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The Neural Control of Movement: Model Systems and Tools to Study Locomotor Function

The Neural Control of Movement: Model Systems and Tools to Study Locomotor Function

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The Neural Control of Movement: Model Systems and Tools to Study Locomotor Function

1,007 pages
11 heures
Aug 12, 2020


From speech to breathing to overt movement contractions of muscles are the only way other than sweating whereby we literally make a mark on the world. Locomotion is an essential part of this equation and exciting new developments are shedding light on the mechanisms underlying how this important behavior occurs.

The Neural Control of Movement discusses these developments across a variety of species including man. The editors focus on highlighting the utility of different models from invertebrates to vertebrates. Each chapter discusses how new approaches in neuroscience are being used to dissect and control neural networks. An area of emphasis is on vertebrate motor networks and particularly the spinal cord. The spinal cord is unique because it has seen the use of genetic tools allowing the dissection of networks for over ten years. This book provides practical details on model systems, approaches, and analysis approaches related to movement control. This book is written for neuroscientists interested in movement control.

  • Provides practice details on model systems, approaches, and analysis approaches related to movement control
  • Discusses how recent advances like optogenetics and chemogenetics affect the need for model systems to be modified (or not) to work for studies of movement and motor control
  • Written for neuroscientists interested in movement control, especially movement disorders like Parkinson’s, MS, spinal cord injury, and stroke
Aug 12, 2020

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The Neural Control of Movement - Academic Press

The Neural Control of Movement

Model Systems and Tools to Study Locomotor Function

First Edition

Patrick J. Whelan

Hotchkiss Brain Institute; Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada

Simon A. Sharples

School of Psychology and Neuroscience, University of St Andrews, Fife, United Kingdom

Table of Contents

Cover image

Title page



About the Editors


Introduction: An interphyletic tool kit to study locomotor function: Past, present, and future directions



Why study locomotion in a variety of species?

Motivational factors

Practical factors

Historical account



Section I: Invertebrates

Chapter 1: Elegantly


In the beginning

C. elegans lends itself to a wide range of experimental approaches

Locomotion behavior

Body mechanics

The locomotion circuit

Rhythm and pattern generation

Analogy to other systems and framework of comparison

Locomotion of the first-stage larva

Completeness and compactness, maps and hope

About the authors

Chapter 2: Small steps and larger strides in understanding the neural bases of crawling in the medicinal leech




Kinematics of crawling

The centrally generated crawl motor pattern

Role of dopamine (DA) and serotonin (5-HT) in locomotor selection

Crawling and the brain

Intersegmental coordination, the cephalic cell R3b-1, and the CV motoneuron

The chronic loss of cephalic inputs and the ability to recover coordinated crawling

Homeostatic plasticity and a new dependence on peripheral information

Remodeling of the stretch receptors during crawl recovery

Principles of flexible locomotor organization and action selection

The reconfiguration of locomotor networks and lessons for spinal cord injury

The next chapter of the leech model: A new, bigger, and better tool kit

Inspiring new neural recording techniques

The leech and new device-related neuromodulation technologies

The leech as an inspiration for the design of biomimetic robots

About the authors

Chapter 3: Studying the neural basis of animal walking in the stick insect




Experimental approaches

Insights into the neural basis of motor control based on research on the stick insect

Task dependence in locomotion

Conclusions for future research

About the authors

Chapter 4: Neural control of flight in locusts


Historical perspectives


Central pattern generation

Sensorimotor integration





About the author

Section II: Vertebrates

Chapter 5: Neural control of swimming in lampreys


Historical perspectives

Important discoveries made in lampreys relative to the control of locomotion

Conclusions and perspectives

About the authors

Chapter 6: Toward a comprehensive model of circuits underlying locomotion: What did we learn from zebrafish?




Advantages of using zebrafish as a research model to investigate locomotor circuits

Molecular and cellular control of locomotor activity: Seeing through the functional diversity of spinal neurons

Stereotyped organization of interneurons in the hindbrain


About the authors

Chapter 7: Neural control of swimming in hatchling Xenopus frog tadpoles


Historical perspectives

Sensory systems and the initiation of swimming (swimming decision-making)

Swimming rhythm generation (deciphering the swim CPG)

Autonomous mechanisms regulating swim episode duration

Neuromodulation and metamodulation

Conclusions and future prospects

About the authors

Chapter 8: Xenopus frog metamorphosis: A model for studying locomotor network development and neuromodulation


Historical perspectives on metamorphosis and locomotion


An evolutionary-developmental perspective

Locomotor system remodeling during metamorphosis

Comparison with mammalian locomotor system development

Other neuronal changes accompanying locomotor circuit remodeling

Comparison with other metamorphosing locomotor systems

Neuromodulation, metamodulation, and locomotor CPG circuit development

Developmental changes in other locomotor-related systems during metamorphosis


About the authors

Chapter 9: The turtle as a model for spinal motor circuits




Experimental model and historical overview

What has the turtle taught us about the circuits for locomotor control?

Population activity and motor behaviors

Challenges using the turtle as a model

About the author

Chapter 10: Development of the locomotor system—Chick embryo



Development of the locomotor system

Embryonic movements

Homeostatic control of embryonic movements and spinal SNA

About the author

Chapter 11: Using mouse genetics to study the developing spinal locomotor circuit



Experimental models

From classical approaches to mouse genetics to assess neural control of movement and locomotion

What have we learned about the spinal locomotor circuit using mouse genetics?


About the authors

Chapter 12: Using mouse genetics to investigate supraspinal pathways of the brain important to locomotion



Experimental models

From classical approaches to mouse genetics

What have we learned about brain locomotor circuits using mouse genetics?

