Integrative and Comparative Biology Advance Access originally published online on May 27, 2007
Integrative and Comparative Biology 2007 47(4):482-504; doi:10.1093/icb/icm037
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Reflections on integrative and comparative movement neuroscience
Department of Physiology, University of Arizona College of Medicine, Tucson, AZ 85724-5051, USA
Correspondence: 1E-mail: dgstuart{at}u.arizona.edu
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Synopsis |
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Integrative movement neuroscience involves blending "inside-out" and "outside-in" approaches in the study of posture and movement. The former is characterized by determining the properties of single cells within the central nervous system (CNS) and then ascertaining how these properties influence the operation of CNS microcircuits, single reflexes, groups of reflexes, and generators of central pattern. This information is then used to theorize about CNS control of overt motor behavior. In contrast, the outside-in approach begins with analysis of the biomechanics of posture and movement and then uses this information to theorize how the mechanics are solved by the CNS and its pathways, circuitry, and even single cells. Studies conducted in the 1960s on CNS circuitry generating locomotor patterns in several invertebrate and vertebrate species, together with work on the treadmill locomotion of brain-stimulated decerebrate cats, led to a subsequent convergence of inside-out and outside-in understanding of the neural control of locomotion in invertebrates, nonmammalian vertebrates, and mammalian vertebrates, even including humans. This convergence of integrative and comparative approaches has been facilitated by modeling and simulation studies. These developments have important implications for doctoral and postdoctoral training programs in movement neuroscience. They can profit greatly by use of a multidisciplinary university-wide faculty who place a strong emphasis on integrative and comparative biology. Furthermore, the next generation of movement neuroscientists will require more familiarity with modeling and simulation than are being provided in most current training programs. To achieve the above, it will be advantageous if university culture and structure truly champion university-wide interdisciplinary research.
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Introduction |
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The symposium "Recent Developments in Neurobiology", which took place at the 2007 annual meeting of the Society for Integrative and Comparative Biology, provided several examples of "inside-out" and "outside-in" approaches in movement neuroscience and their potential interconnectedness. The former is characterized by determining the properties of single cells within the central nervous system (CNS) and then testing for how these properties influence the operation of CNS microcircuits, including central pattern generators [CPGs; also termed "oscillators" in the early CPG literature. The term "central pattern generator (CPG)" first appeared in the refereed literature in the 1960s (Wilson and Wyman 1965
). It is used to describe an ensemble of interneurons and possibly motoneurons, whose combined operation produces the fundamental spatiotemporal patterns of a wide variety of rhythmic movements including the various forms of locomotion. Higher brain centers send command signals to CPGs, which usually initiate their action but do not control fundamental CPG rhythmicity. Similarly, sensory input can influence strongly most aspects of CPG rhythmicity but the fundamental CPG action is nonetheless evident. Furthermore, proprioceptive reflexes are made context-dependent and task-dependent by CPG action, such that the central nervous system selects input–output pathways appropriate for the task at hand. For the broad implications of CPG research, see Grillner (2006)], single reflexes, and groups of reflexes. This information is then used to generate theories on the motor control function of regions of the CNS (sensorimotor cortex, cerebellum, etc.) and their interactions to produce overt motor behavior. In contrast, the outside-in approach begins with analysis of the biomechanics of posture and movement and then uses this information to again generate theories on how the mechanics are solved by the CNS and its pathways, circuitry, and even single cells. Integrative movement neuroscience involves blending the two approaches to the maximum extent possible. Admittedly, few movement neuroscientists have the breadth of biological understanding and arsenal of research techniques required to contribute substantially using both approaches. All, however, have the capacity to appreciate the need for this synthesis, contribute to the overall effort, and benefit from the progress achieved.
My own interest in the importance of this integrative synthesis was greatly accelerated in the late 1960s by examining the neural control of locomotion (Stuart et al. 1972). This interest was deepened in 1971–1972 at Göteborg University, Sweden by interactions with my latter-day mentor, Anders Lundberg and his collaborators and trainees (including, in particular, Elzbieta Jankowska, Sten Grillner, and Hans Hultborn). Their seminal contributions (e.g., Lundberg 1969; Grillner 1975) and allied developments in the study of locomotion (discussed subsequently) continually reinforced the significance of the integrative approach. Much later, the possibility arose of helping develop pre-doctoral and postdoctoral training programs in movement neuroscience at the University of Arizona [the 1982 founding members of the Arizona Movement Neuroscience Group (and their research expertise at that time) included five faculty members at the University of Arizona: Roger Enoka (biomechanics and human skilled motor control), Ziaul Hasan (neurophysiology and vertebrate motor control), Thomas Hixon (speech and language sciences and normal and abnormal speech motor control), Robert Lansing (physiological psychology and human respiratory control), and Douglas Stuart (neurophysiology and mammalian spinal motor control). Terry Bahill (bioengineering and human eye/head/arm movements) joined the group in 1984 as did three colleagues in 1985 from the Barrow Neurological Institute in Phoenix, Arizona: James Bloedel (neurophysiology and mammalian cerebellar motor control), Alan Gibson (physiological psychology/neurobiology and mammalian cerebro–cerebellar interactions), and Thomas Hamm (neurophysiology and mammalian spinal motor control)], which later became a statewide program. From the outset, this program featured an integrative approach.
Also evident at the 2007 symposium was the "interphyletic awareness" of the speakers. I first coined this term to emphasize the need to " ... give equal attention to issues raised concerning the motor control of a variety of animal phyla, classes and species ..." (Stuart 1985, p 96; Stein 1999). It has proven to be of heuristic value to indicate when common principles of motor control are present across phyla (Pearson 1993), when evolutionary deviations have occurred (Fetcho 1992), and when there is insufficient information to form an opinion (Smith 1994). The same is true for other integrative areas of neuroscience, of course, such as olfaction (Hildebrand and Shepherd 1997), oculomotor control (Strausfeld et al. 2006) and learning and memory (Kandel 2001).
