Central pattern generators (CPGs) are self-organizing biological neural circuits that produce rhythmic outputs in the absence of rhythmic input. 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. The ability to function without input from higher brain areas still requires modulatory inputs, and their outputs are not fixed. Flexibility in response to sensory input is a fundamental quality of CPG-driven behavior. To be classified as a rhythmic generator, a CPG requires: "two or more processes that interact such that each process sequentially increases and decreases, and that, as a result of this interaction, the system repeatedly returns to its starting condition."
CPGs are found in humans and most other vertebrates, and in some invertebrates.
Physiology
CPG neurons
CPG neurons can have different intrinsic membrane properties (see schematic). Some neurons fire bursts of action potentials, either endogenously or in the presence of neuromodulatory substances. Other neurons are bistable and generate plateau potentials that can be triggered by a depolarizing current pulse, and terminated by a hyperpolarizing current pulse. Many CPG neurons fire after being released from inhibition (postinhibitory rebound). Another common feature of CPG neurons is a decrease in the frequency of firing during a constant depolarization (spike frequency adaptation).
Rhythm generation
Rhythm generation in CPG networks depends on the intrinsic properties of CPG neurons and their synaptic connections. There are two general mechanisms for rhythm generation: pacemaker/follower and reciprocal inhibition (see schematic).
In a network driven by a pacemaker, one or more neurons act as a core oscillator (pacemaker) that drives other, non-bursting neurons (follower) into a rhythmic pattern. Examples of pacemaker driven networks include the pyloric rhythm of the crustacean stomatogastric ganglion and the vertebrate respiratory rhythms.
In a network driven by reciprocal inhibition, two (groups of) neurons reciprocally inhibit each other. Such networks are known as half-center oscillators. The neurons are not rhythmically active when isolated, but they can produce alternating patterns of activity when coupled by inhibitory connections. (The neurons can also produce activity patterns of other relative phasing, including synchrony, depending on the synaptic properties). The transitions between activated and inhibited states can occur via a number of mechanisms. For example, spike-frequency adaptation in the bursting neuron(s) may slowly release the other neuron(s) from inhibition. Reciprocal inhibition is a core feature of many CPGs, including those involved in locomotion.
Gap junctions also contribute to rhythmic oscillations and neuronal synchrony in CPGs. They act as low-pass filter allowing slow membrane voltage fluctuations to pass more effectively across cells. In neonatal mice, blocking gap junctions results in decreased rhythmic activity and can completely abolish drug induced fictive locomotion. In zebrafish, motor neurons retrogradely control swim frequency via gap junctions.
Short-term synaptic dynamics CPG networks have extensive recurrent synaptic connections including reciprocal excitation and reciprocal inhibition. Synapses in CPG networks are subject to short-term activity dependent modifications. Short-term synaptic depression and facilitation of synapses can play a role in transitions between active and inactive phases of bursting and termination of bursts.
CPG circuits CPG circuits thought to be involved in the control of locomotion consist of motor neurons and spinal interneurons and are located in the lower thoracic and lumbar regions of the vertebrate spinal cord, and in each neuromere of the invertebrate ventral nerve cord. CPG neurons involved in swallowing are located in the brain stem, specifically the hypoglossal nucleus within the medulla.
While the general location of CPG neurons can often be inferred, the specific location and identity of the participating neurons are only beginning to be understood. CPG networks are often distributed and can be flexibly reorganized, making it challenging to identify spinal interneurons. Over the past few decades, molecular and genetic programs that control neuronal patterning have been used to specifically target spinal interneurons in mice and zebrafish. Developing neural tube of embryonic mouse shows expression of distinct transcription factors in domains along the dorso-ventral axis of the spinal cord. 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. The ventral neurons are considered to be members of the spinal CPG network. Each of these interneuron class can be further divided into diverse subpopulations of neurons with distinct neurotransmitter phenotype, axonal projection and function during locomotion. For example, V2 interneurons are ipsilaterally projecting that can be further classified as excitatory V2a and inhibitory V2b. V2s are important for flexor-extensor alternation and provide excitation to motor neurons.