The motor cortex and corticospinal tract

The red nucleus and rubrospinal tract (RST)

The pontomedullary reticular formation (PMRF) and reticulospinal pathways

Midbrain and diencephalic locomotor centers

The mesencephalic locomotor region (MLR)

The Subthalamic locomotor region (SLR)

Modulation and functional connectivity between the SLR and MLR


About the authors

Chapter 13: Fundamental contributions of the cat model to the neural control of locomotion



Historical aspects of the cat model

Strengths and caveats of the cat model

Neural mechanisms controlling locomotion identified in the cat

Current challenges and questions/approaches moving forward

About the author

Chapter 14: The micropig model of neurosurgery and spinal cord injury in experiments of motor control



The pig in biomedical research

Preclinical studies

The pig brain to model human neurosurgical approaches

Pig models for motor control and the advent of porcine SCI models: Porcine vs other large animal models of SCI

Key milestones in the development of porcine SCI models

Anesthetic management for electrophysiological assessments

Management of hypothermia

Postoperative analgesia

Application of the porcine SCI model to motor control

Development and validation of a stereotactic protocol in the Yucatan micropig skull

Stereotactic targeting of the MLR

Surgical implantation of electrodes and electrophysiological testing

What have we learned about the circuits for locomotor control? Testing in unanesthetized animals

Locomotion in the uninjured animal as assessed with manual (animal-driven) or motorized treadmills

Descending control of spinal function—Uncertainties and challenges


About the authors

Chapter 15: What lies beneath the brain: Neural circuits involved in human locomotion



Neural control of locomotion in nonhuman animals

Characteristics of human gait

Is bipedalism a defining feature in human evolution?

A note on methodologies used to study locomotor circuits in humans

Reflexes as a probe to understand the neural control of rhythmic movement

Coordinating activity between the legs

Coordinating activity between the arms

Coordinating activity between the arms and legs

Involuntary stepping in neurologically intact humans

Spontaneous rhythmic stepping in humans with spinal cord injury

Rhythmic stepping induced by spinal cord stimulation humans with spinal cord injury

Rhythmic stepping induced by pharmacology humans with spinal cord injury

Infant stepping

Supraspinal control in human locomotion

Common core neural control during many rhythmic behaviors

Concluding remarks

About the authors

Chapter 16: A tale of many models. Which one creates the best of times?



The foundations of modern motor control neuroscience

What about the translation to human disease?

New tools—Are they wagging the dog?

An argument for the tail wagging the dog


About the authors



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Numbers in parenthesis indicate the pages on which the authors’ contributions begin.

François Auclair     (99), Department of Neurosciences, University of Montreal, Montreal, QC, Canada

Francisco D. Benavides     (349), The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, United States

Rune W. Berg     (205), Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Frederic Bretzner

(237, 269), Centre de Recherche du CHU de Québec, CHUL-Neurosciences

Faculty of Medicine, Department of Psychiatry and Neurosciences, Université Laval, Québec, QC, Canada

Ansgar Büschges     (57), Department of Animal Physiology, Institute of Zoology, University of Cologne, Cologne, Germany

Stephano Chang     (349), The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, United States

Denis Combes     (175), University of Bordeaux, Aquitaine Institute of Cognitive and Integrative Neurosciences, CNRS Research Unit 5287, Bordeaux, France

Lan Deng     (3), Department of Biological Sciences, New Jersey Institute of Technology, Newark, NJ, United States

Réjean Dubuc

(99), Department of Neurosciences, University of Montreal

Research Group in Adapted Physical Activity, University of Quebec at Montreal, Montreal, QC, Canada

Adna S. Dumitrescu

(125), Paris Brain Institute (ICM), Sorbonne Université, INSERM U 1127, CNRS UMR 7225, Paris, France

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom

Kevin Fidelin     (125), Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

Alain Frigon     (315), Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC, Canada

Matthias Gruhn     (57), Department of Animal Physiology, Institute of Zoology, University of Cologne, Cologne, Germany

James D. Guest

(349), The Miami Project to Cure Paralysis

Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States

Maria Belen Harreguy     (3), Department of Biological Sciences, New Jersey Institute of Technology, Newark, NJ, United States

Gal Haspel     (3), Department of Biological Sciences, New Jersey Institute of Technology, Newark, NJ, United States

Maxime Lemieux     (237, 269), Centre de Recherche du CHU de Québec, CHUL-Neurosciences, Québec, QC, Canada

Wen-Chang Li     (153), School of Psychology and Neuroscience, University of St Andrews, St Andrews, United Kingdom

Karen A. Mesce

(31), Departments of Entomology and Neuroscience

Graduate Program in Neuroscience, University of Minnesota, Saint Paul, MN, United States

Morgan Newhoff     (31), Graduate Program in Neuroscience, University of Minnesota, Saint Paul, MN, United States

Brian R. Noga

(349), The Miami Project to Cure Paralysis

Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States

Ioan Opris     (349), The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, United States

Gregory E.P. Pearcey

(385), Rehabilitation Neuroscience Laboratory, University of Victoria, Victoria

Human Discovery Science, International Collaboration on Repair Discoveries (ICORD), Vancouver

Centre for Biomedical Research, University of Victoria, Victoria, BC, Canada

R. Meldrum Robertson     (75), Department of Biology, Queen’s University, Kingston, ON, Canada

Marie Roussel     (237, 269), Centre de Recherche du CHU de Québec, CHUL-Neurosciences, Québec, QC, Canada

Francisco J. Sanchez     (349), The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, United States

Andrea J. Santamaria     (349), The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, United States

Pedro M. Saraiva     (349), The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, United States

Simon A. Sharples     (xxi, 419), School of Psychology and Neuroscience, University of St Andrews, Fife, United Kingdom

Keith T. Sillar     (153, 175), School of Psychology and Neuroscience, University of St Andrews, St Andrews, United Kingdom

John Simmers     (175), University of Bordeaux, Aquitaine Institute of Cognitive and Integrative Neurosciences, CNRS Research Unit 5287, Bordeaux, France

Juan P. Solano     (349), Pediatric Critical Care, Miller School of Medicine, University of Miami, Miami, FL, United States

Zainab Tanvir     (3), Department of Biological Sciences, New Jersey Institute of Technology, Newark, NJ, United States

Louise Thiry     (237), Centre de Recherche du CHU de Québec, CHUL-Neurosciences, Québec, QC, Canada

Luz M. Villamil     (349), The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, United States

Peter A. Wenner     (221), Department of Physiology, School of Medicine, Emory University, Atlanta, GA, United States

Patrick J. Whelan

(xxi, 419), Hotchkiss Brain Institute

Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada

Claire Wyart     (125), Paris Brain Institute (ICM), Sorbonne Université, INSERM U 1127, CNRS UMR 7225, Paris, France

E. Paul Zehr

(385), Rehabilitation Neuroscience Laboratory, University of Victoria, Victoria

Human Discovery Science, International Collaboration on Repair Discoveries (ICORD), Vancouver

Centre for Biomedical Research

Division of Medical Sciences, University of Victoria, Victoria, BC, Canada

About the Editors

Dr. Patrick J. Whelan was born in Dublin, Ireland, and moved to Canada in 1983. He received his PhD in Neuroscience from the University of Alberta in 1996 under the supervision of Dr. Keir Pearson. He then completed his postdoctoral training at the National Institutes of Health in Bethesda, Maryland in the lab of Dr. Michael O’Donovan, before joining the Cumming School of Medicine at the University of Calgary in 2000. He joined the Faculty of Veterinary Medicine in 2005 and is currently a Professor jointly appointed in the Cumming School of Medicine and the Faculty of Kinesiology. His work centers on understanding the descending circuits that control walking in a variety of animal models, including mouse, chick, and cat. Over the years his work has led to a new understanding of the role of sensorimotor function that has identified sets of therapeutic targets to improve locomotor function.