Verbiage like "interphyletic awareness" is also far from unique. It dates back well over a century: consider, e.g., the lifelong dual interests of Auguste Forel (1848–1931) in insect neurobiology and human behavior and their potential points of connection (Parent 2003). My own term was inspired by respect for one of the professors of neuroscience during my 1957–1960 graduate-student days at UCLA almost 50 years ago, Theodore Bullock (1915–2005). His career exemplified a comparative approach in his seminal contributions to a broad array of neuroscientific issues (Leonard 2001). One of Bullock's PhD trainees, Donald Wilson (1933–1970), was a fellow classmate in 1958 in courses in mammalian neuroscience and physiology taken at UCLA. His subsequent contributions on the neural control of locust flight (Wilson 1961, 1968) had an immediate impact on my own and innumerable others’ thinking about CPG activity in the central nervous system. In the mid-1960s, I had several telling conversations with another of Bullock's former UCLA PhD trainees, Donald Maynard (1929–1973), who waxed insightfully on comparative neurobiology. Similarly, after returning from Sweden, I was invited by Paul Stein (a former postdoctoral trainee with Bullock) to participate in a set of transphyletic presentations on the neural control of locomotion that he chaired for the 1972 Annual Meeting of the Society for Neuroscience. This was the beginning of our association of now over 34 years, which has featured our mutual interest in a multidisciplinary approach to the study of locomotion. I was also fortunate to meet François Clarac in 1977. Our conversations over nearly 30 years have focused on the need for interplay between concepts developed by work on both invertebrates and vertebrates including, in more recent years, the historical aspects of such interplay (Clarac 2005a, 2005b, 2007; Clarac and Pearlstein 2007). Also of impact and most enjoyable were (1) my collaboration for 15 years (1969–1984) with the comparative morphologist/neurobiologist, George Goslow, who taught me much about bird flight and other forms of nonmammalian locomotion (Goslow et al. 2000), and (2) the possibility to work closely with like-minded colleagues on a sequence of international symposia that featured integrative and comparative approaches to the study of locomotor control (Herman et al. 1976; Grillner et al. 1986; Stein et al. 1997).
Clearly, the ever-advancing understanding of the neural control of locomotion has progressively reinforced the power of a comparative approach. Also, the above-mentioned training program soon included some invertebrate neurobiologists [the Arizona Movement Neuroscience Group was joined in 1986–1987 by three University of Arizona faculty with expertise in invertebrate neurobiology: Edward Arbas (1950–1995; invertebrate neurophysiology and evolutionary neurobiology), Richard Levine (invertebrate neurophysiology and developmental neurobiology), and Nicholas Strausfeld (evolutionary neurobiology and insect visual control). Next, the invertebrate component was enlarged in 1988, when Richard Satterlie (invertebrate neurobiology and molluscan motor control), who was then at Arizona State University in Tempe, joined the group. Subsequently, further faculty joined the group from all three institutions and from Northern Arizona University, as well], thereby providing the opportunity to optimize not only our trainees’ exposure to this field (Satterlie and Spencer 1985; Arbas et al. 1997) but also to stimulate other members of the training faculty to think across phyla (Hasan and Stuart 1988).
What follows then are some historical and personal reflections on how studies on the neural control of locomotion have continued to reveal how integrative and comparative approaches can advance a field of neuroscientific enquiry. I conclude with some personal views on the training of the next generation of movement neuroscientists and the need for university-wide interdisciplinary research.
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Pre-1960 approaches in movement neuroscience |
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SynopsisIntroduction Pre-1960 approaches in movement... Post-1960 advances using...Post-1960 advances using mammalsValue of modeling and...Value of symposia for...Concluding thoughtsAcknowledgmentsReferences |
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My colleagues and I have written previously on the wide gulf between the outside-in and inside-out approaches to movement neuroscience that existed in physiological circles in both North America and Great Britain prior to the 1960s (Stuart and McDonagh 1998
; Stuart et al. 2001; Stuart 2005). In the 1930s–1950s, for example, the influence of Charles Sherringon (1857–1953) and Edgar Adrian (1889–1997) was deservedly widespread, and they clearly favored an inside-out approach. This was emphasized even further with the advent of intracellular recording from single spinal neurons in surgically-reduced cat preparations in the early 1950s (Brock et al. 1951; Woodbury and Patton 1952). In contrast, the work of Rudolph Hess (1881–1973) in Switzerland, Kurt Wacholder (1893–1961) in Germany (among many other German scientists), and Nikolai Bernstein (1896–1966) in the USSR featured important conceptual advances using an outside-in approach (Jung 1992: Wiesendanger 1997, 1998; Sternard 2001).
I, like most other trainees in physiology of my generation, initially learned little about the outside-in approach in movement neuroscience. For this reason, it was most revealing to read the chapter by Richard Jung (1911–1986) and Rolf Hassler (1914–1984) on the extrapyramidal system (Jung and Hassler 1960) and that by Jacques Paillard (1920–2006), who considerably advanced the field of motor cognition, on the patterning of skilled movements (Paillard 1960). These appeared in the first series of Handbooks of Physiology, which were initially published by the American Physiological Society. This series was edited rigorously by one of my UCLA professors, Victor Hall (1901–1981), a respected teacher and mentor, who frequently discussed his editorial opinions with his appreciative PhD trainees. Admittedly, the seminal work of Hess on CNS control of autonomic function was well known in the 1950s (Gloor 1954), but his contributions to movement neuroscience (Wiesendanger 1997; Stuart 2005) went relatively unnoticed in North America until the article by Jung and Hassler (1960).
