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Animal Models for the Study of Neurological Diseases and Their Link to Sleep

Biomedicines 2025, 13(8), 2005; https://doi.org/10.3390/biomedicines13082005

by Carmen Rubio¹

, Emiliano González-Sánchez²

, Ángel Lee³

, Alexis Ponce-Juárez⁴, Norma Serrano-García¹

and Moisés Rubio-Osornio^4,*

Reviewer 1: Anonymous

Reviewer 2: Anonymous

Biomedicines 2025, 13(8), 2005; https://doi.org/10.3390/biomedicines13082005

Submission received: 4 July 2025 / Revised: 12 August 2025 / Accepted: 14 August 2025 / Published: 18 August 2025

(This article belongs to the Special Issue Animal Models for Neurological Disease Research)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Esta revisión se centra en el estudio de las alteraciones del sueño ocurridas en modelos in vivo e in vitro de enfermedades neurodegenerativas como el Alzheimer, el Parkinson, la enfermedad de Huntington y la epilepsia. Este trabajo pone de manifiesto que la neuroinflamación, el estrés oxitativo, la acumulación de proteínas mal plegadas y la disfunción mitocondrial son procesos que contribullen al avance de estas patologías y a sus síntomas clínicos relacionados con la alteración del sueño. Si bien ciertos factores parecen comunes a todas estas enfermedades neurodegenerativas, cada una presenta peculiaridades.

Minor revisions:
- On line 22, "Neuroinflammation" should be lowercase.
- There are several errors regarding abbreviations; you should review them thoroughly and reconsider the need to use abbreviations such as AD, HD, or SCN. Other abbreviations only appear once.
- AD, HD, and SCN should be entered for the first time on lines 33, 58, and 60, respectively.
- PSD-95, GFAP, 5xFAD, PS19, PS301S, DORA-12, CSF, STZ-ICV, AMPK/SIRT1/PGC-1a. AD and SCN are not in the list of abbreviations.
- Line 79: SWS.
- Line 110: The abbreviation MPTP is added without indicating its meaning.
- Line 118: The abbreviation MPP+ is added without indicating its meaning.
- Line 135: IL-6 is not included in abbreviations.
- Line 138: PARK2 is not included in abbreviations.
- Line 171: Use KA instead of kaitane, an abbreviation already included.
- Line 175: Same with ROS. However, the abbreviation RNS has not been used before and is not included in abbreviations. Consider not using this abbreviation as it only appears once in the text.
- Lines 283 and 365: ROS was already introduced.
- Lines 322 and 406: AD was already introduced.
- Line 376: CNS was already introduced.
- Line 406: HD was already introduced.
- On pages 9 and onward, A-b and amyloid-b are used interchangeably. - Lines 94 and 369 "in vivo" and "in vitro" should be italicized.
- Lines 367 and 369 "Drosophila melanogaster" and "Danio rerio" should be italicized.
- All figures should be cited in the main text in order of appearance.
- The text in all figures should be larger, especially in smaller font, as it is not legible.
- Line 160: Please add "misfolded" α-synuclein.
- Figure 1 uses the abbreviation ROS, but the figure caption does not indicate what this abbreviation stands for.
- Figure 2: The full names of the abbreviations in the figure caption should be provided. Consider summarizing this figure caption; the image is quite understandable, but the caption is more confusing.
- Figure 3: The full names of the abbreviations in the figure caption should be provided. Regarding the image, I don't understand the reason for the arrows between the boxes. It seems that one acts on the other only in the direction shown. This is confusing. Consider removing the arrows.
-Figure 4: It is not necessary to use the abbreviations AD and Ab, as they are not included in the image. The abbreviations SWS and REM should be expanded. Species names are in italics.

Major revisions:
- Line 67. Reconsider changing the beginning of the sentence "Our study is relevant." The importance of the review should be reflected without the need to make this announcement.
- Consider removing the last paragraph of the introduction and adding after the sentence on line 79 "in REM and SWS phases in experimental models of Parkinson's disease, epilepsy, HD, and AD."
- The last sentence (lines 102-107) of M&M does not correspond to this section; consider removing it.
- Line 140: They also contribute to motor symptoms.
- Consider including after M&M a section 3 "Sleep in neurological diseases" to which the following sections belong except the conclusion.

