Whole-brain mapping reveals the divergent impact of ketamine on the dopamine system
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Abstract
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catecholaminergic
As previously mentioned the distinction between dopaminergic and catecholaminergic projections has large implications here. For instance, dopaminergic projections to the sensory cortex are rare, while noradrenergic projections to the striatum are rare. Accounting for these known projection differences when interpreting this data could be very helpful and clarify the effects of ketamine specifically on the dopaminergic system
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Altogether, these results158suggest that the cellular plasticity in the dopaminergic system may be facilitated by the existence159of a much larger pools of untranslated TH mRNA+ neurons to rapidly modulate the number of160available TH+ DA neurons in various regions of the brain
This finding is amazing! How cool.
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further validated
It's really great this validation was done! Could you directly compare the validation results to the suiteWB results? It might help convey the confidence of different results and give a sense of the advantages of suiteWB.
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(DMH)
I'm having a hard time understanding the differences between the effects of 30mg/kg and 100mg/kg across brain areas, and which effects were chosen to be schematized in Fig 1b. For instance, the DMH has reduced TH+ neurons at 30mg/kg but not at 100mg/kg, and Fig1b summarizes this as a reduction, but it's not clear to me why that's the interpretation. Overall it would be really helpful if there was more discussion of where the effects across doses are similar and different, how that matches or defies expectations, and what conclusions are drawn which lead to the schematic in Fig 1b.
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higher-level annotation
I'm not totally sure how to understand the findings at higher vs. lower level annotation. Including how ROI size/number influences detection in this methodology, and a direct comparison of the findings when using different annotation levels would be very clarifying
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1- and 5-110days treatment datasets were not analyzed further
Even though there weren't significant differences detected, this is a huge amount of potentially useful data! Could the data and analysis done to find non-significance be displayed? Also, it would be great to know whether the interpretation here is that there is no true change at 1 and 5 days, or that there was not sufficient information (e.g. statistical power) to tell the effect at these time points
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multi-model image segmentation
Wow, this is great! It seems like it could be a really useful tool for the community. More description of the uses, limitations, and accuracy of this tool could really help others to use this great innovation.
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The 30 mg/kg group, but not80100 mg/kg, exhibited increasing (with days of exposure) locomotion sensitivity 15’-post injection
What an interesting observation! Based on the effects of locomotion on brain circuits and plasticity, how do you think this difference might affect the observed changes in TH+ neurons/axons?
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may only be inferred as catecholaminergic
This seems like an important distinction and I'm glad it was mentioned both here and in the discussion. It wasn't clear to me, however, how this impacts the interpretation of further results, particularly for Figure 5. It would be very helpful to further comment on the nature of the observed TH+ axons, particularly in relation to known projection differences between dopaminergic and noradrenergic neurons.
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