Throughout my PhD training, the gulf was also wide between neuroscientists working on invertebrate and nonmammalian vertebrate species (mainly in university departments of biology and zoology) and those working on largely mammalian species (mainly in medical schools). There were some notable exceptions. At the cellular level of enquiry, workers on mammals instantly recognized the significance and generality of the work on action potentials of the giant axon of the squid by Alan Hodgkin (1914–1998) and Andrew Huxley, and use of frogs to study neuromuscular transmission and the properties of muscle membranes by Bernard Katz (1911–2002) and like-minded electrophysiologists. Similarly, physiologists working with mammals recognized even earlier the significance of work on muscle energetics and mechanics undertaken on frogs by such noteworthy physiologists as Archibald ("AV") Hill (1886–1977) and Wallace Fenn (1893–1971). In contrast, the literature on movement neuroscience of mammals gave little recognition to the work on activation and mechanics of muscles that was undertaken on other nonmammalian and invertebrate species by zoologists such as John Pringle (1912–1982).
Even today, most workers on mammals seem to give, at best, lip service to the integrative implications of the all-round comparative approach as espoused so convincingly by such zoological luminaries as August Krogh (1874–1949), John ("JZ") Young (1907–1997), and Knut Schmidt-Nielsen (1915–2007). In contrast, an emphasis on evolutionary conservation is evident in work on molecular (e.g., genes, ion channels, myosin isoforms, Ca2+ binding proteins) and cellular (e.g., mitosis, metabolic pathways, resting potentials, action potential initiation and propagation, synaptic transmission) mechanisms. A mindset that considers evolutionary comparisons at the systems level is evident among those studying the motor behavior of feeding (Wainright 2002) and locomotion (Stein et al. 1997), but it is certainly less prevalent among those studying many other forms of movement, particularly in humans. In particular, the study of locomotion has thrived these past four decades by exploiting a comparative approach (Orlovsky et al. 1999; Stein 1999).
Emergence of the tripartite control concept in movement neuroscience
Throughout the 1950s, and despite important contributions about central locomotor control across invertebrates and vertebrates, e.g., the imaginative work of Erich von Holst (1908–1962) (von Holst 1935a, 1935b, 1939, 1948, 1954), the opinion prevailed that locomotor rhythmicity was attributable in major part to sensory input from the moving body parts. James Gray (1891–1975), a similarly distinguished zoologist, championed this position (Gray 1950). By the mid-1970s, however, it was well accepted that the neural control of locomotion involves tripartite control with facultative interactions between descending command signals, a central program consisting of interacting CPGs, and sensory feedback (for reviews see Grillner 1975; Orlovsky and Shik 1976; Shik and Orlovsky 1976; Wetzel and Stuart 1976; Delcomyn 1977). This gestalt, which is shown schematically in Fig. 1, required demonstration that the fundamental timing of repetitive movements was due to centrally scored CPGs rather than to sensory feedback from the moving body parts, even though the latter could influence rhythmicity to considerable, but not complete, degree. Particularly, influential and possibly seminal as this epoch began was the statement of Bullock (1961) that " ... Central patterning is the necessary and often sufficient condition for determining the main characteristic features of almost all actions, whether stimulus triggered or spontaneous" (p 56).
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Delcomyn (1980
) provided an insightful review on the explosion of research on CPGs that took place in the 1960s and early 1970s. In that article, he listed relevant work on 13 types of rhythmical movement as undertaken by 50 species of invertebrate and vertebrate animals among 11 classes and four phyla. Table 1 summarizes aspects of this progress in the field of locomotor control and selected allied movements for several animal species. The animal selections were idiosyncratic, simply being the ones I felt were appropriate to emphasize when lecturing on this topic. Table 1 lists seminal and recent work on each animal in the approximate order of its contribution to the understanding of locomotor control rather than in the order in which each animal appeared in the fossil record. In several cases, major advances appeared more-or-less simultaneously for work done both within and across species.
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Post-1960 advances using invertebrates |
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There were several isolated and fragmentary reports of CPG activity (albeit not defined as such) in invertebrate species prior to the 1960s (Ten Cate 1928
; Adrian 1931; Prosser 1936). The modern era of invertebrate CPG research appears to have begun, however, with an article by Hughes and Wiersma (1960) on the crayfish/lobster swimmeret system, which participates in several types of movement, including locomotion. Subsequently, by 1976 evidence supporting CPG operation during different forms of locomotion was obtained from several other invertebrates including the locust, cockroach, marine mollusc, and leech. In each of these and in most other cases, findings usually involved an evolution from a focus on CPG operation and modulation in a single ganglion to coordination between CPGs across ganglia and how the locomotor rhythm is initiated and sustained by descending command signals and sensory feedback (for a detailed review of these and several other invertebrates and vertebrates, see Orlovsky et al. 1999). Similar information is provided for the stomatogastric system in crustacea because such work has proven to be the "gold standard" in the study of both invertebrate and vertebrate CPGs.
Swimmeret beating in crayfish and lobsters
In crayfish and lobsters, pairs of tail appendages contribute to rhythmical movements, including locomotion. Wiersma's laboratory was the first to report that a swimmeret rhythm could be elicited from the isolated and deafferented abdomen of the crayfish, Procambarus clarkii, by the electrical stimulation of single brain cells (Hughes and Wiersma 1960) and that the rhythm was clearly attributable to CPG activity (Ikeda and Wiersma 1964). Subsequently, the swimmeret system was studied intensively in both crayfish and lobsters (Stein 1971; Davis 1973). This effort has continued more-or-less unabated throughout the 1980s and 1990s and up to the present (Hooper and DiCaprio 2004; Mulloney and Hall 2007).
