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Neural bases of goal-directed locomotion in vertebrates—An overview
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v
Review
Neural bases of goal-directed locomotion in vertebrates—An overview Sten Grillner⁎, Peter Wallén, Kazuya Saitoh, Alexander Kozlov, Brita Robertson The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden
A R T I C LE I N FO
AB S T R A C T
Article history:
The different neural control systems involved in goal-directed vertebrate locomotion are
Accepted 20 June 2007
reviewed. They include not only the central pattern generator networks in the spinal cord
Available online 16 August 2007
that generate the basic locomotor synergy and the brainstem command systems for locomotion but also the control systems for steering and control of body orientation
Keywords:
(posture) and finally the neural structures responsible for determining which motor
Basal ganglia
programs should be turned on in a given instant. The role of the basal ganglia is considered
Lamprey
in this context. The review summarizes the available information from a general vertebrate
Central pattern generator
perspective, but specific examples are often derived from the lamprey, which provides the
Tectum
most detailed information when considering cellular and network perspectives.
Brain stem–spinal cord
© 2007 Elsevier B.V. All rights reserved.
Modeling
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. The brainstem–spinal cord locomotor synergy . . . . . . . . . . . . . . . 3. Integration of posture and locomotion—a requirement for all vertebrates 4. The basic machinery underlying steering of locomotor movements . . . 5. Goal-directed aspects of locomotion—mammalian perspective . . . . . . 6. Forebrain control of movement—the lamprey model. . . . . . . . . . . . 7. From the lamprey CPG to the mammalian CPG . . . . . . . . . . . . . . . 8. In conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. Fax: +46 8 349544. E-mail address: [email protected] (S. Grillner). Abbreviations: AE, ankle extensor; AF, ankle flexor; CPG, central pattern generator; cpo, postoptic commissure; D, diencephalon; DA, dopamine; DLR, diencephalic locomotor region; EDB, extensor digitorum brevis; EIN, excitatory interneuron; EmTh, eminentia thalami; FE, foot extensor; FF, foot flexor; HE, hip extensor; HF, hip flexor; Hb, habenula; Hyp, hypothalamus; I, inhibitory interneuron; KE, knee extensor; KF, knee flexor; LPal, lateral pallium; M, motoneuron; MLR, mesencephalic locomotor region; MPal, medial pallium; NCPO, nucleus of the postoptic commissure; ot, optic tract; PO, preoptic nucleus; R, rhombencephalon; RS, reticulospinal neurons; RS(L), left reticulospinal neurons; RS(R), right reticulospinal neurons; sc, spinal cord; SR, stretch receptor neuron; SR-E, excitatory stretch receptor neuron; SR-I, inhibitory stretch receptor neuron; Str, striatum; T, telencephalon 0165-0173/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2007.06.027
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1.
Introduction
In this brief report, we will provide an overview of the different components of the control systems involved in generating goal-directed locomotion in vertebrates. It is written from a general vertebrate perspective, but will provide more detailed examples from the lamprey system. Fig. 1 summarizes the different subsystems that need to be considered and that will be discussed below. The motor pattern itself is generated at the spinal level by central pattern generator networks (CPGs). The CPGs are modulated by movement-related sensory feedback that can adapt the movements to unexpected perturbations (Grillner et al., 1981; Grillner, 1981, 1985, 2003; Rossignol et al., 2006). The level of activity is determined from the brainstem locomotor command systems (see Orlovsky et al., 1999). The basal ganglia plays a critical role for determining which motor program should be active at a given instant. At rest the different motor programs in the brainstem are subject to a powerful tonic inhibition (Grillner et al., 2005a; Hikosaka, 2007). It is only when for instance the MLR is disinhibited that locomotion will be initiated (see Grillner, 2006; Ménard et al., 2007).
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In addition to regulating the level of locomotor activity, a number of other control systems must operate to achieve behaviourally meaningful locomotor movements (see Fig. 1). The movements must be steered towards different targets of interest for the individual, whether fish or primate. Steering commands need to be issued. The optic tectum/superior colliculus plays an important role in this context and the commands are mediated via reticulospinal pathways to the spinal cord (Fagerstedt et al., 2001; Saitoh et al., 2007). The individual must also be able to maintain the body orientation whether swimming, walking or flying. The postural control systems therefore play a critical role. Vestibular receptors provide information about the orientation and movements of the head and sensory input from the limbs and trunk provide important complementary information (Deliagina et al., 2006; Deliagina and Orlovsky, 2002). We will start from the CPG level in Fig. 1 and work our way upwards to the more complex processes underlying the selection of different motor programs, to finally return to the lamprey CPG and whether an understanding of this circuitry can provide an insight into the mammalian CPGs for limb motor control.
2. The brainstem–spinal cord locomotor synergy
Fig. 1 – Subsystems involved in the control of goal-directed locomotion. Selection of a motor program is performed in the basal ganglia, which receives inputs from the cortex (pallium) and the thalamus. The basal ganglia output stage (pallidum) inhibits command centres in the diencephalic locomotor region (DLR) and the mesencephalic locomotor region (MLR) during resting conditions. Through a well-controlled inhibition of pallidal regions, the spinal CPG for locomotion can be activated via the reticulospinal (RS) neurons. In the brainstem, information is further integrated based on visual, sensory and vestibular inputs to control both steering and posture. In all vertebrates, the spinal cord CPG neurons are modulated by local sensory feedback.
In all vertebrates, networks coordinating the basic propulsive movement synergy are located at the spinal level, whether in fish swimming, bird flight or mammalian locomotion. These networks, usually referred to as CPGs, are responsible for the sequential activation of the different motoneuron/muscle groups taking part in the movement (Grillner et al., 1981; Grillner, 1981, 1985, 2003; Rossignol et al., 2006). Below follows a brief account of the intrinsic function of these networks, in terms of cellular and synaptic integration of function. In most cases, these networks are silent at rest and need to be activated from the brainstem command centres, the mesopontine (MLR) and the diencephalic (DLR) locomotor regions, which via reticulospinal neurons regulate the activity level of the spinal CPGs. In some cases, in species which move continuously, the spinal CPGs are active even after a complete spinal transection like in the dogfish (Steiner, 1886; Grillner, 1974). The command regions for locomotion (MLR – DLR) are evolutionarily conserved and stimulation of these regions gives rise to walking, trotting or galloping in tetrapods like cats, depending on stimulation strengths. Stimulation of the same region in a bird gives rise to walking and at higher strengths flapping movements of the wings, and finally in a fish or a lamprey swimming is initiated at progressively higher speeds. MLR is located at the mesopontine boarder at the caudal pole of the cholinergic pedunculopontine and the cuneiform nuclei (see Orlovsky et al., 1999). The output from the locomotor region to the reticulospinal neurons is bilateral, symmetric and comprises a mixed EPSP mediated by both cholinergic (nicotinic) and glutamatergic receptors (Le Ray et al., 2003; Dubuc, this volume; Noga et al., 2003). The link from the MLR/DLR to the reticulospinal neurons and to the CPGs thus provides the direct command for
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propulsion. In addition to the direct glutamatergic control system, a number of modulator systems appear to contribute (see Grillner, 2003; Kettunen et al., 2005; El Manira and Wallén, 2000; Kiehn, 2006) in most, if not all vertebrates, such as the raphespinal 5-HT system (in some vertebrates also an intraspinal 5-HT system) and furthermore the noradrenergic coeruleospinal system. Both these systems are turned on during locomotor activity and seem to promote an optimal mode of operation of the CPGs. These slow conducting systems, which act mostly via G-protein-coupled metabotropic receptors, are able to “optimise” the neuronal properties by modulating different ionic currents/channels and also to be responsible for presynaptic inhibitory/facilitatory mechanisms on the presynaptic terminals of different interneurons and afferents. One can thus assume that the modulator systems set the stage for the fast glutamatergic control mediated by the reticulospinal system that regulates the activity level at the millisecond level.
