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Week 3: Memory Engrams (Ramirez 2013 & 2015)

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This week, we looked at two articles published by Steve Ramirez and colleagues, the first published in 2013, and the second published in 2015. The first article established the idea that false memories could be generated in the hippocampus by activating a specific subpopulation of cells in the dentate gyrus. They did this by using optogenetics to visualize the cells and foot shocks as part of the fear condition to create the memories. It is also important to note that fear conditioning is used to generate these memories, therefore heavily incorporating the amygdala as part of the emotional context of the memory. The second Ramirez article expands on this further by activating cells in various brain regions. This is part of the reason that regardless of the accuracy of the memory (genuine vs false), the mice would still exhibit the emotional fear response. The researchers tried to determine whether activating CA1 cells would also create false memories. However, they were not able to recreate a false memory by stimulating CA1 cells, suggesting that the position of the dentate gyrus within the circuit of memory formation may allow for varied inputs leading to the creation of false memories. 

The second Ramirez article expanded on the ideas introduced in the first by exploring the effect of memory engrams in depression-like behaviors. In the first of their studies, they exposed a set of mice to a “positive experience”, a “neutral experience”, or a stressful “negative experience”. Later, they reactivated dentate gyrus cells that were active during the “positive experiences” and found that reactivating these cells can reverse the behavioral effects of the stress induced by the various tests given to the mice. The next set of experiments aimed to look further at the circuits involved in memory engrams. It is relevant that they looked at the nucleus accumbens and the amygdala because of their involvement in emotional memory encoding and fear/reward circuitry. The nucleus accumbens is one of the regions that receives dopaminergic projections from the ventral tegmental area, which is known to be associated with reward. Further, the amygdala is involved with fear, but more specifically with the emotional context in which these memories are encoded. Recent literature has shown that there is a loop that forms between the VTA and the hippocampus. In this loop, the CA1 projects to the subiculum, which in turn projects to the nucleus accumbens, then through the ventral pallidum to the VTA. The projections from the VTA to the dentate of the hippocampus is important for enhancement of long term potentiation, so it is possible that this mechanism could be involved in the behavioral effect of decreasing depressive-like behaviors seen in this article.

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