Dr. Simon A. Sharples’ interest in motor systems neuroscience was sparked during his undergraduate degree at Wilfrid Laurier University in Waterloo, Ontario, while studying Kinesiology starting in 2006. During this time, he volunteered at an exercise rehabilitation clinic for people with Parkinson’s disease and gained a better appreciation of how much we take our ability to move for granted. In 2009, Sharples joined the lab of Dr. Jayne Kalmar for an honor’s thesis and master’s degree. There, he made use of transcranial magnetic stimulation to study plasticity in cortical circuits that control activation of hand muscles during neuromuscular fatigue and Parkinson’s disease. His interest in learning more about motor control on a circuit level led him to the lab of Dr. Patrick Whelan at the University of Calgary and Hotchkiss Brain Institute in 2012. In 2013, he participated in the Neural Systems and Behaviour Course in Woods Hole, Massachusetts, and gained exposure to tools to study neural function in a variety of model systems and was inspired from insights gained during the course. During his PhD, he made routine use of electrophysiological approaches to understand the network and cellular mechanisms that underlie the state-dependent control of neuromodulators on spinal circuits of the newborn mouse in vitro. This work progressed to a Royal Society-funded postdoctoral fellowship in the laboratory of Prof. Gareth Miles at the University of St Andrews in 2019 where he is working to develop his skills as a cellular neuroscientist.


We have a brain for one reason, and one reason only, and that is to produce complex adaptive movements.

Daniel Wolpert

The diversity of movements across species is astonishing, yet there are also fundamental principles and building blocks common to all. Locomotion is one form of movement that is critical for the survival of many species in the animal kingdom and presents in many different forms. Exciting new developments are shedding light on the mechanisms underlying how these different forms of behavior occur. We believe this is a timely opportunity to discuss these developments across a variety of species, including humans. This book will focus on highlighting the utility of studying locomotion in a variety of invertebrates and vertebrate species. Within each chapter the authors discuss how new approaches in neuroscience have and are continuing to be used to dissect and control neural networks. An area of emphasis will be on motor networks. Here we highlight some of the key animal preparations used and their unique contributions to our understanding of movement. The book is important since it provides practical details on model systems, tools, and analyses to study the control of movement. This volume consolidates the treatment of different animal species in a manner that facilitates comparison of their merits in regard to studies on movement and locomotion.

Introduction: An interphyletic tool kit to study locomotor function: Past, present, and future directions

Simon A. Sharplesa; Patrick J. Whelanb,c, a School of Psychology and Neuroscience, University of St Andrews, Fife, United Kingdom, b Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada, c Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada


The study of locomotor activity has seen a wide variety of animal species that have been used. Over the years, this research has uncovered common principles along with fascinating insights into how neural networks produce unique behaviors. In this chapter we review how the selection of animal species has impacted the field of motor control. We examine some of the principles of neural network function and discuss the four pillars of motor control that has supported the field.


Model systems; Locomotion; Motor control; Central nervous system; Tools; Actuators; Sensors; History


The understanding of movement has always provided critical insights into the function of the brain. Since animals cannot tell us how they feel, we often infer stress, memory, and emotion through indices of movement. For example, commonly employed assays in the rodent include the open field, conditioned place preference or the Morris water maze. Because of this, the field of motor control as a whole provides a basis for understanding underlying multiple areas of neuroscience. The field of movement neuroscience has benefited from a multidisciplinary approach bringing together biomechanics, muscle physiologists, engineers, computer scientists, and biologists. Neuroscience has entered an exciting phase whereby new tools are being developed that allow precise control and monitoring of neural circuits. At the same time, computational power and the ability to use deep-learning approaches to analyze data have increased. Collectively, the development of new sensors and actuators with data analytics promises to transform neuroscience, in particular, the analysis of movement. The use of different animal species provides the opportunity to examine the adaptability of motor networks to achieve unique solutions. This concept was advanced by August Krogh in 1929 who stated that for such a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied [1]. Perhaps more than other fields of neuroscience, the study of motor activity has utilized various animal species providing, as stated by Doug Stuart, an interphyletic awareness[2, 3] that has enriched the field of neuroscience as a whole. The cross-pollination as a result of this diversity of species and approaches has led to conceptual advances in a diverse range of models. What has been interesting to observe is that in spite of this diversity there are common principles in terms of network function that have emerged. Neural networks produce output that is a function of interconnected sets of neurons forming microcircuits within the network, along with their synaptic and cellular properties [4]. These neural networks are particularly important for the generation of rhythmic movements such as locomotion, chewing, breathing, and scratching [5]. These rhythmic movements are controlled by central pattern generators (CPGs), which are defined as an ensemble of neurons which produce rhythmic, patterned output, in the absence of phasic input and first appeared in the literature in 1965 [6]. CPGs receive inputs from other areas of the brain or periphery that can activate or perturb the network, but as per the definition, these inputs do not have to be rhythmic for the network to produce coordinated output. For example, the central pattern generator of the lamprey (Chapter 5) shares many similarities with the tadpole (Chapter 7), yet they are separated by 450 million evolutionary years [7]. Both the lamprey and tadpole provide unique advantages for studying the control of movement. The lamprey provides a preparation with a stereotyped locomotor pattern, but the tadpole provides the ability to study transitions from aquatic to terrestrial locomotion during metamorphosis and can provide insights into how network architecture changes with different environmental demands. When we examine the sensory control of locomotion we can see clear similarities in function between arthropods such as the cockroach, and mammals such as the cat (Chapter 12) and rodent (Chapter 11) [8]. What is interesting is that these different species evolved similar neural adaptations to the same essential evolutionary pressure—namely, the need for rapid movement across uneven terrain. A fundamental principle for all types of movement is that a central neural core produces the basic pattern that is modified by neuromodulators and sensory feedback [9]. These central pattern generators are the building blocks for fundamental movements and work from diverse species such as the stick insect, crayfish, crab, and leech (Chapter 2) has established a solid foundation. In turn, these studies have accelerated discoveries in vertebrate species. On the other hand, the discovery of genetically defined populations of interneurons in mice and zebrafish has been applied to simpler nervous systems of vertebrates and invertebrates and provided the field with a deeper understanding of the mechanisms that govern movement. This interconnected progression in our understanding has encouraged the publication of this book. The authors offer their views on the use of different species to understand movement.