3. Integration of posture and locomotion—a requirement for all vertebrates All vertebrates control their body orientation during locomotion mostly with the dorsal side up except for bipeds like humans. For swimming animals, like the lamprey, the main bases for the control is input from the gravistatic receptors in the vestibular system. These receptors sense any deviation from the normal dorsal side up position (Deliagina and Orlovsky, 2002). In this “desired” position, the vestibular afferents on the two sides have approximately equal and relatively low discharge rate and their activity is in balance (Fig. 2A). Any deviation (roll tilt) will lead to an asymmetric activity so that the receptors on one side increase their discharge rate and those on the other side decrease to a corresponding degree. The input from the vestibular afferents on the two sides is channelled via the vestibular nuclei to the reticulospinal neurons in the different brainstem reticulospinal nuclei (Fig. 2A), which in turn send corrective signals to the different classes of motoneurons controlling the dorsal and ventral muscle segments, respectively (Deliagina and Orlovsky, 2002). Most likely the vestibular system plays the same role for controlling the orientation of the head in tetrapods, but they have in addition a significant input from the limbs that sense the relative load and orientation of each limb. These spinal inputs also play a prominent role for the orientation of the body (see Deliagina et al., 2006). The control of body orientation and posture is clearly fundamental for a successful control of locomotion in a complex natural environment. The control system for propulsion and body orientation thus needs to be integrated. One point at which the integration takes place is the reticulospinal system. The signals for propulsion from the locomotor command regions activate broadly reticulospinal neurons, and the vestibular signals in turn modulate the descending activity in selected groups of reticulospinal neurons (Fig. 2A; Zelenin et al., 2007). There is consequently a sharing of function between these two control systems. In the lamprey, the neurons of the anterior, middle and posterior rhombence-
Fig. 2 – Schematic representation of the control systems for control of body orientation (A) and steering (B). (A) The vestibular system has a key role in the control of body orientation during locomotion. The gravistatic sensors sense the orientation of the head and will thereby detect any deviation of the position of the head from the dorsal side up position (e.g. in lamprey). Via vestibular interneurons, they activate reticulospinal neurons. With the dorsal side up, the input from the vestibular receptors will be symmetric and thereby the activity of the reticulospinal system. In the diagram, the activity of the reticulospinal populations on the right (RS(R)) and on the left side (RS(L)) are represented. Any deviation to the left or right side will lead to an asymmetric activity of the left and right reticulospinal populations. This asymmetry will lead to a correction of body position. (B) The locomotor command system will elicit a symmetric reticulospinal activity on the right R-RS and left (L-RS) side (middle trace – straight). A steering command to the right will be produced by any signal that will enhance the reticulospinal activity on the right side and/or lower it on the left side (right turn). The converse changes would produce a turn to the left (left turn).
phalic reticular nuclei respond to different degrees of tilt, with the anterior being most active when the body orientation is upside down, while the middle and posterior respond maximally at a tilt of 90° and 45°, respectively. Whereas all vertebrates control the body orientation during swimming, the amphioxus, a protochordate, swims in a spiral trajectory with no postural stabilization . It has developed a spinal cord but the brainstem is rudimentary. Many invertebrates, however, actually stabilize their position like arthropods and molluscs, and they have developed
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vestibular gravistatic systems of different kinds (Deliagina et al., 1998).
4. The basic machinery underlying steering of locomotor movements Whereas the propulsive machinery provides the basis for forward movements, a steering control needs to be added to enable the animal to reach different points in the environment. Again the situation in water-living animals, like the lamprey, is relatively simple. The steering commands can be studied in both intact and reduced preparations (Fagerstedt et al., 2001; Kozlov et al., 2002). Swimming movements can be elicited in the lamprey–brainstem spinal cord semi-intact preparations. Under the most simple experimental conditions a cutaneous input via the trigeminal nerve will, via interneurons in the brainstem, give rise to an activation of contralateral reticulospinal neurons (Fig. 2B), which thereby generate a larger and longer burst of activity, which in turn results in a stronger activation of the motoneurons on this side and thereby a turning movement. Essentially an asymmetric activity between the two reticulospinal populations on each side will result in a turning movement. Again the situation is more complex in terrestrial animals including humans. In the latter case the foot is rotated during the swing phase, and when the foot is put down on the ground its orientation will be towards the desired new direction of walking, and the body will then be rotated in the new direction during the following support phase (see Grillner, 1981).
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5. Goal-directed aspects of locomotion— mammalian perspective So far we have described the neural mechanism underlying propulsion, control of body orientation and steering with regard purely to the neural control mechanisms used. In order for these different motor programs to be useful in a behavioural context, they need to be adapted to the environment, which requires a more complex form of sensory–motor integration. The forebrain is required for adaptive movements to occur, in particular the basal ganglia and related structures. It is noteworthy that decorticate mammals like cats and rabbits display a quite advanced adaptive behaviour provided that the basal ganglia remain intact with their thalamic innervation. These decorticate mammals can thus move around in a seemingly normal way, search for food, eat and remember the location of the food, and go through phases of activity and rest (sleep). They can display attack behaviour and sham rage (Bjursten et al., 1976). This shows that basic features of goal-directed behaviour can be generated by subcortical forebrain structures together with the brainstem spinal cord. When the cortex is intact, it obviously contributes via the very extensive corticostriatal projections but also with the direct corticopontine and corticospinal projections. One important role for the corticospinal projections in primates, as well as other mammals, appears to be the generation of skilled hand and finger movements and speech (human) motor coordination. Primates with a selective lesion of the corticospinal tract lose the ability to perform indepen-
Fig. 3 – The basal ganglia control CPG activity – schematic diagram. The cerebral cortex in mammals and the corresponding structures in lower vertebrates (pallium) have an excitatory (red) output to the striatum, the input layer of the basal ganglia, which is also activated from the thalamus directly. The striatum consists of inhibitory (blue) GABAergic neurons (95% projecting medium spiny neurons), which have a very high threshold for activation. They are therefore difficult to activate, and may be regarded as a filter for cortical input. The striatum is composed of different subpopulations of neurons. They inhibit the output layer of the basal ganglia, the pallidum (several different nuclei), which consists of GABAergic neurons with a very high level of resting activity, keeping the different CPGs under tonic inhibition. CPG activity is only released when the appropriate striatal subpopulation is activated and inhibits pallidum, resulting in a disinhibition of a particular CPG. The dopamine (DA) input to the striatum has a powerful effect in controlling the responsiveness of striatal neurons. The basal ganglia thus have a very important role in determining which CPGs should be active at a given instant. This diagram only includes what is often referred to as the direct loop, and not the indirect (“braking”) loop via the subthalamic nucleus.
