Evolution of the vertebrate motor system — from forebrain to spinal cord

A comparison of the vertebrate motor systems of the oldest group of now living vertebrates (lamprey) with that of mammals shows that there are striking similarities not only in the basic organization but also with regard to synaptic properties, transmitters and neuronal properties. The lamprey dorsal pallium (cortex) has a motor, a visual and a somatosensory area, and the basal ganglia, including the dopamine system, are organized in a virtually identical way in the lamprey and rodents. This also applies to the midbrain, brainstem and spinal cord. However, during evolution additional capabilities such as systems for the control of foreleg/arms, hands and fingers have evolved. The findings suggest that when the evolutionary lineages of mammals and lamprey became separate around 500 million years ago, the blueprint of the vertebrate motor system had already evolved.


Introduction
My focus here will be on the evolution of the vertebrate motor system and the changes that occur within the vertebrate phylum. The precursors are the protochordate, such as Ciona intestinalis, that in its larval stage swims with lateral undulations and has a brainstemspinal cord with a limited number of neurons (80e 100) [1], and the cephalochordates (Amphioxus) have a well-developed spinal cord and a brain vesicle but not an actual brain [2e4]. The latter swim with lateral undulations in spirals and does not stabilize the dorsal side up orientation in contrast to vertebrates. These two species differ very significant from cyclostomes (lamprey), which represents the oldest group of extant vertebrates. The lamprey has a fully developed CNS, which includes a small forebrain, with all its components, as well as midbrain, brainstem and spinal cord [5e7]. The cerebellum is, however, vestigial in lampreys. All other groups of vertebrates have a cerebellum, as well as all other parts of the brain, and in addition of course a variety of specializations.
The midbrainebrainstemespinal cord in all vertebrates contains the different neuronal networks that are used for the execution and coordination of standard movements, such as locomotion, postural adjustments, eye and orienting movements and oral motor programs. These parts of the nervous system are thus specialized for the execution of movement, and the different motor programs can actually be performed without the involvement of the forebrain. However, to recruit motor programs in the context of being adapted to the demands of the surrounding world, the involvement of the forebrain is required. It is responsible for interpreting the surrounding world and determining which action to take, that is, which motor program should be called into action. Selection of behaviour, motor learning and cognitive processing are tasks for the forebrain to solve. In this review, I will first discuss the forebrain, and then the networks responsible for the execution of movements in an evolutionary perspective, and mainly compare two extremes, the lamprey representing the oldest group and the newcomers, the mammals.

Pallium/cortex
In the lamprey, the dorsal pallium, the area which later will become the neocortex, comprises three main areas. The first processes visual information from different parts of the retina and is arranged in a retinotopic fashion (as in the mammalian V1). In reptiles, there is a visual representation in the dorsal cortex and the related telencephalic dorsal ventricular ridge, but only the latter is retinotopic [8,9]. The second corresponds to a somatosensory representation and finally a separate motor area [7,10,11] (Figure 1g). Stimulation of the latter area elicits eye and orienting movements, oral movements or locomotion (Figure 1aee). This motor area contains neurons that project to different motor centres, such as the midbrain (tectum/superior colliculus), tegmentum, reticulospinal neurons and rostral spinal cord, and in addition, there are projections to the striatum and thalamus (Figure 1f). This corresponds to the efferent projection pattern of mammalian pyramidal tract projections in the motor areas, such as M1. There are also

Current Opinion in Neurobiology
The lamprey motor pallium. olfactory projections to a primordial piriform cortex in the ventral part of pallium [12] (Figure 1h) as in mammals.
