Nerve fibre regeneration across the peripheral–central transitional zone

Neurons cannot negotiate an elongation across the peripheral (PNS)–central nervous system (CNS) transitional zone and grow into or out of the spinal cord in the mature mammal. The astrocytic rich CNS part of the spinal nerve root is most effective in preventing regeneration even of nerve fibres from transplanted embryonic ganglion cells. Regeneration of severed nerve fibres into the spinal cord occurs when the transition zone is absent as in the immature animal. Before the establishment of a transition zone there is also new growth of neuronal processes from dorsal horn neurons distally to the injured dorsal root. Thus the experimental strategy to reestablish spinal cord to peripheral nerve connectivity has been to delete the transitional region and implant severed ventral or dorsal roots into the spinal cord. Dorsal root implantation resulted in reestablished afferent connectivity by new neuronal processes from secondary sensory neurons in the dorsal horn of the spinal cord extending into the PNS. The ability for plasticity in these cells allowed for a concurrent retention of their original rostral projection. Ventral root implantation into the spinal cord corrected deficit motor function. In a long series of experiments performed in different species, the functional restitution was demonstrated to depend on an initial regrowth of motor neuron axons through spinal cord tissue (CNS). These findings have led to the design of a new surgical strategy in cases of traumatic spinal nerve root injuries.     

EphrinB2 induces tyrosine phosphorylation of NR2B via Src-family kinases during inflammatory hyperalgesia

In recent years a role for EphB receptor tyrosine kinases and their ephrinB ligands in activity-dependent synaptic plasticity in the CNS has been identified. The aim of the present study was to test the hypothesis that EphB receptor activation in the adult rat spinal cord is involved in synaptic plasticity and processing of nociceptive inputs, through modulation of the function of the glutamate ionotropic receptor NMDA (N-methyl-D-aspartate). In particular, EphB receptor activation would induce phosphorylation of the NR2B subunit of the NMDA receptor by a Src family non-receptor tyrosine kinase. Intrathecal administration of ephrinB2-Fc in adult rats, which can bind to and activate EphB receptors and induce behavioral thermal hyperalgesia, led to NR2B tyrosine phosphorylation, which could be blocked by the Src family kinase inhibitor PP2. Furthermore animals pre-treated with PP2 did not develop behavioral thermal hyperalgesia following EphrinB2-Fc administration, suggesting that this pathway is functionally significant. Indeed, EphB1-Fc administration, which competes with the endogenous receptor for ephrinB2 binding and prevents behavioral allodynia and hyperalgesia in the carrageenan model of inflammation, also inhibited NR2B phosphorylation in this model. Taken together these findings support the hypothesis that EphB-ephrinB interactions play an important role in NMDA-dependent, activity-dependent synaptic plasticity in the adult spinal cord, inducing the phosphorylation of the NR2B subunit of the receptor via Src family kinases, thus contributing to chronic pain states.     

Probable corticospinal tract control of spinal cord plasticity in the rat

Descending activity from the brain shapes spinal cord reflex function throughout life, yet the mechanisms responsible for this spinal cord plasticity are poorly understood. Operant conditioning of the H-reflex, the electrical analogue of the spinal stretch reflex, is a simple model for investigating these mechanisms. An earlier study in the Sprague-Dawley rat showed that acquisition of an operantly conditioned decrease in the soleus H-reflex is not prevented by mid-thoracic transection of the ipsilateral lateral column (LC), which contains the rubrospinal, reticulospinal, and vestibulospinal tracts, and is prevented by transection of the dorsal column, which contains the main corticospinal tract (CST) and the dorsal column ascending tract (DA). The present study explored the effects of CST or DA transection on acquisition of an H-reflex decrease, and the effects of LC, CST, or DA transection on maintenance of an established decrease. CST transection prior to conditioning prevented acquisition of H-reflex decrease, while DA transection did not do so. CST transection after H-reflex decrease had been acquired led to gradual loss of the decrease over 10 days, and resulted in an H-reflex that was significantly larger than the original, naive H-reflex. In contrast, LC or DA transection after H-reflex decrease had been acquired did not affect maintenance of the decrease. These results, in combination with the earlier study, strongly imply that in the rat the corticospinal tract (CST) is essential for acquisition and maintenance of operantly conditioned decrease in the H-reflex and that other major spinal cord pathways are not essential. This previously unrecognized aspect of CST function gives insight into the processes underlying acquisition and maintenance of motor skills and could lead to novel methods for inducing, guiding, and assessing recovery of function after spinal cord injury.     

