Circuits For Skilled Reaching and Grasping

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Review in Advance first posted online on April 9, 2012. (Changes may still occur before final publication online and in print.)
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Circuits for Skilled Reaching and Grasping

Annu. Rev. Neurosci. 2012.35. Downloaded from www.annualreviews.org by Korea Advanced Institute of Science and Technology (KAIST) on 04/15/12. For personal use only.
Bror Alstermark,1 and Tadashi Isa2

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Department of Integrative Medical Biology, Section of Physiology, Umea University, S-901 87 Umea , Sweden; email: Bror.Alstermark@physiol.umu.se Department of Developmental Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan; email: tisa@nips.ac.jp
Annu. Rev. Neurosci. 2012. 35:55978 The Annual Review of Neuroscience is online at neuro.annualreviews.org This articles doi: 10.1146/annurev-neuro-062111-150527 Copyright c 2012 by Annual Reviews. All rights reserved 0147-006X/12/0721-0559$20.00
Keywords
corticomotoneuronal pathways, motoneuron, propriospinal neuron, segmental interneuron
Abstract
From an evolutionary perspective, it is clear that basic motor functions such as locomotion and posture are largely controlled by neural circuitries residing in the spinal cord and brain-stem. The control of voluntary movements such as skillful reaching and grasping is generally considered to be governed by neural circuitries in the motor cortex that connect directly to motoneurons via the corticomotoneuronal (CM) pathway. The CM pathway may act together with several brainstem systems that also act directly with motoneurons. This simple view was challenged by work in the cat, which lacks the direct CM system, showing that the motor commands for reaching and grasping could be mediated via spinal interneurons with input from the motor-cortex and brain-stem systems. It was further demonstrated that the spinal interneurons mediating the descending commands for reaching and grasping constitute separate and distinct populations from those involved in locomotion and posture. The aim of this review is to describe populations of spinal interneurons that are involved in the control of skilled reaching and grasping in the cat, monkey, and human.
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Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . REACHING AND GRASPING IN THE CAT AND MACAQUE MONKEY . . . . . . . . . . . . . . . . . . . . . . . . SUBCORTICAL UPDATING OF CORTICAL COMMAND TO THE C3-C4 PROPRIOSPINAL NEURONS . . . . . . . . . . . . . . . . . . . . . . . FEEDBACK INHIBITORY CONTROL OF REACHING VIA C3-C4 PROPRIOSPINAL NEURONS . . . . . . . . . . . . . . . . . . . . . . . PROPRIOSPINAL PATHWAYS IN HUMANS . . . . . . . . . . . . . . . . . . . . . NEW TECHNIQUES FOR INVESTIGATING THE FUNCTION OF NEURAL CIRCUITS . . . . . . . . . . . . . . . . . . . . . . . FUNCTIONAL RECOVERY FOLLOWING SPINAL CORD INJURY . . . . . . . . . . . . . . . . . . . 560
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INTRODUCTION
Neural circuits for skilled reaching and grasping are considered to be mainly located in the motor cortex and exert their effects in motoneurons (MNs) via the direct cortiocomotoneuronal (CM) pathway (Figure 1a,b). This 60-year-old idea has been rmly established because the direct CM pathway is lacking in lower species and becomes more prominent in primates together with a parallel increase in manual dexterity (Bernhard & Bohm 1954). However, most of the descending control from the motor cortex to MNs is mediated via indirect CM pathways with intercalated neurons in the brain stem and spinal cord. The general understanding of interneuronal (IN) circuits in the brain stem and spinal cord is that they mainly control automatic movements such as locomotion and scratching in addition to posture, reexes, and tonus (Figure 1a) and are of less importance for skilled movements. In classical behavioral studies in
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the macaque monkey using pyramidal lesions at the brain-stem level (Lawrence & Kuypers 1968a, 1968b), it was concluded that highly fractionated nger movements in primates primarily depend on the direct CM pathway. From these studies, researchers proposed that a major advantage of the direct CM system was its ability to bypass the INs, which were considered to have too widespread connections with MNs innervating distal hand muscles to be able to mediate the command for independent digit movements (Kuypers 1982). As a result, researchers recently further suggested that the direct CM pathway has replaced one of the indirect CM pathways (Lemon 2008). However, in this review, we describe specialized neural circuits of spinal pre-MN centers controlling reaching and grasping. The focus is on the functional organization of these circuits, with less attention to the details regarding synaptic effects. For the latter, see reviews by Alstermark & Lundberg (1992), Alstermark et al. (2007), and Isa et al. (2007). Sherrington (1906) together with his students laid the foundation for circuit analysis in the spinal cord with classical work on the organization of the stretch reex, reciprocal inhibition, scratch reex, exor and crossed extensor reexes (Creed et al. 1932), and locomotion (Brown 1911) as shown in Figure 1a. Although such circuits included the MNs as the nal common path (Figure 1b), Sherrington also included INs in the common path (Figure 1c) in the sense that it represented the highest degree of communism (Sherrington 1906). The great advantage of INs is that a major integration of sensory and descending signals can be made at a stage just prior to the MNs (Lundberg 1999). Descending supraspinal systems may facilitate or inhibit the signals from the primary afferents to the MNs. By using either excitatory or inhibitory INs, the sign of an effect can be reversed from excitation to inhibition or the reverse (disinhibition). We refer to INs with direct monosynaptic projection to MNs as last-order INs. Modern investigations of the neuronal organization of descending pathways began
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Figure 1 Motor principles. (a) Skilled voluntary movements such as reaching and grasping are commonly considered to be dependent on neural circuits mainly located in the motor cortex, whereas stereotyped motor behavior such as locomotion, scratching, reexes, posture, and tonus are controlled by spinal circuits. However, as described in this review, the descending command for skilled reaching and grasping can also be controlled by spinal circuits. (b) Schematic neural diagram showing monosynaptic input from muscle spindle Ia afferents and descending pathways from higher motor centers in the cortex and brain stem. Sherrington (1906) considered motoneurons to be the nal common path. (c) Schematic neural diagram showing disynaptic input, via an interneuron, from afferents and higher motor centers to motoneurons. Sherrington (1906) also included the interneurons together with the motoneurons in the common path.
with Lloyds (1941) study of pyramidal effects in the cat spinal cord. He used the technique of conditioning monosynaptic test reexes (Renshaw 1940) and showed that temporal facilitation was required to evoke pyramidal excitation in MNs, suggesting that intercalated neurons also mediated the effect for descending systems (illustrated in Figure 2a). A similar approach was used by Lundberg & Voorhoeve (1962), who recorded intracellularly from MNs and found facilitation from the sensorimotor cortex of excitatory and inhibitory segmental reexes. The nal proof of a disynaptic excitatory CM pathway was provided in experiments by Lundberg and colleagues recording from forelimb MNs in the cat (Illert et al. 1977). They showed that disynaptic excitation could be mediated by a group of
INs located in the upper cervical spinal cord segments C3-C4 and termed them C3-C4 propriospinal neurons (PNs) as shown in Figure 2b. The C3-C4 PNs are characterized by an extensive convergence from several descending pathways: the cortico-, rubro-, reticulo-, and tectospinal tracts. These descending systems may also give feed-forward inhibition of subpopulations of PNs via feedforward inhibitory INs (Figure 2b). Whereas the dominating descending input is excitatory, the input from forelimb afferents is predominantly inhibitory via feedback inhibitory INs. In addition to the MN projection, the C3-C4 PNs have an ascending projection to the lateral reticular nucleus (LRN). The LRN mediates the major mossy-ber input to the cerebellum from the spinal cord. The ascending LRN
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projection may thus provide the cerebellum with an efferent copy of the command to the MNs (see below; Figure 6). On the basis of this information, the cerebellum may then interact quickly with the cortical and brain-stem systems to regulate activity in the C3-C4 PNs (see below). Some inhibitory C3-C4 PNs can also mediate disynaptic inhibition in MNs (Figure 2b). These inhibitory PNs have the same extensive descending convergence as the excitatory ones, and they also have an ascending projection to the LRN (see references in Alstermark et al. 2007).
Disynaptic CM excitation can also be mediated via INs located in the same segments as the MNs (Illert & Wiedeman 1984, Alstermark & Sasaki 1985, Kitazawa et al. 1993). Such INs are termed segmental interneurons (sINs) and are shown in Figure 3. To visualize the relative contributions of PNs and sINs to reaching and grasping, two groups of cats were compared using activity-dependent transneuronal uptake of wheat-germ agglutinated horseradish peroxidase (WGA-HRP) into last-order INs following injection into the motor axons of the deltoid muscle (Alstermark & Kummel
Electrophysiological technique for analyzing circuitry

