All-or-none control of the bursting properties of the pacemaker neurons of the labster pyloric pattern generator

In Crustacea the central pattern generator for the pyloric motor rhythm (filtration to the midgut) is known to be located within the stomatogastric ganglion (STG); its cycling activity is known to be organized by three endogenous burster neurons acting as pacemakers and driving 11 follower neurons. In Homarus, recordings from the isolated stomatogastric nervous system (Fig. 1) indicate that (1) the pyloric output can be generated only when the STG is afferented (i.e., connected to the more rostral oesophageal and commissural ganglia) (Fig. 2) and (2) the deafferntation of the STG results in a complete loss of the bursting properties of the pacemaker neurons (Fig. 4). Manipulation of the STG inputs responsible for unmasking the properties of the pacemakers strongly suggests that (1) they are not phasic inputs (Fig. 5) and (2) they are long-term acting inputs (Fig. 6). These results provide evidence for a neural all-or-none control of the bursting properties of the pacemaker neurons of a motor pattern generator.     

The cortex as a central pattern generator

Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound similarities with neocortical circuits. CPGs can produce meaningful functional output in the absence of sensory inputs. Neocortical circuits could be considered analogous to CPGs as they have rich spontaneous dynamics that, similar to CPGs, are powerfully modulated or engaged by sensory inputs, but can also generate output in their absence. We find compelling evidence for this argument at the anatomical, biophysical, developmental, dynamic and pathological levels of analysis. Although it is possible that cortical circuits are particularly plastic types of CPG ('learning CPGs'), we argue that present knowledge about CPGs is likely to foretell the basic principles of the organization and dynamic function of cortical circuits.     

Invertebrate central pattern generator circuits

There are now a reasonable number of invertebrate central pattern generator (CPG) circuits described in sufficient detail that a mechanistic explanation of how they work is possible. These small circuits represent the best-understood neural circuits with which to investigate how cell-to-cell synaptic connections and individual channel conductances combine to generate rhythmic and patterned output. In this review, some of the main lessons that have appeared from this analysis are discussed and concrete examples of circuits ranging from single phase to multiple phase patterns are described. While it is clear that the cellular components of any CPG are basically the same, the topology of the circuits have evolved independently to meet the particular motor requirements of each individual organism and only a few general principles of circuit operation have emerged. The principal usefulness of small systems in relation to the brain is to demonstrate in detail how cellular infrastructure can be used to generate rhythmicity and form specialized patterns in a way that may suggest how similar processes might occur in more complex systems. But some of the problems and challenges associated with applying data from invertebrate preparations to the brain are also discussed. Finally, I discuss why it is useful to have well-defined circuits with which to examine various computational models that can be validated experimentally and possibly applied to brain circuits when the details of such circuits become available.     

Formal analysis of resonance entrainment by central pattern generator

The neuronal circuit controlling the rhythmic movements in animal locomotion is called the central pattern generator (CPG). The biological control mechanism appears to exploit mechanical resonance to achieve efficient locomotion. The objective of this paper is to reveal the fundamental mechanism underlying entrainment of CPGs to resonance through sensory feedback. To uncover the essential principle, we consider the simplest setting where a pendulum is driven by the reciprocal inhibition oscillator. Existence and properties of stable oscillations are examined by the harmonic balance method, which enables approximate but insightful analysis. In particular, analytical conditions are obtained under which harmonic balance predicts existence of an oscillation at a frequency near the resonance frequency. Our result reveals that the resonance entrainment can be maintained robustly against parameter perturbations through two distinct mechanisms: negative integral feedback and positive rate feedback.     

Homologues of serotonergic central pattern generator neurons in related nudibranch molluscs with divergent behaviors

Homologues of a neuron that contributes to a species-specific behavior were identified and characterized in species lacking that behavior. The nudibranch Tritonia diomedea swims by flexing its body dorsally and ventrally. The dorsal swim interneurons (DSIs) are components of the central pattern generator (CPG) underlying this rhythmic motor pattern and also activate crawling. Homologues of the DSIs were identified in six nudibranchs that do not exhibit dorsal–ventral swimming: Tochuina tetraquetra, Melibe leonina, Dendronotus iris, D. frondosus, Armina californica, and Triopha catalinae. Homology was based upon shared features that distinguish the DSIs from all other neurons: (1) serotonin immunoreactivity, (2) location in the Cerebral serotonergic posterior (CeSP) cluster, and (3) axon projection to the contralateral pedal ganglion. The DSI homologues, named CeSP-A neurons, share additional features with the DSIs: irregular basal firing, synchronous inputs, electrical coupling, and reciprocal inhibition. Unlike the DSIs, the CeSP-A neurons were not rhythmically active in response to nerve stimulation. The CeSP-A neurons in Tochuina and Triopha also excited homologues of the Tritonia Pd5 neuron, a crawling efferent. Thus, the CeSP-A neurons and the DSIs may be part of a conserved network related to crawling that may have been co-opted into a rhythmic swim CPG in Tritonia. This material is based upon work supported by the National Science Foundation, under Grant No. 0445768, and a GSU Research Program Enhancement grant to PSK.     