Author Response

Response to Reviewer X Comments
1. Summary
We sincerely thank the reviewer for evaluating our manuscript and for the constructive feedback. We have carefully addressed each point in detail below. All suggested modifications have been incorporated, and, where appropriate, clarifications and improvements have been made to enhance the manuscript’s clarity and consistency.
2. Questions for General Evaluation	Reviewer’s Evaluation	Response and Revisions
Does the introduction provide sufficient background and include all relevant references?	Yes/Can be improved/Must be improved/Not applicable	yes
Are all the cited references relevant to the research?	Yes/Can be improved/Must be improved/Not applicable	yes
Is the research design appropriate?	Yes/Can be improved/Must be improved/Not applicable	yes
Are the methods adequately described?	Yes/Can be improved/Must be improved/Not applicable	yes
Are the results clearly presented?	Yes/Can be improved/Must be improved/Not applicable	yes
Are the conclusions supported by the results?	Yes/Can be improved/Must be improved/Not applicable	yes
3. Point-by-point response to Comments and Suggestions for Authors
Minor Revisions 1. Comment: Line 22 – "Neuroinflammation" should be lowercase. Response: Thank you for your observation. We have corrected the capitalization, and “Neuroinflammation” now appears as “neuroinflammation.” 2. Comment: Several abbreviation issues; please reconsider the use of AD, HD, and SCN. Some abbreviations appear only once. Response: We appreciate your thoughtful suggestion. Following your advice, we thoroughly reviewed all abbreviations. We retained those that are used multiple times throughout the manuscript—such as AD (Alzheimer’s disease) and HD (Huntington’s disease)—as we believe their use improves clarity and flow. However, we replaced abbreviations that appeared only once with the full terms. Specifically, the abbreviation SCN was removed and replaced with the full term "suprachiasmatic nucleus." 3. Comment: AD, HD, and SCN should be introduced on lines 33, 58, and 60, respectively. Response: Thank you for pointing this out. We have defined AD upon its first appearance (now in line 30) and HD in line 58. In response to your earlier comment (Comment 2), we removed the abbreviation SCN and used the full term instead. 4. Comment: Abbreviations such as PSD-95, GFAP, 5xFAD, PS19, PS301S, DORA-12, CSF, STZ-ICV, AMPK/SIRT1/PGC-1a, AD, and SCN are not listed. Response: Thank you for this helpful observation. We have now included all of the listed abbreviations in the abbreviations section. Kindly note that PS301S is not present in the manuscript, and SCN was removed as an abbreviation following your earlier suggestion. 5. Comment: Line 79 – SWS should be listed as an abbreviation. Response: Thank you. We have now added SWS (slow-wave sleep) to the list of abbreviations. 6. Comment: Line 110 – MPTP is used without explanation. Response: We appreciate your careful review. We have added the full term “1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine” upon first mention of MPTP. 7. Comment: Line 118 – MPP+ is introduced without explanation. Response: Thank you. We have now included the full term “1-methyl-4-phenylpyridinium” when introducing MPP+. 8. Comment: Line 135 – IL-6 is not listed in abbreviations. Response: Thank you for catching that. IL-6 (interleukin-6) has now been added to the list of abbreviations. 9. Comment: Line 138 – PARK2 is not listed. Response: We appreciate the suggestion. PARK2 (parkin RBR E3 ubiquitin protein ligase) has been included in the abbreviations list. 10. Comment: Line 171 – use KA instead of “kainate.” Response: Thank you. We have replaced “kainate” with KA, as this abbreviation had already been introduced earlier in the manuscript. 11. Comment: Line 175 – same with ROS; however, RNS is used only once and not listed. Response: We agree with your assessment. We have kept the abbreviation ROS (reactive oxygen species), which is used consistently throughout the manuscript, and removed the abbreviation RNS to avoid unnecessary abbreviation use. 12. Comment: Lines 283 and 365 – ROS was already introduced. Response: Thank you. We have ensured that ROS is not redefined in these lines. However, upon verification, we found that neither the abbreviation ROS nor its full form appears specifically in lines 283 or 365, so no action was needed in those locations. 13. Comment: Lines 322 and 406 – AD was already introduced. Response: Acknowledged. AD is not redefined in these lines. Also, we verified that the term “AD” does not appear in line 406. 14. Comment: Line 376 – CNS was already introduced. Response: Thank you. We reviewed this line and nearby text, but the abbreviation CNS does not appear in or near line 376. Nonetheless, we have ensured it is introduced appropriately earlier in the manuscript. 15. Comment: Line 406 – HD was already introduced. Response: Thank you for noting this. We verified that HD is not used in line 406 or in the concluding section. Therefore, no further clarification was necessary. 16. Comment: Pages 9 and onward – Aβ and amyloid-β are used interchangeably. Response: Thank you for pointing this out. We have now standardized the terminology by using the full term “amyloid-β (Aβ)” upon first mention and using only “Aβ” in subsequent references to maintain consistency and clarity. 17. Comment: Lines 94 and 369 – "in vivo" and "in vitro" should be italicized. Response: These Latin expressions are now correctly italicized throughout the text. 18. Comment: Lines 367 and 369 – “Drosophila melanogaster” and “Danio rerio” should be italicized. Response: Both species names are now italicized as required. 19. Comment: All figures should be cited in order of appearance. Response: We have revised the text to ensure all figure citations follow the correct sequence. 20. Comment: Text in figures is too small to read. Response: We have enlarged the text into all figures for improved readability. 21. Comment: Line 160 – Please add “misfolded” α-synuclein. Response: “Misfolded α-synuclein” has been added accordingly. 22.Comment: Figure 1 uses ROS, but it is not defined in the caption. Response: We have updated the figure legend to define ROS as “reactive oxygen species.” 23. Comment: Figure 2 – Add full names of abbreviations; caption could be shortened. Response: We have added all full terms and simplified the figure legend for clarity. 24. Comment: Figure 3 – Same as above; arrow directions are unclear and confusing. Response: We added the full names of abbreviations in the caption and removed the directional arrows to avoid confusion. 25.Comment: Figure 4 – AD and Aβ abbreviations are unnecessary; SWS and REM should be written out; species names in italics. Response: We have removed the unnecessary abbreviations and now display SWS (slow-wave sleep) and REM (rapid eye movement sleep) in full. Species names are now italicized. Major Revisions Comment: Line 67 – reconsider using “Our study is relevant.” Response: We rephrased the sentence to emphasize the relevance of the review without self-referential language. Comment: Consider removing the last paragraph of the introduction and integrating the sentence after line 79. Response: We have removed the final paragraph of the introduction and incorporated the relevant information into line 79 as suggested. Comment: Lines 102–107 in M&M are not suitable for this section. Response: We have removed this sentence, as it did not pertain to Materials and Methods. Comment: Line 140 – Please add that these processes also contribute to motor symptoms. Response: We have included this point, highlighting that these processes also contribute to motor symptoms. Comment: Add a new section 3 titled “Sleep in neurological diseases” for the following disease-related content. Response: We thank the reviewer for this constructive suggestion. We have some doubts with the reviewer's requirement since the work in which we specifically address sleep alterations in experimental models of Parkinson's disease, epilepsy, Huntington's disease, and Alzheimer's disease. This section highlights the distinct features of sleep disruption associated with each disease model, while integrating the cellular and molecular mechanisms discussed throughout the manuscript. This restructuring improves clarity and emphasizes the disease-specific context of sleep disturbances.
Response to Comments on the Quality of English Language
Point 1:
Response 1: The English of the manuscript has been carefully reviewed
6. Additional clarifications: None. We appreciate the reviewer helpful comments. Sincerely, Corresponding Author: Moisés Rubio-Osornio, PhD Instituto Nacional de Neurología y Neurocirugía, M.V.S. Insurgentes Sur 3877, Ciudad de México 14269, México Phone: (55) 5606 3822 Ext. 2021 Email: moises.rubio@innn.edu.mx / mrubio@innn.edu.mx ORCID: 0000-0001-9236-0609 (M.R.O.)

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This review is dedicated to the interplay between the neurodegeneration modeling and sleep disruptions. It makes a great impression, starting from the original idea, consisting of an interesting and new angle of consideration, to a good execution, consisting of a processing of the latest literature data.

I have two major recommendations.

Conclusion section lacks comparative remarks on the above-described pathologies: may the shared features of neuropathologies and their interplay on the level of sleep/wake regulation be used in the development of therapeutic approaches.
Some sections lack information on possible medications related to sleep/wake. For PD it can be as follows PMID: 39654780.

Minor outflow detected: abbreviation SCN (the suprachiasmatic nucleus) occurs 3 times but is not in the list.

Author Response

We are deeply appreciative of the reviewer's insightful and supportive remarks about the uniqueness and quality of our review. We greatly value the helpful criticism, which has greatly raised the manuscript's calibre and readability. Please find our thorough answers to each point below.
1. Question: Conclusion section lacks comparative remarks on the above-described pathologies: may the shared features of neuropathologies and their interplay on the level of sleep/wake regulation be used in the development of therapeutic approaches.
Response: We sincerely appreciate this valuable observation. In response to your comment, we would like to highlight that we have already included in the Conclusion section a comparative discussion of the described neurological pathologies, emphasizing their shared features in relation to sleep/wake cycle dysregulation particularly involving mechanisms such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurotransmission impairments.
Furthermore, to provide a clearer and more systematic overview of these similarities and differences, we have added a comparative table summarizing the main sleep disturbances associated with each neurological disease addressed in the manuscript. We believe this addition strengthens the discussion and may help guide the development of therapeutic strategies targeting the common underlying mechanisms.
We are grateful once again for your insightful suggestion, which allowed us to further improve this important section of our work.

2. Question: Some sections lack information on possible medications related to sleep/wake. For PD it can be as follows PMID: 39654780.
Information about potential sleep/wake-related drugs is missing from several sections. For PD, it may be like this: 39654780 is the PMID.
Response: I agree, and I appreciate your great proposal. Information about pharmacological strategies aimed at regulating sleep and wakefulness, has been included.
A small observation:
Despite appearing three times, the acronym "SCN" (suprachiasmatic nucleus) was not included in the section on abbreviations.

Reaction:
I appreciate you pointing out this error. "SCN: suprachiasmatic nucleus" is now part of the list of abbreviations.

We would like to thank you once more for your invaluable suggestions and support during the evaluation process.
Warm regards,
Moises Rubio-Osornio PhD

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