The lamprey cortex/pallium is three-layered with a molecular layer, containing few neurons, an inner and outer cellular layer with altogether 22% GABA interneurons and the remainder being glutamatergic cells. The latter include thalamorecipient cells, the pyramidal tract projections-type neurons mentioned previously, and neurons that project to the contralateral pallium and the striatum, intratelencephalic neurons. Single-cell RNA-seq has not yet been performed on the lamprey forebrain, but it can be noted that in the dorsal cortex of the turtle, the GABA interneurons appear to be conserved when compared with the mouse [13,14]. The situation is less clear with the glutamatergic neurons, and in mice, there is a large variety [15]. There are thus visual, somatosensory and motor areas present in the lamprey that represent essential building blocks of the mammalian neocortex, as well as the basic cellular types of the cortical circuitry. The number of neurons in the neocortex has increased dramatically during evolution from lamprey to mouse and man. This will, of course allow, for a more elaborate processing and interpretation of the surrounding world, but the essential 'Bauplan' was developed already very early in vertebrate evolution.
Basal ganglia and the dopamine system The lamprey basal ganglia are organized in a very similar way to that of mammals (Figure 2a and b) with regard to cell types, transmitters, neuropeptides and connectivity [6,16]. It contains all parts of what is usually called the direct pathway involving the striatal projection neurons expressing D1-receptors that project to the spontaneously active basal ganglia output neurons in the substantia nigra, pars reticulata (SNr) (Figure 2a). This pathway promotes movement initiation because it inhibits the inhibitory SNr neurons, which project to different brainstem motor centres eliciting, for example, locomotion or saccadic eye movements. The basal ganglia also have all components of the indirect pathway with striatal projection neurons expressing D2 receptors, the net effect of which is to enhance the inhibitory output from the SNr and hence terminate ongoing motor actions. With regard to the striatal interneurons, cholinergic and fast-spiking interneurons have been identified in the lamprey [17,18] but whether some of the newly identified mammalian interneurons [19,20] are present is still unknown. The mammalian arkypallidal 'stop-cells' [21e23] have not been identified in the lamprey. Evidence is accumulating that the striatum is subdivided into a number of discrete modules connected to specific compartments of SNr that, in turn, control individual motor programs (e.g. a type of eye movement). During vertebrate evolution, the number of such modules has increased with a gradually more varied movement repertoire [6], but the basic design of each module has remained virtually the same.
With regard to the dopamine system, the lamprey substantia nigra, pars compacta (SNc), has virtually the same input and output structures as in rodents and the same type of dopamine receptors (Figure 2c) [24e26]. The diagram in Figure 2c actually applies to both rodents and lamprey. Dopamine denervation gives similar hypokinetic symptoms in both groups [27]. The SNc neurons are activated by salient visual (or other senses) stimuli. These effects are conveyed via the tectum/superior colliculus in both the lamprey and rodents [24,28]. In rodents, practically every episode of locomotion is preceded by a burst of dopamine activity [29,30], which then facilitates direct pathway neurons in the striatum. Dopamine can trigger activity in the striatal modules that already have elevated excitability because of input from the cortex/thalamus and lead to action.
A critical element in motor learning is that each attempt to perform a movement should be evaluated, as to whether it is better or worse than the preceding attempt. This serves as the basis for reinforcement learning. The striatum has a 'matrix' compartment that is concerned with movement control, while around 20% is referred to as the striosomal compartment with input primarily from the limbic system [31,32]. The striosomes contain GABAergic projection neurons that directly inhibit the dopamine neurons in SNc (Figure 2d) [31]. Strisomes also acts on the dopamine neurons through another pathway via an excitatory relay (GPh; see Figure 2d) that, in turn, controls the level of activity in the lateral habenula that mainly activates an inhibitory relay [33] that inhibits dopamine neurons. This entire circuit for evaluation, first demonstrated in the lamprey [34,35], is now established in the mouse [36,37]. The striosomal projections via the habenula and directly to the dopamine neurons will thus determine whether an action will lead to an enhanced 'reward' dopamine burst or a pause as a negative sign. The phasic changes in dopamine activity will determine if an action will be promoted as reinforcement learning or conversely will receive less support through a reduced dopamine activity. In both the lamprey and rodents, the striosome compartment of the striatum is involved both directly and through the GPh and habenula in the evaluation of an action d a critical factor in motor learning.
