This week an article by Ramirez et al. 2013, introduces the ability to create false memories in the hippocampus by optically stimulating cells that are associated with positive memory during negative events. This idea is then implemented two years later in the paper by Ramirez et al. 2015, where they activate cells associated with positive memory to suppress depression like behaviors in mice.
The 2013 paper began by identifying a small population of granule cells in the dentate gyrus of the hippocampus that coded for contextual memory. They utilized doxycycline (DOX) fed mice and upon withdrawal to DOX and introduction of these mice into a novel context A, the cells of the DG that encoded this environment were activated. These mice also contained the transgene TRE-ChR2-mCherry, that upon DOX withdrawal elicited fluorescent expression allowing for the labelling of the specific cells that encoded the context A. (Fig 1B,C) Then to determine whether a novel fear memory could be encoded as a “false memory” associated with context A, they used optogenetics and upon light illumination of the particular cells encoding context A, they exposed the mice to a fear conditioning context B (foot shock). They then exposed the mice either back to context A or a novel context C. The animals placed back in context A displayed increased levels of A relative to context C and control mice expressing only mCherry. The rest of the experiments in this paper focused on experiments control for potential confounding variables such as; mCherry influence, different brain structures that may be involved (CA1) and the interaction between the false and fear memories. To me the most important part of the 2013 paper by Ramirez et al. was their supported hypothesis of the ability to induce false fear memories by optogenetic light activation. This idea was then carried forward by them for therapeutic effects for depression in their 2015 paper.
The 2015 paper by Ramirez et al. used the previous work to test whether activating positive memories, stored in memory engram cells of the dentate gyrus, artificially was enough to suppress depression like behaviors. They did this using the previously mentioned methods of DOX withdrawal. Upon withdrawal, cells in the DG expressing ChR2-mCherry were activated allowing for fluorescent labelling and optogenetic light activation during positive, neutral or negative experiences. The mice were then exposed to 10 days of chronic immobilization stress (CIS) and put through tests of anxiety (as we have learned through previous papers) such as: open field test, elevated plus maze, tail suspension test and sucrose preference test. The CIS group as expected displayed a decreased time in struggling and preference for sucrose. They then used light to activate the DG cells associated with the positive experience and noticed an acute increase in time spent struggling and levels of sucrose preference that matched the unstressed group. (Fig. 1 b,c) They also noticed decreased latency to feed in the novelty suppressed feeding test. This set of experiments support their hypothesis that activating positively associated cells in the DG suppress depressive like behaviors induced in mice. The rest of the paper includes experiments to understand the neural mechanisms underlying this process. They observed the necessary projections of the DG to the basolateral amygdala to the nucleus accumbens for the functionality of these memory engram cells. And finally looked at whether chronic activation of positive memory cells would elicit long lasting depression related behaviors.
There is a lot to unpack within the 2015 paper, however, my favorite part of this week's readings were the information I described about each of the papers and how the discovery of a method for false memory encoding was able to instigate research in the direction of psychological disorder therapeutics. This is entirely what I find interesting about scientific research and the reason I chose Neuroscience as a major. It is fascinating to watch the development and progression of therapeutic research in such a short time as shown by the quick succession of work between 2013 and 2015 by Ramirez et al.
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