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dent finger movements but are otherwise minimally affected with regard to motor behaviour (Lawrence and Kuypers, 1968). In the context of locomotion, the corticospinal pathway contributes in precision walking requiring an exact foot placement in, for instance, an uneven terrain (Bretzner and Drew, 2005; Drew, this volume). The optic tectum or the superior colliculus in mammals serves as a centre for eye and orientation movements of the body and can also induce locomotor movements. The tectum contains a detailed motor map, which can elicit eye and orientation movements in different directions and of different amplitudes (Hikosaka et al., 2000; Sparks, 2002; Isa, 2002). In addition, there is a retinotopic projection to the tectum, which matches the motor map, so that input from a given point of the retina may result in a movement that rotates the eye in this direction, so that the image is projected in the fovea centralis or corresponding areas to obtain as detailed an image as possible. An image that falls on the retina and for some reason is considered to be of interest may thus result in an eye movement and an orientation movement of the head and body, which may result in a goal-directed action like locomotion towards an object of interest, like a prey or a partner. In amphibians, targeted movements of the extended tongue to catch insects flying by are also generated via the tectum. For the optic tectum to generate a movement, another factor is also required which is a removal of the tonic inhibition that is produced from the pallidal output nuclei of the basal ganglia (substantia nigra, zona reticulata). It appears that subpopulations of pallidal neurons are involved in the control of different types of eye and orientation movements and also of other brainstem motor centres like those controlling locomotion and posture (Fig. 3). These output structures have a very high level of resting inhibitory GABAergic activity, the purpose of which appears to be to keep all motor centres under inhibitory control so that an unintended movement is not triggered. The release of a movement can therefore be initiated only when the inhibition has been lifted off a particular region of the tectum or a brainstem command centre like the MLR. What is the mechanism by which a disinhibition can be achieved? Basically the output nuclei receive an inhibitory input from the striatum, the input layer of the basal ganglia. The striatal inhibitory medium's spiny projection neurons are silent at rest and very difficult to activate due to particular membrane properties (K+ current – inward rectifiers). Only a strong activation from the cortex or the thalamus can lead to a sufficient depolarisation with an “upstate” with action potentials. When these cells are activated, they will produce a powerful inhibition of the pallidal output stage which in turn leads to a disinhibition of the target structures (Fig. 3). The sensitivity of the medium spiny neurons is powerfully modulated by dopaminergic neurons. All vertebrates appear to have this type of organisation with a striatum that is difficult to activate and, more or less, serves as a filter for cortical and thalamic inputs (see Grillner et al., 2005b; Grillner, 2006). This striatal filter depends critically on the dopamine innervation. The striatal neurons are very difficult to activate without a concurrent dopamine activity. Without appropriate dopamine innervation, a Parkinson-like condition will consequently develop. The converse is true when too much
dopamine is released, which can give rise to hyperkinesias and unintended movements. The pallidal output neurons can also be rapidly turned on by a direct activation from the cortex to the subthalamic nucleus, which provides glutamatergic excitation to the GABAergic pallidal output neurons, and thereby an efficient inhibition of the pallidal target structures. This nucleus can also be activated via a subset of medium spiny neurons, which via the external globus pallidus can influence the subthalamic nucleus. The latter nucleus appears to have a very precisely organised somatotopic control from the cortex. The striato-pallidal complex thus has a very prominent role in the control of movement – most likely it is practically impossible to elicit any goal-directed behaviour without the involvement of the basal ganglia. The striatum, however, receives a dedicated corticostriatal input from pyramidal neurons in layer 5 in a number of different cortical areas (Bolam et al., 2006). These neurons target the spines on the medium spiny neurons, presumably an indication that synaptic plasticity is a prominent feature of these synapses, and most likely they contribute to motor learning, which is considered to be an important feature of the basal ganglia, at least in mammals. In addition, the striatum receives an extensive input from the thalamus and in particular from the intralaminar nuclei, which partially project directly on to the shafts of the dendrites and thus avoid the spines (Lacey et
Fig. 4 – Forebrain networks in the selection of eye, orientation and locomotor movements. Information from different parts of the retina impinges in a retinotopic fashion on the tectum to form a retinotopic sensory map that, via tectal interneurons, contact the deeper motor layer. Different parts of this motor map triggers saccadic eye movements in different directions, and longer stimuli also activates orientation movements of the body – corresponding to eye neck coordination in higher vertebrates. In the lamprey, a further prolongation of the stimulus can also elicit locomotion. An additional direct retinal projection reaches the thalamus and then the cortex (in lower vertebrates called the pallium). The thalamus, in addition, provides input to the striatum that also receives input from the pallium/cortex. This pattern is conserved throughout the vertebrates. The GABAergic projection neurons in the striatum project to the pallidum, which contains tonically active inhibitory neurons that project to the different motor centres in the brainstem (tectum, MLR, and DLR).
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al., 2007). It is possible that they provide input to trigger activity in striatal subpopulations and could represent more automatic response patterns that bypass the cortex.
6. Forebrain control of movement—the lamprey model Recent studies have aimed at elucidating the neural structures rostral to the lower brainstem–spinal cord in the lamprey, which has been reviewed extensively before (Grillner, 2003), in the context of motor control. These studies have involved the control of eye, orientation and locomotor movements and also the postural adjustments adapted to different patterns of behaviour like the dorsal light response (Saitoh et al., 2007; Robertson et al., 2006, 2007). One important aspect is the demonstration that the lamprey retina provides a retinotopic projection to the tectum (Fig. 4), and that stimulation of the tectum gives rise to site-
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specific eye movements towards different points in space, and with a longer stimulation duration, also orientation movements correlated to the eye movements and finally also locomotor movements (Saitoh et al., 2007; Jones et al., 2007). These results indicate that with regard to eye and orientation movements, the lamprey tectum is organized in a similar fashion to that of higher vertebrates and that this is a conserved function within the vertebrate phylum. The lamprey tectum has the same general anatomical structure as in other vertebrates in terms of input layer for retinal afferents and a deeper output layer (Nieuwenhuys and Nicholson, 1998). The microcircuitry of the tectum is as yet not well studied. The output layer from the tectum projects to the MLR but also directly to reticulospinal neurons as a tectoreticular pathway (Zompa and Dubuc, 1998; Ménard et al., 2007). In other vertebrates, including fish, it has been demonstrated that there is a horizontal and a vertical gaze centre that can direct both eye and orientation movements of the body. The combined activation of the two can produce movement in
Fig. 5 – The lamprey basal ganglia. The upper left figure shows a transverse section of the lamprey forebrain with the striatum indicated by a red circle. Neurons of the striatum project to (see red arrows) the ventral part of the lateral pallium (LPal.) and caudally to a ventral subpallial part of the medial pallium (MPal) close to the eminentia thalami (EmTh) as indicated in the drawing to the right. These two areas contain GABAergic neurons that project either to the tectum or to both the MLR and the DLR as indicated by the blue arrows. The lower left shows a side view of the lamprey brain with the location of the striatum indicated in red. The dendrite to the right from a striatal neuron has a number of dendritic spines. Other abbreviations are cpo, postoptic commissure; D, diencephalon; Hb, habenula; Hyp, hypothalamus; NCPO, nucleus of the postoptic commissure; ot, optic tract; PO, preoptic nucleus; R, rhombencephalon; sc, spinal cord; Str, striatum; T, telencephalon.
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any direction. It is as yet unknown if this organization has been developed in cyclostomes. The lamprey has the same organisation as other vertebrates with regard to the different cranial eye motor nuclei (Fritzsch et al., 1990), and it would seem likely that the interface between the tectum and the eye motor nuclei would be organised in a similar fashion. The other structure, which is ultimately linked to the tectum and the control of movement, is the basal ganglia. In mammals, it is well known that both the tectum/superior colliculus, the MLR and postural centres receive input from GABAergic output neurons (substantia nigra, zona reticulata) of the basal ganglia, and that they provide a tonic inhibition of these respective centres. As noted above, a prerequisite for a movement to occur is that the respective motor centre is disinhibited, that is the tonic inhibition from the basal ganglia needs to be removed (Hikosaka et al., 2000; Grillner et al., 2005a). With regard to the lamprey, we have now shown that both the tectum, the MLR and the DLR receive projecting GABAergic neurons from the forebrain in an area presumed to correspond to the pallidum (Ménard et al., 2006, 2007; Robertson et al., 2006). One major location for these GABAergic projection neurons is the caudoventral part of the medial pallium close to eminentia thalami (Fig. 5), which may correspond to the entopeduncular nucleus (globus pallidus interna) as defined in the zebrafish (Wullimann and Mueller, 2004). In addition, an area in the ventral part of the lateral pallium contains GABAergic neurons projecting to these motor centres (Pombal et al., 1997b; Ménard et al., 2006, 2007). These three motor command structures appear to be under tonic GABAergic inhibition also in the lamprey, since a local injection of Gabazine (a GABAA antagonist) releases the appropriate motor activity or lowers the threshold for evoking it (Ménard et al., 2006, 2007; Robertson et al., 2007). The input layer of the lamprey striatum is composed of GABAergic spiny neurons (Fig. 5) that project to the areas in the caudo-ventral medial pallium and the ventral part of the lateral pallium, in which GABAergic projection neurons have been identified (see above). Histochemically neurons within the striatum display immunoreactivity towards enkephalins, tachykinins, acetylcholine-esterase and DARPP-32 (Pombal et al., 1997a,b; Ménard et al., 2006). Ongoing studies of the electrophysiological properties of these neurons show that one group of neurons has the hallmarks of mammalian spiny neurons in terms of being hyperpolarised at rest, expressing an inward rectifying current and an IH. Other neurons have a very brief afterhyperpolarisation and the characteristics of fast spiking interneurons (Ericsson et al., 2007a,b). The lamprey striatum receives input from the thalamus and the pallium (corresponding to the cortex in mammals) and modulatory input from dopaminergic neurons corresponding to those of the mammalian substantia nigra, as well as from 5-HT and histaminergic neurons ( Brodin et al., 1986, 1990; Pombal et al., 1997b). The question of the functional role of the dopaminergic system in the lamprey has been addressed by using MPTP, a drug that causes a dopamine denervation. MPTP induces a severe hypokinesia and difficulties in eliciting motor activity. The hypokinetic dysfunction can be restored by injection of apomorphine, which indicates that the MPTP-induced hypokinesia is due to the dopamine depletion (Grillner et al., 2000). These findings
taken together with those discussed above suggest that the structure and function of the basal ganglia with regard to input striatal structure and output has been conserved throughout vertebrate evolution and thus was present when the lamprey diverged from the main vertebrate line more than 500 million years ago.