Learning, memory and a respiratory central pattern generator

In an attempt to elucidate the causal mechanisms underlying learning and memory we have developed a model system, aerial respiration in the pond snail Lymnaea stagnalis. A three-neuron central pattern generator (CPG) whose sufficiency and necessity have been demonstrated mediates this behaviour. Aerial respiration, while an important homeostatic behaviour, is inhibited by the activation of the whole body withdrawal response that the animal uses to protect itself. We found that it was possible to operantly condition snails not to perform aerial respiration in a situation, a hypoxic environment, where aerial respiration should predominate. Operant conditioning was achieved by eliciting the pneumostome withdrawal response, part of the whole body withdrawal response, each time the animal attempted to open its pneumostome to breathe. Yoked control animals did not demonstrate an alteration in breathing behaviour. Subsequently we determined neural correlates of this associative behaviour and found that neuronal changes are distributed throughout the CPG. This preparation may afford us the opportunity to determine the casual neuronal changes that underlie learning and memory of associative conditioning.     

Modular neuromuscular control of human locomotion by central pattern generator

The central pattern generators (CPG) in the spinal cord are thought to be responsible for producing the rhythmic motor patterns during rhythmic activities. For locomotor tasks, this involves much complexity, due to a redundant system of muscle actuators with a large number of highly nonlinear muscles. This study proposes a reduced neural control strategy for the CPG, based on modular organization of the co-active muscles, i.e., muscle synergies. Four synergies were extracted from the EMG data of the major leg muscles of two subjects, during two gait trials each, using non-negative matrix factorization algorithm. A Matsuoka׳s four-neuron CPG model with mutual inhibition, was utilized to generate the rhythmic activation patterns of the muscle synergies, using the hip flexion angle and foot contact force information from the sensory afferents as inputs. The model parameters were tuned using the experimental data of one gait trial, which resulted in a good fitting accuracy (RMSEs between 0.0491 and 0.1399) between the simulation and experimental synergy activations. The model׳s performance was then assessed by comparing its predictions for the activation patterns of the individual leg muscles during locomotion with the relevant EMG data. Results indicated that the characteristic features of the complex activation patterns of the muscles were well reproduced by the model for different gait trials and subjects. In general, the CPG- and muscle synergy-based model was promising in view of its simple architecture, yet extensive potentials for neuromuscular control, e.g., resolving redundancies, distributed and fast control, and modulation of locomotion by simple control signals.     

Multiple transmitter neurons in Tritonia. III. Modulation of central pattern generator controlling feeding

Feeding behavior in the gastropod mollusc Tritonia diomedea is controlled by a central pattern generator (CPG) in the buccal ganglia. The medially located, large dorsal white cells (B11) have been shown to contain two small cardioactive peptides (SCPs). A smaller nearby neuron (B12) also appears to contain the SCPs. B11's have also been shown to contain acetylcholine (ACh), whereas B12's do not. We have shown earlier that intracellular stimulation of B11's drives contractions of the foregut. Here we show that intracellular electrical stimulation of B11's also elicits excitation of neurons B5 and stimulates the patterned motor output of the CPG. We showed earlier that B12's also stimulate contractions in the foregut, but they are in the opposite direction from those elicited by B11. We show here that electrical stimulation of B12's inhibits the output of the CPG. We showed earlier that superfusion of the isolated gut with SCPB enhances peristalsis, and here we report that superfusion of the buccal ganglion with SCPB elicits enhanced coordinated motor output from the CPG. The peptide has two effects on the bursting output of motor neurons. It produces an increase in (1) the rate of bursting and (2) the spike frequency during each burst. On the other hand, we reported earlier that ACh applied directly to isolated foregut inhibits ongoing peristalsis. Here we demonstrate that ACh superfusion of the buccal ganglion also inhibits the CPG output. Our evidence supports the view that in addition to stimulating foregut contractility, B11's modulate the output of the swallowing CPG by releasing a peptide from central terminals. We suggest roles for B11, B12, the SCPs, and ACh in controlling both central and peripheral aspects of feeding behavior.     