The execution of movementevolutionary perspective The transition from swimming to tetrapod walking One basic behaviour is locomotion. Cyclostomes swim like an eel with undulatory movements coordinated by the spinal cord itself. They have no appendages, and therefore have to rely fully on movements of the trunk for forwards or backward swimming or navigation. There is only a medial motor column present in the spinal cord that activates the different segments in the appropriate sequence ( Figure 3). As the pectoral and anal fins develop later in evolution in elasmobranchs (sharks and rays), a lateral motor column emerged 420 million years ago to control the appendages that later became the  tetrapod limb [38]. In fact, the pelvic fins can produce alternating movements that can move the ray forward if it rests on the bottom of the sea. Already at this stage, the spinal cord has developed the characteristic combination of transcription factors for motoneurons and the subtypes of interneurons that is present in mammals [38e40].
Animals that swim with lateral undulations, such as the lamprey, most fish and salamanders, generate alternation at the segmental level. Essentially, there are on each side of the spinal cord, a group of excitatory neurons that drive the motoneurons on the same side, and then inhibitory commissural neurons that ensure lefteright alternating activity as found in both the lamprey and frog larval tadpole [41]. This type of coordination has been detailed in the adult zebrafish [42e44] in which the slow, intermediate and fast motoneurons receive input from three different subtypes of excitatory interneurons of the V2a subtype (central pattern generator network, CPG). In slow locomotion, the slow subgroup of interneurons that mutually excite each other, drives the locomotor activity. With more excitatory supraspinal drive, the intermediate group of interneurons is recruited, and they also receive input from the slow subtype of interneurons. A combination of the membrane properties of the interneurons and motoneurons and their connectivity determine the rhythmic burst generation. In addition, a novel sensory receptor [45] located at the edge of the spinal cord and connected to the wall of the vertebrate canal sense lateral movements in each swim-cycle. It is integrated into the segmental CPG. The segmental network can, through experiments in the zebrafish, be regarded as understood at a detailed level.
The next stage of the evolution of tetrapod locomotion is the condition in which the limbs not only propel the animal but also support the body against the action of gravity. In this case, the CPG needs to provide four different phases of the movement (support, lift up, flexion phase and then touch down). The transition between a swimming CPG with simple lefteright alternation and the more complex situation that adds alternation between flexors and extensors on the same side, as during walking, has been studied in the frog tadpole. It initially swims with lefteright alternation before developing limb buds for walking. In a transition phase, the pure swimming pattern occurs together with brief bouts of flexoreextensor alternation [46,47]. The walking and swimming patterns thus coexist. These data can be taken to indicate that the swimming CPG is further subdivided, at this stage, into two circuits at this stage that produces ipsilateral flexoreextensor alternation. As shown by Jung et al. [38], the molecular machinery for developing both motoneurons and interneurons for ipsilateral alternation, as in the limb CPG, is available already in elasmobranchs.
The cellular composition of the mouse limb CPG has been examined over the last decade but is not yet fully understood. One subgroup of electrically coupled interneurons expressing Shox2 is thought to play an important role in burst generation [48]. In addition, HB9 and V2a interneurons and the inhibitory V2b and V1 interneurons may play a role in this context [49e52].
Coordination between the left and the right limb can take the form of alternation as in walk and trot or be active largely in phase as in a gallop. Commissural interneurons are responsible for this coordination, and deletion of one subtype, V0d interneurons, leads to a loss of walking. The deletion of V0v leads instead to loss of trot, and finally, when both are deleted, alternation is lost altogether, and the mouse can only gallop [53]. The three different types of locomotion are thus served by three different patterns of commissural interneuron activity. Propriospinal neurons also play a major role [54] in the coordination between fore-and hindlimbs.