7. CPG
From the lamprey CPG to the mammalian
Now let us return to where we started, the CPG level, and ask ourselves if the knowledge from the well-studied lamprey CPG
Fig. 6 – Locomotor network of the lamprey. Schematic representation of the forebrain, brainstem and spinal components of the neural circuitry that generates rhythmic locomotor activity. All neuron symbols denote populations rather than single cells. The reticulospinal (RS), glutamatergic neurons excite all classes of spinal interneurons and motoneurons. The excitatory interneurons (E) excite all types of spinal neurons, i.e. the inhibitory glycinergic interneurons (I) that cross the midline to inhibit all neuron types on the contralateral side and the motoneurons (M). The stretch receptor neurons are of two types; one excitatory (SR-E), which excites ipsilateral neurons and one inhibitory (SR-I), which crosses the midline to inhibit contralateral neurons. RS neurons receive excitatory synaptic input from the diencephalic and the mesencephalic locomotor regions (DLR and MLR), which in turn receive input from the basal ganglia as well as visual and olfactory input. In addition, metabotropic receptors are also activated during locomotion and are an integral part of the network (5-HT, GABA and mGluR).
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can provide insights into the operation of the mammalian more complex CPG. The main players in the lamprey segmental burst-generating network are the excitatory glutamatergic premotor interneurons (EINs) that activate motoneurons via both NMDA and AMPA receptors. EINs form a pool within each segment and excite each other, and provide the burst generating kernel (Buchanan and Grillner, 1987; Cangiano and Grillner, 2005). They are activated by reticulospinal neurons and the level of excitatory drive determines the burst rate (Fig. 6). Each population burst is determined by the synaptic interactions within the excitatory pool and by the membrane properties of EINs (Fig. 6). The entrance of calcium ions (via voltage-dependent Ca2+ channels and NMDA receptors) during the burst will activate calcium dependent potassium channels that will hyperpolarise the individual neurons and thereby close the NMDA channels and decrease the mutual facilitation within the EIN population. In addition to generating the individual bursts, the EINs also activate crossed inhibitory interneurons that coordinate the EIN kernels on the two sides so that an alternating pattern emerges. The inhibitory interneurons coordinate the reciprocal action, and also lower the burst frequency of the segmental network and make the burst pattern more robust. This system has been studied extensively
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both experimentally and through modelling. In the latter case, the different types of interneurons have been modelled in great detail with the different ion channel subtypes and also the properties of the synaptic transmission (see Grillner, 2003 and Grillner et al., in press). The lamprey CPG at the segmental level, with alternation between two sides, is thus comparatively simple. The situation is more complex in mammalian locomotion, in which each limb can be regarded as being controlled by an independent limb–CPG. The different limb–CPGs can be coupled in alternation as during walking, or in phase as in a gallop (Fig. 7, left diagram). Moreover, the two main phases of the movement can be unequal, whereas the flexion phase remains largely constant; the extension (support) phase can vary dramatically in duration from a slow walk to fast running or a gallop (Fig. 8, left diagram). Moreover, flexors and extensors generally alternate, but some particular muscles are activated in intermediate phases like certain biarticular muscles (e.g. semitendinosus). This complex pattern can be generated without sensory feedback (Grillner and Zangger, 1975). The network for a single limb also needs to be flexible, to allow the generation of locomotor movements with different limb configurations and also walking forwards, backwards
Fig. 7 – Systems of interacting unit CPGs – intralimb coordination – forward locomotion. The diagram to the left shows the four limb CPGs of a tetrapod and possible modes of coordination (in phase or alternation for fore- and hindlimbs, respectively). The CPGs are turned on by the descending drive from the MLR or the DLR. Middle diagram: Within each limb CPG there is most likely a further subdivision in unit CPGs controlling the synergists at one joint like hip (H), knee (K), ankle (A) and foot (F) extensors (E) or flexors (F). EDB (extensor digitorum brevis) has a particular pattern. The normal pattern of activity results from the interaction between the different unit CPGs at different joints. The advantage is that the unit CPGs may be recombined as in backward or forward walking, in the same way as with the different limb CPGs that can be recombined in the different gaits. Circles indicate inhibition, and forks/triangles excitation. Right: Exploratory simulation of locomotor activity, with a network arranged as in the diagram in which each unit CPG is designed in a similar way to the lamprey unit CPGs consisting of 100 excitatory interacting neurons – and the interaction between the 9-unit CPGs arranged as in the middle diagram. The output of the model network captures essential features of the locomotor output.
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Fig. 8 – Systems of interacting unit CPGs – intralimb coordination – backward locomotion. Left: The graph show that the flexion phase can be kept constant at different cycle durations, while the extension phase can vary markedly. Middle: Note that the connectivity pattern between the hip unit CPGs and the lower limb unit CPGs has been modified. Weakened synaptic projections are shown with thin lines. Right: Same representation of the motor pattern to the different muscles as in Fig. 7, during simulated backward locomotion.
and sideways. Based on lesion experiments and a variety of other evidence it was proposed that the CPG for each limb could be subdivided in different parts, unit CPGs, each of which controls one muscle group (e.g. hip flexors, hip extensors, knee flexors, etc.) (Grillner et al., 1981; Fig. 7, middle diagram). During forward locomotion the unit CPGs for extensors would be mutually excitatory and be activated together, while the flexors would be activated in a reciprocal fashion. The muscles that are active between the two main groups like hip–extensor–knee flexor muscles (semitendinosus) and some toe muscles would discharge in between the main flexor and extensor bursts. During for instance backward locomotion, the phase relationships between hip and the lower limb would be reversed (Fig. 8, middle diagram). A motor CPG organisation like this would retain maximal flexibility and could generate the whole range of coordination required to generate the different varieties of limb movements occurring during goal directed locomotion (see Fig. 7). Let us now consider if the lamprey network with the segmental excitatory kernels, simulated with a hundred EINs in each hemi-segment, can be used as a unit CPG in simulations of the limb CPG. Fig. 7 (traces to the right) shows that a motor pattern similar to that of standard forward locomotion actually can be easily generated by such a network. The pattern of model interneuronal activity is shown below. With regard to the asymmetric adaptation of flexors and extensors to the speed of locomotion, this can also be modelled with this unit CPG network configuration (Fig. 8, left diagram). With a constant excitatory drive to the flexor unit CPGs this phase can be kept constant, while the drive to the extensor unit CPGs can be varied and be made to
change in a tenfold range as during normal locomotion. A pattern appropriate for a form of backward locomotion could also be generated by changing the connectivity pattern between hip unit CPGs and the lower limb unit CPGs (Fig. 8, connectivity pattern in the middle, traces to the right). Also other possible patterns can be produced, like walking on the knees without using the feet as a child crawling on all four limbs. A model of this type is most likely a drastic simplification, but it does show that kernels of EINs forming unit CPGs in considerable detail can reproduce the complex motor pattern of the mammalian limb during locomotion. A fairly simple and flexible design of the limb CPG is thus possible to consider.
8.
In conclusion
We have provided a brief survey of the neural control of goaldirected locomotion in vertebrates, and the different control systems required to generate this complex aspect of the mammalian motor repertoire. Detailed accounts of the many different aspects of these control systems will be presented in the different chapters of this volume.