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1990). Investigators pursued this study because the deltoid MNs are active in the reaching, grasping, as well as locomoting groups, but they may also be differentially controlled. One group performed unrestrained locomotion, and the other combined target reaching and grasping to remove a morsel of food from a small tube with the forelimb. As shown in Figure 3, reaching consists of rapid elbow exion followed by combined shoulder and elbow extension. During this lifting and protraction phase of reaching, the forepaw is dorsi-exed and the toes adducted just prior to the insertion into the tube. Inside the tube, the digits are abducted and exed to grasp the morsel of food. After grasping, the forepaw is supinated during retraction out from the tube and then brought to the mouth (Alstermark et al. 1981b). Figure 3 also shows the transverse and longitudinal distributions of last-order labeled spinal INs. In the locomoting group, only a few labeled cells were found in the C2-C4 segments, whereas many labeled cells were located in C5-Th1 with two peaks in the C6 and C7 segments. In contrast, labeled cells were found from C2 to Th1 in the cats performing reaching and grasping with a peak in the C6 segment. These results suggest that spinal INs devoted to the control of reaching and grasping exist all the
way from C2 to Th1, whereas INs involved in the generation of locomotion are mainly conned to the C5-Th1 segments. Why the spinal INs involved in the control of reaching and grasping are also distributed rostral to the forelimb segments is still not known. The sINs are not as well characterized with respect to the descending systems; also unclear is whether they project to the LRN. Although transneuronal labeling of lastorder INs with WGA-HRP revealed a greater number of sINs than C3-C4 PNs (Alstermark & Kummel 1990), the synaptic strength is similar for the CM pathway via the C3-C4 PNs (Alstermark & Sasaki 1985). Apparently, the sINs constitute heterogenous groups, with only a part receiving strong corticospinal input. Disynaptic CM pathways via C3-C4 PNs have also been shown in the macaque monkey (Alstermark et al. 1999) and in humans (Malmgren & Pierrot-Deseilligny 1988), but they are absent in the rat (Alstermark et al. 2004) and mouse (Alstermark & Ogawa 2004). As illustrated in Figure 3, corticoreticulospinal (Peterson et al. 1979, Alstermark & Sasaki 1986, Riddle et al. 2009) and corticorubrospinal (Fujito & Aoki 1995) pathways can also mediate disynaptic CM excitation; these pathways constitute phylogenetically old

Figure 2 Electrophysiological techniques for analyzing circuitry. The excitability of motoneurons (MNs) can be tested by using the monosynaptic Ia reex pathway as described by Renshaw (1940) and Lloyd (1941). Although this is usually technically easier than stimulating last-order interneurons (INs) directly, researchers were able to stimulate last-order INs in case of the C3-C4 propriospinal neurons (PNs) because of their ascending projection to the lateral reticular nucleus (LRN) (Alstermark et al. 1981a) (not shown in gure). However, last-order INs can also be activated synaptically, as in the case of the C3-C4 PN, by stimulating one of their descending inputs, e.g., the corticospinal tract (indicated here as a supraspinal neuron). Such a disynaptic pathway usually requires temporal summation of excitatory postsynaptic potentials (EPSPs) in the intercalated neurons (in this case, the C3-C4 PNs) to make them re. When ring, a disynaptic EPSP can be recorded in the MNs. To investigate the convergence onto common intercalated spinal INs, two different inputs to the last-order INs can be stimulated together, producing spatial facilitation indicated by the large EPSP in the MNs. Within the C3-C4 propriospinal system, PNs receive monosynaptic excitation from the cortico-, rubro-, reticulo-, and tectospinal tracts. Via activation from these descending systems, the PNs may evoke disynaptic excitation in forelimb MNs. In addition, the PNs have ascending collaterals to the LRN. All the descending systems may evoke disynaptic inhibition in the PNs, denoted as feed-forward inhibition. There is only a weak and sparse monosynaptic excitation from the forelimb afferents. The major effect from the forelimb afferents is disynaptic inhibition, denoted as feedback inhibition. In addition to the excitatory PNs, a population of inhibitory PNs has a descending convergence similar to that of excitatory PNs. Inhibitory PNs, as well as the inhibitory INs mediating feedback inhibition, also project to the LRN.
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Differential activation of last-order interneurons during reaching and grasping versus locomotion
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Figure 3 Longitudinal and transverse location of last-order spinal interneurons (INs) active during combined reaching and grasping or locomotion. (Center diagonal image) The organization of descending pathways controlling propriospinal and segmental interneurons (PNs and sINs, respectively); (upper right corner) the reaching and grasping movement sequences (from Alstermark et al. 1981b) and the longitudinal distribution of labeled INs in two groups of cats performing either combined reaching and grasping (light blue line) or unrestrained overground locomotion (dark yellow line); (lower left corner) the transverse distribution of labeled INs for the two groups of cats. The detailed images of the paw are courtesy of L.G. Pettersson. Wheat-germ agglutinated horseradish peroxidase was injected into the motor nerve of the deltoid muscle and was then taken up transneuronally from the motoneurons (MN) into last-order INs in an activity-dependent manner. The direct cortiocomotoneuronal (CM) pathway and monosynaptic MN connections from the rubrospinal (RuST) and reticulospinal (ReST) tracts are not shown. Other abbreviation: CST, corticospinal tract. Adapted with permission from Alstermark & Kummel (1990).
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systems (Shapovalov 1975). In primates, there is also a direct CM pathway (Bernhard & Bohm 1954, Landgren et al. 1962). It appears that an evolution of the CM pathways has taken place via indirect corticobulbospinal and corticopropriospinal pathways as well as a direct CM pathway. We describe evidence showing how these direct and indirect CM pathways are used to control reaching and grasping.
REACHING AND GRASPING IN THE CAT AND MACAQUE MONKEY