Flying by locusts
In a study of the locust, Schistocerca gregaria, Wilson (1961) reduced the animal to little more than its head, thoracic nerve cord, and a ventral cuticular strip and was able to demonstrate a fictive flight rhythm at 10 Hz versus the normal 18 Hz. In subsequent studies, he further strengthened this initially strong evidence of CPG activity in locust flight (Wilson 1966a), including a study with Wyman (Wilson and Wyman 1965). Valuably, Wilson emphasized the similarities between his findings on locusts and emerging work on rhythmic activity in the mammalian spinal cord (Wilson and Waldron 1968). Subsequent work revealed that locust flight could be initiated by both central command and sensory feedback, with the command neurons including those for flight initiation, equilibrium, and steering (Hensler and Rowell 1990). More recently, work has appeared on neural correlates of higher-order flight behavior: e.g., the more intense flight behavior and improved flight performance of gregarious locusts compared to solitary ones (Fuchs et al. 2003; Ayali et al. 2004).
Walking by cockroaches
In a study of the cockroach, Periplaneta americana, Pearson and Iles (1970) deafferented all the legs and the thorax of headless preparations and recorded extracellularly from the axons of selected motoneurons. In response to mechanical stimulation of the cerci, they observed a rhythmic pattern of activity that resembled the pattern in the same motoneurons during walking (Milburn 1963; Wilson 1966b), because the remaining sensory input from the abdominal connectives bore no phase relation to the rhythmic motor activity. Subsequent work first emphasized, in particular, the powerful effect exerted on locomotor CPG activity by sensory input (Bässler and Büschges 1998), which at times might appear to override CPG control in stick insects (Büschges 2005; Quimby et al. 2006). Descending control possibilities have also come to the forefront (Ridgel et al. 2007).
Swimming by marine molluscs
Willows (1967) showed how intracellular recording from brain neurons could be made in a marine mollusc that was restrained in a way that allowed normal swimming movements. He described the swim pattern of Tritonia gilberti, and demonstrated sets of central neurons that fired bursts of activity during the various phases of the swim cycle. In a subsequent collaboration using the same mollusc, he and his colleagues proved that CPGs were active in this animal's swimming movements (Dorsett et al. 1969, 1973). Subsequently, understanding of the swim network in Tritonia was considerably advanced by Getting (1986) and CPG studies on several Aplysia species and other marine molluscs soon appeared. Among the latter, Fig. 2 shows that Clione limacina proved to be particularly appropriate for advancing understanding of swim circuitry (Arshavsky et al. 1998; Satterlie 1989) and this effort, too, continues up to the present, with detailed information now available on descending command mechanisms for the speed and intensity of swimming (Pirtle and Satterlie 2006), and on postural and equilibrium control (Deliagina et al. 2006).
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Swimming and crawling by leeches
In a study of the leech, Hirudo medicinalis, Kristan and Calabrese (1976
) showed in contrast to the far earlier influential report of Gray et al. (1938) that rhythmical bursts of motoneuron discharge could be recorded extra-axonally in completely isolated nerve-cord preparations. By comparing such activity to that in a semi-intact preparation, they were able to propose how interactions between sensory input and CPG activity could optimize the swimming rhythm in this animal. Subsequently, the Kristan laboratory, among several others, focused on leech locomotion, with some remarkable recent findings, including a study in which a combination of electrophysiological and optical imaging techniques was used to characterize multiple CNS neurons’ activity, when the leech crawled or swam in response to the same sensory stimulus. It was shown that hyperpolarizing a single neuron, previously shown to connect swim-initiating circuitry to swim-CPG circuitry, could bias the leech to swim, whereas depolarizing the same neuron biased the animal to crawl or at least to delay swimming (Briggman et al. 2005). Such research extends invertebrate neurobiology into the realm of cognitive neuroscience (Briggman et al. 2006).
The stomatogastric system in crustacea
Selverston (1976) created much interest among locomotion researchers, when he emphasized that for at least its heuristic value, they should stay abreast of CPG work on the stomatogastric ganglion of crustacea, whose 30 neurons (23 of which are motoneurons) innervate striated musculature in these animals’ stomachs. Somewhat earlier, Maynard (1972) had reviewed rapidly evolving evidence, from the late 1960s, that this ganglion uses CPG activity to generate two rhythms, a faster pyloric and a slower gastric one. Shortly thereafter, Selverston and colleagues provided a remarkable detailed account of this ganglion's CPG function (Selverston 1974; Selverston et al. 1976). Since then, as summarized by Marder et al. (2005) and Clarac and Pearlstein (2007), work on this ganglion has continued at an ever-expanding pace, such that more is currently known about the nuances of its CPG operation than in any other invertebrate CPG circuitry including the specific details of the cellular, synaptic, and network properties, whose combined actions and modulation produce the two stomatogastric rhythms.
Post-1960 advances using nonmammalian vertebrates
As with advances made in the study of invertebrates, there were examples of centrally controlled locomotor rhythms in nonmammalian vertebrates well before 1960. Much of this work involved noting near-normal locomotion after deafferentation of the tested portion of the moving body parts (von Holst 1935a, 1935b, 1939; Weiss 1936, 1950). Again, however, Gray's viewpoints emphasizing a predominant sensory (chain-reflex) control of locomotor rhythmicity remained dominant, even when his own studies on deafferentation pointed to primary central control (Gray and Lissman 1940, 1946). In reviewing this history, Grillner (1975) emphasized the significance for subsequent inferential CPG research of findings on the hatchling chick (Straznicky 1963) and the newt (Székely 1963; Székely et al. 1969). It would seem, however, that among the nonmammalian vertebrates much of the past 40 or more years of progress on CPG aspects of locomotor control has come from work on the lamprey and frog embryo. Subsequent work on motor patterns of the chick embryo and work on scratch reflexes of the turtle have stimulated vertebrate CPG research in a fashion analogous to that of stomatogastric ganglion research on invertebrate locomotor CPGs.