Plasticity from muscle to brain

Recognition that the entire central nervous system (CNS) is highly plastic, and that it changes continually throughout life, is a relatively new development. Until very recently, neuroscience has been dominated by the belief that the nervous system is hardwired and changes at only a few selected sites and by only a few mechanisms. Thus, it is particularly remarkable that Sir John Eccles, almost from the start of his long career nearly 80 years ago, focused repeatedly and productively on plasticity of many different kinds and in many different locations. He began with muscles, exploring their developmental plasticity and the functional effects of the level of motor unit activity and of cross-reinnervation. He moved into the spinal cord to study the effects of axotomy on motoneuron properties and the immediate and persistent functional effects of repetitive afferent stimulation. In work that combined these two areas, Eccles explored the influences of motoneurons and their muscle fibers on one another. He studied extensively simple spinal reflexes, especially stretch reflexes, exploring plasticity in these reflex pathways during development and in response to experimental manipulations of activity and innervation. In subsequent decades, Eccles focused on plasticity at central synapses in hippocampus, cerebellum, and neocortex. His endeavors extended from the plasticity associated with CNS lesions to the mechanisms responsible for the most complex and as yet mysterious products of neuronal plasticity, the substrates underlying learning and memory. At multiple levels, Eccles' work anticipated and helped shape present-day hypotheses and experiments. He provided novel observations that introduced new problems, and he produced insights that continue to be the foundation of ongoing basic and clinical research. This article reviews Eccles' experimental and theoretical contributions and their relationships to current endeavors and concepts. It emphasizes aspects of his contributions that are less well known at present and yet are directly relevant to contemporary issues.     

GABAergic and glycinergic interneuron expression during spinal cord development: Dynamic interplay between inhibition and excitation in the control of ventral network outputs

A key objective of neuroscience research is to understand the processes leading to mature neural circuitries in the central nervous system (CNS) that enable the control of different behaviours. During development, network-constitutive neurons undergo dramatic rearrangements, involving their intrinsic properties, such as the blend of ion channels governing their firing activity, and their synaptic interactions. The spinal cord is no exception to this rule; in fact, in the ventral horn the maturation of motor networks into functional circuits is a complex process where several mechanisms cooperate to achieve the development of motor control. Elucidating such a process is crucial in identifying neurons more vulnerable to degenerative or traumatic diseases or in developing new strategies aimed at rebuilding damaged tissue.The focus of this review is on recent advances in understanding the spatio-temporal expression of the glycinergic/GABAergic system and on the contribution of this system to early network function and to motor pattern transformation along with spinal maturation. During antenatal development, the operation of mammalian spinal networks strongly depends on the activity of glycinergic/GABAergic neurons, whose action is often excitatory until shortly before birth when locomotor networks acquire the ability to generate alternating motor commands between flexor and extensor motor neurons. At this late stage of prenatal development, GABA-mediated excitation is replaced by synaptic inhibition mediated by glycine and/or GABA. At this stage of spinal maturation, the large majority of GABAergic neurons are located in the dorsal horn. We propose that elucidating the role of inhibitory systems in development will improve our knowledge on the processes regulating spinal cord maturation.     

Nervous system reorganization following injury

Contrary to the classical view of a pre-determined wiring pattern, there is considerable evidence that cortical representation of body parts is continuously modulated in response to activity, behavior and skill acquisition. Both animal and human studies showed that following injury of the peripheral nervous system such as nerve injury or amputation, the somatosensory cortex that responded to the deafferented body parts become responsive to neighboring body parts. Similarly, there is expansion of the motor representation of the stump area following amputation. Reorganization of the sensory and motor systems following peripheral injury occurs in multiple levels including the spinal cord, brainstem, thalamus and cortex. In early-blind subjects, the occipital cortex plays an important role in Braille reading, suggesting that there is cross-modal plasticity. Functional recovery frequently occurs following a CNS injury such as stroke. Motor recovery from stroke may be associated with the adjacent cortical areas taking over the function of the damaged areas or utilization of alternative motor pathways. The ipsilateral motor pathway may mediate motor recovery in patients who undergo hemispherectomy early in life and in children with hemiplegic cerebral palsy, but it remains to be determined if it plays a significant role in the recovery of adult stroke. One of the challenges in stroke recovery is to identify which of the many neuroimaging and neurophysiological changes demonstrated are important in mediating recovery. The mechanism of plasticity probably differs depending on the time frame. Rapid changes in motor representations within minutes are likely due to unmasking of latent synapses involving modulation of GABAergic inhibition. Changes over a longer time likely involve other additional mechanisms such as long-term potentiation, axonal regeneration and sprouting. While cross-modal plasticity appears to be useful in enhancing the perceptions of compensatory sensory modalities, the functional significance of motor reorganization following peripheral injury remains unclear and some forms of sensory reorganization may even be associated with deleterious consequences like phantom pain. An understanding of the mechanism of plasticity will help to develop treatment programs to improve functional outcome.     

Expression of the N-methyl-D-aspartate receptor subunit NR3B regulates dendrite morphogenesis in spinal motor neurons

During postnatal development, the dendrites of spinal motor neurons are refined in an activity-dependent manner that can be influenced by blocking activation of N-methyl-D-aspartate (NMDA) receptors. In late postnatal life, dendritic refinement ceases, and dendrite architecture is unaffected by NMDA antagonists; however the molecular substrate for limiting dendritic plasticity is not understood. During late postnatal development, expression of the NR3B NMDA receptor subunit, a putative dominant-negative subunit that reduces glutamate-induced ionic currents, is upregulated within motor neurons. To investigate whether increasing NR3B expression may contribute to the loss in late development of activity-dependent dendritic reorganization in the spinal cord, we over-expressed NR3B in cultured rat spinal motor neurons, and compared its effects on dendrite morphology with the effects of pharmacological blockade of NMDA receptors. We found that over-expression of the NR3B receptor subunit increased the length and complexity of dendritic arbor, and increased numbers of dendritic filopodia, suggesting that NR3B promotes the addition of branch segments in developing motor neurons. In contrast, blockade of NMDA receptor activity by the NMDA antagonist DL-2-amino-5-phosphonovalerate (AP5) had little effect on the overall length or complexity of dendritic arbor. Instead, treatment with AP5 resulted in significant reorganization of dendritic arbor in a manner that favored addition of dendritic segments of high branch orders, at the expense of those closer to the cell body. These results suggest that expression of the NR3B subunit may participate in activity-dependent reorganization of dendritic architecture, but via a mechanism that may be inconsistent with loss of NMDA receptor activity.     

Developmental regulation of N-methyl-D-aspartate- and kainate-type glutamate receptor expression in the rat spinal cord.