The above experiments using WGA-HRP suggest that spinal INs may be active during both reaching and grasping. To investigate the relative contribution of C3-C4 PNs and sINs to reaching and grasping, the corticospinal and rubrospinal tracts were lesioned in C5 in the cat (Alstermark et al. 1981a, Alstermark & Sasaki 1985) and the macaque monkey (Alstermark et al. 1999, Sasaki et al. 2004, Alstermark et al. 2011) (Figure 4). This lesion eliminates the cortico- and rubrospinal inputs to the sINs but spares them to the C3-C4 PNs. The lesions were conrmed electrophysiologically. In the cat, intracellular recording from MNs showed that the disynaptic pyramidal excitatory postsynaptic potential (EPSP) could still be evoked after the C5 lesion, although the amplitude was decreased owing to the interruption of the input to the sINs. In the cat, fast and accurate reaching of the forelimb could be observed during the rst postoperative week (Figure 4). However, after the forepaw was inserted into the tube, the cats could not use their digits to grasp the morsel of food and instead made a raking movement. In the monkey, the lesion interrupted the inputs to the sINs as well as the direct CM pathways. In this species, after a complete lesion to the corticospinal tract that spared the majority of the propriospinal axons, both reaching to the tube and the precision grip formed by exion and opposition of the index nger and thumb, which were observed preoperatively, could be performed during the rst postoperative week (see
Supplemental Movie 1. Follow the Supplemental Material link from the Annual Reviews home page at http://www.annualreviews. org). Transient decits during the rst two weeks were seen in the preshaping of the digits before insertion and coexion of the other digits. These ndings suggest that, in the cat, C3-C4 PNs can mediate the command for reaching, whereas the command for grasping requires sINs. In contrast, in the macaque monkey, the C3-C4 PNs seem capable of mediating the commands for reaching and grasping. The early decits in digit control indicate that the sINs and the direct CM pathway play a critical role in preshaping and also in fractionated digit movements. To test whether the reaching that remained in the cat and the reaching and grasping in the macaque monkey could be ascribed to transmission via the C3-C4 PNs or via the ventral corticoreticulospinal system, a dorsal lesion was made in C2 as shown in Figure 5. This lesion interrupts the cortico- and rubrospinal tracts to the C3-C4 PNs as well as to the sINs, but it spares the corticoreticular input. This lesion abolished the disynaptic pyramidal EPSP in forelimb MNs in both the cat and monkey; it also abolished the monosynaptic pyramidal EPSP in the monkey. Both reaching and grasping were severely impaired in the cat and monkey. In both species, reaching toward the tube could still be initiated, but precision was impaired in aiming toward the tube opening and in the coordination between joints. Although reaching recovered after approximately one month, ne-digit grasping was still abolished (see Supplemental Movie 2). Taken together, the results following the dorsal C5 and C2 lesions show that C3-C4 PNs can mediate the command for reaching in the cat and for reaching and grasping in the macaque monkey. A lesion of the propriospinal axons made by transecting the ventral part of the lateral funiculus in C5 in the cat (Alstermark et al. 1981b, Pettersson et al. 1997) resulted in ataxia during reaching near the target (see section below) (Figure 6d ), even though grasping was still intact. On the basis
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Effects on reaching and grasping after lesion of CST and RuST in C5
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Cat Annu. Rev. Neurosci. 2012.35. Downloaded from www.annualreviews.org by Korea Advanced Institute of Science and Technology (KAIST) on 04/15/12. For personal use only.
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Figure 4 Behavioral and electrophysiological testing of propriospinal versus segmental interneurons (PNs and sINs, respectively) in the control of reaching and grasping after lesion of the cortico- and rubrospinal tracts in the C5 segment. The transection of these pathways (center diagonal image; red ) eliminated the input to the sINs but spared the input to the C3-C4 PNs. In the cat (top panels), reaching was normal, whereas grasping with the digits was abolished. In the monkey (middle panels), reaching was normal and precision grip could be performed with some decits in preshaping and conjoint extension in the other digits: (middle upper row) preoperative condition and (middle lower row) postoperative day 1. Abbreviations: CST, corticospinal tract; MCx, motor cortex; MN, motoneuron; ReST, reticulospinal tract; RuST, rubrospinal tract. Adapted from Alstermark et al. (1981b) and Sasaki et al. (2004) with permission.
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Figure 5 Behavioral and electrophysiological testing of propriospinal and segmental interneurons (PNs and sINs, respectively) versus corticoreticulospinal pathway in the control of reaching and grasping after lesion of the cortico- and rubrospinal tracts in C2. The transection of these pathways (bottom diagonal image; red ) eliminated the input both to the C3-C4 PNs and sINs but spared the input to the corticoreticulospinal pathway. In the cat (top panels), reaching and grasping were defective. In the monkey (center panels), reaching was impaired and precision grip could not be performed: (center upper row) preoperative condition and (center lower row) postoperative day 1. Abbreviations: CST, corticospinal tract; MCx, motor cortex; MN, motoneuron; ReST, reticulospinal tract; RuST, rubrospinal tract. Adapted from Alstermark et al. (1981b, 2011) with permission.
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Figure 6 Subcortical visual updating via C3-C4 propriospinal neurons. (a) New visual information about changing target position can be mediated via both cortical and subcortical pathways: (blue boxes) reaching to the left target and switching from the left to the right target. (b) Schematic circuit consisting of the C3-C4 propriospinal system, efferent loop via the cerebellar cortex, and bulbospinal systems and the motor cortex. This circuit may be used to update the cortical command for reaching. (c) Ventral lesion in C5 of the reticulospinal and propriospinal pathways sparing the cortico- and rubrospinal pathways to segmental interneurons. Intracellular recordings from motorneurons (MNs) revealed reduced disynaptic corticospinal tract (CST) excitation. (d ) Reaching behavior after the ventral C5 lesion, showing ataxia near the tube opening. Other abbreviations: CST, corticospinal tract; MCx, motor cortex; ReST, reticulospinal tract; RuST, rubrospinal tract.
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of this observation, researchers proposed that sINs can mediate the command for grasping in the cat (Alstermark et al. 1981b). However, these results do not exclude the possibility that sINs can also help control reaching, because reaching, although defective, could be executed even when the axons of the PNs had been transected. Thus, the dual control of reaching and grasping by the PNs in the monkey may have developed because precision grip requires ne control of the upper arm (Alstermark et al. 2011). In addition to its important role in controlling skilled reaching and grasping via the direct CM pathway in primates, the spinal cord contains separate neural circuits that are capable of conveying the descending motor commands from higher motor centers to the MNs. These spinal centers are presumably complementary to the higher centers in the motor cortex and brain stem. If so, what advantage could such integration at a stage just prior to the nal common path provide? Illert et al. (1977) proposed that the descending cortical command could be updated on its way to the MNs via subcortical systems that have convergent input to the C3-C4 PNs and sINs.
SUBCORTICAL UPDATING OF CORTICAL COMMAND TO THE C3-C4 PROPRIOSPINAL NEURONS

During reaching, if the target suddenly changes its position in space, the movement trajectory has to be corrected using visual information. There are visual pathways to both the cortex and subcortical systems including the cerebellum and bulbospinal systems (Figure 6a). Cortical visual pathways play an important role in the control of reaching (Goodale & Westwood 2004), usually with latencies longer than 200 msec for correction of an ongoing movement. However, shorter latencies in the range of 120-160 msec have been proposed to be subcortically mediated in humans (Day & Lyon 2000) as well as in subjects with complete corpus callosum agenesis (Day & Brown 2001)
or whose primary visual area was temporarily blocked (Christensen et al. 2008). Recently, using electromyography recordings, researchers observed latencies around 100 msec in humans (Pruszynki et al. 2010). To test the hypothesis of subcortical updating via the C3-C4 propriospinal system, cats were trained to perform reaching to one of two or three tubes. The correct tube was illuminated, and during reaching, the illumination could be switched to another tube with variable delay. The cats (Figure 6a) showed remarkably short latencies for the correction of the movement trajectory, down to 50-60 msec after the light shift (Alstermark et al. 1990, Pettersson et al. 1997, Pettersson & Perliev 2002). Latencies longer than 100 msec were also observed. If transmission in the bulbospinal systems was interrupted by lesions in C2 of the rubro- and reticulospinal tracts, the cats could still correct the trajectory but only with latencies longer than 100 msec (Pettersson et al. 1997). In those cases, the new visual information was most likely processed at a cortical level. These results are compatible with the neural circuitry known to control the C3-C4 propriospinal system (Figure 6b), because bulbospinal systems receive very fast visual information (Werner 1993). However, a major problem is how to correct the ongoing cortical descending command via the C3-C4 PNs. As described above, the PNs, in addition to the MN projection, have ascending collaterals to the LRN in the lower brain stem (Illert & Lundberg 1978, Alstermark et al. 1981a, Alstermark & Ekerot 1992, Isa et al. 2006). The LRN is a major mossy-ber input from the spinal cord to the cerebellum (Clendenin et al. 1974, Ekerot 1990). The cortical input to the LRN is separate from the corticospinal tract (Alstermark & Lundberg 1982, Alstermark & Ekerot 1992, Matsuyama & Drew 1997), which may control transmission via specic ascending spinocerebellar pathways such as the C3-C4 propriospinal system. The rubroand reticulospinal neurons with projection to the C3-C4 PNs receive input from the motor cortex and the deep cerebellar nuclei (Illert
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Figure 7 Feedback inhibition of the C3-C4 propriospinal neurons (PNs) during reaching. (a) Recording from PNs and feedback inhibitory interneurons (INs) in the C3-C4 segments during skin stretching revealed strong inhibition in the PNs. (b) Lesion of the dorsal column in C5 eliminates the feedback inhibition and results in the hypermetria in reaching. Abbreviation: MN, motorneuron.
et al. 1977). The ascending projection from the C3-C4 PNs may provide the cerebellum with an efferent copy of the descending command for reaching to the forelimb MNs (Alstermark et al. 1981b, Alstermark 1983). Using the new visual information, the cerebellum may then calculate a correction of the ongoing movement trajectory and issue new additional inputs to the C3-C4 PNs via the bulbospinal systems. The corrective signal will be matched by the new efferent copy until the activity level of the PNs has changed to correct for the new trajectory. This hypothesis has received indirect support from behavioral testing of reaching following transection of the propriospinal axons in C5 (Figure 6c). After this lesion, the cats had no problem initiating reaching toward the tube opening, but near the tube opening, they displayed severe ataxia during deceleration (Figure 6d ) (Alstermark et al. 1981b). In this case, transmission via the C3-C4 PNs to the MNs was interrupted, but because of the remaining ascending projection to the LRN, the cerebellum may be misinformed, resulting in the ataxia (Alstermark 1983).
FEEDBACK INHIBITORY CONTROL OF REACHING VIA C3-C4 PROPRIOSPINAL NEURONS