The locust frontal ganglion: a multi-tasked central pattern generator

The locust frontal ganglion (FG) constitutes a major source of innervation to the foregut dilator muscles and thus plays a key role in control of foregut movements. This paper reviews our recent studies on the generation and characteristics of FG motor outputs in two distinct and fundamental locust behaviors: feeding and molting. In an in vitro preparation, isolated from all descending and sensory inputs, the FG was spontaneously active and generated rhythmic multi-unit bursts of action potentials, which could be recorded from all efferent nerves. Thus the FG motor pattern is generated by a central pattern generator within the ganglion. Intracellular recordings suggest that only a small fraction (10-20%) of the FG 100 neurons demonstrate rhythmic activity. The FG motor output in vivo was relatively complex, and strongly dependent on the locust's physiological and behavioral state. Rhythmic activity of the foregut was found to depend on the amount of food present in the crop; animals with full crop demonstrated higher FG burst frequency than those with empty crop. At the molt, the FG generates a distinct motor pattern that could be related to air-swallowing behavior.     

A sodium leak current regulates pacemaker activity of adult central pattern generator neurons in Lymnaea stagnalis

The resting membrane potential of the pacemaker neurons is one of the essential mechanisms underlying rhythm generation. In this study, we described the biophysical properties of an uncharacterized channel (U-type channel) and investigated the role of the channel in the rhythmic activity of a respiratory pacemaker neuron and the respiratory behaviour in adult freshwater snail Lymnaea stagnalis. Our results show that the channel conducts an inward leak current carried by Na(+) (I(Leak-Na)). The I(Leak-Na) contributed to the resting membrane potential and was required for maintaining rhythmic action potential bursting activity of the identified pacemaker RPeD1 neurons. Partial knockdown of the U-type channel suppressed the aerial respiratory behaviour of the adult snail in vivo. These findings identified the Na(+) leak conductance via the U-type channel, likely a NALCN-like channel, as one of the fundamental mechanisms regulating rhythm activity of pacemaker neurons and respiratory behaviour in adult animals.     

Dynamic control of the central pattern generator for locomotion

We show that an ongoing locomotor pattern can be dynamically controlled by applying discrete pulses of electrical stimulation to the central pattern generator (CPG) for locomotion. Data are presented from a pair of experiments on biological (wetware) and electrical (hardware) models of the CPG demonstrating that stimulation causes brief deviations from the CPG’s limit cycle activity. The exact characteristics of the deviation depend strongly on the phase of stimulation. Applications of this work are illustrated by examples showing how locomotion can be controlled by using a feedback loop to monitor CPG activity and applying stimuli at the appropriate times to modulate motor output. Eventually, this approach could lead to development of a neuroprosthetic device for restoring locomotion after paralysis. R. J. Vogelstein and F. Tenore contributed equally to this work.     

Molecular mechanisms of homeostatic plasticity in central pattern generator networks

Central pattern generator (CPG) networks rely on a balance of intrinsic and network properties to produce reliable, repeatable activity patterns. This balance is maintained by homeostatic plasticity where alterations in neuronal properties dynamically maintain appropriate neural output in the face of changing environmental conditions and perturbations. However, it remains unclear just how these neurons and networks can both monitor their ongoing activity and use this information to elicit homeostatic physiological responses to ensure robustness of output over time. Evidence exists that CPG networks use a mixed strategy of activity‐dependent, activity‐independent, modulator‐dependent, and synaptically regulated homeostatic plasticity to achieve this critical stability. In this review, we focus on some of the current understanding of the molecular pathways and mechanisms responsible for this homeostatic plasticity in the context of central pattern generator function, with a special emphasis on some of the smaller invertebrate networks that have allowed for extensive cellular‐level analyses that have brought recent insights to these questions.     

Travelling wave patterns in a model of the spinal pattern generator using spiking neurons

The aim of this study is to produce travelling waves in a planar net of artificial spiking neurons. Provided that the parameters of the waves – frequency, wavelength and orientation – can be sufficiently controlled, such a network can serve as a model of the spinal pattern generator for swimming and terrestrial quadruped locomotion. A previous implementation using non-spiking, sigmoid neurons lacked the physiological plausibility that can only be attained using more realistic spiking neurons. Simulations were conducted using three types of spiking neuronal models. First, leaky integrate-and-fire neurons were used. Second, we introduced a phenomenological bursting neuron. And third, a canonical model neuron was implemented which could reproduce the full dynamics of the Hodgkin–Huxley neuron. The conditions necessary to produce appropriate travelling waves corresponded largely to the known anatomy and physiology of the spinal cord. Especially important features for the generation of travelling waves were the topology of the local connections – so-called off-centre connectivity – the availability of dynamic synapses and, to some extent, the availability of bursting cell types. The latter were necessary to produce stable waves at the low frequencies observed in quadruped locomotion. In general, the phenomenon of travelling waves was very robust and largely independent of the network parameters and emulated cell types.     

