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Ramirez et al. 2013 & 2015

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Ramirez et al. (2013 & 2015) presents a very interesting and novel approach towards not only understanding mnemonic circuitry but also gaining temporally precise control of synthetic memory activation. Amongst both papers, the tet-tag system is used to recruit and reactivate engrams of neurons, a powerful tool when it comes to understanding how encoded memories of context or social interaction can modulate an animal’s ability to respond to stress. 
            The first paper, published in 2013, presents initial convincing data on the efficacy of this technique.  When the initial context (A) is encoded into the same engram as a shocking stimulus, although the mouse can be placed in an entirely different context, when the initial context is activated, along with it a fear response is activated. One very interesting dimension of the data shown is the competitive encoding and retrieval of contexts and fear. For example, when the initial context is not encoded with the shock stimulus, but is activated in the secondary foot shock context, freezing behavior decreases drastically. This is an interesting concept being that both contexts are being activated and eliciting a push-pull effect on the behavioral output, reducing the behavioral by nearly half as compared to baseline. As it is natural for many different contextual inputs to converge in any given situation it is most likely that salience comes into play when differentiating a threat. This would certainly be an interesting avenue to study if it would be possible to utilize this technique in determining not only a new memory, but which engram bears the highest weight during a stressful situation. This has great implications in the study of PTSD, as it shows the true gravity of context in responding effectively to threat. For instance, if an individual struggling with PTSD after fighting in the war walks through the street and hears a loud noise which elicits an extreme behavioral response, the war context is likely playing a role in the fear response even though they are no longer in the context of war.
            The second paper published in 2015 shows a more specific circuit-based approach to understanding the effects of positive associations on stress response. More specifically it is not just shown that false positive memories can improve on depression-like behaviors, it is shown that the BLA-NaCC circuity is necessary to produce this effect. This is very intriguing as this pathway is involved in reward-based fear response and decision making. It is widely known that contextual salience is highly involved in choosing outcomes. So, maybe it is possible that this pathway somehow is not just necessary but is modulating which memory engrams can elicit the largest response on behavior. 
            Overall, the tet-tag and optogenetic system seems to be an effective tool in modulating encoded memories and behavior but may come with some worry. It is possible that the large amount of antibiotic treatment as well as genetic manipulations through promoters and AAVs may cause downstream disturbances of physiology. As optogenetics is under fire currently for its possible side effects, it is likely that if tet-tag becomes a prominent tool, the same will be happy. Therefore, I think more studies are needed to truly understand the ramifications of using a tool as such.

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