Why study locomotion in a variety of species?

Studying locomotion is interesting in its own right, and the range of locomotor behaviors is quite large. From the graceful movement of a ray, to an armadillo rolling down a hill, locomotion can be divided into four main types: aerial, terrestrial, fossorial (underground), and aquatic. Within each type there are several subtypes of behavior that can be cataloged. This creates an interesting choice for a researcher—what should we study and why? The focus of this book is on the networks that control these movements, but we need to acknowledge that the reasons for using different species are often as diverse as the behaviors being studied. These range from motivational factors such as gaining insight into the fundamental building blocks of networks or identification of novel therapeutic targets to combat human pathology. Practical factors also influence the use of different species to study. These include the cost of animal acquisition and husbandry to the ability to use new tools or the simple fact that it was the one encountered during training. The use of genetic tools has also driven researchers’ choice of preparation with the use of genetic tools among vertebrates being greatest in the zebrafish, with the mouse being the mammalian model of choice.

Motivational factors

The first motivation for adopting a particular species to study locomotor behavior is intrinsic to the need to understand the fundamental network operating mechanisms that govern locomotor behaviors. Studying motor systems provides an excellent opportunity to understand neural network function as the motor behaviors are the direct output of the network. Understanding the range of behaviors that networks produce requires that we study different species. Such an approach presents an understanding of how networks fundamentally operate and gives us a sense of how versatile networks are. We have also learned of similarities in networks across many species from lamprey to mouse to humans.

Locomotor behaviors in vertebrates can be broadly classified as either undulatory whereby the axial muscles surrounding the spine are engaged in a propagating wave-like sequence or ambulatory by reciprocally engaging antagonist muscles of limbs. Examination of locomotor behaviors of animals that produce undulatory and ambulatory locomotor movements has served as one approach to providing insights into the similarities [10] and differences between networks. For example, upon examination of the gross anatomy of animals such as the lamprey (Chapter 5) and the salamander, it would be immediately evident which animal would produce undulatory or ambulatory locomotor movements. However, when one studies the locomotor movements it becomes clear that the movements performed by these two species are similar; as salamanders, although have limbs that allow them to occupy terrestrial environments, heavily rely on the movement of axial muscles. Despite their similarities in network architecture for the generation of these movements, phasic input from mechanosensory stretch receptors from the axial musculature in salamanders may be critical for generating rhythmic limb activity [11]. When comparing circuit elements that compose locomotor networks, it is important to consider the biological constraints placed upon the networks that drove the network architectures to support such functions. For example, the locust flight system (Chapter 4) has different challenges than those imposed on a stick insect (Chapter 3). High-frequency flying requires rapid adaptation to air currents within milliseconds and a network architecture that is tuned to these tasks compared to that of the stick insect, which traverses uneven terrain but would require neural adaptation to these changes on a longer time scale.

Frog metamorphosis (Chapter 8) provides an exceptional opportunity to study the progression from undulatory to ambulatory locomotor behaviors over the lifespan of a single animal. Frogs in their tadpole stage are exclusively aquatic and swim by generating undulatory movements of their axial musculature. But during metamorphosis, limbs emerge, and spinal networks produce both axial swimming and limb-based locomotor movements. As a result, neural elements that generate both axial and limb-based locomotor movements must be integrated and efficiently controlled. In juvenile and adult frogs, limb-based movements produce the sole form of locomotion whether on land or in the water.

Recent work in the little skate challenges the notion that ambulatory and undulatory locomotor behaviors evolved sequentially and is an excellent example of how the study of niche behaviors can provide insight into the conservation of neural elements that compose locomotor circuits of the spinal cord. The little skate is a cartilaginous fish that during embryonic development produces primarily undulatory locomotor movements much like other cartilaginous fish such as sharks. However, as adults, the little skate, and many other species of ray, produce ambulatory locomotor movements using their pectoral fins. The paired pectoral fins are organized in antagonistically arranged dorsal (elevator) and ventral (depressor) set of muscles and thus resemble primitive appendages [12]. Ray and skate swimming is suggestive of activity in antagonist muscles of limbed vertebrates. What is remarkable about the little skate is that it also has the capacity to engage its pelvic fins to produce walking-like movements when on the seafloor. Interestingly, the underlying neural elements that generate these different locomotor movements are highly conserved and share similar elements with ambulation or walking in rodents [13]. Thus, this work provides valuable insight into the identity of genetically defined neural populations that may underlie the production of ambulatory locomotor movements commonly observed in terrestrial species.

Since the development of genetic tools, the mouse has emerged as the most common species currently used in neuroscience (Chapters 11 and 12). While many do indeed adopt rodent preparations based on these tools, there are examples where genetic tools in mice are employed to complement observations made in non-lab mouse or non-rodent species. For example, in the laboratory setting, many investigators will study the neural mechanisms underlying the generation of alternating stepping patterns. For some terrestrial species including the kangaroo, rabbit, and or the kangaroo mouse, ambulation consists of hopping. The generation of mice with a mutation of Ephrin receptors, which respond to guidance cues during development, results in the abnormal crossing of excitatory commissural interneurons. As a result, mutant mice display a hopping gait [14]. This mutation provides insight into modifications in spinal circuits that might facilitate hopping gaits in the kangaroo rat for example. Another interesting example comes from Icelandic horses, which display a gait called the Tolt, giving them the ability to produce gaits that are entirely distinct from other horses. The unique types of gait produced by Icelandics are linked to a mutation in the doublesex- and mab-related transcription factor (DMRT) gene. Subsequent investigation in DMRT null mice revealed that mutant mice displayed marked difficulties while locomoting at higher speeds and impaired central pattern generator function when assayed in vitro [15]. This work provided insight into potential spinal mechanisms for the generation of different gaits in non-rodent species.

Another motivation in the selection of a species is to gain insight into human pathology and identifying novel therapeutic targets to help treat disease or injury. While past studies have used rodents, cats, larger quadrupedal species and nonhuman primates, other invertebrate or vertebrate preparations are providing new insights into motor pathology. For example, both Drosophila and zebrafish (Chapter 6) contribute superior genetic tools to record and manipulate neural network activity and these are being integrated seamlessly with the genetic models of human disease that are readily available in these species. The axolotl is widely used in research and is an amphibian that does not enter metamorphosis, retains its gills, and walks on the bottom of lakes. It has been used in spinal cord injury research because of its ability to regenerate axons centrally and recover function [16, 17]. Work into the mechanisms of plasticity and recovery following spinal cord injury in vertebrates such as the lamprey [18] has capitalized on the detailed understanding of lamprey spinal locomotor networks. The leech is also used to examine circuit (Chapter 2) plasticity and examine rehabilitative strategies for recovery from nerve cord injury [19–21].

Practical factors

Investigators are influenced by several practical factors when selecting a species to study in the lab. Whether they are new or experienced, the first or primary reason for their choice is their previous experience using a particular animal. This is readily confirmed historically. In the early 1900s Charles Sherrington routinely worked with cats and dogs as teaching and research aids and much of the later pioneering work was conducted in cats by Eccles who in turn influenced several prominent investigators, including Lundberg, and his many trainees [22]. In fact, the cat was the primary species used by motor control researchers through to the late 1980s (Chapter 13).

The next practical factor is cost. A common scenario is an investigator who is attempting to establish a lab in a new institution. Confronted with a limited budget, the investigator may choose a more economical species than the one they may have worked with during their training. For example, many motor control researchers conducted their graduate training in cats, but switched to rodents, since they have lower husbandry costs and more genetic tools. That said, the demand for multiple genetic lines of mice for many experiments often increases the cost of experiments using rodents.

The lifespan and progeny of the species are also important considerations. Some animals have a shorter life span and produce a greater number of offspring. Animals with a shorter lifespan incur fewer husbandry costs per animal, and also generate new mutant lines more rapidly. They are ideal for investigations on aging and development. Zebrafish (Chapter 6) are a notable example of how adoption of a short-lifespan species can yield important findings.

The accessibility to available tools acting as actuators or sensors of neural activity also affects the choice of research species. Indeed, this is likely one of the most influential factors that have driven the development or adaptation of different animal preparations from a historical perspective. Regardless of the species used, what is common is that a motor behavior or a fictive correlate can be easily elicited. Our understanding of how the nervous system generates movement is linked to the available tools and the ways they are employed to answer fundamental questions. For example, during the mid-1900s, many investigators adopted invertebrates to study motor systems with larger neurons that could be easily impaled with sharp intracellular electrodes to obtain electrophysiological recordings. The end of the 20th century saw a boom in genetic approaches and, as a result, motor control welcomed a variety of genetically tractable animal species, including the fruit fly, nematode, zebrafish, and mouse.

Historical account


Perhaps the first experimentalist to appreciate that organisms would provide insights common to other species was Aristotle, the ancient Greek philosopher. He experimented with insects, likely millipedes or centipedes, and studied the effects of leg amputation, along with whole-body segmentation. He concluded that each segment was independently capable of producing locomotion, heralding perhaps the concept of segmental pattern generators [23, p. 503]. Moving onwards, observations on movement may have been made in the dark ages but were not reflected in the written account. The time of Leonardo da Vinci reveals a resurgence of interest in the study of movement. Sketches of bears and horses show how Leonardo captured the details of gait centuries ahead of Muybridge (see following picture). In Da Vinci’s illustration of the bear, the fore-hindlimb and alternating limb gait is realistically portrayed (Fig. 1A).

Fig. 1 (A) Figure of a bear drawn by Leonardo da Vinci. Note the correct phasing of the forelimb compared to the hindlimb illustrated by the arrows. (B) Photographic plate. (C) Picture of the treadmill and lab setup of a decerebrate cat locomoting in 1941. The work was not published. ((A) Reproduced from the Metropolitan Museum of Art, New York. (B) Reproduced from work of Muybridge and illustrated in Animals in Motion (Muybridge E. Animals in motion. Courier Corporation; 2012). (C) Reproduced from Stuart DG, Hultborn H. Thomas Graham Brown (1882–1965), Anders Lundberg (1920-), and the neural control of stepping. Brain Res Rev 2008;59:74–95.) Adapted with permission.

The great Italian anatomist of the Renaissance, Andreas Vesalius (1514–1564), also experimented with living as well as deceased animals. He concluded that For as regards the structure of the brain, the monkey, dog, horse, cat, and all quadrupeds which I have hitherto examined, and indeed all birds, and many kinds of fish, resemble man in almost every particular. [24, p. 258]. Vesalius also demonstrated that cutting nerves stopped muscle contractions. With amazing foresight, he suggested that muscles were under the control of descending projections from the brain. Indeed, Vesalius may be regarded as one of the first comparative motor control experimentalists. Later, German Physiologist, Friedrich Goltz (1834–1902), worked with dogs, which were commonly used in the 19th century, to show that decorticate preparations retained locomotor abilities. Other preparations to study movement during that time were the monkey, rabbit, frog, cat, and even the goat. In 1872, Leland Stanford commissioned a photographer Eadweard Muybridge (1830–1904) to resolve the question of whether all limbs of the trotting horse were off the ground at once. Muybridge used a staggered series of cameras triggered in sequence by the moving horse. He presented these sequences using a zoopraxiscope that projected the images onto a screen and confirmed that at a specific point during a trot, all limbs were off the ground. Thus, Muybridge is also known as the father of motion-picture photography (Fig. 1B) [25]. Muybridge led a controversial life, killing a man he accused of having an affair with his wife, and launching a lawsuit against Stanford who claimed that Muybridge overstated his role in the discovery.

