This manuscript, “Sex and estradiol effects in the dorsal striatum” by Lewitus et al, is a timely and appropriate review that covers a topic of substantial interest. It has become increasingly apparent just how much impact sex and hormones have on both normal brain function and pathophysiological outcomes. This review nicely sums up data focused on the effects of estrogen on the dorsal striatum, a region of significant importance in behavioral and cognitive processing. I would particularly like to compliment the authors on their use of detailed tables to collect and summarize the data reviewed in the article and to make the literature more accessible and the results clearer to readers. While overall my opinion is positive of this review, I do have a few suggestions to the authors to improve their manuscript.

1. On page 3, you mention the presence of aromatase, which converts testosterone into E2, in the striatum as a localized source of E2, you might want to mention how the testosterone is reaching the striatum.

2. On page 4, during your discussion of ERs, you mention that there are no differences in ER density in the dorsal striatum. While this is true in adulthood, it may be worth mentioning that there are some sex differences in density the caudate-putamen during development, as shown by Krentzel et al. 2021 (DOI:10.1002/cne.24978).

3. A small comment, but on the last paragraph of page 6 and the first paragraph of page 7, you use the terms “estrus mice” and “diestrus mice”. As estrus and diestrus are not adjectives, I do not believe this is grammatically correct.

4. In your discussion on page 8, you speak about E2’s effects on basal dopamine levels and some of the conflicting data. It would also be valuable to touch on the potential interaction of progesterone with E2 on dopamine at this point, as it would be relevant (Becker et al., 1994; doi: 10.1016/0006-8993(84)91410-0; Becker and Ramirez, 1981; doi: 10.1016/0006-8993(81)90595-3). You do touch on interactions between E2 and progesterone in the behavior section, so it would be a nice tie in to do it here as well.

5. On the top of page 9, you say the following: “However, experiments demonstrating an E2 effect in coronal slices of dorsal striatum, where only dopamine terminals are present, indicate that the effect is likely local to the dorsal striatum.” However, the citation from these experiments is not included, please do so.

6. On page 9, you also talk about the effects of E2 on DAT. Here, It would be valuable to touch on the mechanism by which E2 influences DAT levels, as there have been papers examining this (Alyea and Watson, 2009: https://doi.org/10.1186/1471-2202-10-59).

7. The learning section in the behavior part of the review might benefit from a little more description regarding how hippocampus- and striatum-based learning are distinguished in these paradigms, as estrogen can impact both regions and both regions work in complimentary manners in memory processing (Ferbinteanu, 2020; doi: 10.1523/JNEUROSCI.1084-20.2020; Copenhaver and LeGates, 2024; DOI: 10.1523/JNEUROSCI.0100-24.2024). Might also be worth citing Zurkovsky et al., 2006 (DOI: 10.1016/j.neuroscience.2006.09.002) as well, who looks at the effects of estrogen on different types of learning in the hippocampus and dorsal striatum.

8. While the focus of the paper is in the dorsal striatum, it might be timely to briefly mention the nucleus accumbens and some of the differences in estrogen effects between regions – i.e. that spine density is altered by E2 administration (Staffend et al. 2011, Peterson et al., 2015).

9. The Conclusions section of the review felt a bit rushed; a little extra time put into synthesizing the data presented and how it might relate to sex differences in human neuropathology would emphasize the value of their hard work in this review.

The review by Lewitus et al., “Sex and estradiol effects in the rodent dorsal striatum” remains a timely and important piece that covers a topic of strong relevance and importance to the scientific field. The significant impact of sex hormones on the brain becomes more and more apparent as research progresses. The authors do an excellent job summing up the recent data covering the impact of estrogen on the caudate putamen, a region of great importance in regulating a variety of behaviors.
The reviewers did an excellent job addressing the concerns posed previously by this reviewer and others. The expanded conclusion is especially descriptive compared to previously, and gives a nice summary of where this research could expand next. The added figures are also quite nice and add visuals to some of the data and conclusions presented. We might suggest that in Figure 3, that Da be fully capitalized to DA, as is more standard in the field, but otherwise, feel that this manuscript is ready for publication.