Genetic dissection of rhythmic motor networks in mice

doi:10.1016/B978-0-444-53613-6.00002-2

Progress in Brain Research

Volume 187, 2010, Pages 19-37

https://doi.org/10.1016/B978-0-444-53613-6.00002-2 Get rights and content

Abstract

Simple motor behaviors such as locomotion and respiration involve rhythmic and coordinated muscle movements that are generated by central pattern generator (CPG) networks in the spinal cord and hindbrain. These CPG networks produce measurable behavioral outputs and thus represent ideal model systems for studying the operational principles that the nervous system uses to produce specific behaviors. Recent advances in our understanding of the transcriptional code that controls neuronal development have provided an entry point into identifying and targeting distinct neuronal populations that make up locomotor CPG networks in the spinal cord. This has spurred the development of new genetic approaches to dissect and manipulate neuronal networks both in the spinal cord and hindbrain. Here we discuss how the advent of molecular genetics together with anatomical and physiological methods has begun to revolutionize studies of the neuronal networks controlling rhythmic motor behaviors in mice.

Section snippets

Rhythmic motor circuits in the hindbrain and spinal cord

The core neuronal networks that control rhythmic respiratory and locomotor motor behaviors reside in the hindbrain and spinal cord, respectively. These CPG networks generate simple organized motor rhythms in an autonomous manner. Initial efforts to decipher the general organization of these simple motor CPGs in vertebrates relied heavily on electrophysiological and pharmacological approaches. Such efforts were greatly aided by the development of in vitro hindbrain–spinal cord preparations in

The developmental program of the caudal neuroaxis

The developmental events that pattern the caudal neural tube play a central role in assembling sensorimotor circuits in the hindbrain and spinal cord (Goulding, 2009, Jessell, 2000). The position that a progenitor cell occupies along the dorsoventral (DV) axis confers a specific genetic code to these cells and thus serves as a major determinant of cell identity (Fig. 1a). This DV patterning program segregates newborn neurons into generic populations that are arrayed as longitudinal columns

Genetically defined interneuronal populations that shape the locomotor rhythm

The identification of genetic markers for different spinal interneuronal populations has laid the foundation for functional studies aimed at assessing the contribution that genetically defined cell types make to the CPG networks controlling locomotor or respiratory rhythmogenesis (Chapter 3 in this book). These efforts have been centered on broad interneuron classes including the V0, V1, V2a, and V3 interneurons (Stepien and Arber, 2008); however, attention is now turning to subtypes within

New genetic approaches for studying motor circuits in the spinal cord

The elaboration of a genetic classification scheme for the interneuron cell types involved in spinal motor control has opened up new routes for manipulating the spinal motor system and determining how specific motor behaviors are generated. The approaches used so far involve deleting or inactivating broad interneuron classes and assessing how this affects network activity (Table 2). This is usually achieved by generating transgenic animals in which a recombination event such as Cre-mediated

Conclusion

The delineation of the transcriptional code for neuronal cell populations in the ventral spinal cord and the emergence of several genetic approaches to manipulate cells of interest have paved the way for genetically and functionally dissecting the neural circuits controlling locomotion. The embryonic building blocks that make up these motor circuits are shared between the networks controlling respiration and locomotion. Thus, understanding how neuronal cell populations that comprise the

Acknowledgments

K. S. G. is funded by a Feodor Lynen Fellowship from Alexander von Humboldt Foundation. Research in the Goulding lab is supported by grants from the National Institutes of Health (NS031249, NS031978 and NS037075) and the Christopher and Dana Reeve Foundation. We would particularly like to thank Tim Hendricks, Floor Stam, and other members of the Goulding Lab for allowing us to cite their unpublished findings.

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Chapter 2 - Genetic dissection of rhythmic motor networks in mice

Abstract

Section snippets

Rhythmic motor circuits in the hindbrain and spinal cord

The developmental program of the caudal neuroaxis

Genetically defined interneuronal populations that shape the locomotor rhythm

New genetic approaches for studying motor circuits in the spinal cord

Conclusion

Acknowledgments

Neuron

Cell

Neuron

Current Opinion in Neurobiology

Neuron

Developmental Biology

Neuron

Neuron

Cell

Neuron

Neuron

Neuron

Neuron

Brain Research

Neuron

Neuron

Neuron

Journal of Neuroscience Methods

Neuron

Neuron

Neuron

Neuron

Photostimulation of retrotrapezoid nucleus phox2b-expressing neurons in vivo produces long-lasting activation of breathing in rats

The Journal of Neuroscience

Heterogeneity of V2-derived interneurons in the adult mouse spinal cord

The European Journal of Neuroscience

Postnatal phenotype and localization of spinal cord V1 derived interneurons

The Journal of Comparative Neurology

Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand

Proceedings of the National Academy of Sciences of the United States of America

Cryptic boundaries in roof plate and choroid plexus identified by intersectional gene activation

Nature Genetics

Forelimb locomotor generators and quadrupedal locomotion in the neonatal rat

The European Journal of Neuroscience

Millisecond-timescale, genetically targeted optical control of neural activity

Nature Neuroscience

Localization of rhythmogenic networks responsible for spontaneous bursts induced by strychnine and bicuculline in the rat isolated spinal cord

The Journal of Neuroscience

Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling

Nature

PAX2 is expressed in multiple spinal cord interneurons, including a population of EN1+ interneurons that require PAX6 for their development

Development

Calbindin D28k expression in immunohistochemically identified Renshaw cells

NeuroReport

Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli

Proceedings of the National Academy of Sciences of the United States of America

Localization and organization of the central pattern generator for hindlimb locomotion in newborn rat

The Journal of Neuroscience

Interactions between dorsal-ventral patterning genes lmx1b, engrailed-1 and wnt-7a in the vertebrate limb

The International Journal of Developmental Biology

Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates

Nature Neuroscience

Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function

Nature

Sim1 and Sim2 expression during chick and mouse limb development

The International Journal of Developmental Biology

In mice lacking V2a interneurons, gait depends on speed of locomotion

The Journal of Neuroscience

A regulatory network involving Foxn4, Mash1 and delta-like 4/Notch1 generates V2a and V2b spinal interneurons from a common progenitor pool

Development