Synchronization properties in C. elegans: Relating behavioral circuits to structural and functional neuronal connectivity

PLOS Computational Biology

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Reviewers' comments:

Comments to the Authors:

Please note that one review is uploaded as an attachment.

Reviewer #1: The review is uploaded as an attachment.

Reviewer #2: In their manuscript “Synchronization properties in C. elegans: Relating behavioral circuits to structural and functional neuronal connectivity,” the authors construct a computational model of the nematode C. elegans nervous system. In this model, each neuron is represented as a single electrical compartment by a set of differential equations that compute its membrane potential in response to synaptic and gap-junction inputs, based on a published connectivity dataset. The authors examine the response of the nervous system model to prolonged depolarizations in single neurons and focus on the synchronization of neuronal subpopulations. The most interesting result is that neuronal types are not explicitly encoded in the equations, and their categorization emerges from the connectome. The authors also offer three structure-function hypotheses in their conclusions.

This study is interesting, the approach is clear, and the choices are usually explained. My main concerns are that the relevance to behavior is sometimes overstated, and details about the behaviors are not addressed and lost; it is unclear which connectivity dataset(s) are used, and some neurons are ignored, although their function is known.

Major comments:

The term behavior is used loosely in this manuscript. For example, while locomotion and klinotaxis are behaviors, chemosensation and mechanosensation are not. A behavior requires muscle contraction and movement. Focusing on klino-, chemo-, and mechanotaxis, the circuits of these behaviors will include the locomotion circuit, and while mechanotaxis is usually negative (aversive), klino- and chemotaxis in C. elegans can be positive (attractive) or negative (aversive), introducing mixed effects on the activity of the locomotion circuit (note also that forward locomotion could be towards or away from a stimulus). I do not think this complexity can be introduced to the current study, but it should be represented in the introduction and discussion.

The concepts of synchrony and phase relationships are central to the study. However, calculating those without specific neuronal identities misses the point that coordinate anti-phase activity of antagonistic motor pools is a hallmark of locomotion (and any other rhythmic) behavior. Even a Kuramoto order parameter (Z) that indicates half the neurons are in antiphase with the other half might not represent locomotion behavior if these neurons are not dorsoventral pairs. If such a measure is beyond the scope of the study, the claim of behavior-like output should be weakened and qualified.

Clarify which connectivity dataset was used. Some datasets have known limitations (for example, Refs 1-2 are missing the posterior portion of the ventral cord and are a composite of several animals; Cook et al. (Ref 52) include an intuitive “interpolation” of that gap). Some information is provided in the “Data Availability” section, citing references 1-6 (only 1-2 provide a reconstructed connectivity dataset). Yet a clear description of the dataset used should be included in the methods section.

Some neurons with known function are missing. Notably, the motor neurons of classes AS, DD, VD, and VC could be added to both forward and backward “locomotion circuits”. Specifically, the DDs and VDs are among the most connected neurons, as evident in Fig. 1, and are 19 of the 26 GABAergic neurons mentioned in L115.

Minor comments:

(Most of those comments are examples of similar issues throughout the text and should be applied everywhere.)

Results should be written in the past tense.

Equations are clearly explained.

The discussion is well developed and well written.

By lines:

L9-10: Add citations of N. Cohen and S. Flavel for computational models and whole-brain recording, respectively.

L46: ref 25 seems to be in the wrong place, or missing citation for computational approach earlier in the sentence.

L49-50: Cited references demonstrate the existence of action potentials in body wall muscle and some neurons, contrary to the text. Correct the text to be more accurate.

L122: Motor neurons in C. elegans generate the coordinated activity; it is relayed to the muscle by the muscle arms (see Haspel et al., 2020; Elegantly)

L696: behavior is not a “property”. Edit to “…behavior emerges from structure and function.”

L751: Edit. There is no one-to-one correspondence.

L892-894: The hypotheses are insightful. Hypothesis #3 could be less study-specific, for example: “Neurons that are not connected by gap junctions could serve as organizers that elicit synchronized activity in downstream circuits.

Figures

Fig. 1, 4: The color scheme is inconsistent between figures. Red (e.g., motor) and magenta (e.g., sensory) colors are too close and hard to distinguish.

Fig. 3B: Should “I ext” be “Re(lambda i)”, as in A?

Fig 10B: missing axis titles.

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Reviewer #1: No:  The authors included a link to a GitHub repo but the link does not work.

Reviewer #2: Yes

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Reviewer #1: Yes:  Megan Morrison

Reviewer #2: Yes:  Gal Haspel

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Attachments

Attachment

Submitted filename: Review_PLOS_Synchronization.pdf

Dear Prof. Davidsen,

We are pleased to inform you that your manuscript 'Synchronization properties in C. elegans: Relating behavioral circuits to structural and functional neuronal connectivity' has been provisionally accepted for publication in PLOS Computational Biology.

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Barbara Webb

Academic Editor

PLOS Computational Biology

Lyle Graham

Section Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have responded to all of my questions and concerns and have done substantial new work to address the points that I raised.

Reviewer #2: As noted by the authors, the revision has greatly improved the manuscript. The authors added new analyses that include more (about twofold!) motoneuron classes and address the known functions of motoneuron classes. They also clarified parts of the original text and added behavior-minded insights to the introduction and discussion. The new analyses and insights are on point. For example, the explicit insights about the distinct roles of GJ and chemical synapses. The new discussion sections “Comparing model simulations and experimental observations" (following reviewer 1's suggestion) and “Synchronization of different motor neuron classes in the locomotion circuits” provide context to the findings and insights.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes:  Gal Haspel