In addition to reaching, aiming and nal positioning of the paw are critical for a successful grasp. Such control may depend heavily on afferent information. The C3-C4 PNs receive excitation from forelimb muscle and skin afferents, but the dominating effect is inhibition (Alstermark et al. 1984a, 1984b, 1986b). As shown in Figure 7a, stretching the skin of the forelimb evokes ring of feedback inhibitory INs and concomitant inhibition in the PNs in the C3-C4 segments. To investigate the function of inhibitory feedback control of the C3C4 PNs, researchers compared cats performing target reaching after dorsal column transection in C5 or C2. The C5 lesion interrupted the feedback inhibition to the PNs, although it was spared after the C2 lesion. Both lesions abolished the ascending information to higher centers. Interestingly, severe hypermetria in reaching was observed after the C5, but not after the C2, dorsal column lesion; the C2
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lesion resulted only in dysmetria near the tube opening (Alstermark et al. 1986a) (Figure 7b). The hypermetria was not compensated until after approximately one week of testing, presumably with the help of vision. These results suggest that feedback inhibition of PNs may be used conjointly with the descending command controlling reaching. Deceleration and correct termination of the forepaw may be difcult to control with only vision and may require multimodal control (Alstermark et al. 1986a). The INs mediating the inhibition of the PNs receive cortical input. Thus, the motor and sensory cortices could activate them as well as the PNs during reaching. The INs may then become activated by spatial facilitation from forelimb afferents when reaching close to the target. Similar to the PNs, the medial INs providing feedback inhibition of the PNs have ascending collaterals to the LRN and to the cuneate nucleus (Alstermark et al. 1984b). In analogy with the discussion above on the role of the efferent copy from the PNs to the LRN, the C5 dorsal column lesion may cause erroneous signaling from the feedback INs that could also contribute to the hypermetria. The dorsal column transections in both C5 and C2 eliminate afferent information to higher centers, which may be the cause of the dysmetria mainly observed after the C2 lesion. The additional hypermetria after the C5 dorsal column lesion suggest that the inhibitory INs are essential for inhibition of the C3-C4 PNs during reaching in its terminal phase close to the target.
segments in which the PNs are located. However, in one patient with a spinal cord injury at the C6-C7 segmental junction restricted to the ventral and lateral funicles on one side, the propriospinally mediated excitation was abolished on the side of the lesion but remained intact on the nonlesioned side (Marchand-Pauvert et al. 2001). This nding, together with the systematically longer latency of propriospinally mediated excitation to more caudally located motor nuclei, suggests that the cervical PNs in humans are located rostral to C6. In the patient with a restricted lesion of the propriospinal pathway on one side, reaching and precision grip were normal on the nonlesioned side. On the lesioned side, researchers observed decits in reaching close to the target with transient ataxia as well as difculties in holding small objects with the thumb and index nger (B. Alstermark & L.G. Pettersson, unpublished observations). Surprisingly, transcranial magnetic stimulation revealed a similar short-latencyevoked cortical electromyography response on both the lesioned and the nonlesioned sides, indicating that transmission in the direct CM pathway was not signicantly impaired (Marchand-Pauvert et al. 2001). These ndings agree well with the behavioral observations described above for the monkey. Transmission via sINs in humans was not accessible within a similar investigation, but it likely plays an essential role as does the direct CM pathway.
PROPRIOSPINAL PATHWAYS IN HUMANS

Using indirect electrophysiological techniques, researchers found propriospinal pathways in the cervical and lumbar spinal cord segments of humans (for a review, see Pierrot-Deseilligny & Burke 2005). The cervical propriospinal pathway shares several properties with those in the cat and monkey, e.g., descending inhibition and strong feedback inhibition evoked by skin afferents. A difculty in the study of humans when using indirect techniques is to determine the
NEW TECHNIQUES FOR INVESTIGATING THE FUNCTION OF NEURAL CIRCUITS

As described in Reaching and Grasping in the Cat and Macaque Monkey (section above), most of the behavioral work was performed using selective spinal cord lesions (but see above for a description of the technique using activity-dependent transneuronal labeling) (Alstermark & Kummel 1990). The lesioning technique has several limitations such as causing changes in excitability in both the acute and chronic states and with compensatory
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mechanisms in the nonlesioned systems (see section below). With this technique, it is also difcult for researchers to make exactly similar lesions from one experiment to another. The lesion resulting from this technique will also unavoidably affect other axons with a location similar to that of the targets. To demonstrate directly the function of the C3-C4 PNs in the intact state, a novel technique to manipulate the activity of the C3-C4 PNs without a lesion would be desirable. For this purpose, we established a novel genetic tool of pathway-specic and reversible transmission block and applied it to macaque monkeys (M. Kinoshita, R. Matsui, S. Kato, T. Hasegawa, H. Kasahara, K. Isa, A. Watakabe, T. Yamamori, Y. Nishimura, B. Alstermark, D. Watanabe, D. Kobayashi, and T. Isa, unpublished observations) as shown in Figure 8. First, we injected a highly efcient retrogradely transported (HiRet) lentivirus vector carrying the enhanced GFP and enhanced tetanus neurotoxin (eTeNT) in the downstream of the tetracycline responsive element into the motor nuclei of the C6-Th1 segments. This caused infection through the axonal terminals of the bers terminating in the motor nuclei. Seven to ten days later, the second vector, the adenoassociated vector carrying a highly efcient Tet-ON sequence, rtTAV16, was injected in a section ranging from the caudal C2 to the rostral C5 segments. These injections caused infection via the cell somata, but it was not transported retrogradely to the motor cortex. Together, the lentivirus (via axons) and adenovirus (somata) would specically infect INs with somata located in C2-C5 with projection to forelimb motor nuclei in the C6-Th1 segments. In this condition, the enhanced GFP and eTeNT were transcribed under the presence of doxycycline (Dox), a tetracycline derivative, in the C3-C4 PNs with double infection. One to two months after the virus injections, Dox was orally administered to the monkeys. Two to ve days after Dox application, allowing time for the expression of eTeNT, the monkeys showed decits in reaching and/or grasping movements. The monkeys
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exhibited weakness in the index nger and thumb precision grip, grasping movements became slower, and, in some monkeys, reaching showed dysmetria. Terminal electrophysiological experiments under anesthesia showed that the synaptic transmission through the C3-C4 PNs was markedly reduced, presumably owing to the eTeNT that reduced synaptic release (Yamamoto et al. 2003). As shown in Figure 8c, stimulation of the corticospinal tract evoked mainly the monosynaptic eld but not the disynaptic eld mediated via the C3C4 PNs. Also, stimulation of the ascending axons of the PNs in the LRN revealed a large block in transmission of the monosynaptic eld. These electrophysiological ndings also showed that the direct CM pathway was not affected by the virus injections. In addition, with anti-GFP immunohistochemistry, researchers were able to visualize the location of the somata of the C3-C4 PNs whose transmission had been blocked. These somata were located mainly in the lateral part of the intermediate zone of the C3-C4 segments, which transneuronal labeling with WGA-HRP revealed was also where the C3-C4 PNs were located (Alstermark & Kummel 1990). Another ad vantage of using this technique is its ability to visualize the axons all the way through the somata to the terminals. We found that the axons terminated on presumed MNs in the C6-Th1 segments and on neurons in the LRN. These results conrmed that the neurons affected by eTeNT during Dox administration belong to the group of C3-C4 PNs. Taken together with the previous behavioral ndings, these new results demonstrate that C3-C4 PNs play a critical role in the control of reaching and grasping movements in macaque monkeys both under normal conditions and after spinal cord lesions.
FUNCTIONAL RECOVERY FOLLOWING SPINAL CORD INJURY