A central pattern generator underlies crawling in the medicinal leech

Crawling in the medicinal leech has previously been thought to require sensory feedback because the intact behavior is strongly modulated by sensory feedback and because semi-intact preparations will only crawl if they can move freely. Here we show that an isolated leech nerve cord can produce a crawling motor pattern similar to the one seen in semi-intact preparations, which consists of an anterior-to-posterior wave of alternating excitatory circular and longitudinal motor neuron bursts in each segment. The isolated cord also reproduces the patterns of activity seen in semi-intact preparations for several other kinds of cells: the dorsal inhibitor cell 1, the ventral excitor cell 4, and the annulus erector motor neuron. Because this correspondence is so strong, there must be a central pattern generator in the isolated cord that can produce the basic motor pattern for crawling without sensory feedback. A quantitative analysis of the isolated motor pattern, however, reveals that isolated and semi-intact preparations have longer periods than the intact behavior and that there are deficiencies in the timing of motor neuron bursts in the isolated pattern. These results suggest that sensory feedback modulates the isolated central pattern generator to help produce the normal motor pattern.     

A reconsideration of the central pattern generator concept for locust flight

Summary Although it is generally agreed that locusts can generate flight similar rhythmic motor activity in the absence of sensory feedback from the wings, recent studies indicate that functional deafferentation produces significant changes in the flight motor pattern (Hedwig and Pearson 1984). These findings have raised doubts on the adequacy of the central pattern generator concept for the locust flight system (Pearson 1985). In this paper, we re-investigate the effects of deafferentation on the capacity of adult migratory locusts to generate the flight motor pattern. For this purpose, the experimental animals were dissected to various degrees, ranging from head-ventral nerve cord, to isolated pterothoracic nerve cord, and finally single isolated ganglion preparations. Flight motor activity was released by either wind stimulation, the more traditional method, or by applying octopamine (Sombati and Hoyle 1984; Stevenson and Kutsch 1986). In all cases the released motor activity was analysed, giving details of latency, and phase relationships between specific synergistic and antagonistic motor units, and then compared with the flight motor pattern generated by intact tethered locusts.This analysis shows that deafferentation, although reducing the frequency, does not necessarily disrupt the basic flight motor pattern. By using octopamine we could show that even isolated thoracic nerve cord preparations can generate activity, which in all major aspects corresponds to this motor program. This could also be shown for the fully isolated metathoracic ganglion and we provide some evidence that the mesothoracic ganglion may be capable of a similar performance. In addition to releasing flight activity, octopamine was also found to enhance the responsiveness of deafferentated locusts to wind stimulation. This resulted in a considerable elevation of the frequency and prolongation of the flight motor activity to values comparable to the performance of intact tethered locusts.     

Intersegmental coordinating system of the lamprey central pattern generator for locomotion

Summary In the lamprey,Ichthyomyzon unicuspis, the wave of activity required for normal swimming movements can be generated by a central pattern generator (CPG) residing in the spinal cord. A constant phase coupling between spinal segments can be organized by intersegmental coordinating neurons intrinsic to the cord. The rostral and caudal segmental oscillators of the CPG have different preferred frequencies when separated from each other. Therefore the system must maintain the segmental oscillators of the locomotor CPG at a single common frequency and with the proper relative timing. Using selective lesions and a split-bath, it is demonstrated that the coordinating system is comprised of at least 3 subsystems, short-axon systems in the lateral and medial tracts and a long axon system in the lateral tracts. Each alone can sustain relatively stable coordinated activity.Abbreviations CPG central pattern generator - NMDA N-methyl-D-aspartate - VR ventral root     

On the definition of central pattern generator and its sensory control

A central pattern generator (CPG) is defined here as a neural network responsible for the production of the timing cues of a rhythmic motor output pattern in the isolated CNS. For the intact animal, model considerations show that this term is neither clearly delimited from the concept of a reflex chain nor from the concept of a pattern generator with functional principles different from those of the CPG. Therefore, it cannot be concluded from the existence of a CPG in the isolated nervous system that this CPG also provides the decisive timing cues in the intact animal. Consequences for the study of the neural basis of rhythmic movements are shown.