Swimming by lampreys
The Grillner laboratory obtained the first hard evidence of spinal locomotor CPG activity in the lamprey (Cohen and Wallén 1980). A little earlier, Grillner et al. (1976) obtained analogous results in the dogfish shark. Presumably, his laboratory's subsequent focus on the lamprey was influenced strongly by seminal papers from Rovainen's laboratory (Rouvainen 1974; Poon 1980). Today, largely due to the efforts of Grillner and Wallén and their many colleagues and trainees, more is known about the operation (Fig. 3), and modeling and simulation (Fig. 4), of overall locomotor circuity of the lamprey, from the basal ganglia to the musculature (Grillner 2003; Einum and Buchanan 2006), than in any other vertebrate. This focus on delving into locomotor mechanisms in the lamprey, which now involves 
15 laboratories (main focus 8; secondary focus 7), and comparing the results to those obtained in other vertebrate and invertebrate species, seems on the rise for the foreseeable future (Grillner 2006).
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Swimming by frog embryos and hatchling tadpoles
Following compelling evidence (Roberts et al. 1981
; Kahn and Roberts 1982) for a locomotor CPG in late embryos of the clawed toad, Xenopus laevis, the details of such CPG operation were revealed progressively using frog embryos and hatchling tadpoles (Dale and Roberts 1985; Roberts et al. 1986; Arshavsky et al. 1993). Today, knowledge of the details of spinal CPG of circuitry of these animals rivals with that known about spinal networks of the lamprey. Also as with the lamprey, descending command signals to the spinal CPGs for swimming are now being revealed (Li et al. 2006) as are the neural mechanisms underlying the developmental transition from undulatory swimming to quadrupedal locomotion (Ramanathan et al. 2006).
Motor patterns of chick embryos
Following work on the functions of limbs innervated by heterotopic spinal cord segments in the hatchling chick (Straznicky 1963) and in salamanders (Székely 1965) and demonstration of crude, locomotor-like motility in the 7 day chick embryo in the absence of sensory feedback, which Hamburger et al. (1966) attributed to then-as-yet unidentified spinal interneurons, there was immediate interest in the progressive refinement of this model's CPG for locomotion. EMG analysis suggested that some of the CPG was in near-normal operation by 10
days of incubation (Bekoff et al. 1975; Landmesser and O’Donovan 1984), albeit there was evidence at that time of further refinement throughout the 20/21-day incubation period and even for a few hours after hatching (Bekoff 1986). Extra-axonal recordings from muscle nerves in the isolated in ovo spinal cord (at day 13) was achieved in the early 1980s (O’Donovan 1984) but intracellular recording from tiny spinal motoneurons and interneurons, which are a feature of post-1960 CPG research in both invertebrate and nonmammalian vertebrate models, continues to be elusive in the chick embryo. In recent years, this problem has been obviated to some extent by calcium-imaging studies, which, combined with extra-axonal recordings, have permitted the visualization of the spatiotemporal pattern of spinal interneuronal activity during rhythmic motor behavior in isolated spinal-cord preparations in chick embryos (O’Donovan et al. 2005). This technical advance, also achieved in the neonatal mouse (Bonnot et al. 2002), has much to offer the study of locomotor CPG activity.
Scratch reflexes of the turtle
The spinal turtle can use three types of scratch reflex, each involving a different scratch site on the carapace, and each employing a different combination of muscles and limb end points. Each reflex makes use of a spinal CPG, with overlapping elements, as first shown in the Paul Stein laboratory (Robertson et al. 1985) using fictive forms of the three scratch types in paralyzed preparations. This research has attracted much attention in movement neuroscience because blends of the three reflexes and their CPGs are also evident. Unraveling the spinal interneuronal mechanisms of the various forms of turtle scratching gives insight into task-dependency and context-dependency in the operation of CNS circuitry (Stein et al. 1986). The spinal turtle preparation has also been of value for demonstrating subcomponents (see subsequently) of generalized vertebrate spinal CPGs (Stein 2005), and a core of spinal interneurons that participate in both right-side and left-side CPG activity during one form of scratching (Stein et al. 1995). Recently, both intracellular and extracellular recordings have shown that some scratch CPG interneurons are maximally active during a specific form of scratching, but also active in more than one form (Berkowitz 2005; Stein 2005). Another recent finding challenges traditional concepts of the cellular mechanisms that provide alternating flexor–extensor activity in spinal CPG activity (Berg et al. 2007; Kristan 2007). The generality of the above findings on turtle scratching and their relation to locomotor control are of continuing interest.
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Post-1960 advances using mammals |
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A key integrative development for both mammalian and nonmammalian research occurred before 1960: the publication of the USSR journal Biofizika in 1955 and its English translation, Biophysics. This gave Western workers, very few with expertise in the Russian language, exposure to the work of many outstanding Soviet workers, including, in particular, those advancing on the findings and concepts of Nicolai Bernstein (1896–1996). Some of Bernstein's own work then became available in English translation (Bernstein 1967
). Thereafter, Western interest in Bernstein's integrative ideas became widespread (for a chronological review of this development, see Gelfand et al. 1966/1971; Whiting 1984; Latash and Turvey 1996; Latash 1998; Bongaardt 2001; Latash 2006). Today, much of his work is available in English, with the unfortunate exception of Bernstein (1947), which contained many of his most important ideas, and Bernstein (2003), a monograph that was actually written in 1936 (Latash 2006). A 1995 biography of Bernstein (Feigenberg 2005) is also available, but only in Russian (Latash 2005).