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v
Review
Neural bases of goal-directed locomotion in vertebrates—An overview Sten Grillner⁎, Peter Wallén, Kazuya Saitoh, Alexander Kozlov, Brita Robertson The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, SE-17177 Stockholm, Sweden
A R T I C LE I N FO
AB S T R A C T
Article history:
The different neural control systems involved in goal-directed vertebrate locomotion are
Accepted 20 June 2007
reviewed. They include not only the central pattern generator networks in the spinal cord
Available online 16 August 2007
that generate the basic locomotor synergy and the brainstem command systems for locomotion but also the control systems for steering and control of body orientation
Keywords:
(posture) and finally the neural structures responsible for determining which motor
Basal ganglia
programs should be turned on in a given instant. The role of the basal ganglia is considered
Lamprey
in this context. The review summarizes the available information from a general vertebrate
Central pattern generator
perspective, but specific examples are often derived from the lamprey, which provides the
Tectum
most detailed information when considering cellular and network perspectives.
Brain stem–spinal cord
© 2007 Elsevier B.V. All rights reserved.
Modeling
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. The brainstem–spinal cord locomotor synergy . . . . . . . . . . . . . . . 3. Integration of posture and locomotion—a requirement for all vertebrates 4. The basic machinery underlying steering of locomotor movements . . . 5. Goal-directed aspects of locomotion—mammalian perspective . . . . . . 6. Forebrain control of movement—the lamprey model. . . . . . . . . . . . 7. From the lamprey CPG to the mammalian CPG . . . . . . . . . . . . . . . 8. In conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author. Fax: +46 8 349544. E-mail address: [email protected] (S. Grillner). Abbreviations: AE, ankle extensor; AF, ankle flexor; CPG, central pattern generator; cpo, postoptic commissure; D, diencephalon; DA, dopamine; DLR, diencephalic locomotor region; EDB, extensor digitorum brevis; EIN, excitatory interneuron; EmTh, eminentia thalami; FE, foot extensor; FF, foot flexor; HE, hip extensor; HF, hip flexor; Hb, habenula; Hyp, hypothalamus; I, inhibitory interneuron; KE, knee extensor; KF, knee flexor; LPal, lateral pallium; M, motoneuron; MLR, mesencephalic locomotor region; MPal, medial pallium; NCPO, nucleus of the postoptic commissure; ot, optic tract; PO, preoptic nucleus; R, rhombencephalon; RS, reticulospinal neurons; RS(L), left reticulospinal neurons; RS(R), right reticulospinal neurons; sc, spinal cord; SR, stretch receptor neuron; SR-E, excitatory stretch receptor neuron; SR-I, inhibitory stretch receptor neuron; Str, striatum; T, telencephalon 0165-0173/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2007.06.027
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1.
Introduction
In this brief report, we will provide an overview of the different components of the control systems involved in generating goal-directed locomotion in vertebrates. It is written from a general vertebrate perspective, but will provide more detailed examples from the lamprey system. Fig. 1 summarizes the different subsystems that need to be considered and that will be discussed below. The motor pattern itself is generated at the spinal level by central pattern generator networks (CPGs). The CPGs are modulated by movement-related sensory feedback that can adapt the movements to unexpected perturbations (Grillner et al., 1981; Grillner, 1981, 1985, 2003; Rossignol et al., 2006). The level of activity is determined from the brainstem locomotor command systems (see Orlovsky et al., 1999). The basal ganglia plays a critical role for determining which motor program should be active at a given instant. At rest the different motor programs in the brainstem are subject to a powerful tonic inhibition (Grillner et al., 2005a; Hikosaka, 2007). It is only when for instance the MLR is disinhibited that locomotion will be initiated (see Grillner, 2006; Ménard et al., 2007).
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In addition to regulating the level of locomotor activity, a number of other control systems must operate to achieve behaviourally meaningful locomotor movements (see Fig. 1). The movements must be steered towards different targets of interest for the individual, whether fish or primate. Steering commands need to be issued. The optic tectum/superior colliculus plays an important role in this context and the commands are mediated via reticulospinal pathways to the spinal cord (Fagerstedt et al., 2001; Saitoh et al., 2007). The individual must also be able to maintain the body orientation whether swimming, walking or flying. The postural control systems therefore play a critical role. Vestibular receptors provide information about the orientation and movements of the head and sensory input from the limbs and trunk provide important complementary information (Deliagina et al., 2006; Deliagina and Orlovsky, 2002). We will start from the CPG level in Fig. 1 and work our way upwards to the more complex processes underlying the selection of different motor programs, to finally return to the lamprey CPG and whether an understanding of this circuitry can provide an insight into the mammalian CPGs for limb motor control.
2. The brainstem–spinal cord locomotor synergy
Fig. 1 – Subsystems involved in the control of goal-directed locomotion. Selection of a motor program is performed in the basal ganglia, which receives inputs from the cortex (pallium) and the thalamus. The basal ganglia output stage (pallidum) inhibits command centres in the diencephalic locomotor region (DLR) and the mesencephalic locomotor region (MLR) during resting conditions. Through a well-controlled inhibition of pallidal regions, the spinal CPG for locomotion can be activated via the reticulospinal (RS) neurons. In the brainstem, information is further integrated based on visual, sensory and vestibular inputs to control both steering and posture. In all vertebrates, the spinal cord CPG neurons are modulated by local sensory feedback.
In all vertebrates, networks coordinating the basic propulsive movement synergy are located at the spinal level, whether in fish swimming, bird flight or mammalian locomotion. These networks, usually referred to as CPGs, are responsible for the sequential activation of the different motoneuron/muscle groups taking part in the movement (Grillner et al., 1981; Grillner, 1981, 1985, 2003; Rossignol et al., 2006). Below follows a brief account of the intrinsic function of these networks, in terms of cellular and synaptic integration of function. In most cases, these networks are silent at rest and need to be activated from the brainstem command centres, the mesopontine (MLR) and the diencephalic (DLR) locomotor regions, which via reticulospinal neurons regulate the activity level of the spinal CPGs. In some cases, in species which move continuously, the spinal CPGs are active even after a complete spinal transection like in the dogfish (Steiner, 1886; Grillner, 1974). The command regions for locomotion (MLR – DLR) are evolutionarily conserved and stimulation of these regions gives rise to walking, trotting or galloping in tetrapods like cats, depending on stimulation strengths. Stimulation of the same region in a bird gives rise to walking and at higher strengths flapping movements of the wings, and finally in a fish or a lamprey swimming is initiated at progressively higher speeds. MLR is located at the mesopontine boarder at the caudal pole of the cholinergic pedunculopontine and the cuneiform nuclei (see Orlovsky et al., 1999). The output from the locomotor region to the reticulospinal neurons is bilateral, symmetric and comprises a mixed EPSP mediated by both cholinergic (nicotinic) and glutamatergic receptors (Le Ray et al., 2003; Dubuc, this volume; Noga et al., 2003). The link from the MLR/DLR to the reticulospinal neurons and to the CPGs thus provides the direct command for
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propulsion. In addition to the direct glutamatergic control system, a number of modulator systems appear to contribute (see Grillner, 2003; Kettunen et al., 2005; El Manira and Wallén, 2000; Kiehn, 2006) in most, if not all vertebrates, such as the raphespinal 5-HT system (in some vertebrates also an intraspinal 5-HT system) and furthermore the noradrenergic coeruleospinal system. Both these systems are turned on during locomotor activity and seem to promote an optimal mode of operation of the CPGs. These slow conducting systems, which act mostly via G-protein-coupled metabotropic receptors, are able to “optimise” the neuronal properties by modulating different ionic currents/channels and also to be responsible for presynaptic inhibitory/facilitatory mechanisms on the presynaptic terminals of different interneurons and afferents. One can thus assume that the modulator systems set the stage for the fast glutamatergic control mediated by the reticulospinal system that regulates the activity level at the millisecond level.