Spinal motor neurons undergo experience-dependent development during a critical period in early postnatal life. It has been suggested that the repertoire of glutamate receptor subunits differs between young and mature motor neurons and contributes to this activity-dependent development. In the present study we examined the expression patterns of N-methyl-D-aspartate- and kainate-type glutamate receptor subunits during the postnatal maturation of the spinal cord. Young motor neurons express much higher levels of the N-methyl-D-aspartate receptor subunit NR1 than do adult motor neurons. Although there are eight potential splice variants of NR1, only a subgroup is expressed by motor neurons. With respect to NR2 receptor subunits, young motor neurons express NR2A and C, while adult motor neurons express only NR2A. Young motor neurons express kainate receptor subunits GluR5, 6 and KA2 but we are unable to detect these or any other kainate receptor subunits in the adult spinal cord. Other spinal cord regions display a distinct pattern of developmental regulation of N-methyl-D-aspartate and kainate receptor subunit expression in comparison to motor neurons. Our findings indicate a precise spatio-temporal regulation of individual subunit expression in the developing spinal cord. Specific combinations of subunits in developing neurons influence their excitable properties and could participate in the emergence of adult neuronal form and function.     

Ontogeny of rhythmic motor patterns generated in the embryonic rat spinal cord

Patterned spontaneous activity is generated in developing neuronal circuits throughout the CNS including the spinal cord. This activity is thought to be important for activity-dependent neuronal growth, synapse formation, and the establishment of neuronal networks. In this study, we examine the spatiotemporal distribution of motor patterns generated by rat spinal cord and medullary circuits from the time of initial axon outgrowth through to the inception of organized respiratory and locomotor rhythmogenesis during late gestation. This includes an analysis of the neuropharmacological control of spontaneous rhythms generated within the spinal cord at different developmental stages. In vitro spinal cord and medullary-spinal cord preparations isolated from rats at embryonic ages (E)13.5-E21.5 were studied. We found age-dependent changes in the spatiotemporal pattern, neurotransmitter control, and propensity for the generation of spontaneous rhythmic motor discharge during the prenatal period. The developmental profile of the neuropharmacological control of rhythmic bursting can be divided into three periods. At E13.5-E15.5, the spinal networks comprising cholinergic and glycinergic synaptic interconnections are capable of generating rhythmic activity, while GABAergic synapses play a role in supporting the spontaneous activity. At late stages (E18.5-E21.5), glutamate drive acting via non- N-methyl-d-aspartate (non-NMDA) receptors is primarily responsible for the rhythmic activity. During the middle stage (E16.5-E17.5), the spontaneous activity results from the combination of synaptic drive acting via non-NMDA glutamatergic, nicotinic acetylcholine, glycine, and GABA(A) receptors. The modulatory actions of chloride-mediated conductances shifts from predominantly excitatory to inhibitory late in gestation.     

Postsynaptic endocannabinoid release is critical to long-term depression in the striatum

The striatum functions critically in movement control and habit formation. The development and function of cortical input to the striatum are thought to be regulated by activity-dependent plasticity of corticostriatal glutamatergic synapses. Here we show that the induction of a form of striatal synaptic plasticity, long-term depression (LTD), is dependent on activation of the CB1 cannabinoid receptor. LTD was facilitated by blocking cellular endocannabinoid uptake, and postsynaptic loading of anandamide (AEA) produced presynaptic depression. The endocannabinoid necessary for striatal LTD is thus likely to be released postsynaptically as a retrograde messenger. These findings demonstrate a new role for endocannabinoids in the induction of long-term synaptic plasticity in a circuit necessary for habit formation and motor control.     

Recovery from spinal cord injury achieved by 3 months of coordination dynamic therapy

Coordination dynamic therapy was applied to 18 patients (average age 31 years) after a spinal cord injury between C4/5 and L4/5; the therapy was administered on average 5 years after the injury for a minimum of 3 months. All complete spinal cord lesions became incomplete, i.e. motor functions improved below the lesion level, including trunk stability and arm, hand and leg functions. The organization of the CNS, quantified by the coordination dynamics between arm and leg movements, improved by 42% for forward and by 49% for backward moving when exercising on a special coordination dynamic therapy device. The improvements of the coordination dynamics were 53%, 32% and 48% for lesions in the cervical, thoracic, and lumbar range, respectively. The plasticity for spinal cord lesions was thus higher when the intumescence was lesioned. Since the coordination dynamics did not change substantially prior to coordination dynamic therapy, did further improve with continued therapy, and worsened when the therapy was terminated, it is concluded that the improvement of CNS functioning above and below the spinal cord lesion level was due to the therapy. Since in stroke and traumatic brain lesion the CNS functioning further improved if the therapy was continued over longer time periods beyond 3 months, it is suggested that spinal cord lesions can partly be cured if coordination dynamic therapy is administered for 1 to 2 years.     

Anatomy and function of cholinergic C bouton inputs to motor neurons

Motor control circuitry of the central nervous system must be flexible so that motor behaviours can be adapted to suit the varying demands of different states, developmental stages, and environments. Flexibility in motor control is largely provided by neuromodulatory systems which can adjust the output of motor circuits by modulating the properties and connectivity of neurons within them. The spinal circuitry which controls locomotion is subject to a range of neuromodulatory influences, including some which are intrinsic to the spinal cord. One such intrinsic neuromodulatory system, for which a wealth of anatomical information has recently been combined with new physiological data, is the C bouton system. C boutons are large, cholinergic inputs to motor neurons which were first described over 40 years ago but whose source and function have until recently remained a mystery. In this review we discuss how the convergence of anatomical, molecular genetic and physiological data has recently led to significant advances in our understanding of this unique neuromodulatory system. We also highlight evidence that C boutons are involved in spinal cord injury and disease, revealing their potential as targets for novel therapeutic strategies.     

CNS-derived glia ensheath peripheral nerves and mediate motor root development

Motor function requires that motor axons extend from the spinal cord at regular intervals and that they are myelinated by Schwann cells. Little attention has been given to another cellular structure, the perineurium, which ensheaths the motor nerve, forming a flexible, protective barrier. Consequently, the origin of perineurial cells and their roles in motor nerve formation are poorly understood. Using time-lapse imaging in zebrafish, we show that perineurial cells are born in the CNS, arising as ventral spinal-cord glia before migrating into the periphery. In embryos lacking perineurial glia, motor neurons inappropriately migrated outside of the spinal cord and had aberrant axonal projections, indicating that perineurial glia carry out barrier and guidance functions at motor axon exit points. Additionally, reciprocal signaling between perineurial glia and Schwann cells was necessary for motor nerve ensheathment by both cell types. These insights reveal a new class of CNS-born glia that critically contributes to motor nerve development.     

Large diameter primary afferent input is required for expression of the Cat-301 proteoglycan on the surface of motor neurons

The expression of a cell surface proteoglycan, recognized by monoclonal antibody Cat-301, is regulated by neuronal activity in early life. Here we report that the expression of the Cat-301 proteoglycan on motor neurons depends on primary afferent input in the early postnatal period. Previously we showed that in two different systems, Y-cells in the cat lateral geniculate nucleus and motor neurons in the hamster spinal cord, the expression of the Cat-301 antigen requires neuronal activity during a circumscribed period in development. Disrupting the activity of Y-cells (by dark rearing or by monocular lid suture) or of motor neurons (by sciatic nerve crush or by spinal cord lesion) during the early postnatal period prevents Cat-301 expression. Disrupting neuronal activity in adults has no effect on Cat-301 expression. The onset of Cat-301 expression corresponds to the end of the period of activity-dependent development. In order to further dissect the components of the segmental reflex are required for the expression of Cat-301 on motor neurons, here we evaluated the effect of deafferentation by dorsal rhizotomy. In adult animals two weeks after deafferentation all sciatic motor neurons continue to express Cat-301. In contrast, in neonates two weeks after deafferentation the normal developmental expression of Cat-301 is reduced and less than 50% of sciatic motor neurons express Cat-301. We next selectively lesioned the small diameter afferents using the neurotoxin capsaicin. In contrast to rhizotomy, neonatal deletion of small diameter afferents has no effect on the development of Cat-301 expression on motor neurons. These results imply that input relayed by large diameter primary afferents (probably those conveying muscle and/or joint information) is required for normal maturation of motor neuronal properties during early life. They also provide further evidence for activity-dependent maturation of motor neurons.     

