Central pattern generator

[3][4][5] They are the source of the tightly-coupled patterns of neural activity that drive rhythmic and stereotyped motor behaviors like walking, swimming, breathing, or chewing.

In neonatal mice, blocking gap junctions results in decreased rhythmic activity and can completely abolish drug induced fictive locomotion.

Over the past few decades, molecular and genetic programs that control neuronal patterning have been used to specifically target spinal interneurons in mice[35] and zebrafish.

[36] Developing neural tube of embryonic mouse shows expression of distinct transcription factors in domains along the dorso-ventral axis of the spinal cord.

[37] These domains give rise to distinct population of neurons that have been classified as dorsal (dI1-dI6) and ventral (V0-V3) cardinal classes of spinal interneurons.

[35] Each of these interneuron class can be further divided into diverse subpopulations of neurons with distinct neurotransmitter phenotype, axonal projection and function during locomotion.

[44] For example, in the lobster stomatogastric nervous system the neuropeptide, red pigment concentrating hormone, can strengthen synapses between two different networks to create a single, combined rhythm.

"[3] A study by Gottschall and Nichols examined the hindlimb of a decerebrate cat during walking (a CPG controlled function) in response to changes in head pitch.

Proprioceptive (Golgi tendon organs and muscle spindles) and exteroreceptive (optic, vestibular and cutaneous) receptors work alone or in combination to adjust the CPG to sensory feedback.

As early as 1911, it was recognized, by the experiments of Thomas Graham Brown, that the basic pattern of stepping can be produced by the spinal cord without the need of descending commands from the cortex.

As early as 1983, Ayers, Carpenter, Currie and Kinch proposed that there was a CPG responsible for most undulating movements in the lamprey including swimming forward and backward, burrowing in the mud and crawling on a solid surface, that although not surprisingly did not match the activity in the intact animal, nevertheless provided the basic locomotor output.

[56][57] However, this neural circuit model[58] of the lamprey CPG, including three classes (one excitatory and two inhibitory) of neurons but omitting sub-cellular details, provides a system level understanding of the CPG-generated locomotion whose speed and direction (swimming forward, backward, or turning) are set by non-rhythmic external inputs (from the brainstem) to the circuit.

[64] Commissural and long propriospinal neurons are a likely target of supraspinal and somatosensory afferent inputs to adjust interlimb coordination and gait to different environmental and behavioral conditions.

"The movements (i) involved alternating flexion and extension of his hips, knees, and ankles; (ii) were smooth and rhythmic; (iii) were forceful enough that the subject soon became uncomfortable due to excessive muscle 'tightness' and an elevated body temperature; and (iv) could not be stopped by voluntary effort."

After extensive study of the subject, the experimenters concluded that "these data represent the clearest evidence to date that such a [CPG] network does exist in man.

"[72] Four years later, in 1998, Dimitrijevic, et al. showed that the human lumbar pattern generating networks can be activated by drive to large-diameter sensory afferents of the posterior roots.

Subsequent studies showed that these lumbar locomotor centers can form a large variety of rhythmic movements by combining and distributing stereotypical patterns to the numerous lower limb muscles.

Preliminary evidence of efficacy was also found using videotape and electromyographic recordings since doses below MTD could acutely induce rhythmic locomotor-like leg movements in groups with Spinalon, but not in those with placebo (cornstarch).

[73] If step cycle durations and muscle activations were fixed, it would not be possible to change body velocity and adapt to varying terrain.

It has been suggested that the mammalian locomotor CPG comprises a "timer" (possibly in the form of coupled oscillators) which generates step cycles of varying durations, and a "pattern formation layer," which selects and grades the activation of motor pools.

The CPG timer produces the appropriate cadence and phase durations and the pattern formation layer modulates the motoneuronal outputs.

[82] The activated muscles resist stretch through their own intrinsic biomechanical properties, providing a rapid form of length and velocity feedback control.

Reflexes mediated by Golgi tendon organ and other afferents provide additional load compensation, but the main role of sensory input may be to adjust or override the CPG at stance-swing-stance transitions.

Swallowing involves the coordinated contraction of more than 25 pairs of muscles in the oropharynx, larynx and esophagus, which are active during an oropharyngeal phase, followed by the primary esophageal peristalsis.

A study showed that lung ventilation in the tadpole brainstem may be driven by a pacemaker-like mechanism, whereas the respiratory CPG adapts in the adult bullfrog as it matures.

[90] Thus, CPGs hold a broad range of functions in the vertebrate animal and are widely adaptable and variable with age, environment and behavior.

"Because of this, it has been suggested that PIR may contribute to the maintenance of oscillatory activity in neural networks that are characterized by mutual inhibitory connections, like those involved in locomotor behaviors.

The latter conclusion has stood the test of time, marking PIR as a robust property of CNS neurons in a wide variety of contexts.

[99] Other examples of CPGs in invertebrate animals include a CPG modulating reflexive withdrawal, escape swimming and crawling in the mollusc Tritonia,[100] and to control the heartbeat of leeches.

One theory that reconciles the role of sensory feedback during rhythmic locomotion is to redefine CPGs as "state estimators" as opposed to rhythm generators.

Intrinsic properties of CPG neurons. Adapted from Marder and Bucher (2001). [ 12 ]
Mechanisms of rhythm generation in CPGs. Adapted from Marder and Bucher (2001). [ 12 ]
Fig. 1. Schematic of the locomotor central pattern generator in the mammalian nervous system. A command signal specifying increasing body velocity descends from deep brain nuclei via the MLR to the spinal cord and drives the timing element of the spinal locomotor CPG to generate cycles of increasing cadence. Extensor phase durations change more than flexor phase durations. The command signal also drives the pattern formation layer to generate cyclical activation of flexor and extensor motoneurons. Loading of the activated muscles (e.g. supporting the moving body mass) is resisted by the muscles' intrinsic spring-like properties. This is equivalent to displacement feedback. Force and displacement sensed by muscle spindle and Golgi tendon organ afferents reflexly activate motoneurons. A key role of these afferents is to adjust the timing of phase transitions, presumably by influencing or overriding the CPG timer. Modified from [ 82 ]