Contemporary motor control history

Modern motor control, like every field of science, rests on the shoulders of its predecessors. When we look at motor control our conceptual knowledge largely rests on three pillars (Fig. 2). The first is the legacy of Sherrington who advanced our conceptual understanding of the spinal and descending control of motor function and ensured that his legacy reached today by training a new generation of motor controllers. The second is the contribution from scientists who focused on understanding motor output in small circuits of a diverse area of species. The findings not only advanced our knowledge of how networks produce diverse motor output, but also provided a conceptual toolkit of synaptic, cellular, and network function that greatly influenced vertebrate neurobiology. The final pillar was that of the developmental biologists, especially Tom Jessell (1951–2019), who found a range of transcriptional markers that delineated the classes of interneurons and motoneurons in the spinal cord.

Fig. 2 A timeline summarizing the integration of various species and tools to study locomotor control. While many of these species were employed to study different behaviors or other aspects of neural function, we present the approximate points in time and their integration for studies of the neural mechanisms that govern locomotion.

Pillar 1: Sherrington and his influence

At the end of the 19th century, Charles Sherrington began a series of experiments utilizing first the dog [26] and later the cat preparation. A highly skilled experimentalist, he dominated the spinal control of movement field for several decades. Sherrington performed experiments outlining the participation of supraspinal centers in the initiation of locomotion, but within the field of motor control he is best remembered for his work on inhibitory control of reflexes, for which he won a Nobel Prize in 1932. He did not fully recognize the central spinal control of locomotion as compared to his own sensory reflex-chain hypothesis [27, 28]. His trainee and colleague, Thomas Graham-Brown published a seminal set of discoveries in 1911 using the cat preparation. He demonstrated that the spinal cord could elicit rhythmic alternating activity in the absence of sensory inputs from the limbs following complete transection of the spinal cord and dorsal roots [29]. This important finding lay dormant for several decades. During World War II, Graham-Brown was able to show dramatic film footage of a decerebrate cat walking to members of the Royal Society (Fig. 1C). While this work was not published, a portion of video can be accessed online with the full film available on request to the Royal Society [22] and is also highlighted in work by Lundberg and Phillips in the Journal of Physiology in 1973 [30].

Electrophysiology, Eccles, and cats

Eccles, who was a trainee of Sherrington in Oxford, had a remarkable influence on motor control, with his work on the spinal cord and cerebellum. His work on postsynaptic inhibition was recognized by his Nobel Prize in 1963. Indeed, interest in spinal networks was eclipsed by exciting work by Eccles in the 1950s who capitalized on the recent development of techniques for recording electrical properties of individual excitable cells with sharp intracellular electrodes. This was first demonstrated in muscle cells [31–33] followed shortly by recordings of myelinated nerve fibers within the spinal cord [34]. Eccles readily adopted this new technique to record from spinal neurons of cats providing foundational insights into the function of spinal motoneuron and reflexes [35, 36]. A detailed account of the events that transpired during this time can be found in a review by Brownstone [37]. Several key findings also emerged from the lab of Anders Lundberg. Using the cat preparation, and harnessing the power of levodopa, Lundberg [35, 36] provided conceptual details on the rhythm generator [38]. These findings, based on electroneurogram results from paralyzed cats, were later supplemented by electromyogram recordings from multiple muscles in intact stepping cats. As discussed by Stuart and Hultborn [22], work using levodopa not only led to inferences regarding the function of the CPG but also influenced many scientists. Nevertheless, the relationship between Lundberg and his colleagues was not always collegial [39].

Pillar 2: Invertebrates in motor control neuroscience

The field acquired a detailed understanding of cellular function as well as conceptual ideas of central pattern generator organization from the mid-1960s onward. These developments were facilitated by investigations on the control of locomotor and non-locomotor rhythmic movements in invertebrate nervous systems. The first account that rhythmic locomotor movements in invertebrates could be generated centrally in the absence of sensory afferents came from independent work in two different arthropod species: Hughes and Wiersma (1961) highlighted studies of the crayfish swimmeret system and Donald Wilson, of the locust flight system (Chapter 4) [40]. In brief, both investigations found that rhythmic activities generated by central circuits persisted in the absence of sensory input from the effector organs (i.e., the swimmerets and wings). To our knowledge, the first use of the term central pattern generator was in a paper by Wilson and Wyman in 1965 that concluded that the flight control system of the locust was produced by a central nervous pattern generator [6].

Given this discovery, invertebrates became a more tractable system to study the central control of rhythmic movements. Investigators were enabled by new tools such as intracellular electrodes capable of recording the electrical properties of individual or multiple neurons as well as the synaptic connectivity of neurons within the circuit [41, 42]. In relatively simpler nervous systems, neurons are fewer in number, larger, and can be individually identified, permitting the same neuron type to be studied in several different animals. With fewer cells in the circuit, experiments detailing correlation, sufficiency, and necessity of circuit elements while simultaneously monitoring circuit output with extracellular electrodes from peripheral nerves can be performed. For example, necessity could be tested by removing a single cell from the circuit by photoablation or injecting hyperpolarizing current into the cell providing insight into the specific contribution of that cell to circuit output. As a consequence of these powerful approaches, invertebrate circuits were relatively quickly but painstakingly dissected and the fundamental principles that govern the generation of rhythmic activities began to be revealed.

For example, the relative simplicity of Caenorhabditis elegans nervous system (Chapter 1), comprising only 302 neurons with 10,000 synapses, accommodated the imaging of the whole organism with electron microscopy. This led to the reconstruction of the connectome for the entire organism. With the anatomical wiring diagram defined by White and colleagues [43], subsequent investigations could test function by ablating individual or groups of neurons and observe resultant changes in behavior. While powerful, such approaches at the time seemed limited with respect to the underlying network dynamics; in particular how the neurons that form the circuits produce the underlying activity patterns responsible for the generation of behavior.

