Therefore, in this study, we used a neural computational model that includes both monosynaptic and multisynaptic corticospinal pathways interacting with a propriospinal neuronal network. A virtual arm model is driven by the central oscillation signal to simulate tremor activity behavior. Cortical descending commands are classified as alpha or gamma through monosynaptic or multisynaptic corticospinal pathways, which converge respectively on alpha or gamma motoneurons in the spinal cord. Several scenarios are evaluated based on the central oscillation signal passing down to the spinal motoneurons via each descending pathway. The simulated behaviors are compared with clinical essential tremor characteristics to identify the corticospinal pathways responsible for transmitting the central oscillation signal. A propriospinal neuron with strong cortical inhibition performs a gating function in the generation of essential tremor. Our results indicate that the propriospinal neuronal network is essential for relaying the central oscillation signal and the production of essential tremor.

Autophagy in long propriospinal neurons is activated after spinal cord injury in adult rats.

Spinal cord injury (SCI) is a common disease worldwide that causes permanent neuronal dysfunction without an effective treatment. Long propriospinal neurons (LPSNs) that are spared from injury play a key role in spontaneous recovery after SCI. Traumatic injury of the central nervous system can activate autophagy, which could be a target in the development of a new therapeutic strategy to prevent neuronal loss. Our research focused on whether autophagy is involved in the loss of LPSNs after introducing spinal cord injury in adult rats. Different sacrifice time points were chosen to characterize autophagy and apoptosis. Autophagy and a blocked autophagy flux reached their peaks at 3 d after injury, while apoptosis reached its peak at 7 d after injury when the number of LPSNs significantly decreased. Both autophagy and apoptosis contributed to the loss of LPSNs, and apoptosis was the main cause of cell death. However, autophagy may prevent programmed LPSN cell death (apoptosis), which could promote cell survival.

Coordinated alpha and gamma control of muscles and spindles in movement and posture.

Mounting evidence suggests that both α and γ motoneurons are active during movement and posture, but how does the central motor system coordinate the α-γ controls in these tasks remains sketchy due to lack of in vivo data. Here a computational model of α-γ control of muscles and spindles was used to investigate α-γ integration and coordination for movement and posture. The model comprised physiologically realistic spinal circuitry, muscles, proprioceptors, and skeletal biomechanics. In the model, we divided the cortical descending commands into static and dynamic sets, where static commands (α s and γ s ) were for posture maintenance and dynamic commands (α d and γ d ) were responsible for movement. We matched our model to human reaching movement data by straightforward adjustments of descending commands derived from either minimal-jerk trajectories or human EMGs. The matched movement showed smooth reach-to-hold trajectories qualitatively close to human behaviors, and the reproduced EMGs showed the classic tri-phasic patterns. In particular, the function of γ d was to gate the α d command at the propriospinal neurons (PN) such that antagonistic muscles can accelerate or decelerate the limb with proper timing. Independent control of joint position and stiffness could be achieved by adjusting static commands. Deefferentation in the model indicated that accurate static commands of α s and γ s are essential to achieve stable terminal posture precisely, and that the γ d command is as important as the α d command in controlling antagonistic muscles for desired movements. Deafferentation in the model showed that losing proprioceptive afferents mainly affected the terminal position of movement, similar to the abnormal behaviors observed in human and animals. Our results illustrated that tuning the simple forms of α-γ commands can reproduce a range of human reach-to-hold movements, and it is necessary to coordinate the set of α-γ descending commands for accurate and stable control of movement and posture.

The lateral reticular nucleus; integration of descending and ascending systems regulating voluntary forelimb movements.

Cerebellar control of movements is dependent on mossy fiber input conveying information about sensory and premotor activity in the spinal cord. While much is known about spino-cerebellar systems, which provide the cerebellum with detailed sensory information, much less is known about systems conveying motor information. Individual motoneurones do not have projections to spino-cerebellar neurons. Instead, the fastest route is from last order spinal interneurons. In order to identify the networks that convey ascending premotor information from last order interneurons, we have focused on the lateral reticular nucleus (LRN), which provides the major mossy fiber input to cerebellum from spinal interneuronal systems. Three spinal ascending systems to the LRN have been investigated: the C3-C4 propriospinal neurones (PNs), the ipsilateral forelimb tract (iFT) and the bilateral ventral flexor reflex tract (bVFRT). Voluntary forelimb movements involve reaching and grasping together with necessary postural adjustments and each of these three interneuronal systems likely contribute to specific aspects of forelimb motor control. It has been demonstrated that the command for reaching can be mediated via C3-C4 PNs, while the command for grasping is conveyed via segmental interneurons in the forelimb segments. Our results reveal convergence of ascending projections from all three interneuronal systems in the LRN, producing distinct combinations of excitation and inhibition. We have also identified a separate descending control of LRN neurons exerted via a subgroup of cortico-reticular neurones. The LRN projections to the deep cerebellar nuclei exert a direct excitatory effect on descending motor pathways via the reticulospinal, vestibulospinal, and other supraspinal tracts, and might play a key role in cerebellar motor control. Our results support the hypothesis that the LRN provides the cerebellum with highly integrated information, enabling cerebellar control of complex forelimb movements.