3. Integration of posture and locomotion—a requirement for all vertebrates All vertebrates control their body orientation during locomotion mostly with the dorsal side up except for bipeds like humans. For swimming animals, like the lamprey, the main bases for the control is input from the gravistatic receptors in the vestibular system. These receptors sense any deviation from the normal dorsal side up position (Deliagina and Orlovsky, 2002). In this “desired” position, the vestibular afferents on the two sides have approximately equal and relatively low discharge rate and their activity is in balance (Fig. 2A). Any deviation (roll tilt) will lead to an asymmetric activity so that the receptors on one side increase their discharge rate and those on the other side decrease to a corresponding degree. The input from the vestibular afferents on the two sides is channelled via the vestibular nuclei to the reticulospinal neurons in the different brainstem reticulospinal nuclei (Fig. 2A), which in turn send corrective signals to the different classes of motoneurons controlling the dorsal and ventral muscle segments, respectively (Deliagina and Orlovsky, 2002). Most likely the vestibular system plays the same role for controlling the orientation of the head in tetrapods, but they have in addition a significant input from the limbs that sense the relative load and orientation of each limb. These spinal inputs also play a prominent role for the orientation of the body (see Deliagina et al., 2006). The control of body orientation and posture is clearly fundamental for a successful control of locomotion in a complex natural environment. The control system for propulsion and body orientation thus needs to be integrated. One point at which the integration takes place is the reticulospinal system. The signals for propulsion from the locomotor command regions activate broadly reticulospinal neurons, and the vestibular signals in turn modulate the descending activity in selected groups of reticulospinal neurons (Fig. 2A; Zelenin et al., 2007). There is consequently a sharing of function between these two control systems. In the lamprey, the neurons of the anterior, middle and posterior rhombence-
Fig. 2 – Schematic representation of the control systems for control of body orientation (A) and steering (B). (A) The vestibular system has a key role in the control of body orientation during locomotion. The gravistatic sensors sense the orientation of the head and will thereby detect any deviation of the position of the head from the dorsal side up position (e.g. in lamprey). Via vestibular interneurons, they activate reticulospinal neurons. With the dorsal side up, the input from the vestibular receptors will be symmetric and thereby the activity of the reticulospinal system. In the diagram, the activity of the reticulospinal populations on the right (RS(R)) and on the left side (RS(L)) are represented. Any deviation to the left or right side will lead to an asymmetric activity of the left and right reticulospinal populations. This asymmetry will lead to a correction of body position. (B) The locomotor command system will elicit a symmetric reticulospinal activity on the right R-RS and left (L-RS) side (middle trace – straight). A steering command to the right will be produced by any signal that will enhance the reticulospinal activity on the right side and/or lower it on the left side (right turn). The converse changes would produce a turn to the left (left turn).
phalic reticular nuclei respond to different degrees of tilt, with the anterior being most active when the body orientation is upside down, while the middle and posterior respond maximally at a tilt of 90° and 45°, respectively. Whereas all vertebrates control the body orientation during swimming, the amphioxus, a protochordate, swims in a spiral trajectory with no postural stabilization . It has developed a spinal cord but the brainstem is rudimentary. Many invertebrates, however, actually stabilize their position like arthropods and molluscs, and they have developed
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vestibular gravistatic systems of different kinds (Deliagina et al., 1998).
4. The basic machinery underlying steering of locomotor movements Whereas the propulsive machinery provides the basis for forward movements, a steering control needs to be added to enable the animal to reach different points in the environment. Again the situation in water-living animals, like the lamprey, is relatively simple. The steering commands can be studied in both intact and reduced preparations (Fagerstedt et al., 2001; Kozlov et al., 2002). Swimming movements can be elicited in the lamprey–brainstem spinal cord semi-intact preparations. Under the most simple experimental conditions a cutaneous input via the trigeminal nerve will, via interneurons in the brainstem, give rise to an activation of contralateral reticulospinal neurons (Fig. 2B), which thereby generate a larger and longer burst of activity, which in turn results in a stronger activation of the motoneurons on this side and thereby a turning movement. Essentially an asymmetric activity between the two reticulospinal populations on each side will result in a turning movement. Again the situation is more complex in terrestrial animals including humans. In the latter case the foot is rotated during the swing phase, and when the foot is put down on the ground its orientation will be towards the desired new direction of walking, and the body will then be rotated in the new direction during the following support phase (see Grillner, 1981).
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5. Goal-directed aspects of locomotion— mammalian perspective So far we have described the neural mechanism underlying propulsion, control of body orientation and steering with regard purely to the neural control mechanisms used. In order for these different motor programs to be useful in a behavioural context, they need to be adapted to the environment, which requires a more complex form of sensory–motor integration. The forebrain is required for adaptive movements to occur, in particular the basal ganglia and related structures. It is noteworthy that decorticate mammals like cats and rabbits display a quite advanced adaptive behaviour provided that the basal ganglia remain intact with their thalamic innervation. These decorticate mammals can thus move around in a seemingly normal way, search for food, eat and remember the location of the food, and go through phases of activity and rest (sleep). They can display attack behaviour and sham rage (Bjursten et al., 1976). This shows that basic features of goal-directed behaviour can be generated by subcortical forebrain structures together with the brainstem spinal cord. When the cortex is intact, it obviously contributes via the very extensive corticostriatal projections but also with the direct corticopontine and corticospinal projections. One important role for the corticospinal projections in primates, as well as other mammals, appears to be the generation of skilled hand and finger movements and speech (human) motor coordination. Primates with a selective lesion of the corticospinal tract lose the ability to perform indepen-
Fig. 3 – The basal ganglia control CPG activity – schematic diagram. The cerebral cortex in mammals and the corresponding structures in lower vertebrates (pallium) have an excitatory (red) output to the striatum, the input layer of the basal ganglia, which is also activated from the thalamus directly. The striatum consists of inhibitory (blue) GABAergic neurons (95% projecting medium spiny neurons), which have a very high threshold for activation. They are therefore difficult to activate, and may be regarded as a filter for cortical input. The striatum is composed of different subpopulations of neurons. They inhibit the output layer of the basal ganglia, the pallidum (several different nuclei), which consists of GABAergic neurons with a very high level of resting activity, keeping the different CPGs under tonic inhibition. CPG activity is only released when the appropriate striatal subpopulation is activated and inhibits pallidum, resulting in a disinhibition of a particular CPG. The dopamine (DA) input to the striatum has a powerful effect in controlling the responsiveness of striatal neurons. The basal ganglia thus have a very important role in determining which CPGs should be active at a given instant. This diagram only includes what is often referred to as the direct loop, and not the indirect (“braking”) loop via the subthalamic nucleus.