While Bernstein focused on the study of human movement, essays in his dexterity monograph demonstrated his interest and grasp of evolutionary and developmental aspects of movement (Latash and Turvey 1996; Bernstein's Essays 3 and 4). Presumably, this contributed to subsequent developments in interdisciplinary research in movement neuroscience in Moscow (see subsequently). Today Bernstein is most widely known for his work, along with that of Arturo Rosenblueth (1900–1970) and Norbert Weiner (1894–1964), on self-controlling biological systems. Among movement neuroscientists he is also recognized for his quantitative experimental and theoretical studies on the intact and brain-damaged human and in the development of prosthetic devices for the latter (Stuart 2005).
Studies on mammalian quadrupeds
As with invertebrates and nonmammalian vertebrates, there was evidence of spinal pattern generation in mammalian quadrupeds well before 1960. A young Scottish clinician, Thomas Graham Brown (1882–1965) undertook experiments in 1910–1914 that revealed the capability of the spinal cord in the guinea pig and cat to generate intrinsically a locomotor output pattern. Sadly, this seminal work, which was published largely between 1911 and 1916 (for details see Wetzel and Stuart 1976), was considered inconsequential by most of Graham Brown's peers, with the possible exception of Sherrington, who waxed and waned on the value of the work (Stuart et al. 2001; Stuart 2005).
Lundberg's contributions to spinal locomotor-pattern generation
Lundberg rescued Graham Brown's concepts from obscurity in a sequence of widely read articles and reviews, which were published largely between 1965 and 1969 (Jankowska et al. 1965, 1967; Lundberg 1969). Graham Brown had proposed mutually inhibitory connections between a pair of flexor and extensor "half-centers" on each side of the spinal cord, focusing usually on connections between motoneurons but sometimes adding interneurons. Lundberg, Jankowska, and their colleagues added compelling and still relevant evidence for the interneuronal circuitry underlying half-center organization in the cat. Figure 5 shows one aspect of their approach, which involved technically demanding spinal intracellular and extracellular recording and spinal neurochemical stimulation. Lundberg (1969) supported his electrophysiological results with kinematic and kinetic measurements made on freely locomoting animals.
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Current views on the spinal CPG for cat locomotion
Much effort and technical ingenuity have been expended on the spinal cord of the cat (and now of the rat and the mouse) to evaluate the half-center concept, but the details of spinal interneuronal interactions for the operation of locomotor CPGs have remained elusive. An enduring problem is recording intracellularly from the spinal interneurons that may contribute to pattern generation (McDonagh et al. 1999
). Progress is occurring with their extracellular recording, however (Angel et al. 2005). There is evidence in the cat and nonmammalian vertebrates that more rostral interneurons in hindlimb CPGs have the primary responsibility for generating rhythmicity and that the overall CPG has subcomponents that provide rhythmicity for each degree of freedom in the step cycle: i.e., for hip flexion, hip extension, etc. (Grillner 1981; Stein 2005; Grillner 2006; Kiehn 2006). Figure 6 is an example of other work, which suggests that the spinal CPG for cat locomotion consists of a half-center rhythm generator for flexor–extensor switching and a pattern formation network for the timing of the various activations of muscles (Rybak et al. 2006). Still other findings suggest that this CPG has three, rather than two, phases, as in scratching (Berkinblit et al. 1978). What is now clear to a considerable, but certainly not complete, extent are the powerful effects of sensory input on the CPG's interneuronal network, thereby altering the step-cycle pattern to extensive, but not complete, extent (Pearson 2004, 2007) and the capability of the CPG to modulate spinal reflex activity, thereby making it appropriate for the locomotor task at hand (Stuart 2002). At the output stage of the spinal cord, there is also clear-cut evidence that the interneuronal CPG operates on a functional unit consisting of 
and 
motoneurons, Renshaw cells and Ia inhibitoty interneurons (Orlovsky et al. 1999). It is likely that Graham Brown would be delighted but not surprised by these various developments!
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Bernstein-inspired studies on controlled cat locomotion
In parallel with Lundberg's 1960s’ contributions to spinal pattern generation, Fig. 7 shows an animal model used in Moscow, USSR to advance dramatically the concept of a tripartite system for the control of locomotion. As reviewed elsewhere (Stuart and McDonagh 1998
), three relatively young Russian workers, Shik, Orlovsky, and Fyodor Severin (1942–1968) showed that the controlled (by brainstem stimulation) locomotion of a high decerebrate cat could be used to demonstrate interactions between descending command signals, presumed spinal CPGs for each limb, and sensory feedback (Shik et al. 1966a, 1966b; Severin et al. 1967). Their work thereby supported ideas promulgated by Bernstein (1947) on the basis of research he had undertaken over a 30-year period largely on human subjects.
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The significance of the initial Moscow sequence of studies on the Fig. 7 preparation, which was reported between 1966 and 1974, and included the participation of eight more Moscow workers (including, in particular, Arshavsky and Feldman) was grasped immediately by Western workers, several of whom quickly made use of the model. [Only three Western scientists had the opportunity to work in Moscow during early work there on controlled locomotion: Sten Grillner (1971), Shigemi Mori (1973–1974, 1983), and Claude Perret (1975–1976) from Sweden, Japan, and France, respectively. For brief description of their collaborative research in Moscow, see McDonagh and Stuart (1998)]. For present purposes, three findings on the Fig. 7 model deserve brief mention (for further details and key citations see Stuart and McDonagh 1998
). (1) The gait of the high-decerebrate cat can be converted from walking to trotting to galloping by either increasing the strength of brainstem stimulation or by increasing the speed of the treadmill belt. This shows that the timing of spinal CPGs to each limb can be altered by either descending command signals or sensory feedback (Shik et al. 1966a). (2) During a constant command signal, sensory feedback can uncouple the CPGs for the right-side and left-side limbs. This can be shown by having the right-side limbs locomote on one treadmill belt, while the left-side limbs locomote on another belt moving at a different speed (Kulagin and Shik 1970). (3) By paralyzing the high decerebrate cat it is possible with the same brainstem stimulation to evoke fictive locomotion (Shik et al. 1966b), thereby permitting extracellular and intracellular recording within the CNS. Subsequent use of this approach in several laboratories has considerably advanced understanding of the CNS circuitry used to elaborate locomotion.
