1. Author Response

    Reviewer #1 (Public Review):

    The manuscript is somewhat readable but the many acronyms for the cell types in model and biology make it difficult to follow. Is there a reason why the biological neuron names cannot be used in the model?

    We agree that the field would benefit from not having yet another set of acronyms for the different spinal neurons. We have changed the names of the neurons to their putative molecular identity.

    The presentation of data in figures can be more powerful. In many cases, the data in figures and the supplemental videos show apparently different results. This can be an artifact of how the videos were made and if yes, these can be improved. Tail tip coordinates can be plotted to show the behaviors in much better detail.

    Especially for beat and glide swimming, the points regarding burst firing, inhibition, etc. have not been robustly made.

    We have had to revise the beat-and-glide model. In the revised version, burst firing is no longer required for beat-and-glide swimming to occur. For inhibition, we hope that the presentation of the data has been improved. We now point out that despite reduced left-right coordination, the continued presence of some left-right alternation, especially in the rostral segments, will still cause the body to exhibit left-right tail beats. The kinematics will be altered (see Figure 6 video 2 and Figure 6 - figure supplement 2), but left-right tail beats will still be present. To the best of our knowledge, no studies have shown that loss of left-right coordination blocks the generation of left-right tail beats in swimming fish.

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  2. Reviewer #3 (Public Review):

    Computational models, provide a way to understand emergent network function, and at their best provide a canvas for experimentalists to probe hypotheses regarding function. In this manuscript, Bui and colleagues provide a set of iterative models to describe the locomotor development of larval zebrafish at key developmental stages. These include coil, double coil, and swimming behavior that leads to 'beat-and-glide' behavior. During development, the model steadily moves from gap junction mediated connectivity to more complex synaptic-based network models. In my opinion, this is a very interesting foundation that can be used as a catalyst for future research for experimentalists or to develop more involved models. Like any model it is possible to be critical of the assumptions made. But I expect that it will not be static and be revised over the years. It is important to realize that these sets of models are unique in that they strive to provide models for motor control of a single species across development. The zebrafish is an excellent example since genetic models are widely used, development is swift, and there is active research to understand the physiology of locomotion.

    Strengths and weaknesses:

    The key strength of this manuscript is the detailing of a set of related models detailing the motor output of the larval zebrafish across key stages of development. The models should form a basis for future research. It also a first of its kind - I don't know of similar models focusing on development of locomotor function. The main weakness is the reliance on assumptions of model connectivity. But I suggest that if the model is treated as a basis for the community to refine and validate it will be incredibly useful.

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  3. Reviewer #2 (Public Review):

    This study presents iteratively constructed network models of spinal locomotor circuits in developing zebrafish. These models are shown to generate different locomotor behavior of the developing zebrafish, in a manner that is supported by electrophysiological and anatomical data, and by appropriate sensitivity analyses. The broad conclusions of the study result in the hypothesis that the circuitry driving locomotor movements in zebrafish could switch from a pacemaker kernel located rostrally during coiling movements to network-based spinal circuits during swimming. The study provides a rigorous quantitative framework for assessing behaviorally relevant rhythm generation at different developmental regimes of the zebrafish. The study offers an overarching hypothesis, and specific testable predictions that could drive further experimentation and further refinement of the model presented here. The models and conclusions presented here point to important avenues for further investigation, and provide a quantitative framework to address constituent questions in a manner that is directly relatable to electrophysiological recordings and anatomical data. The study would benefit from additional sensitivity analyses, and from the recognition that biological systems manifest degeneracy and significant variability along every scale of analysis.

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  4. Reviewer #1 (Public Review):

    The manuscript is somewhat readable but the many acronyms for the cell types in model and biology make it difficult to follow. Is there a reason why the biological neuron names cannot be used in the model? The presentation of data in figures can be more powerful. In many cases, the data in figures and the supplemental videos show apparently different results. This can be an artifact of how the videos were made and if yes, these can be improved. Tail tip coordinates can be plotted to show the behaviors in much better detail.

    Especially for beat and glide swimming, the points regarding burst firing, inhibition, etc. have not been robustly made.

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  5. Evaluation Summary:

    In this manuscript, Roussel et al., build models of spinal networks capable of generating coiling and swimming behaviors of embryonic and larval zebrafish. The models use details obtained from earlier experimental studies and insert novel network elements, thus providing testable ideas for rhythm generation. The study will be of high value to those interested in motor pattern generation in general and zebrafish spinal cord function in specific.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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