Neuromodulation Organisms must adapt their behavior to meet the needs of their internal and external environments. Central pattern generators, as part of the neural circuitry of an organism, can be modulated to adapt to the organism's needs and surroundings. Three roles of neuromodulation have been found for CPG circuits: Modulation is intrinsic to CPG network or required for its activation Modulation changes the functional configuration of CPGs to produce different outputs Modulation alters CPG neuron complement by switching neurons between networks and fusing formerly separate networks into larger entities
Neuromodulatory synapses may be part of the CPG network itself. For example, the CPG underlying the escape swim response in Tritonia diomedea contains intrinsic neuromodulatory neurons. These neuromodulatory neurons can enhance neurotransmitter release from another neuron in the circuit and its neuromodulatory actions are thought to be important for producing swim motor program. Neuromodulatory inputs can also activate CPG networks and can be necessary for generation of rhythmic output. Loss of neuromodulatory inputs can abolish rhythmic activity from pyloric network. In vertebrates, application of neuromodulators have been shown to evoke locomotor activity.
Neuromodulators can alter the synaptic strength as well as intrinsic properties of neurons. These actions can alter the frequency and the phase relationships between neurons and thereby change the output pattern of the circuit. For example, exogenous application of various neuromodulators can elicit triphasic motor pattern in the STG where each modulator results in generation of a different motor pattern. Neuromodulatory projections expressing a common modulator can also elicit different patterns from the same network. Stimulation of different proctolin-containing projection neurons in the STG results in a distinct motor pattern from the same network due to differences in cotransmitter complement of these projection neurons.
The effects of neuromodulators are distributed throughout the CPG network. Specially, dopamine was shown to affect cellular and synaptic properties of nearly all components of the crustacean pyloric network. Moreover, dopamine can have opposing effects on different components of the network. As such, the final output of the network reflects a combination of modulatory actions on individual components.
Modulation alters CPG neurons Neuronal composition of CPGs can vary with the state of the system. Neuromodulators can activate or inhibit neurons of the CPGs and can even combine different networks into one. 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. Neuromodulators can also result in switching of neurons from one network to another.
Sensory feedback Although the theory of central pattern generation calls for basic rhythmicity and patterning to be centrally generated, CPGs can respond to sensory feedback to alter the patterning in behaviorally appropriate ways. Alteration of the pattern is difficult because feedback received during only one phase may require changed movement in the other parts of the patterned cycle to preserve certain coordination relationships. For example, walking with a pebble in the right shoe alters the entire gait, even though the stimulus is only present while standing on the right foot. Even during the time when the left foot is down and the sensory feedback is inactive, action is taken to prolong the right leg swing and extend the time on the left foot, leading to limping. This effect could be due to widespread and long-lasting effects of the sensory feedback on the CPG or due to short-term effects on a few neurons that in turn modulate nearby neurons and spread the feedback through the entire CPG in that way. Some degree of modulation is required to allow one CPG to assume multiple states in response to feedback.
Additionally, the effect of the sensory input varies depending on the phase of the pattern in which it occurs. For example, during walking, resistance to the top of the swinging foot (e.g., by a horizontal stick) causes the foot to be lifted higher to move over the stick. However, the same input to the standing foot cannot cause the foot to lift or the person would collapse. Thus, depending on the phase, the same sensory input can cause the foot to be lifted higher or held more firmly to the ground. "This change in motor response as a function of motor pattern phase is called reflex reversal, and has been observed in invertebrates (DiCaprio and Clarac, 1981) and vertebrates (Forssberg et al., 1977). How this process occurs is poorly understood, but again two possibilities exist. One is that sensory input is appropriately routed to different CPG neurons as a function of motor pattern phase. The other is that the input reaches the same neurons at all phases, but that, as a consequence of the way in which the network transforms the input, network response varies appropriately as a function of motor pattern phase."
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. This study describes the differences in gait and body position of cats walking uphill, downhill and on level surfaces. 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. The study explored the effects of neck proprioceptors (giving information about the relative location of the head and body) and vestibular receptors (giving information about the orientation of the head relative to gravity). Decerebrate cats were made to walk on a level surface with their heads level, tilted up or tilted down. Comparing the decerebrate cats to normal cats showed similar EMG patterns during level walking and EMG patterns that reflected downhill walking with the head titled up and uphill walking with the head tilted down. This study proved that neck proprioceptors and vestibular receptors contribute sensory feedback that alters the gait of the animal. This information may be useful for treatment of gait disorders.
Functions Central pattern generators can serve many functions. CPGs can play roles in movement, breathing, rhythm generation and other oscillatory functions. Below are several key functions of CPGs.
Locomotion