Current understanding of descending command signals for cat locomotion
Figure 8 summarizes current understanding of the volitional, emotional, and automatic processes contributing to the descending control of locomotion. Work on these topics has been undertaken in many laboratories in several countries. There is agreement that the pontomedullary strip of the reticulospinal projection is the final common pathway to the spinal locomotor CPGs (as accessed facultatively by several supraspinal regions; including, in particular, the mesencephalic and subthalamic locomotor regions shown originally by the Moscow workers in the 1960s), the fastigial nucleus of the cerebellum (Mori et al. 2004), and the basal ganglia and hypothalamus (reviewed in Takakusaki et al. 2006). When locomoting over obstacles and presumably other uneven surfaces, new evidence suggests that the posterior parietal cortex "plans" and the motor cortex "ensures" visually guided control of the necessary modifications in gait (Drew et al. 2007). There has also been interesting comparative conjecture on the extent to which the CNS circuitry for visually guided locomotion by the cat is analogous to that for arm reaching by nonhuman primates (Grillner et al. 1997).
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Developmental studies in the rat
Analogous to frog and chick preparations discussed earlier, Fig. 8 shows that late-fetal and neonatal rat preparations have proven valuable for giving insight into the maturation of mammalian locomotor networks. A photographic analysis showed that locomotor-like hindlimb movements appear in the late fetal stage (E20) (Bekoff and Lau 1980
) and this was subsequently confirmed with EMG recordings in an in vitro preparation, which was first studied at birth (Kudo and Yamada 1987) and subsequently, back to E14.5 (i.e., 8 days before birth) when chemo-stimulated rhythmic motor activity was demonstrated in ventral root neurograms (Kudo et al. 2004). Clarac et al. (2004) have presented their own and others’ evidence that the locomotor patterns shown by use of outside-in techniques (e.g., photography, kinematics) in Fig. 9 correspond to the progressive maturation of locomotor networks in the CNS, as studied with inside-out neuroanatomical and electrophysiological techniques. Much could also be said about recent work identifying interneurons implicated in the spinal CPG (Butt and Kiehn 2003), the role of serotonin in refining the developing locomotor networks (Pearlstein et al. 2005) and its supraspinal control (Liu and Jordan 2005).
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Genetic and other molecular biological studies in the mouse
Following technical advances made largely in the 1990s and early 2000s (for review, Kiehn 2006
), evidence has been presented quite recently about genetically identified spinal interneurons in the mouse, which are strong candidates for components of the spinal CPG for locomotion (e.g., Kullander et al. 2003; Lanuza et al. 2004). Subsequent progress was presented recently at an international symposium held in Stockholm, SWE in 2006 (see Table 1 for relevant articles in Grillner et al. 2007). As this exciting field develops, as it surely will, it will be of interest to see if advances in the identity of interneurons contributing to the locomotor CPG continue to far outstrip advances in the mechanisms underlying the function of such interneurons during the operation of the network. Despite this cautionary note, Fig. 10 from the Brownstone laboratory shows that progress is indeed being made on the latter issue (see also relevant Table 1 citations) by use of genetic and other molecular biological techniques (for a succinct summary of these developments, see Grillner 2006).
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Indirect evidence of spinal pattern generation in the human
The idea that spinal CPGs operate in the human, just as they do in other animals, can be traced back to at least the kinematic study of von Holst (1938
) on intact subjects and some briefly described observations on subjects with a spinal-cord injury (SCI) (e.g., Holmes 1915; Kuhn 1950). Locomotor-like movements have been measured in human fetuses at 10 gestational weeks (for review, De Vries and Fong 2006), and once born, the neonatal infant will often exhibit rhythmical stepping movements if weight supported (McGraw 1945, p 22–23). Subsequently, this ability is lost for many months due to mechanical (Thelen and Fisher 1982), and possibly neural developmental factors (Forrsberg 1985). It can be retained, however, if the infant is trained daily (Zelazo 1983). The current prevailing viewpoint appears to acknowledge that encephalization masks spinal pattern generation in the adult human (Forssberg et al. 1991) but, nonetheless, indirect evidence is compelling for its existence (Duysens and van de Crommert 1998; Dietz 2003; Zehr 2005; Wolpaw 2006a). For example, findings of particular interest on this topic are those of Dietz et al. (1994b) and Gurfinkel et al. (1998; Fig. 11) on intact subjects, Lajoie et al. (1996) on a subject with proprioceptive deafferentation below the neck, and observations now from several sources on SCI patients (Dimitrijevic et al. 1998; Wolpaw 2006a; Minassian et al. 2007).
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Significance of locomotor training in patients with injury to the spinal cord
Following demonstration that training restores weight-supported hindlimb locomotion in spinally transected cats (Shurrager and Dykman 1951
) and its application to human SCI subjects (Visintin and Barbeau 1989; Wernig and Müller 1991; Dietz et al. 1994a), there is now substantial evidence from several laboratories and rehabilitation centers that treadmill training or similarly intensive overground standing/stepping training promotes the recovering of locomotion as executed by body parts beneath the level of spinal cord transection or injury (Dietz and Colombo 2004; Edgerton et al. 2004; Wolpaw 2006a, 2006b). The recent work in this area advances both understanding of spinal locomotor networks in the human and the motor habilitation and wellbeing of SCI subjects.
