Circadian Rhythms of the Hypothalamus: From Function to Physiology

Round 1

Reviewer 1 Report

Thank you very much for allowing me to review the review article entitled “Circadian Rhythms of the Hypothalamus: From Function to Physiology” (clockssleep-1084953).

The aim of this review was profound role of the extra-SCN hypothalamic nuclei in rhythmically regulating and coordinating body-wide functions.

A review of 319 articles, published between 1972 to 2020, is carried out.

 An assessment of the subject is made from a physiological and pathophysiological basis, integrating all the knowledge on the subject.

The manuscript is very well written.

Author Response

We appreciate the positive comments regarding the review “The Role of the Hypothalamus: From Function to Physiology.” We have corrected minor format and spelling errors to provide a strengthened review. Thank you again for considering of our review.

Reviewer 2 Report

The authors discuss the role of hypothalamic structures outside of the SCN, underlying rhythmic feeding and other behaviors. Previous literature on molecular mechanisms, as well as brain circuitry, is correctly combined and mostly explained. The figures also help to obtain a more clear view of the authors’ focus and the review’s content. The manuscript is well written, citing a good amount of previous literature, especially with regards to feeding anticipatory activity and energy metabolism. I mention below several points, which if answered, will rather strengthen the quality of the manuscript.

1) My main issue is an evident mismatch between the title and abstract, and the content of the review. More specifically, there are five sections about molecular mechanisms and hypothalamic circuitry underlying metabolism and energy homeostasis, as well as one section for neurodegeneration and one for therapeutics. There is however little focus on other systems, such as the sleep homeostat or fluid equilibrium, intertwined highly intertwined with feeding and metabolism. The title and the abstract feel thus way more general than the actual content of the review. A better defined title (e.g. ”Hypothalamic rhythms of feeding: from function to physiology” or ”Circadian rhythms of energy homeostasis: from function to physiology”) and subsequent abstract could resolve this issue. A different solution would be to add a section on the hypothalamic circuitry underlying metabolism-sleep or circadian-sleep interactions, particularly when a lot of neurodegeneration processes are directly linked to aberrant sleep behavior. A similar section on thirst anticipation and its underlying hypothalamic structures is also suggested, (see Zimmerman et al., Nat Rev Neurosci, 2017; Gizowski et al., Nature, 2016) to achieve a more complete picture of the interacting systems that define circadian behavior in mammals.

2) Line 103. “A combination of ablation studies and clinical psychiatric observations..”. In each study that is cited, mention the species, or the larger cluster (nocturnal/ diurnal, rodents, mammals etc) that the study was performed on. It facilitates the assessment of the finding, as well as the interpretation of the observation by the reader.

3) Line 218. “To examine specifically the extra-SCN hypothalamic regions, 218 the NK2 homeobox 1 driver was used..“. Add a sentence explaining and adding supporting citation why the NK2 homeobox 1 driver is preferred to create such knockouts.

4) Line 229. A sentence should be added regarding REV-ERBa involvement in advancing sleep/wake distribution relative to the LD cycle, and if possible, how that might interact with feeding anticipation (see Mang et al, Sleep, 2016).

5) Line 307. “reveal that the PVN is still heavily dependent on the SCN for rhythmic activity”. Please also cite the most recent publication of Ono et al., Sci. Adv., 2020 on SCN-CRF PVN-LH circuitry, and particularly mention their notion of the PVN as a “pulse generator” whose excitability is regulated by SCN projections.

6) Line 601. Also cite Ono et al., Sci. Adv., 2020, and the role of PVN-CRF projections to the LH regulating wake behavior in mice.

7) References. Better consistency is needed in the reference list, where sometimes “et al.”, sometimes the full reference is used.

Comments for author File: Comments.docx

Author Response

Please see attachement

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

The authors took the effort to address to all my concerns, and have even added two sections, one on fluid homeostasis and another on hypothalamic contributions to sleep behavior. The paper at its current state should be a fine contribution to the field, summarizing observations on hypothalamic physiology and function, as its title dictates. I have no further comments, if only to congratulate the authors for their detailed and wholesome work.