Receptor tyrosine kinases and respiratory motor plasticity

Protein kinases are a family of enzymes that transfer a phosphate group from adenosine tri-phosphate to an amino acid residue on a protein. The receptor tyrosine kinases (RTKs) are expressed on the outer cell membrane, bind extracellular protein ligands, and phosphorylate tyrosine residues on other proteins-essentially permitting communication between cells. Such activity regulates multiple aspects of cellular physiology including cell growth and differentiation, adhesion, motility, cell death, and morphological and synaptic plasticity. This review will focus on the role of RTKs in respiratory motor plasticity, with particular emphasis on long-term changes in respiratory motoneuron function. Reflecting the predominant literature, specific attention will be devoted to the role of tropomyosin-related kinase type B (TrkB) activation on phrenic motoneuron activity. However, many RTKs share similar patterns of expression and mechanisms of ligand-induced activation and downstream signaling. Thus, a perspective based on TrkB-induced phrenic motor plasticity may provide insight into the potential roles of other RTKs in the neural control of breathing. Finally, understanding how different RTKs affect respiratory motor output in the long-term may provide future avenues for pharmacological development with the goal of increasing respiratory motor output in disorders such as obstructive sleep apnea and after spinal cord injury. This is best illustrated in recent studies where we have used small, highly diffusible molecules to transactivate TrkB receptors near phrenic motoneurons to improve breathing after cervical spinal cord injury.     

Regional distribution of a novel peptide (P7 of 1B236) immunoreactivity in the human central nervous system

The regional distribution of a novel peptide (P7 of 1B236) in the human central nervous system (CNS) was examined. P7-like-immunoreactivity (p7-LI) was shown to be distributed throughout the CNS, with a chromatographic pattern closely similar to that previously described in rat. In the brain the concentrations of P7-LI were higher in the globus pallidus and substantia nigra than in any other regions. Considerable amounts of P7-L1 were also found in the cerebellum. In the spinal cord the concentration of P7-L1 was slightly higher in the ventral than in the dorsal cord, though no difference in concentration was found between cervical, thoracic, lumbar and sacral regions. The distribution pattern of this novel peptide reveals its predominance in sub-cortical motor areas. Studies of its pharmacological effects and possible role in movement disorders are awaited with interest.     

Evolutionary Aspects of the Compensation for the Functions of the Damaged Spinal Cord

The phylo-ontogenetic characteristics of the establishment of plasticity and the high level of potential of the central nervous system in conditions of a damaged spinal cord are demonstrated. Compensation and increases in the potential of plasticity during phylogenesis are identified, along with the importance of ecological-biological characteristics and the higher parts of the central nervous system and hypothalamus. An important role is established for sympathetic innervation; the roles of ATP, ATPase, and changes in the structural-functional pattern of the damaged spinal cord are discussed, as are the roles of scarring and various endocrine glands (adrenals, pancreas, thyroid). Plasticity at the early stages of ontogenetic development and phylogenesis is shown to be extensive. The favorable influences of enzymes on the process of recovery of the damaged spinal cord are identified.     

Spinal and supraspinal effects of long-term stimulation of sensorimotor cortex in rats

Sensorimotor cortex (SMC) modifies spinal cord reflex function throughout life and is essential for operant conditioning of the H-reflex. To further explore this long-term SMC influence over spinal cord function and its possible clinical uses, we assessed the effect of long-term SMC stimulation on the soleus H-reflex. In freely moving rats, the soleus H-reflex was measured 24 h/day for 12 wk. The soleus background EMG and M response associated with H-reflex elicitation were kept stable throughout. SMC stimulation was delivered in a 20-day-on/20-day-off/20-day-on protocol in which a train of biphasic 1-ms pulses at 25 Hz for 1 s was delivered every 10 s for the on-days. The SMC stimulus was automatically adjusted to maintain a constant descending volley. H-reflex size gradually increased during the 20 on-days, stayed high during the 20 off-days, and rose further during the next 20 on-days. In addition, the SMC stimulus needed to maintain a stable descending volley rose steadily over days. It fell during the 20 off-days and rose again when stimulation resumed. These results suggest that SMC stimulation, like H-reflex operant conditioning, induces activity-dependent plasticity in both the brain and the spinal cord and that the plasticity responsible for the H-reflex increase persists longer after the end of SMC stimulation than that underlying the change in the SMC response to stimulation.     