However, parallel work studying rhythmic activities with electrophysiological approaches contributed to the discovery of several mechanisms underlying CPG function. Although not detailed here, the stomatogastric nervous system controlling the rhythmic filtering and chewing movements of the foregut in the crab and lobster has been fundamental to our understanding of how nervous systems produce rhythmic behavior [44–46]. One of the chief contributions in this ~  30 neuron circuit was that neuromodulators could significantly alter the output of circuits and this put to bed the idea that circuits were hard-wired. Another contribution was that there was degeneracy within circuits since numerous modulators, activating diverse receptors, could elicit a rhythm. And another notable contribution is that disparate combinations of intrinsic and synaptic properties can produce virtually identical outputs in a three-cell model of the pyloric rhythm [47]. This suggests that considerable interanimal variability can exist in network properties, yet the output can remain the same. Through the study of invertebrate systems with electrophysiological tools as sensors, it was detailed that rhythmic activity could be generated through a number of different mechanisms, one of which resembles the half-center oscillator initially proposed by T.G. Brown from his seminal work on the cat [29]. Several of these principles discovered in invertebrate systems were elegantly laid out by Peter Getting in 1989 [4] and built on by Eve Marder and Ron Calabrese in 1996 [9].

New approaches and cross-fertilization of the vertebrate field

Our understanding of the vertebrate nervous system has benefited greatly from discoveries made in invertebrate systems. This flow of information has been facilitated by the movement of investigators from invertebrate to vertebrate systems using tools that evolved from the late 1900s to the 2000s. Excellent examples of this include contributions from Keir Pearson (locust, cockroach, and cat), Ron Harris-Warrick (lobster STG, mouse spinal cord), Francois Clarac (crayfish, rat), Paul Stein (crayfish, turtle), Nino Ramirez (locust, rodent), Turgay Akay (stick insect, mouse), and Keith Sillar (lobster, crayfish, tadpole), and others. The shift in the vertebrate world from cat to lamprey, turtle, tadpole, and rodent to study spinal circuits occurred partly because in vitro preparations galvanized many investigators to initiate studies anchored around network, synaptic and intrinsic properties, many of which were described in invertebrates due to accessibility to networks.

It is worth emphasizing that work in the invertebrate sphere provided a springboard for those who adopted and developed vertebrate models. This was facilitated by the development of in vitro approaches that catered to obtaining intracellular recordings from individual or multiple neurons in a system that could be readily manipulated and controlled. Sakmann and Nehr’s development of whole-cell patch-clamp recording, which allowed recordings to be obtained from visually identified neurons in slice or whole animal preparations. And so, across neuroscience, including motor systems, a push to understand mechanisms of cellular function within networks became apparent, and in vivo work became somewhat out of vogue.

Aquatic species such as the lamprey, turtle, and tadpole were adopted as the first vertebrate preparations for the study of spinal circuits for similar reasons as invertebrates but with the added interest of being a vertebrate. These preparations produced viable patterns of rhythmic swimming activity in vitro and were more accessible to the available electrophysiological tools due to a nervous systems composed of relatively fewer and larger neurons than mammals. Sten Grillner, for example, began working with cats [48, 49] and transitioned to the dogfish [50, 51], before adopting the lamprey [52]. Indeed, the lamprey model has been critical to our understanding of vertebrate motor systems. Alan Roberts came from the opposite direction and made a shift from the crayfish to develop approaches to study spinal circuits in the larval Xenopus tadpole [53]. Adult turtles provided a vertebrate preparation to study ambulatory locomotor networks (Chapter 9). As turtles dive and hibernate in aquatic environments, their nervous systems have developed resiliency to anoxic conditions in adulthood. Another advantage is that the isolated preparation in vitro could produce a repertoire of rhythmic movements of the hindlimbs. This preparation provided key insight into the modularity of the adult vertebrate spinal motor system (reviewed by Ref. [54]) and served as a tool to interrogate hypotheses such as the unit burst oscillator proposed by Grillner based on observations made in the cat [55] and supported by subsequent work in the lamprey [56, 57]. Paul Stein first adopted this preparation in the mid-70s after initial works on the crayfish swimmeret system [58, 59] and has since provided supporting evidence for the unit burst oscillator hypothesis [60–62]. Jorn Hounsgaard adopted an in vitro preparation of the turtle spinal cord and Doug Stuart used an in vitro slice preparation to document important mechanisms that mediate the control of motoneuron intrinsic properties [63–65]. This included the modulation of persistent inward currents by serotonin [65] that was initially discovered in decerebrate cats [66, 67].

In vitro preparations of the neonatal rat spinal cord were first developed in 1974 to examine segmental reflexes [68]. More than ten years later two separate labs demonstrated that the isolated brainstem-spinal cord of a neonatal rat could produce rhythmic movements of the hindlimbs and the underlying rhythms could be recorded from ventral nerve roots when excitation was provided [69, 70]. Early experiments left the hindlimbs intact with electromyograms recorded from muscles to demonstrate that activation of spinal networks in vitro would elicit stepping movements [69]. Parallel work by a separate group demonstrated that alternating rhythms could be recorded in ventral roots of the left and right sides of the cervical and lumbar spinal cord following bath application of excitatory amino acids or neuromodulators, cutaneous stimulation of the tail or disinhibition of the brainstem [70, 71]. It was later demonstrated that monoamines could also evoke locomotor-like patterns of rhythmicity in vitro [72]. Overall this preparation allowed for many of the advantages of the lamprey and tadpole in vitro preparations to be ported to a mammalian preparation. While rhythmic patterns of activity consistent with walking could be readily elicited and recorded in this preparation, it was nevertheless an immature preparation with marked changes in circuit architecture, excitability, and locomotor behavior documented during the first two postnatal weeks as animals begin to bear weight and begin to walk around (for reviews, see Ref. [73, 74]). Furthermore, the available tools to manipulate circuit elements were restricted to pharmacological methods or targeted lesioning of the cord.

Pillar 3: Influence of developmental biologists

Many of these challenges were addressed with the integration of genetic tools available in mice and zebrafish into the motor control field that had been employed over the preceding decades for studies in neural development. Additional developments of opto and chemogenetics were subsequently introduced, which allowed for the interrogation of circuit elements using traditional approaches in greater detail than had ever been done before. The mouse and zebrafish preparations were integrated through the modification of established approaches in other species for work in locomotor control. For example, David McLean expanded the tool kit available in the larval zebrafish [75, 76] after joining the lab of Joe Fetcho from optical imaging-based approaches to include methods that he had used in Xenopus tadpoles (Chapters 7 and 8) during his doctoral studies with Keith Sillar (personal communication with Prof. Keith Sillar) [77, 78]. This work was facilitated by the parallel development of a fictive-locomoting preparation within the lab by Mark Masino [79]. Abdel El Manira similarly built upon foundations established with Sten Grillner in the lamprey, and worked in collaboration with Ron Calabrese who was visiting the Karolinska Institute, to develop an in vitro preparation of the adult zebrafish spinal cord [80]. Although not detailed in this volume, the adult zebrafish has been used to demonstrate the modularity of spinal circuits for the generation of swimming movements (see Ref. [81]). Finally, in vitro approaches commonly employed in the rat isolated spinal cord were seamlessly transposed to the mouse and genetic tools readily employed [14, 82–84]. Decerebrate approaches used in the cat were also modified to study locomotion in adult rodents and vivo approaches were later developed in freely behaving adult animals to study not only spinal circuits but also areas of the brain that provide descending control of spinal circuits for locomotion [85–88].

