Review Reports - Neuroimmune Mechanisms in Alcohol Use Disorder: Microglial Modulation and Therapeutic Horizons

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review "Neuroimmune Mechanisms in Alcohol Use Disorder: Microglial Modulation and Therapeutic Horizons" compiles information on the role of microglia in the pathogenesis of alcohol use disorders. The review is fairly easy to read, as it contains numerous lists, many of which, unfortunately, do not include references to the source literature. There are also a number of unclear issues:

The Methods section lists the databases that the authors used to search for information, which already raises questions about the quality of this information. For example, the ACL Anthology and dblp databases are aggregators of articles on computer science, so it is unclear what neurobiology has to do with this.

Medline is part of PubMed. arXiV is a collection of preprints that may never become full-fledged articles. Given that the review discusses possible therapeutic strategies for AUD, it is unclear why the Cochrane library and ClinicalTrials.gov were not used.

Overall, the review contains a lot of information that is not referenced.

For example:

133-137 Additionally, sex-specific differences in P2RY12 expression suggest that microglial responses to ethanol may vary between males and females, influencing AUD susceptibility. Targeting P2RY12-mediated pathways could offer a neuroprotective strategy, preserving microglial homeostasis while mitigating ethanol-induced neuroinflammation. – It is not very clear on what basis this conclusion was made.

In sections listing differences

Key sex differences in microglial responses related to AUD include: only 2 references: 44 and 45, it is unclear where the other conclusions came from

Section 3.6.1. Hormonal Modulation of Microglial Priming does not contain any references to sources of information

In section 3.7. Therapeutic Interventions Targeting Microglial Activation in AUD

There are no references to clinical studies in the ClinicalTrials.gov database, as is the case throughout the text, although the review focuses precisely on the prospects for the medical use of the knowledge gained.

In our opinion, the review is superficial and should be seriously revised with the addition of specialized databases and references to the literature.

Author Response

Response: Medline, arXiV have been deleted.

Overall, the review contains a lot of information that is not referenced.

Response: Many references have been added.

For example:

Response: Many references have been added. The basis of conclusion has been added.

In sections listing differences

Key sex differences in microglial responses related to AUD include: only 2 references: 44 and 45, it is unclear where the other conclusions came from

Response: Many references (references: 65-80) have been added, which provided clearer evidence for the conclusions

Section 3.6.1. Hormonal Modulation of Microglial Priming does not contain any references to sources of information

Response: Many references have been added (References:66-80)

In section 3.7. Therapeutic Interventions Targeting Microglial Activation in AUD

Response: References have been added (references 5-101).

In our opinion, the review is superficial and should be seriously revised with the addition of specialized databases and references to the literature.

Response: The review has been seriously revised. Many references have been added.

Reviewer 2 Report

Comments and Suggestions for Authors

Authors of the manuscript titled “Neuroimmune Mechanisms in Alcohol Use Disorder: Microglial Modulation and Therapeutic Horizons” (psychoactives-3653302 ) presented an interesting and comprehensive review of microglial activation as a central mechanism in AUD pathology. The manuscript is well-written and presents a relevant topic. The Authors present recent data (2025) from clinical and pre-clinical studies. The sex-based stratification especially adds original value to the review.

There are a few suggestions for the manuscript improvement:

Consider adding a brief discussion of comorbidities (e.g., depression, PTSD), which often co-occur with AUD and may involve shared neuroimmune mechanisms.
Please, expand slightly on limitations of current imaging tools beyond TSPO, such as variability in expression and non-specific binding.
Consider briefly mentioning alternative immune cells (e.g., astrocytes, peripheral monocytes) in AUD, even if only to clarify that the focus is primarily on microglia.
Please enhance the resolution and quality of both figures.
Please add references to sections lacking them, e.g. lines 125-153, 210-261.

Author Response

There are a few suggestions for the manuscript improvement:

Consider adding a brief discussion of comorbidities (e.g., depression, PTSD), which often co-occur with AUD and may involve shared neuroimmune mechanisms.

Response: A brief discussion of comorbidities (e.g., depression, PTSD) has been added (lines 446-454)

Please, expand slightly on limitations of current imaging tools beyond TSPO, such as variability in expression and non-specific binding.

Response: We have added a slight expansion in limitations of current imaging tools beyond TSPO, such as variability in expression and non-specific binding (lines 529-536)

Consider briefly mentioning alternative immune cells (e.g., astrocytes, peripheral monocytes) in AUD, even if only to clarify that the focus is primarily on microglia.

Response: A brief mentioning of alternative immune cells (e.g., astrocytes, peripheral monocytes) in AUD (lines 529-536)

Please enhance the resolution and quality of both figures. Done as suggested.

Please add references to sections lacking them, e.g. lines 125-153, 210-261.

Response: References to sections have been added.

Reviewer 3 Report

Comments and Suggestions for Authors

In this review paper, the authors summarize data about microglia in relation to AUD. While very interesting, there were many technical issues, mainly the lack of citations. In most review papers, a citation appears every 1-2 sentences. In this manuscript, there are whole sections missing citations. Additionally, the list of sex differences on pages 6-7 should have a citation for each point, but only a few have citations. This should be edited and citations included in all areas. I have also put comments in the attached pdf of the manuscript.

Additional comments:

Heavy reliance on citation numbered 2, Cui et al., 2014, which itself is a review paper. The authors should be finding the original texts from that review to cite in their paper.
Section 3.6.1 has no citations
The lists on pages 6 and 7 could be organized a bit better. There looks like there might be subheadings, but it blends in with the main list.
Table 2 should be placed closer to the section that describes it (page 7-8 instead of 11).
Section 6- Future Research Priorities has NO citations and seems more like a specific aims page of a grant rather than conclusions from this review. It seems a bit much and a little repetitive with the section before that.

After some editing and reworking of the manuscript, it would be acceptable for publication.

Comments for author File: Comments.pdf

Author Response

Response: Many citations have been added.

Additionally, the list of sex differences on pages 6-7 should have a citation for each point, but only a few have citations. This should be edited and citations included in all areas. I have also put comments in the attached pdf of the manuscript.

Response: The list of sex differences on pages 6-7 have added citation for each point.

Additional comments:

Heavy reliance on citation numbered 2, Cui et al., 2014, which itself is a review paper. The authors should be finding the original texts from that review to cite in their paper.

Response: the original texts from that review have been cited.

Section 3.6.1 has no citations

Response: Many citations have been added.

The lists on pages 6 and 7 could be organized a bit better. There looks like there might be subheadings, but it blends in with the main list.

Response: The lists on pages 6 and 7 have been organized a bit better

Table 2 should be placed closer to the section that describes it (page 7-8 instead of 11).

Response: Done as suggested.

Section 6- Future Research Priorities has NO citations and seems more like a specific aims page of a grant rather than conclusions from this review. It seems a bit much and a little repetitive with the section before that.

Response: This has been revised. Citations have been added (line 567-584, References 85,86).

After some editing and reworking of the manuscript, it would be acceptable for publication.