The transition from whole-body locomotor commands to the fine forelimb control Locomotion can be initiated from an area referred to as the mesencephalic locomotor region (MLR) in all vertebrates investigated, thus an evolutionarily conserved area [41,55e57]. In the lamprey, cholinergic and glutamatergic neurons drive the reticulospinal neurons, which in turn activate the spinal CPGs [56,57]. In mammals, the identity of the subtypes of neurons affected by the MLR stimulation was for a long time unclear. However, with a combination of virus technology and optogenetics, it could be shown that the cuneiform pathway activated a small area, the lateral paragigantocellular nucleus, that in turn activates the CPGs in the spinal cord [58e61]. Neurons in the pedunculopontine nucleus also contribute but to a lesser degree [58].
In addition to supporting the body during locomotion and standing, the forelimbs contribute to steering and eventually to grasping and securing external objects. Mammals such as rodents, cats and primates can grasp objects with their paw/hand and even perform fine manipulations, such as pealing the hull off a piece of seed [62,63]. In rodents, it has now been possible to identify a subpopulation of neurons in the lateral rostral medulla concerned with reaching out for an object, grasping or handling a small object like a seed. These commands are only concerned with one limb [63,64]. In primates, the corticospinal system allows for the control of individual finger movements and allow us to master playing the piano [65]. Thus, in contrast to the MLR/ lateral paragigantocellular nucleus inducing whole-body movements, these areas in the rostral medulla are concerned with specific parts of an integrated movement and represent a type of control not available in phylogenetically older groups of vertebrates.
Eye and orienting movements towards points in the surrounding space The superior colliculus/tectum in the midbrain is a structure that has evolved to generate eye or orienting movements of the head towards a salient stimulus in the surrounding space. Vision, but also other senses, convey information that is represented as a map of the surrounding space located in the superficial layers of the superior colliculus/tectum. Stimuli from a given point in space elicit neuronal activity in one location of the map. Aligned with this spatial map, in the deeper layers of tectum/superior colliculus lies a motor map from which eye movements to the same point of the surrounding space can be elicited [66,67]. The neurons in the motor map also elicit orienting movements of the head and body. A separate set of neurons generates movement in the opposite direction helps to avoid collision with an object, an important function, for instance, during navigation in a complex terrain [68e72]. The superior colliculus/tectum neurons in the motor map also receive inhibitory input from the basal ganglia that can prevent, for instance, saccadic eye movements. Conversely, excitatory input from the cortex can facilitate eye movements to a given point in space (e.g. from the frontal eye field).
The superior colliculus/tectum is well-developed in the lamprey, as is the input from the basal ganglia and cortex/pallium [68e73], an arrangement present in all vertebrates [67]. It is likely that there is a more refined sensory processing in the superficial layer with input from different classes of retinal ganglion cells in zebrafish and mammals [74]. The superior colliculus/tectum thus provides another example of an essential part of the motor system that emerged early in vertebrate evolution and has retained its basic features.

Concluding remarks
The last few years have shown that all essential building blocks of the forebrain, including the 'cortex', the basal ganglia and the dopamine system are present in the lamprey, an animal that belongs to the oldest group of now living vertebrates. This also applies to the midbrain and brainstemespinal cord. The similarities are not limited to the overall organization but include the detailed design with synaptic properties, transmitters, neuropeptides and expression of ion channels (see Figure 2b). The inference is that these structures had already evolved when the lamprey lineage separated from that leading to mammals, some 500 million years ago. During evolution, new functions have been added with the development of limbs and separate control of the forelimbs allowing independent hand and finger movements, language and cognitive functions, but the essential 'Bauplan' of the vertebrate nervous system evolved very early in vertebrate evolution. Given the remarkable and detailed similarities between the lamprey brain and that of mammals, convergent evolution cannot possibly account for these findings. Contrary to our initial belief the basic design of the vertebrate brain dates back to the dawn of vertebrate evolution.

Funding
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Conflict of interest statement
Nothing declared.