Although the macaque monkeys could perform the precision-grip exercise following lesion
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AAV2-CMV-rtTAV16
ITR CMV rtTAV16 WPRE
Sv40 pA
c
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Figure 8 Selective and reversible blockade of synaptic transmission through the C3-C4 PNs via a double viral vector system. (a) Schematic diagram of the vector injections, showing how HiRet-TRE-eGFP/eTeNT (red dots) and AAV2-CMV-rtTAV16 ( green dots) interact in the double-infected cells. The former vector could infect PNs, sINs, and corticospinal neurons in the MCx; the double infection occurred only in the C3-C4 PNs. The AAV2-CMV-rtTAV16 vector is not transported retrogradely. (b) Injection of vectors in the motor nuclei in C6-Th1 (red ) and close to the PNs in C3-C4 ( green). Schematic diagram showing that the eGFP and eTeNT that were transcribed in the presence of Dox and eTeNT cleave VAMP2, leading to the blockade of the synaptic transmission. (c) Extracellular recordings from the motor nuclei in C6-Th1, obtained while stimulating the axons of the PNs directly in the LRN or by stimulating the corticospinal tract in the contralateral pyramid. Single and double asterisks indicate the monosynaptic and disynaptic eld potentials, respectively. (d ) Impairment of the precision grip on the second day after initiation of Dox administration in a monkey with double vector infection. Abbreviations: Dox, doxycycline; CST, corticospinal tract; eGFP, enhanced GFP; eTeNT, enhanced tetanus neurotoxin (eTeNT); HiRet, highly efcient retrogradely transported; LRN, lateral reticular nucleus; MCx, motor cortex; MN, motorneuron; PN, propriospinal neuron; sIN, segmental interneuron.
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of the cortico- and rubrospinal tracts in C5 (as described above), they showed decits in their grasping movements: Independent nger control and their ability to preshape their digits accurately were both impaired. With daily training, lesioned monkeys showed a marked recovery, and all showed near-full recovery of precision grip within two weeks to two months post lesion (Sasaki et al. 2004; Nishimura et al. 2007, 2009). However, after a similar lesion in C2, monkeys displayed only partial, at best, recovery of precision grip. These results suggest that the C3-C4 PNs are, in addition to their normal function, involved in the postlesion recovery of dexterous hand movements within the direct CM pathway. In the cat, which lacks direct CM connections, the postlesion recovery of digit grasping within the cortico-and rubrospinal tracts in C5-C6 depends on takeover via C3-C4 PNs and the corticoreticulospinal pathway (Alstermark et al. 1987, Blagovechtchenski et al. 2000, Pettersson et al. 2007). Researchers have used brain imaging with positron emission tomography to study cerebral activation during functional recovery after
lesion of the cortico- and rubrospinal tracts in C5 in the macaque monkey (Nishimura et al. 2007). During the early phase of recovery (1 month), increased activation was present bilaterally in the primary motor cortex (M1), and during the late stage of recovery (3-4 months after lesion), activation was present in an extended area of the contralateral M1 and bilaterally in the ventral premotor cortex. These results suggest that a number of different pathways may be involved during the recovery process. Studies of humans who have had a stroke suggest that the corticoreticulospinal with projection to the propriospinal system may contribute to recovery (Pierrot-Deseilligny & Burke 2005). To summarize, the experimental models reviewed here offer good opportunities to extend the research on motor recovery of voluntary movements after spinal cord injury. Recently, a vast literature (see Flynn et al. 2011, Nishimura & Isa 2011) argues for the involvement of PNs in functional recovery after spinal cord injury. Researchers may be able to take advantage of the ability of PNs to control object-oriented reaching and dexterous hand movements to develop future therapeutic strategies.
SUMMARY POINTS AND FUTURE ISSUES 1. The control of skilled reaching and grasping involves not only cortical circuits with direct CM connection, but also indirect CM pathways via PNs and sINs in the spinal cord. In the cat, the C3-C4 PNs are specialized to control reaching, whereas grasping is more dependent on the sINs. In the macaque monkey, the C3-C4 PNs can also convey the command for precision grip involving the thumb and index ngers. These spinal circuits are different from other spinal networks involved in locomotion. 2. The motor cortex yields parallel control of the PNs and sINs via the corticospinal and bulbospinal pathways. Sending visual information to the bulbospinal pathway, the spinal circuits can quickly update the descending cortical command. An efferent copy from the PNs to the cerebellum via the LRN may play a critical role during reaching in updating the cortical command to a moving target. In addition to visual control, feedback inhibition of the C3-C4 PNs sent from the cutaneous receptors in the forelimb is critical for correct deceleration and accurate termination of reaching at the target location.
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3. Future work remains to be performed on the sINs to investigate the descending convergence pattern. Research needs to determine whether sINs also have an ascending projection to the LRN. Molecular work must also contend with the challenges of characterizing and possibly nding differential markers for the C3-C4 PNs and sINs. From an evolutionary point of view, it is also interesting to understand why the PNs are located rostral to the forelimb segments. 4. In humans and rodents, a cervical propriospinal system also exists, but its normal function remains to be claried.
5. So far, most behavioral work has been conducted using lesions. A new technique based on a specic infection of PNs using double viral vectors has enabled pathway-selective and reversible inactivation of the C3-C4 propriospinal system. In monkeys, this inactivation happened within days, resulting in decits in reaching and grasping. It is also necessary to develop new techniques in which reversible inactivation of discrete circuits can be performed at a millisecond time resolution. The newly established optogenetic technique may be most important in this respect. Genetic techniques based on unique cell identity may also offer a new possibility for manipulating specic neural circuits. 6. The behavioral work using lesions has given new interesting results with respect to plastic changes during the early phase of recovery. These ndings may be used to improve functional recovery after spinal cord injury in humans.
DISCLOSURE STATEMENT
The authors are not aware of any afliations, memberships, funding, nancial holdings, or any other conicts of interest that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
B.A. is supported by the Swedish Research Council and Human Frontier Science Program. T.I. is supported by the Strategic Research Program of Brain Sciences by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The authors thank Dr. Pettersson for constructive criticism on an earlier version of this article.
LITERATURE CITED
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Alstermark B, Isa T, Pettersson LG, Sasaki S. 2007. The C3-C4 propriospinal system in the cat and monkey: a spinal pre-motoneuronal centre for voluntary motor control. Acta Physiol. Oxf. 189:12340 Alstermark B, Johannisson T, Lundberg A. 1986b. The inhibitory feedback pathway from the forelimb to C3-C4 propriospinal neurones investigated with natural stimulation. Neurosci. Res. 5:45156 Alstermark B, Kummel H. 1990. Transneuronal transport of wheat germ agglutinin conjugated horseradish peroxidase into last order spinal interneurones projecting to acromio- and spinodeltoideus motoneurones in the cat. 2. Differential labelling of interneurones depending on movement type. Exp. Brain Res. 80:96 103 Alstermark B, Lindstrom S, Lundberg A, Sybirska E. 1981a. Integration in descending motor pathways controlling the forelimb in the cat. 8. Ascending projection to the lateral reticular nucleus from C3-C4 propriospinal also projecting to forelimb motoneurones. Exp. Brain Res. 42:28298 Alstermark B, Lundberg A. 1982. Electrophysiological evidence against the hypothesis that corticospinal bres send collaterals to the lateral reticular nucleus. Exp. Brain Res. 47:14850 Alstermark B, Lundberg A. 1992. The C3-C4 propriospinal system: target-reaching and food-taking. In Muscle Afferents and Spinal Control of Movement, ed. L Jami, E Pierrot-Deseilligny, D Zytnicki, pp. 32754. Oxford/New York/Seoul/Tokyo: Pergamon Alstermark B, Lundberg A, Norrsell U, Sybirska E. 1981b. Integration in descending motor pathways controlling the forelimb in the cat. 9. Differential behavioural defects after spinal cord lesions interrupting dened pathways from higher centres to motoneurones. Exp. Brain Res. 42:299318 Alstermark B, Lundberg A, Pettersson LG, Tantisira B, Walkowska M. 1987. Motor recovery after serial spinal cord lesions of dened descending pathways in cats. Neurosci. Res. 5:6873 Alstermark B, Lundberg A, Sasaki S. 1984a. Integration in descending motor pathways controlling the forelimb in the cat. 10. Inhibitory pathways to forelimb motoneurones via C3-C4 propriospinal neurones. Exp. Brain Res. 56:27992 Alstermark B, Lundberg A, Sasaki S. 1984b. Integration in descending motor pathways controlling the forelimb in the cat. 11. Inhibitory pathways from higher motor centres and forelimb afferents to C3-C4 propriospinal neurones. Exp. Brain Res. 56:293307 Alstermark B, Ogawa J. 2004. In vivo recordings of bulbospinal excitation in adult mouse forelimb motoneurones. J. Neurophysiol. 