Peer review of: Preventing and treating PTSD-like memory by trauma contextualization (2020)


Reviewers' Comments: 
 
Reviewer #1: 
Remarks to the Author: 
While the revised manuscript has been improved, my comments 1, 2, and 4 (as originally stated below) have not been 
properly addressed. 
 
1. The pre-tone freezing levels during the tone test in a familiar chamber are comparably high in all groups (e.g., Fig. 
1a,b; Fig. 3), which would indicate generalized fear between trained and familiar chambers (both are round with 20 cm 
diameter). If so, shouldn’t there be some re-contextualization going on during the tone test? 
 
The re-contextualization explanation does not work because the pre-T freezing is comparably high between familiar vs. 
trained chambers. To rigorously test the authors’ claim, I strongly recommend that a different familiar chamber (i.e., a 
novel chamber where there is minimal context generalization) be used. 
 
2. The post-training cort injection producing PTSD-like effects require some explanation. For example, is the cort effect due 
to its action on dCA1 cells since the dCA1 inhibition during fear conditioning mimics post-training cort effect, whereas the 
dCA1 activation offsets post-training cort effect? If so, this should be tested by applying optogenetic inhibition, not only 5 
minutes before and during fear conditioning (as shown in Fig 1b,c) but also right after fear condition. 
 
If post-training optogenetic inhibition manipulation does not mimic post-training cort effects on producing PTSD-like 
effects, this would argue against the authors claim. I cannot follow the authors’ logic getting around this issue. 
 
4. (Fig 1a, Tone Test) For the Laser OFF/Veh group, the % freezing during the Tone period is lower than % freezing during 
the Pre-T period. If so, why is the Tone Ratio shown as being greater than 0? This seems to be the case for all Tone Ratio 
figures shown in Figure 1. 
 
The authors state that the tone ratio is calculated as: [% freezing during tone presentation – (% pre-tone period freezing 
+ % post-tone period freezing)/2]/[% freezing during tone presentation + (% pre-tone period freezing + % post-tone 
period freezing)/2]. 
What is the rationale (or basis) or dividing by 2? Please provide literature supporting the tone ratio calculation. 
 
5. Are the n sizes for the four experiments before or after histological verification? Providing both before and after 
histology n size information would be helpful. 
 
The revised manuscript (below) does not show the n sizes before excluding the animals based on histological analysis. : 
The group sizes (after histological verification) were as follows: 
- Experiment 1 [optogenetic inhibition/activation of dCA1 (vs. dCA2 and dCA3) during fear conditioning (vs. before 
conditioning)]: n = 8 to 17 mice per group. 
- Experiment 2 (trauma “re-contextualization”): n = 9 to 10 mice per group. 
- Experiment 3 (optogenetic inhibition of dCA1 during trauma “re-contextualization”): n = 7 mice per group. 
- Experiment 4 (assessment of the persistence of PTSD-like and “re-contextualized” fear memory on day 30): these mice 
are the same as in experiments 2 and 3. 
 
 
 
Reviewer #2: 
Remarks to the Author: 
Th authors adequately responded to concerns.