Contributions of h- and Na + /K + pump currents to the generation of episodic and continuous rhythmic activities
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Summary: Both reviewers found that the analysis of data was too shallow and that the HCO model was insufficiently justified in the context of spinal cord CPGs. The reviewers argue that a more robust analysis including a discussion of the dynamic properties of the model (in the context of dynamic switching) was needed to support conclusions.
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Abstract
Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-centre oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na + /K + ATPase pump (I Pump ) and hyperpolarization-activated currents (I h ) playing key roles. Modulation of either I PumpMax or I h produced transitions between episodic and continuous rhythms and silence. As I Pump increased, the episode duration and period increased along with a reduction in interepisode interval. Increasing I h increased the episode period along with an increase in episode duration. Pharmacological manipulations of I h with ZD7288 and I Pump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modelling and experimental results highlight key roles of I h and I Pump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity.
Significance statement
The ability of a single CPG to produce and transition between multiple rhythmic patterns of activity is poorly understood. We deployed a complementary computational half-centre oscillator model and an isolated spinal cord experimental preparation to identify key currents whose interaction produced episodic and continuous rhythmic activity. Together, our experimental and modelling approaches suggest mechanisms in spinal networks that govern diverse rhythms and transitions between them. This work sheds light on the ability of a single CPG to produce episodic bouts observed in behavioural and pathological contexts.
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Reviewer #2:
The topic of this manuscript is the basis of continuous and episodic bursting electrical activity in developing spinal cords. The approach used is to employ a simple mathematical model as a representation of the central pattern generator underlying the bursting pattern, and examine how the properties of bursting change with variation in three key system parameters. Some of the model predictions are tested in an actual in vitro spinal cord preparation. Although I enjoyed reading the manuscript, I have some serious concerns about the model that is employed, which I discuss below.
Major concerns:
The model is a half-center oscillator (HCO) in which one cell inhibits the other, resulting in anti-phasic electrical activity of the two cells. (Each "cell" actually represents a cell population, so the model is a mean field model.) …
Reviewer #2:
The topic of this manuscript is the basis of continuous and episodic bursting electrical activity in developing spinal cords. The approach used is to employ a simple mathematical model as a representation of the central pattern generator underlying the bursting pattern, and examine how the properties of bursting change with variation in three key system parameters. Some of the model predictions are tested in an actual in vitro spinal cord preparation. Although I enjoyed reading the manuscript, I have some serious concerns about the model that is employed, which I discuss below.
Major concerns:
The model is a half-center oscillator (HCO) in which one cell inhibits the other, resulting in anti-phasic electrical activity of the two cells. (Each "cell" actually represents a cell population, so the model is a mean field model.) This is certainly one way to get electrical bursts. However, it is not at all clear that such a HCO structure exists in the developing spinal cord, or that there are neural populations with this anti-phasic activity. If such data exists, it is not mentioned in the paper or cited. Indeed, the recordings in Supp. Fig. 1 show extracellular neurogram recordings from ventral roots in different lumbar segments and in which the bursting appears to be synchronous. So I see no evidence that the HCO model reflects the actual neural circuit, other than the fact that it can produce bursting and episodic bursting. This does not mean that such a phenomenological model is without value, but it should be made clear to the reader that that is what the model is. Also, the next two points below do appear to cast doubt on the utility of this model.
In Fig. 3 it is shown that the inter-episode interval (IEI) is increased in the model when the conductance g_h is reduced. Because of this, the episode period (EP) also increases. The data, also in Fig. 3, show the opposite. They show that blocking the h-type current decreases the EP. This seems like a flaw in the model, since it is the h-type current that is responsible for episode production (at least I think it is, see point 4 below). The discrepancy is mentioned in the manuscript, but only briefly and it should be fully addressed.
In Fig. 5 it is shown that, in the model, there is a very small interval of g_NaP where episodic bursting is produced. Otherwise, the model produces continuous bursting (for larger g_NaP values) or silent cells (for smaller g_NaP values). However, the data that is also shown in the figure indicates that blocking the NaP channels has little effect on episodic bursting. This is another serious discrepancy between the model and the experimental data.
Points for clarification:
It appears from Fig. 1 that episodes stop when h-type current activation slowly moves to an insufficient level to kick off a new burst. Logically, a new episode would start once that activation grows back to a sufficiently large value. Is this right? The mechanism for episode production is never discussed, and it should be.
The model is deterministic, yet there is variation in burst duration and episode duration (see Fig. 3). What is the source of the variation? Does this mean that the episodes are not periodic?
The model has a multistable region in parameter space, and much is made of this in the Results and the Discussion. In Fig. 6, it was demonstrated that hyperpolarizing pulses could switch the system from one behavior to another. Can this be done experimentally in the in vitro prep? If so, was it tried?
Other:
Discussion is too long and touches on things that were far from the focus of the manuscript. For example, there is about a page and a half of text discussing short term motor memory (STMM) although the Results section did not focus at all on homeostatic functions of the circuit or STMM. Furthermore, some points were made several times during the Discussion, where one time would have been sufficient.
Almost two pages of the Discussion was dedicated to multistable zones, yet in the model the multistable zone was tiny, and there was no evidence that the experimental prep lies in or near that zone. The authors state that in actual neural circuitry there could be a much larger multistable zone, which is true, but there also may be none at all. This discussion appears irrelevant.
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Reviewer #1:
The present paper addresses the very topical problem of understanding of dynamic switching in central pattern generators. The paper investigates switching between bursting and spiking modes in spinal cord neurons. This is modelled using a multichannel HCO that identifies narrow regions in parameters where the system is bistable. It is argued that neurotransmitters drive invertebrate CPGs to favourable bistable regimes that allow rapid switching from one oscillatory state to another (e.g. foraging to escape) to be enacted by fast electrical stimuli. The paper is generally well-written and does a good job at interpreting observations.
I have two major comments:
The authors seem to ignore the switching between phasic and antiphasic oscillatory states, even though this is shown in Fig.1, and more generally between the …
Reviewer #1:
The present paper addresses the very topical problem of understanding of dynamic switching in central pattern generators. The paper investigates switching between bursting and spiking modes in spinal cord neurons. This is modelled using a multichannel HCO that identifies narrow regions in parameters where the system is bistable. It is argued that neurotransmitters drive invertebrate CPGs to favourable bistable regimes that allow rapid switching from one oscillatory state to another (e.g. foraging to escape) to be enacted by fast electrical stimuli. The paper is generally well-written and does a good job at interpreting observations.
I have two major comments:
The authors seem to ignore the switching between phasic and antiphasic oscillatory states, even though this is shown in Fig.1, and more generally between the polyrhythms that would occur in larger inhibitory networks. The latter switching may be at least as relevant to gait generation as the switching from bursting to spiking. Polyrhythms have also been shown experimentally and theoretically to produce robust multistable states that overlap over a wide parameter space. It would therefore be useful if the authors could comment on the relative robustness of spiking/bursting multistability vs polyrhythm multistability.
It is argued that an hyperpolarizing Ip pulse will induce a transition from continuous spiking to bursting and conversely a depolarizing pulse induces the reverse transition from bursting to continuous spiking. Transitions are a dynamic process which will depend, among other things, on the timing when the pulse is applied during the heteroclinic cycle. In the absence of more information on the dynamics of the system such claims look over-simplistic.
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Summary: Both reviewers found that the analysis of data was too shallow and that the HCO model was insufficiently justified in the context of spinal cord CPGs. The reviewers argue that a more robust analysis including a discussion of the dynamic properties of the model (in the context of dynamic switching) was needed to support conclusions.
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