In this invited mini-review, Dr. Grattan provides a critical evaluation of the scientific evidence for prolactin production in the Brain. The author addresses from the classic early reports to up-to-date genetically modified animal models. The review is concise and easy to read while comprehensive, critical, and thoughtful. It stands as a valuable contribution to the fields of basic and clinical endocrinology and neuroendocrinology. Overall, the existence of brain prolactin is a difficult old dogma because, although unlikely, it has been suggested by several laboratories over many years. Many of those works are respectfully, but critically, revisited in light of the current knowledge and new technologies, and the author emphasizes the concern about the prevailing lack of negative evidence due to the bias towards the publication of positive data in the scientific literature. Thus, the author and editors of JNE are to be commended for the important initiative of publishing this review. I have only minor specific comments about the manuscript that are provided below.
1. Introduction. Please correct where in the sentence “…and disccus where some situations where more work is required…”.
2. Distribution of prolactin receptors in the brain. About the sentence “The Allen Brain atlas (https://mouse.brain-map.org) provides a useful unbiased resource to evaluate expression of gene in the mouse brain (33).”, it would be important to include a comment on why this is considered unbiased.
3. Evidence for brain production of prolactin. In the sentence “The first report of “prolactin-like immunoreactivity” was appropriately conservative…”, why use prolactin-like immunoreactivity with quotation marks? Although the labeling can be a false positive (as is the case for any unvalidated antibody), this terminology reflects what was intended to be measured in that work.
4. Please, correct lateral in the sentence “cell bodies in the laternal arcuate nucleus and extensive neuronal projections throughout the brain (39).”
5. It would be worth commenting if the same or different antibodies were used in the first studies reporting prolactin-like immunoreactivity in the hypothalamus, discussed as references from 38 to 41.
6. Please, correct the duplicate in the sentence “…it turned out the the new antibody used here cross-reacted…”.
7. In the sentence “Collectively, there have been over 20 different studies reporting prolactin-like imunoreactivity in the brain (eg (47-53)).”, references 38 to 42 might also be cited.
8. Please, correct explain in the sentence “…subsequently identified off-target cross-reactivities of the antibodies explan the observed data…”.
9. In the sentence “…prolactin is push-pull perfusion of the brain. Using this approach, prolactin can be detected in perfusates from specific hypothalamic regions (20)”, the citation of reference 20 seems incorrect. Is it reference 65?
10. In discussing reference 65, the author comments “These are compelling data, but given the apparent lack of prolactin mRNA in these regions, is it possible that these studies were actually detecting prolactin of pituitary origin, entering the brain from the blood?”. However, in this work, Torner et al. provided data on supposed prolactin mRNA in dissections of the whole hypothalamus. Thus, for clarity and consistency, this sentence might be rephrased to make clear where the view of lack of prolactin mRNA originated.
11. In the sentence “levels of prolactin in the cerebrospinal fluid (CSF) tend to change in parallel with changing concentrations of prolactin in blood, consistent with the hypothesis that prolactin detected in CSF predominantly originates from the pituitary gland (71-74)” provides an important concept for the prolactin presence in the brain. However, the study of Peake et al. (74) found such a correlation between serum and CSF for beta-hCG and placental lactogen but not for prolactin in pregnant women. This contradiction should be commented on and, hopefully, explained in this section.