92:195862 Alstermark B, Ogawa J, Isa T. 2004. Lack of monosynaptic corticomotoneuronal EPSPs in rats: disynaptic EPSPs mediated via reticulospinal neurones and polysynaptic EPSPs via segmental interneurones. J. Neurophysiol. 91:183239 Alstermark B, Pettersson LG, Nishimura Y, Yoshino-Saito K, Tsuboi F, et al. 2011. Motor command for precision grip in the macaque monkey can be mediated by spinal interneurons. J. Neurophysiol. 106:122 26 Alstermark B, Sasaki S. 1985. Integration in descending motor pathways controlling the forelimb in the cat. 13. Corticospinal effects in shoulder, elbow, wrist, and digit motoneurones. Exp. Brain Res. 59:35364 Alstermark B, Sasaki S. 1986. Integration in descending motor pathways controlling the forelimb in the cat. 15. Comparison of the projection from excitatory C3-C4 propriospinal neurones to different species of forelimb motoneurones. Exp. Brain Res. 63:54356 Bernhard CG, Bohm E. 1954. Cortical representation and functional signicance of the corticomotoneuronal system. Arch. Neurol. Psychiat. 72:473502 Blagovechtchenski E, Pettersson LG, Perliev S, Krasnochokova E, Lundberg A. 2000. Control of digits via C3-C4 propriospinal neurones in cats; recovery after lesions. Neurosci. Res. 38:1037 Brown TG. 1911. The intrinsic factors in the act of progression in the mammal. Proc. R. Soc. Lond. Ser. B 84:30919 Christensen MS, Kristiansen L, Rowe JB, Nielsen JB. 2008. Action-blindsight in healthy subjects after transcranial magnetic stimulation. Proc. Natl. Acad. Sci. USA 105:135357 Clendenin M, Ekerot CF, Oscarsson O. 1974. The lateral reticular nucleus in the cat. III. Organization of component activated from the ipsilateral forelimb tract. Exp. Brain Res. 21:50113 Creed RS, Denny-Brown DE, Eccles JC, Liddell EGT, Sherrington CS. 1932. Reex Activity of the Spinal Cord. London: Oxford Univ. Press
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Day BL, Brown P. 2001. Evidence for subcortical involvement in the visual control of human reaching. Brain 124:183240 Day BL, Lyon IN. 2000. Voluntary modication of automatic arm movements evoked by motion of a visual target. Exp. Brain Res. 130:15968 Ekerot CF. 1990. The lateral reticular nucleus in the cat. VI. Excitatory and inhibitory paths. Exp. Brain Res. 79:10919 Flynn JR, Graham BA, Galea MP, Callister RJ. 2011. The role of propriospinal interneurons in recovery from spinal cord injury. Neuropharmacology 60:80922 Fujito Y, Aoki M. 1995. Monosynaptic rubrospinal projections to distal forelimb motoneurons in the cat. Exp. Brain Res. 105:18190 Goodale MA, Westwood DA. 2004. An evolving view of duplex vision: separate but interacting cortical pathways for perception and action. Curr. Opin. Neurobiol. 2:20311 Illert M, Lundberg A. 1978. Collateral connections to the lateral reticular nucleus from cervical propriospinal neurones projecting to forelimb motoneurones in the cat. Neurosci. Lett. 7:16772 Illert M, Lundberg A, Tanaka R. 1977. Integration in descending motor pathways controlling the forelimb in the cat. 3. Convergence on propriospinal neurones transmitting disynaptic excitation from the corticospinal tract and other descending tracts. Exp. Brain Res. 29:32346 Illert M, Wiedemann E. 1984. Pyramidal actions in identied radial motor nuclei of the cat. Pugers Arch. 41:13242 Isa T, Ohki Y, Alstermark B, Pettersson LG, Sasaki S. 2007. Direct and indirect cortico-motoneuronal pathways and control of hand/arm movements. Physiology 22:14552 Isa T, Ohki Y, Seki K, Alstermark B. 2006. Properties of propriospinal neurons in the C3-C4 segments mediating disynaptic pyramidal excitation to forelimb motoneurones in the Macaque monkey. J. Neurophysiol. 95:367485 Kitazawa S, Ohki Y, Sasaki M, Xi M, Hongo T. 1993. Candidate premotor neurons of skin reex pathways to T1 forelimb motoneurons of the cat. Exp. Brain Res. 95:291307 Kuypers HG. 1982. A new look at the organization of the motor system. Prog. Brain Res. 57:381403 Landgren S, Phillips CG, Porter R. 1962. Cortical elds of origin of the monosynaptic pyramidal pathways to some alpha motoneurones of the baboons hand and forearm. J. Physiol. 161:11225 Lawrence DG, Kuypers HGJM. 1968a. The functional organization of the motor system in the monkey. I. The effects of bilateral pyramidal lesions. Brain 91:114 Lawrence DG, Kuypers HGJM. 1968b. The functional organization of the motor system in the monkey. II. The effects of lesions of the descending brain-stem pathways. Brain 91:1536 Lemon RN. 2008. Descending pathways in motor control. Annu. Rev. Neurosci. 31:195218 Lloyd DPC. 1941. The spinal mechanism of the pyramidal system in cats. J. Neurophysiol. 4:52546 Lundberg A. 1999. Descending control of forelimb movements in the cat. Brain Res. Bull. 50:32324 Lundberg A, Voorhoeve P. 1962. Effects from the pyramidal tract on spinal reex arcs. Acta Physiol. Scand. 56:20119 Malmgren K, Pierrot-Deseilligny E. 1988. Evidence for non-monosynaptic Ia excitation of human wrist exor motoneurones, possibly via propriospinal neurones. J. Physiol. 405:74764 Marchand-Pauvert V, Mazevet D, Pradat-Diehl P, Alstermark B, Pierrot-Deseilligny E. 2001. Interruption of a relay of corticospinal excitation by a spinal lesion at C6-C7. Muscle Nerve 24:155461 Matsuyama K, Drew T. 1997. Organization of the projections from the pericruciate cortex to the pontomedullary brainstem of the cat: a study using the anterograde tracer Phaseolus vulgaris-leucoagglutin. J. Comp. Neurol. 389:61741 Nishimura Y, Isa T. 2011. Cortical and subcortical compensatory mechanisms after spinal cord injury in monkeys. Exp. Neurol. Epub ahead of print Nishimura Y, Morichika Y, Isa T. 2009. A subcortical oscillatory network contributes to recovery of hand dexterity after spinal cord injury. Brain 132:70921 Nishimura Y, Onoe H, Morichika Y, Perliev S, Tsukada H, Isa T. 2007. Time-dependent central compensatory mechanisms of nger dexterity after spinal cord injury. Science 318:115055 Peterson B, Pitts NG, Fukushima K. 1979. Reticulospinal connections with limb and axial motoneurons. Exp. Bran Res. 36:120
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Pettersson LG, Alstermark B, Blagovechtchenski E, Isa T, Sasaki S. 2007. Skilled digit movements in feline and primate-recovery after selective spinal cord lesions. Acta Physiol. 189:14154 Pettersson LG, Lundberg A, Alstermark B, Isa T, Tantisira B. 1997. Effect of spinal cord lesions on forelimb target-reaching and on visually guided switching of target-reaching in the cat. Neurosci. Res. 29:24156 Pettersson LG, Perliev S. 2002. Descending pathways controlling visually guided updating of reaching in cats. Eur. J. Neurosci. 16:134960 Pierrot-Deseilligny E, Burke D. 2005. The Circuitry of the Human Spinal Cord. Cambridge, UK: Cambridge Univ. Press Pruszynki JA, King GL, Boisse L, Scott S, Flanagan JR, Munoz DP. 2010. Stimulus-locked responses on human arm muscles reveal rapid neural pathway linking visual input to arm motor output. Eur. J. Neurosci. 32:104957 Renshaw B. 1940. Activity in the simplest spinal reex pathways. J. Neurophysiol. 3:37387 Riddle CN, Edgley SA, Baker SN. 2009. Direct and indirect connections with upper limb motoneurons from the primate reticulospinal tract. J. Neurosci. 29:499399 Sasaki S, Isa T, Pettersson LG, Alstermark B, Naito K, et al. 2004. Dexterous nger movements in primate without monosynaptic corticomotoneuronal excitation. J. Neurophysiol. 92:314247 Shapovalov AI. 1975. Neuronal organization and synaptic mechanisms of supraspinal motor control in vertebrates. Rev. Physiol. Biochem. Pharmacol. 72:154 Sherrington CS. 1906. The Integrative Action of the Nervous System. New Haven, CT/London: Yale Univ. Press Werner W. 1993. Neurons in the primate superior colliculus are active before and during arm movements to visual targets. Eur. J. Neurosci. 5:33540 Yamamoto M, Wada N, Kitabatake Y, Watanabe D, Anzai M, et al. 2003. Reversible suppression of glutamatergic neurotransmission of cerebellar granule cells in vivo by genetically manipulated expession of tetanus neurotoxin light chain. J. Neurosci. 23:675967
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Circuits For Skilled Reaching and Grasping

