The shal gene encodes the transient potassium current (I(A)) in neurons of the lobster stomatogastric ganglion. Overexpression of Shal by RNA injection into neurons produces a large increase in I(A), but surprisingly little change in the neuron's firing properties. Accompanying the increase in I(A) is a dramatic and linearly correlated increase in the hyperpolarization-activated inward current (I(h)). The enhanced I(h) electrophysiologically compensates for the enhanced I(A), since pharmacological blockade of I(h) uncovers the physiological effects of the increased I(A). Expression of a nonfunctional mutant Shal also induces a large increase in I(h), demonstrating a novel activity-independent coupling between the Shal protein and I(h) enhancement. Since I(A) and I(h) influence neuronal activity in opposite directions, our results suggest a selective coregulation of these channels as a mechanism for constraining cell activity within appropriate physiological parameters.

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Key pointsr Coordination of neuronal activity between left and right sides of the mammalian spinal cord is provided by several sets of commissural interneurons (CINs) whose axons cross the midline. Genetically identified inhibitory V0 D and excitatory V0 V CINs and ipsilaterally projecting excitatory V2a interneurons were shown to secure left-right alternation at different locomotor speeds.r We have developed computational models of neuronal circuits in the spinal cord that include left and right rhythm-generating centres interacting bilaterally via three parallel pathways mediated by V0 D , V2a-V0 V and V3 neuron populations.r The models reproduce the experimentally observed speed-dependent left-right coordination in normal mice and the changes in coordination seen in mutants lacking specific neuron classes.r The models propose an explanation for several experimental results and provide insights into the organization of the spinal locomotor network and parallel CIN pathways involved in gait control at different locomotor speeds.Abstract Different locomotor gaits in mammals, such as walking or galloping, are produced by coordinated activity in neuronal circuits in the spinal cord. Coordination of neuronal activity between left and right sides of the cord is provided by commissural interneurons (CINs), whose axons cross the midline. In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified inhibitory (V0 D ) and excitatory (V0 V ) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0 V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce and suggest mechanistic explanations for several experimental observations. These phenomena include: different speed-dependent contributions of V0 D and V0 V CINs and V2a interneurons to left-right alternation of neural activity, switching gaits between the left-right alternating walking-like activity and the left-right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN pathways and suggest explanations for how these pathways maintain alternating and synchronous gaits at different locomotor speeds. The models propose testable predictions about the neural organization and operation of mammalian locomotor circuits.

Key points• The organization of the spinal circuitry responsible for the generation of locomotor rhythm and control of locomotion in mammals is largely unknown, though several types of spinal interneurons involved in the rodent locomotor network have been identified. • Ventral root recordings of spinal motoneurons during fictive locomotion in the isolated mouse spinal cord show spontaneous deletions of activity. The majority of deletions in the isolated neonatal mouse spinal cord are non-resetting: they do not change the phase of subsequent motor cycles. Flexor and extensor motoneurons express asymmetric responses during deletions: flexor deletions are accompanied by tonic ipsilateral extensor activity, while extensor deletions do not perturb rhythmic ipsilateral flexor activity. Non-resetting deletions on one side of the cord do not perturb rhythmic activity on the other side of the cord and can occur in isolated hemicords.• We have characterized the activity of motoneurons and identified interneurons during spontaneous motor deletions. The motoneurons and a subset of V2a interneurons fall silent during non-resetting motor deletions while a second subset of V2a interneurons and commissural interneurons continue unperturbed rhythmic firing. This allowed us to suggest their involvement at different levels of the locomotor network operation.• We have developed a computational model of the central pattern generator that reproduces, and proposes a mechanistic explanation for, our experimental results. The model provides novel insights into the organization of spinal locomotor networks.Abstract We explored the organization of the spinal central pattern generator (CPG) for locomotion by analysing the activity of spinal interneurons and motoneurons during spontaneous deletions occurring during fictive locomotion in the isolated neonatal mouse spinal cord, following earlier work on locomotor deletions in the cat. In the isolated mouse spinal cord, most spontaneous deletions were non-resetting, with rhythmic activity resuming after an integer number of cycles. Flexor and extensor deletions showed marked asymmetry: flexor deletions were accompanied by sustained ipsilateral extensor activity, whereas rhythmic flexor bursting was not perturbed during extensor deletions. Rhythmic activity on one side of the cord was not perturbed during non-resetting spontaneous deletions on the other side, and these deletions could occur with no input from the other side of the cord. These results suggest that the locomotor CPG has a two-level organization with rhythm-generating (RG) and pattern-forming (PF) networks, in which only the flexor RG network is intrinsically rhythmic. To further explore the neuronal organization of the CPG, we monitored activity of motoneurons and selected identified

Serotonin and octopamine, injected into the circulation of freely moving lobsters and crayfish, produce opposite behavioral effects. Octopamine injection produces sustained extension of the limbs and abdomen; serotonin injection produces sustained flexion. Neurophysiological analyses show that these postures can be accounted for by opposing, coordinated effects of these amines on patterns of motoneuron activity recorded from the ventral nerve cord.

The fast transient potassium or A current (IA) plays an important role in determining the activity of central pattern generator neurons. We have previously shown that the shal K+ channel gene encodes IA in neurons of the pyloric network in the spiny lobster. To further study how IA shapes pyloric neuron and network activity, we microinjected RNA for a shal-GFP fusion protein into four identified pyloric neuron types. Neurons expressing shal-GFP had a constant increase in IA amplitude, regardless of cell type. This increase in IA was paralleled by a concomitant increase in the hyperpolarization-activated cation current Ih in all pyloric neurons. Despite significant increases in these currents, only modest changes in cell firing properties were observed. We used models to test two hypotheses to explain this failure to change firing properties. First, this may reflect the mislocalization of the expressed shal protein solely to the somata and initial neurites of injected neurons, rendering it electrically remote from the integrating region in the neuropil. To test this hypothesis, we generated a multicompartment model where increases in IA could be localized to the soma, initial neurite, or neuropil/axon compartments. Although spike activity was somewhat more sensitive to increases in neuropil/axon versus somatic/primary neurite IA, increases in IA limited to the soma and primary neurite still evoked much more dramatic changes than were seen in the shal-GFP-injected neurons. Second, the effect of the increased IA could be compensated by the endogenous increase in Ih. To test this, we modeled the compensatory increases of IA and Ih with a cycling two-cell model. We found that the increase in Ih was sufficient to compensate the effects of increased IA, provided that they increase in a constant ratio, as we observed experimentally in both shal-injected and noninjected neurons. Thus an activity-independent homeostatic mechanism maintains constant neuronal activity in the face of dramatic increases in IA.

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Central Pattern Generator (CPG) networks, which organize rhythmic movements, have long served as models for neural network organization. Modulatory inputs are essential components of CPG function: neuromodulators set the parameters of CPG neurons and synapses to render the networks functional. Each modulator acts on the network by many effects which may oppose one another; this may serve to stabilize the modulated state. Neuromodulators also determine the active neuronal composition in the CPG, which varies with state changes such as locomotor speed. The pattern of gene expression which determines the electrophysiological personality of each CPG neuron is also under modulatory control. It is not possible to model the function of neural networks without including the actions of neuromodulators.