Genetic dissection of rhythmic motor networks in mice

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. Keywordslocomotion; respiration; spinal cord; CPG; interneuron; mouse genetics Rhythmic motor outputs such as locomotion, respiration and mastication are, in their simplest forms, highly stereotyped motor behaviors. In fish and tadpoles locomotion primarily consists of repetitive lateral bending movements of the axis, which are produced by waves of contraction and relaxation that propagate rostrocaudally along the body axis. In contrast, terrestrial vertebrates propel themselves by flexing and extending their limbs. This more complex mode of locomotion requires extensive coordination between the forelimbs and hindlimbs on each side of the animal and between individual limb joints. The additional demands of land-based locomotion appear to have driven the evolutionary elaboration of the spinal motor circuitry in terrestrial vertebrates, both in terms of numbers and types of neurons, as well as sensory and supraspinal connectivity. In higher vertebrates, the spinal locomotor system has thus evolved into a highly dynamic network that produces a varied and flexible array of motor outputs in response to sensory feedback pathways and descending influences from rubrospinal, reticulospinal, vestibulospinal and corticospinal pathways. Rhythmic motor circuits in the hindbrain and spinal cordThe 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 Correspondence to M.G.: goulding@salk.edu 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 neonatal rodents (Kudo and Yamada, 1987;Smith and Feldman, 1987). In addition to enabling investigators to localize two rhythmic CPGs in the medulla that drive respiratory movements, the preBötzinger complex and parafac...

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