In this paper the authors established a new sheep model of Parkinson's disease by unilaterally infusing the neurotoxin 6-hydroxydopamine into the substantia nigra. This caused dopaminergic imbalance and induced rotational behavior with dopaminergic receptor agonists. The use of dopamine agonists induced rotational behavior confirming dopamine depletion. The post-mortem study certified the extent of the 6- hydroxydopamine lesions and included levels of catecholamines measured by HPLC.

Overall, the paper is well written and interesting. It is highly novel in the sense that it is the first sheep model of PD and, thus add important information to the PD literature and deserves publication. The study is well design and well performed. Methods are well explained. The Discussion is a really good and appropriate. The only drawback (in my opinion) is that they have not done any quantitative analysis of the substantia nigra. This does not invalidate the interpretation of the results, or the model, but adding this information, if possible, would significantly improve the paper. I only have a minor suggestion to improve this already good study:

-Please revise carefully all abbreviations trough the manuscript (second paragraph Parkinson’s Disease, etc…)

-Honesty, in the Introduction the literature can be updated a little with more recent references.
-Regarding MPTP I don’t think this sentence is correct, MPTP only affect dopaminergic neurons:
“…its drawbacks are that neuronal death is poorly localized…”

-In the method section “Quantification of tyrosine hydroxylase immunoreactivity” the authors stated that quantification of striatal and nigral TH-ir was performed, but they only explain how striatal quantification was done. This can be amended.

-In fact, nigral measurement has not been done. It would have been complete to add some quantification of the substantia nigra (stereology of quantification of neurons) as explained above.
-In figure 5 I would suggest inserting A, B and C in the upper row, and then the HPLC data (DA, DOPAC, HVA) in the bottom row altogether.

-Also, magnification images can be inserted, it is very difficult to appreciate the neuronal loss in the VTA especially, for example.

-Authors should be careful when refering to the analysis of their data, as an example, in the results section:

“…left hemisphere, which showed much weaker TH-staining (Figure 5A; bottom panel). Similarly, the contrast index was measured to quantify the TH-staining in relation to the background, between control and lesioned animals for both caudate nucleus and putamen...”
Do the authors mean between control and lesioned sides? (not animals?) Sometimes is confusing trough the manuscript to know whether the authors have used only unilateral animals or there are some bilateral because of this. Please, revise this appropriately.

-For HPLC, the whole caudate and the hole putamen (5 mm) were used for the analysis? Of did the authors used selected tissue? This can be specified

-Number of animals of each experiment could be inserted in the all-figure legends. Indeed, a better explanation of how many animals and the experimental design could be add in the Methods section. Sometimes is a bit confusing to follow the design of each experiment (for each figure).

Thank you for considering my comments and making the changes. I think the article has improved with the suggestions of all the reviewers.