Two summary thoughts
Two features stand out in my mind when the post-1960 developments are considered in their entirety. First, for each animal model presented, and many others not covered in this article, active research is continuing with results that are sure to advance understanding of the neural control of locomotion. This broad effort seems likely to continue, albeit with progressively increasing focus on the models amenable to genetic manipulation: notably the fruit fly (Clarac and Pearlstein 2007), zebra fish (Drapeau et al. 2002; Fetcho 2006), and mouse (Kiehn 2006) among invertebrates, nonmammalian vertebrates, and mammals, respectively. Second, the extent to which there has been a cross-fertilization of ideas based on findings made on these three animal groupings is striking. For example, the discussion sections of virtually all of the articles cited earlier demonstrate this point.
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Value of modeling and simulation for advancing movement neuroscience |
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The CPG circuitry of the stomatogastric ganglion is the most fully delineated among all the invertebrate CPGs studied to this point (Marder et al. 2005
), with modeling and simulation now playing a prominent role in explaining the ganglion's overall function and in suggesting avenues of future research (Marder and Bucher 2007). Similarly, modeling and simulation is prominent in current research on the lamprey, from the cellular/molecular to the behavioral level of analysis (Grillner et al. 2005; Kozlov et al. 2007). For mammals, the need for modeling and simulation is acute, given the complexity of the CNS networks already implicated in the control of locomotion. For this reason, Prochazka (1993) made a timely and particularly appealing contribution: the idea that engineering principles should be applied to the problem. An example is shown in Fig. 12. Note its relevance to both integrative and comparative movement neuroscience.
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Value of symposia for promulgating integrative and comparative approaches |
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Following some earlier noteworthy symposia held in 1962 (Reiss 1962
), 1966 (Wiersma 1967), 1967 (Brazier 1969), and 1973 (Stein et al. 1973; see also p 36 in Stuart and McDonagh 1998), symposia of particular significance for stimulating integrative and comparative work on the neural control of locomotion were held in Philadelphia, USA (1975), Stockholm, Sweden (1985), Tucson, USA (1995), New York City, USA (1998), and again Stockholm (2006). For the subsequent symposia volumes, see in their chronological order Herman et al. (1976), Grillner et al. (1986), Stein et al. (1997), Kiehn et al. (1998), and again Grillner et al. (2007). It is widely known that these latter five symposia have emphasized integrative and comparative approaches to the study of locomotor control and, in addition, have stimulated international cooperation and collegiality in advancing the field (Stein 1999). It was an honor and a privilege to be involved in the organization of three of these symposia (1975, 1985, 1995) and to attend the other two. |
Concluding thoughts |
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While my own research has focused largely on other issues in movement neuroscience, my performance as a member of the university community has been influenced strongly by keeping abreast, to at least some degree, of developments in the study of locomotor control. This has been evidenced in my teaching, research mentoring, and committee work on graduate and postdoctoral training, thereby prompting me to conclude these reflections with two thoughts about university structure.
Significance of training programs in movement neuroscience
To contribute to the developments described earlier, and for that matter any truly worthwhile endeavor in biological science, graduate, and postdoctoral trainees now need to apply ever-more-demanding and difficult techniques to a narrowly focused problem somewhere along the spectrum from the cellular/molecular to the behavioral level of analysis. Over the years, trainees have repeatedly asked me how they can do this and yet maintain not only a broad view of their field as a whole, but also of intellectual enquiry in general. This problem has been exacerbated by the current need for virtually all such trainees to gain mastery of how to interact effectively with colleagues in the physical sciences in the modeling and simulation of their contributions, and to appreciate what robotics research is now bringing to movement neuroscience and vice versa (Delcomyn 2004). In my opinion, interdisciplinary training programs offer the best possibility. For example, in the field of movement neuroscience, trainees need the opportunity to interact with other trainees and faculty who approach the field from a variety of perspectives and levels of analysis. Without this opportunity, it is the rare trainee indeed who can remain well balanced while working intently on a tightly focused research topic.
Implications for university structure
The division between main-campus evolutionary biology and zoology and medical-school physiology, which is still evident today, has not served biology well. Apart from its inherent intellectual limitations, it exacerbates tendencies for research universities to develop silos of research endeavor rather than interdisciplinary university-wide enterprises. The next generation of life scientists suffers accordingly. PhD and postdoctoral training programs that feature a university-wide faculty and outlook, including a strong emphasis on integrative and comparative biology, as well as modeling and simulation, are offsetting these tendencies to some degree but not completely so in North America. To foster such programs, a university culture is required that continually emphasizes and supports campus-wide interdisciplinary research.
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Acknowledgments |
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This article is from the symposium on "Recent Developments in Neurobiology" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 3–7 2007, at Phoenix, Arizona. I thank Richard Satterlie for organizing the symposium and the other participants, who comprised five combinations of a laboratory director and one of his junior, or once-junior, collaborators (Roger Enoka–Benjamin Barry, Richard Levine–Carsten Duch, Keir Pearson–David McVea, Arthur Prochazka–Sergiy Yakovenko, and Richard Satterlie–Thomas Pirtle). François Clarac and Paul Stein are also thanked for reviewing the penultimate draft of this manuscript, as are Robert Brownstone, Hans Hultborn and Kaoru Takakusaki for advice on selected figures, and Mark Latash and Wulfila Gronenberg for their help in translating some Russian and German literature, respectively.
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Footnotes |
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From the symposium "Recent Developments in Neurobiology–A Tribute to Professor Douglas G. Stuart" presented at the annual meeting of the Society for Integrative and Comparitive Biology, January 3–7 2007, at Phoenix, Arizona.
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