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dent finger movements but are otherwise minimally affected with regard to motor behaviour (Lawrence and Kuypers, 1968). In the context of locomotion, the corticospinal pathway contributes in precision walking requiring an exact foot placement in, for instance, an uneven terrain (Bretzner and Drew, 2005; Drew, this volume). The optic tectum or the superior colliculus in mammals serves as a centre for eye and orientation movements of the body and can also induce locomotor movements. The tectum contains a detailed motor map, which can elicit eye and orientation movements in different directions and of different amplitudes (Hikosaka et al., 2000; Sparks, 2002; Isa, 2002). In addition, there is a retinotopic projection to the tectum, which matches the motor map, so that input from a given point of the retina may result in a movement that rotates the eye in this direction, so that the image is projected in the fovea centralis or corresponding areas to obtain as detailed an image as possible. An image that falls on the retina and for some reason is considered to be of interest may thus result in an eye movement and an orientation movement of the head and body, which may result in a goal-directed action like locomotion towards an object of interest, like a prey or a partner. In amphibians, targeted movements of the extended tongue to catch insects flying by are also generated via the tectum. For the optic tectum to generate a movement, another factor is also required which is a removal of the tonic inhibition that is produced from the pallidal output nuclei of the basal ganglia (substantia nigra, zona reticulata). It appears that subpopulations of pallidal neurons are involved in the control of different types of eye and orientation movements and also of other brainstem motor centres like those controlling locomotion and posture (Fig. 3). These output structures have a very high level of resting inhibitory GABAergic activity, the purpose of which appears to be to keep all motor centres under inhibitory control so that an unintended movement is not triggered. The release of a movement can therefore be initiated only when the inhibition has been lifted off a particular region of the tectum or a brainstem command centre like the MLR. What is the mechanism by which a disinhibition can be achieved? Basically the output nuclei receive an inhibitory input from the striatum, the input layer of the basal ganglia. The striatal inhibitory medium's spiny projection neurons are silent at rest and very difficult to activate due to particular membrane properties (K+ current – inward rectifiers). Only a strong activation from the cortex or the thalamus can lead to a sufficient depolarisation with an “upstate” with action potentials. When these cells are activated, they will produce a powerful inhibition of the pallidal output stage which in turn leads to a disinhibition of the target structures (Fig. 3). The sensitivity of the medium spiny neurons is powerfully modulated by dopaminergic neurons. All vertebrates appear to have this type of organisation with a striatum that is difficult to activate and, more or less, serves as a filter for cortical and thalamic inputs (see Grillner et al., 2005b; Grillner, 2006). This striatal filter depends critically on the dopamine innervation. The striatal neurons are very difficult to activate without a concurrent dopamine activity. Without appropriate dopamine innervation, a Parkinson-like condition will consequently develop. The converse is true when too much
dopamine is released, which can give rise to hyperkinesias and unintended movements. The pallidal output neurons can also be rapidly turned on by a direct activation from the cortex to the subthalamic nucleus, which provides glutamatergic excitation to the GABAergic pallidal output neurons, and thereby an efficient inhibition of the pallidal target structures. This nucleus can also be activated via a subset of medium spiny neurons, which via the external globus pallidus can influence the subthalamic nucleus. The latter nucleus appears to have a very precisely organised somatotopic control from the cortex. The striato-pallidal complex thus has a very prominent role in the control of movement – most likely it is practically impossible to elicit any goal-directed behaviour without the involvement of the basal ganglia. The striatum, however, receives a dedicated corticostriatal input from pyramidal neurons in layer 5 in a number of different cortical areas (Bolam et al., 2006). These neurons target the spines on the medium spiny neurons, presumably an indication that synaptic plasticity is a prominent feature of these synapses, and most likely they contribute to motor learning, which is considered to be an important feature of the basal ganglia, at least in mammals. In addition, the striatum receives an extensive input from the thalamus and in particular from the intralaminar nuclei, which partially project directly on to the shafts of the dendrites and thus avoid the spines (Lacey et
Fig. 4 – Forebrain networks in the selection of eye, orientation and locomotor movements. Information from different parts of the retina impinges in a retinotopic fashion on the tectum to form a retinotopic sensory map that, via tectal interneurons, contact the deeper motor layer. Different parts of this motor map triggers saccadic eye movements in different directions, and longer stimuli also activates orientation movements of the body – corresponding to eye neck coordination in higher vertebrates. In the lamprey, a further prolongation of the stimulus can also elicit locomotion. An additional direct retinal projection reaches the thalamus and then the cortex (in lower vertebrates called the pallium). The thalamus, in addition, provides input to the striatum that also receives input from the pallium/cortex. This pattern is conserved throughout the vertebrates. The GABAergic projection neurons in the striatum project to the pallidum, which contains tonically active inhibitory neurons that project to the different motor centres in the brainstem (tectum, MLR, and DLR).
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al., 2007). It is possible that they provide input to trigger activity in striatal subpopulations and could represent more automatic response patterns that bypass the cortex.
6. Forebrain control of movement—the lamprey model Recent studies have aimed at elucidating the neural structures rostral to the lower brainstem–spinal cord in the lamprey, which has been reviewed extensively before (Grillner, 2003), in the context of motor control. These studies have involved the control of eye, orientation and locomotor movements and also the postural adjustments adapted to different patterns of behaviour like the dorsal light response (Saitoh et al., 2007; Robertson et al., 2006, 2007). One important aspect is the demonstration that the lamprey retina provides a retinotopic projection to the tectum (Fig. 4), and that stimulation of the tectum gives rise to site-
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specific eye movements towards different points in space, and with a longer stimulation duration, also orientation movements correlated to the eye movements and finally also locomotor movements (Saitoh et al., 2007; Jones et al., 2007). These results indicate that with regard to eye and orientation movements, the lamprey tectum is organized in a similar fashion to that of higher vertebrates and that this is a conserved function within the vertebrate phylum. The lamprey tectum has the same general anatomical structure as in other vertebrates in terms of input layer for retinal afferents and a deeper output layer (Nieuwenhuys and Nicholson, 1998). The microcircuitry of the tectum is as yet not well studied. The output layer from the tectum projects to the MLR but also directly to reticulospinal neurons as a tectoreticular pathway (Zompa and Dubuc, 1998; Ménard et al., 2007). In other vertebrates, including fish, it has been demonstrated that there is a horizontal and a vertical gaze centre that can direct both eye and orientation movements of the body. The combined activation of the two can produce movement in
Fig. 5 – The lamprey basal ganglia. The upper left figure shows a transverse section of the lamprey forebrain with the striatum indicated by a red circle. Neurons of the striatum project to (see red arrows) the ventral part of the lateral pallium (LPal.) and caudally to a ventral subpallial part of the medial pallium (MPal) close to the eminentia thalami (EmTh) as indicated in the drawing to the right. These two areas contain GABAergic neurons that project either to the tectum or to both the MLR and the DLR as indicated by the blue arrows. The lower left shows a side view of the lamprey brain with the location of the striatum indicated in red. The dendrite to the right from a striatal neuron has a number of dendritic spines. Other abbreviations are cpo, postoptic commissure; D, diencephalon; Hb, habenula; Hyp, hypothalamus; NCPO, nucleus of the postoptic commissure; ot, optic tract; PO, preoptic nucleus; R, rhombencephalon; sc, spinal cord; Str, striatum; T, telencephalon.
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any direction. It is as yet unknown if this organization has been developed in cyclostomes. The lamprey has the same organisation as other vertebrates with regard to the different cranial eye motor nuclei (Fritzsch et al., 1990), and it would seem likely that the interface between the tectum and the eye motor nuclei would be organised in a similar fashion. The other structure, which is ultimately linked to the tectum and the control of movement, is the basal ganglia. In mammals, it is well known that both the tectum/superior colliculus, the MLR and postural centres receive input from GABAergic output neurons (substantia nigra, zona reticulata) of the basal ganglia, and that they provide a tonic inhibition of these respective centres. As noted above, a prerequisite for a movement to occur is that the respective motor centre is disinhibited, that is the tonic inhibition from the basal ganglia needs to be removed (Hikosaka et al., 2000; Grillner et al., 2005a). With regard to the lamprey, we have now shown that both the tectum, the MLR and the DLR receive projecting GABAergic neurons from the forebrain in an area presumed to correspond to the pallidum (Ménard et al., 2006, 2007; Robertson et al., 2006). One major location for these GABAergic projection neurons is the caudoventral part of the medial pallium close to eminentia thalami (Fig. 5), which may correspond to the entopeduncular nucleus (globus pallidus interna) as defined in the zebrafish (Wullimann and Mueller, 2004). In addition, an area in the ventral part of the lateral pallium contains GABAergic neurons projecting to these motor centres (Pombal et al., 1997b; Ménard et al., 2006, 2007). These three motor command structures appear to be under tonic GABAergic inhibition also in the lamprey, since a local injection of Gabazine (a GABAA antagonist) releases the appropriate motor activity or lowers the threshold for evoking it (Ménard et al., 2006, 2007; Robertson et al., 2007). The input layer of the lamprey striatum is composed of GABAergic spiny neurons (Fig. 5) that project to the areas in the caudo-ventral medial pallium and the ventral part of the lateral pallium, in which GABAergic projection neurons have been identified (see above). Histochemically neurons within the striatum display immunoreactivity towards enkephalins, tachykinins, acetylcholine-esterase and DARPP-32 (Pombal et al., 1997a,b; Ménard et al., 2006). Ongoing studies of the electrophysiological properties of these neurons show that one group of neurons has the hallmarks of mammalian spiny neurons in terms of being hyperpolarised at rest, expressing an inward rectifying current and an IH. Other neurons have a very brief afterhyperpolarisation and the characteristics of fast spiking interneurons (Ericsson et al., 2007a,b). The lamprey striatum receives input from the thalamus and the pallium (corresponding to the cortex in mammals) and modulatory input from dopaminergic neurons corresponding to those of the mammalian substantia nigra, as well as from 5-HT and histaminergic neurons ( Brodin et al., 1986, 1990; Pombal et al., 1997b). The question of the functional role of the dopaminergic system in the lamprey has been addressed by using MPTP, a drug that causes a dopamine denervation. MPTP induces a severe hypokinesia and difficulties in eliciting motor activity. The hypokinetic dysfunction can be restored by injection of apomorphine, which indicates that the MPTP-induced hypokinesia is due to the dopamine depletion (Grillner et al., 2000). These findings
taken together with those discussed above suggest that the structure and function of the basal ganglia with regard to input striatal structure and output has been conserved throughout vertebrate evolution and thus was present when the lamprey diverged from the main vertebrate line more than 500 million years ago.