The Nogo receptor,its ligands and axonal regeneration in the spinal cord; a review

At least three proteins present in CNS myelin, Nogo, MAG and OMgp are capable of causing growth cone collapse and inhibiting neurite outgrowth in vitro. Surprisingly, Nogo and OMgp are also strongly expressed by many neurons (including neocortical projection cells). Nogo expression is increased by some cells at the borders of CNS lesion sites and by cells in injured peripheral nerves, but Nogo and CNS myelin are largely absent from spinal cord injury sites, which are none the less strongly inhibitory to axonal regeneration. Nogo is found on growing axons during development, suggesting possible functions for neuronal Nogo in axon guidance. Although Nogo, MAG and OMgp lack sequence homologies, they all bind to the Nogo receptor (NgR), a GPI-linked cell surface molecule which, in turn, binds p75 to activate RhoA. NgR is strongly expressed by cerebral cortical neurons but many other neurons express NgR weakly or not at all. Some neurons, such as DRG cells, respond to Nogo and CNS myelin in vitro although they express little or no NgR in vivo which, with other data, indicates that other receptors are available for NgR ligands. NgR expression is unaffected by injury to the nervous system, and there is no clear correlation between NgR expression by neurons and lack of regenerative ability. In the injured spinal cord, interactions between NgR and its ligands are most likely to be important for limiting regeneration of corticospinal and some other descending tracts; other receptors may be more important for ascending tracts. Antibodies to Nogo, mainly the poorly-characterised IN-1 or its derivatives, have been shown to enhance recovery from partial transections of the spinal cord. They induce considerable plasticity from the axons of corticospinal neurons, including sprouting across the midline and, to a limited extent, regeneration around the lesion. Regeneration of corticospinal axons induced by Nogo antibodies has not yet been demonstrated after complete transections or contusion injuries of the spinal cord. It is not clear whether antibodies against Nogo act on oligodendrocytes/myelin or by binding to neuronal Nogo, or whether they can stimulate regeneration of ascending axons in the spinal cord, most of which express little or no NgR. Despite these uncertainties, however, NgR and its ligands offer important new targets for enhancing plasticity and regeneration in the nervous system.An erratum to this article can be found at     

Molecular mechanisms underlying monosynaptic sensory‐motor circuit development in the spinal cord

Motor behaviors are precisely controlled by the integration of sensory and motor systems in the central nervous system (CNS). Proprioceptive sensory neurons, key components of the sensory system, are located in the dorsal root ganglia and project axons both centrally to the spinal cord and peripherally to muscles and tendons, communicating peripheral information about the body to the CNS. Changes in muscle length detected by muscle spindles, and tension variations in tendons conveyed by Golgi tendon organs, are communicated to the CNS through group Ia /II, and Ib proprioceptive sensory afferents, respectively. Group Ib proprioceptive sensory neurons connect with motor neurons indirectly through spinal interneurons, whereas group Ia/II axons form both direct (monosynaptic) and indirect connections with motor neurons. Although monosynaptic sensory‐motor circuits between spindle proprioceptive sensory neurons and motor neurons have been extensively studied since 1950s, the molecular mechanisms underlying their formation and upkeep have only recently begun to be understood. We will discuss our current understanding of the molecular foundation of monosynaptic circuit development and maintenance involving proprioceptive sensory neurons and motor neurons in the mammalian spinal cord. Developmental Dynamics 247:581–587, 2018. © 2017 Wiley Periodicals, Inc.