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Ramirez et al.: 2013 and 2015 Papers

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In these papers, Ramirez et al. strive to understand how memory encoding via optogenetic manipulation of engram-bearing cells in the hippocampus, specifically the dentate gyrus, can affect an animal’s response to a stressful context. 
The first paper, published in 2013, was crucial to the field as it introduced this very exciting technique; in this paper, Ramirez et al. use tet-tag to manipulate brain circuity and establish associations between two contexts. Throughout the paper, this is referred to as “false memories.” Using these artificial memories, the investigators are able to manipulate the animal’s fear response in a specific context. Specifically, after the animals are conditioned to a repeated fearful stimulus (a foot shock, in context B), activation of the involved DG cells in a different context (context A’) will also initiate a fear response (in absence of any foot shock). In this experiment, the false memory is used to create an unnatural fear association in a given context. It is also interesting to note that while it was possible to create a false memory via manipulation of the DG, this was not possible when the cells in the CA1 were similarly manipulated. The authors hypothesize that this is a result of contextual engrams relying on synchronous timing of neural firing. While not explicitly implied in the paper, I believe that this could have greater implications for determining the distinct circuity involved in disorders such as generalized anxiety, in which inappropriate contextual feedback can lead to a stress response. 
The second paper, published in 2015, describes a more direct application, in which optogenetic activation of a positive memory can alter a depression-like phenotype. In this paper, Ramirez et al. attempt to modulate stress response by using positive association (presence of a female mouse, specifically). By activating positive encoded memories in the DG while the mice endured various tests of anxiety, active/passive escape behavior, and anhedonia, the researchers were able to rescue stress-induced depression-related behaviors. Essentially, this research implies that the memory of a positive experience may outcompete the stressful stimuli.
It should also be noted that in the 2015 paper, a test of necessity was used to conclude that the projection of the basal lateral amygdala (BLA) to the nucleus accumbens (NAcc) is necessary for the positive memory stimulation to have an effect on overall reactivity to stress. It would also be interesting to run tests of sufficiency to determine if activating this pathway could increase the ability of the animals to respond effectively to stress. Would this increase their sucrose preference from baseline? Would it increase the animal’s tendency to engage in escape-like behavior?

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