7. CPG
From the lamprey CPG to the mammalian
Now let us return to where we started, the CPG level, and ask ourselves if the knowledge from the well-studied lamprey CPG
Fig. 6 – Locomotor network of the lamprey. Schematic representation of the forebrain, brainstem and spinal components of the neural circuitry that generates rhythmic locomotor activity. All neuron symbols denote populations rather than single cells. The reticulospinal (RS), glutamatergic neurons excite all classes of spinal interneurons and motoneurons. The excitatory interneurons (E) excite all types of spinal neurons, i.e. the inhibitory glycinergic interneurons (I) that cross the midline to inhibit all neuron types on the contralateral side and the motoneurons (M). The stretch receptor neurons are of two types; one excitatory (SR-E), which excites ipsilateral neurons and one inhibitory (SR-I), which crosses the midline to inhibit contralateral neurons. RS neurons receive excitatory synaptic input from the diencephalic and the mesencephalic locomotor regions (DLR and MLR), which in turn receive input from the basal ganglia as well as visual and olfactory input. In addition, metabotropic receptors are also activated during locomotion and are an integral part of the network (5-HT, GABA and mGluR).
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can provide insights into the operation of the mammalian more complex CPG. The main players in the lamprey segmental burst-generating network are the excitatory glutamatergic premotor interneurons (EINs) that activate motoneurons via both NMDA and AMPA receptors. EINs form a pool within each segment and excite each other, and provide the burst generating kernel (Buchanan and Grillner, 1987; Cangiano and Grillner, 2005). They are activated by reticulospinal neurons and the level of excitatory drive determines the burst rate (Fig. 6). Each population burst is determined by the synaptic interactions within the excitatory pool and by the membrane properties of EINs (Fig. 6). The entrance of calcium ions (via voltage-dependent Ca2+ channels and NMDA receptors) during the burst will activate calcium dependent potassium channels that will hyperpolarise the individual neurons and thereby close the NMDA channels and decrease the mutual facilitation within the EIN population. In addition to generating the individual bursts, the EINs also activate crossed inhibitory interneurons that coordinate the EIN kernels on the two sides so that an alternating pattern emerges. The inhibitory interneurons coordinate the reciprocal action, and also lower the burst frequency of the segmental network and make the burst pattern more robust. This system has been studied extensively
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both experimentally and through modelling. In the latter case, the different types of interneurons have been modelled in great detail with the different ion channel subtypes and also the properties of the synaptic transmission (see Grillner, 2003 and Grillner et al., in press). The lamprey CPG at the segmental level, with alternation between two sides, is thus comparatively simple. The situation is more complex in mammalian locomotion, in which each limb can be regarded as being controlled by an independent limb–CPG. The different limb–CPGs can be coupled in alternation as during walking, or in phase as in a gallop (Fig. 7, left diagram). Moreover, the two main phases of the movement can be unequal, whereas the flexion phase remains largely constant; the extension (support) phase can vary dramatically in duration from a slow walk to fast running or a gallop (Fig. 8, left diagram). Moreover, flexors and extensors generally alternate, but some particular muscles are activated in intermediate phases like certain biarticular muscles (e.g. semitendinosus). This complex pattern can be generated without sensory feedback (Grillner and Zangger, 1975). The network for a single limb also needs to be flexible, to allow the generation of locomotor movements with different limb configurations and also walking forwards, backwards
Fig. 7 – Systems of interacting unit CPGs – intralimb coordination – forward locomotion. The diagram to the left shows the four limb CPGs of a tetrapod and possible modes of coordination (in phase or alternation for fore- and hindlimbs, respectively). The CPGs are turned on by the descending drive from the MLR or the DLR. Middle diagram: Within each limb CPG there is most likely a further subdivision in unit CPGs controlling the synergists at one joint like hip (H), knee (K), ankle (A) and foot (F) extensors (E) or flexors (F). EDB (extensor digitorum brevis) has a particular pattern. The normal pattern of activity results from the interaction between the different unit CPGs at different joints. The advantage is that the unit CPGs may be recombined as in backward or forward walking, in the same way as with the different limb CPGs that can be recombined in the different gaits. Circles indicate inhibition, and forks/triangles excitation. Right: Exploratory simulation of locomotor activity, with a network arranged as in the diagram in which each unit CPG is designed in a similar way to the lamprey unit CPGs consisting of 100 excitatory interacting neurons – and the interaction between the 9-unit CPGs arranged as in the middle diagram. The output of the model network captures essential features of the locomotor output.
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Fig. 8 – Systems of interacting unit CPGs – intralimb coordination – backward locomotion. Left: The graph show that the flexion phase can be kept constant at different cycle durations, while the extension phase can vary markedly. Middle: Note that the connectivity pattern between the hip unit CPGs and the lower limb unit CPGs has been modified. Weakened synaptic projections are shown with thin lines. Right: Same representation of the motor pattern to the different muscles as in Fig. 7, during simulated backward locomotion.
and sideways. Based on lesion experiments and a variety of other evidence it was proposed that the CPG for each limb could be subdivided in different parts, unit CPGs, each of which controls one muscle group (e.g. hip flexors, hip extensors, knee flexors, etc.) (Grillner et al., 1981; Fig. 7, middle diagram). During forward locomotion the unit CPGs for extensors would be mutually excitatory and be activated together, while the flexors would be activated in a reciprocal fashion. The muscles that are active between the two main groups like hip–extensor–knee flexor muscles (semitendinosus) and some toe muscles would discharge in between the main flexor and extensor bursts. During for instance backward locomotion, the phase relationships between hip and the lower limb would be reversed (Fig. 8, middle diagram). A motor CPG organisation like this would retain maximal flexibility and could generate the whole range of coordination required to generate the different varieties of limb movements occurring during goal directed locomotion (see Fig. 7). Let us now consider if the lamprey network with the segmental excitatory kernels, simulated with a hundred EINs in each hemi-segment, can be used as a unit CPG in simulations of the limb CPG. Fig. 7 (traces to the right) shows that a motor pattern similar to that of standard forward locomotion actually can be easily generated by such a network. The pattern of model interneuronal activity is shown below. With regard to the asymmetric adaptation of flexors and extensors to the speed of locomotion, this can also be modelled with this unit CPG network configuration (Fig. 8, left diagram). With a constant excitatory drive to the flexor unit CPGs this phase can be kept constant, while the drive to the extensor unit CPGs can be varied and be made to
change in a tenfold range as during normal locomotion. A pattern appropriate for a form of backward locomotion could also be generated by changing the connectivity pattern between hip unit CPGs and the lower limb unit CPGs (Fig. 8, connectivity pattern in the middle, traces to the right). Also other possible patterns can be produced, like walking on the knees without using the feet as a child crawling on all four limbs. A model of this type is most likely a drastic simplification, but it does show that kernels of EINs forming unit CPGs in considerable detail can reproduce the complex motor pattern of the mammalian limb during locomotion. A fairly simple and flexible design of the limb CPG is thus possible to consider.
8.
In conclusion
We have provided a brief survey of the neural control of goaldirected locomotion in vertebrates, and the different control systems required to generate this complex aspect of the mammalian motor repertoire. Detailed accounts of the many different aspects of these control systems will be presented in the different chapters of this volume.
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