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NE35CH26-Alstermark

Circuits for Skilled Reaching and Grasping

Bror Alstermark,1 and Tadashi Isa2

Higher motor centers

Higher motor centers

Interneuron Common path Motoneuron

Final common path

Primary afferent Muscle spindle

Joint Muscle Skin

Electrophysiological technique for analyzing circuitry

Spatial facilitation of disynaptic EPSP Stimuli 2 and 3 2 3 2 1

The C3 C4 propriospinal system

ReST RuST CST

Reaching + grasping Locomotion

sIN Locomotion oco ot o

REACHING AND GRASPING IN THE CAT AND MACAQUE MONKEY

Effects on reaching and grasping after lesion of CST and RuST in C5

Effects on reaching and grasping after lesion of CST and RuST in C2

PN C5 Intracellular recording from MN C6 Th1

www.annualreviews.org Circuits for Reaching and Grasping

Bulbospinal systems Lateral reticular nucleus Efferent copy

ReST RuST CST C2

C5 Intracellular recording from MN

SUBCORTICAL UPDATING OF CORTICAL COMMAND TO THE C3-C4 PROPRIOSPINAL NEURONS

Inhibitory feedback control of reaching

Extracellular 250 275 350 400

Rest PN C3C4 Lesion C6 Th1 MN Skin afferent Stretch IN Stretch

FEEDBACK INHIBITORY CONTROL OF REACHING VIA C3-C4 PROPRIOSPINAL NEURONS

PROPRIOSPINAL PATHWAYS IN HUMANS

NEW TECHNIQUES FOR INVESTIGATING THE FUNCTION OF NEURAL CIRCUITS

FUNCTIONAL RECOVERY FOLLOWING SPINAL CORD INJURY

Motor nuclei extracellular fields

PEST eGFP eTeNT WPRE LTR

Extracellular recording from motor nuclei

Dox rtTAV16 eGFP eTeNT TRE

www.annualreviews.org Circuits for Reaching and Grasping

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