This led to a flurry of studies in mouse and zebrafish spinal cord that identified candidate interneuronal populations that contribute to the generation and coordination of locomotion [81, 89]. The integration of genetic tools in both zebrafish and mouse, together with the introduction of optogenetics, facilitated a push to manipulate classes of interneurons with temporal precision that genetic knockouts could not provide. Thus, neuroscientists could examine questions of necessity and sufficiency for these classes of interneurons. It became evident that silencing of classes of interneurons did not abolish the rhythm generating kernel, consistent with a degenerate network architecture distributed across the spinal cord [90, 91]. While acquiring the ability to classify subpopulations of interneurons increased, investigators realized that activating and inactivating subpopulations, at least in terms of identifying the kernel, would be a time-consuming exercise. The likelihood being that the numerous interneuron classes identified would not on their own be necessary for network function [92]. This is not surprising however when one considers some of the lessons learned from studying systems of invertebrates whereby similar outputs can be generated through several different mechanisms [47]. Even though the kernel may be distributed, there have been numerous breakthroughs attributed to genetic tools, in terms of commissural interneuron anatomy and function [83, 93], premotor microcircuits [94], and the contribution of afferent inputs to locomotion [95]. Many of these genetically defined populations have also been identified in vertebrates including zebrafish, tadpoles, the little skate and invertebrates such as Drosophila.

Looking back while moving forward

Motor systems neuroscience has come a long way since the proposal of a half-center oscillator for the generation of rhythmic alternating movements of the limbs. Later discoveries made in invertebrates not only supported this notion but led to the discovery of a host of mechanisms whereby motor circuits can generate rhythmic movements. Advances in tools used to manipulate and record neural network function have allowed us to revisit some of these discoveries made in invertebrates and vertebrate species.

Through the collective studies of multiple species, we have learned that we must work toward specific goals to attain full comprehension of nervous system function. Yet much of what we now know were part of a prescient list by Peter Getting published in 1986 [96]. It is instructive to repeat this list here (Points 1–8).

(1)Description of behavior:

The motor behavior needs to be described. Increasingly sophisticated ways to accomplish this are becoming available [97].

(2)Characterization of motor behavior:

After the behavior is defined the next step is to record the motor pattern so that the behavior can be quantified. This is often done by with electromyography recorded from the muscles or electroneurograms from the nerves [98, 99]. Today new tools are making this easier. In the zebrafish, the developmental motor program is being captured and predictions made on performance of motor behaviors [100], while in mice similar work is starting to capture behavior [97].

(3)Identification of motor neurons and interneurons:

The next step is to identify neurons, which participate in the behavior. This is often an easier task in invertebrate species, where fewer neurons can be identified based on activity patterns and connectivity. The advent of genetic-based approaches has allowed classes of interneurons that participate in generation of motor patterns to be identified [101].

(4)Localization of rhythm generating circuits:

As we move along the next logical step is to examine the subset of neurons that generate the rhythmic pattern. If a pattern is dependent on the subset then perturbing the subset should reset the rhythm. This is not as easy as it might seem. Within vertebrate networks the available data suggest that there are degenerate subsets of interneurons responsible for the rhythm. More success has been had by studying invertebrate networks.

(5)Mapping of synaptic connectivity:

Assuming one can identify the neurons, the next step is to examine the connectivity between them. Getting suggested that the sign is important (excitatory or inhibitory) and this is probably still the best approach. However, the sign can depend on the activity of the network, receptors present, and developmental state to name a few. Short-term synaptic dynamics are also important and can create synaptic facilitation or depression. Termination location on the postsynaptic neuron is another factor that can also make a difference in terms of action.

Historically synaptic connectivity was mapped with paired intracellular recordings, which provided the means to define the circuit diagrams for many systems, including the STG, Xenopus, and lamprey, to name a few. More modern approaches can also be employed to accomplish this aim such as serial electron micrograph reconstruction as was done for the C. elegans connectome and also a host of viral tracers in combination with modern genetic tools and whole-tissue clearing such as CLARITY. Of note, in some systems, a defined connectome detailing connections of individual cells such as has been accomplished in the C. elegans or the STG, may not be possible. However, it might be accomplished by detailing a rudimentary circuit diagram defining the connectome of populations or classes of cells such as has been done in the lamprey, Xenopus, zebrafish, or rodent.

(6)Characterization of cellular properties:

Intrinsic properties define many neuronal functions, including input-output relationships, firing properties, and subthreshold membrane voltage behaviors. For example, some cells have pacemaker properties and act as endogenous or conditional oscillators. Others may express hyperpolarization activated cation channels or low-voltage activated calcium channels contributing to postinhibitory rebound for burst initiation following removal of inhibitory synaptic input.

(7)Manipulation of network, synaptic, or cellular properties:

Historically, this was accomplished by ablating or hyperpolarizing individual cells within small circuits or altering synaptic and intrinsic properties with pharmacology. The advent of genetic tools accompanied by optogenetics has made it possible to directly manipulate cellular classes.

(8)Reconstruction of the pattern generator, motor output, and behavior:

Within the vertebrate system this has often taken the form of computer models, which are starting to come of age. But the real insight has come from invertebrate systems such as the STG where millions of network configurations can be modeled and outputs predicted [47].

This is Getting’s original list from his 1986 paper [96]. Getting acknowledged that there were significant issues with extrapolating this list from small networks in invertebrates to larger ones [96]. These have become manifest in mammalian systems where degenerate networks exist, making steps 4 and 5 difficult to resolve. With the passage of time there are some additional factors, which need to be considered.


Neuromodulators are not only released on a single synapse level but in a paracrine mode and can thus influence neural output on

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