PONE-D-19-33471

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

PLOS ONE

Dear Dr Gilbertson,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Unfortunately I was only able to secure one review for this manuscript; however, I will act based on this one review as it's possible another review might lead to the same outcome, but with a longer delay.  As you can see the reviewer is quite critical of this work and argues for rejection.  After reading the manuscript myself I came very close to rejecting it, but I would like to give you the opportunity to revise the manuscript if you think you can address the reviewer's concerns.  If you choose to revise it then I will likely send it back to the original reviewer and also try to find a new reviewer.

We would appreciate receiving your revised manuscript by Mar 12 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Darrell A. Worthy, Ph.D

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data 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 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—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The research aims to reproduce a risk neutral behavior from human patients with mutated TOR1A gene. The study used a common reinforcement learning model and used weight (Wn) in updating action value (A) to represent synaptic strength. Furthermore, they made the change in synaptic strength (plasticity) influenced by dopamine (delta d). Then, they got the dopamine level for each trial and simulated the RPE. Finally, they adapt the competitive action selection model for the output of the D1- and D2-MSNs. The overall model looks good. However, the quality of the paper is severely harmed by several major issues.

1. The finding of the study doesn’t provide any insights. Although they claim their results on simulate D2-MSNs LTP is not in line with an in vitro data, this can also due to the limitation of the model not necessarily means additional factors existed. Note that the authors didn’t fully discuss the limitation of the model.

2. Authors seem cannot distinguish some basic ideas: cortico-striatal plasticity, synaptic strength, D1R- or D2R-expressing medium spiny neuron (or direct- and indirect-medium spiny neuron). For example, author wrote, "... post-synaptic abnormality in D2R transmission as the principle cause for ... ". There is no such receptor transmission. The idea might be dopamine transmission onto D2R-MSNs. Another example is "...D2R striato-pallidal LTP...". Authors should be aware that cortico-striatal LTP/LTD has nothing to do with the striato-pallidal and striato-nigral LTP. The cortico-striatal LTP/LTD does influence the output of D1- and D2-MSNs to GPe and SNr, but it doesn’t imply anything on striato-pallidal or -nigral LTP. Another relevant noticeable error is “… D1R-LTP…”. There is no such D1R-LTP. LTP cannot be induced on a receptor (let alone is a metabotropic receptor). I guess the authors want to express the idea: D1R-MSNs or D1-MSNs LTP. There are many more errors, which cause a huge misleading to non-field reader and research, like these above.

3. Citations are not appropriate. They mentioned the competition model but they didn’t cite Bariselli et al 2018 Brain Research paper, which proposed the competitive model to explain the action selection in the basal ganglia. Kravitzer et al., 2012 in the introduction cannot support RPE idea in the sentence. Frank 2005 in the introduction is also misleading. Frank did talk about how DA level affects plasticity. But, no direct statement about how positive and negative PRE shape or rely (actually are two different thing). The author also need to cite one more paper to support “rodent models” in the sentence “…proposed that patients with the TOR1A mutation should exhibit a learning strategy that is contingent with the abnormal plasticity seen in rodent models …’.

4. The late part of the manuscript has largely focused on the idea of RPE. But, the authors didn’t mention anything in the abstract. Actually, directly use DA level concept, but not RPE, will be more related to the cortico-striatal plasticity concept. Authors try to borrow a fancy idea like RPE but fail to test it. Although phasic dopamine level change correlates with the RPE, which has been shown in many studies, a direct way to do so is to do the regression on the behavior instead of just claim RPE because of dopamine level change. Taken together, using the concept of RPE doesn’t provide extra credit to paper.

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Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-19-33471R1

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

PLOS ONE

Dear Dr Gilbertson,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I sent your manuscript back to the original reviewer.  The reviewer found the paper to be much improved, but noted a few things that need to be addressed before the paper is suitable for publication.  

We would appreciate receiving your revised manuscript by Apr 19 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Darrell A. Worthy, Ph.D

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data 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 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—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The revision significantly improve the manuscript. However, there are several things remain to be clarified.

1. Please try only use either direct-pathway/indirect-pathway MSN (dMSNs/iMSNs) or D1-/D2-MSNs (D1-/D2-MSNs) through out the manuscript. Because dMSNs can also express D2R and iMSNs can also express D1R. They are very similar idea but not equivalent.

2. Please revise the sentence, “Given the indirect pathways net inhibitory influence on cortical excitability ...”. I am not sure if this is some new findings that you found the GPi can back modulate cortical inputs in the striatum or this is pure wiring issue. I guess the information you try to delivery here is that the iMSNs play a negative role so that stimulation the corticostriatal activity onto iMSNs will suppresses the likelihood of a choice with an aversive outcome. So, please rephrase your sentence and make it more clear.

3. I think it also worthy to cite Ma et al., 2018, Nature Neuroscience paper. They are first few labs direct demonstrate how LTP and LTD on mPFC—> D1-MSNs and mPFC—> D2-MSNs change the behavior outcome and they also showed that of course block D1R and D2R affect the LTP and LTD induction on those two types of neurons.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Opposing patterns of abnormal D1 and D2 receptor dependent cortico-striatal plasticity explain increased risk taking in patients with DYT1 dystonia

PONE-D-19-33471R2

Dear Dr. Gilbertson,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Darrell A. Worthy, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: