Ramirez’s research group explores the role of the dentate gyrus in both false memory formation and repression of depressive like behaviors in papers published two years apart. These papers complement each other as the second 2015 elaborates and grows from the previous 2013 paper.
Ramirez et al’s 2013 paper explored the effects of stimulating the Dentate Gyrus (DG) to create a false memory. To do this, mice were first exposed to context A. While exploring this novel environment, the neurons activated were located and marked. Then, the mice were fear conditioned with foot shocks in context B while the same neurons that were activated in context A were reactivated. Ultimately, the mice were exposed to context A’ again as well as a control novel context C. The mice then responded with a fear response of freezing in context A, despite never having been fear conditioned within the context, but showed no response in context C. This same response was not seen when the CA1 region of the hippocampal neurons were targeted. These specific neurons also had much more overlap during the two distinct contexts. These results suggest that the fear memory was recreated to be observed in Context A, despite it having occurred in context B. The researchers induced a ‘false memory’ by manipulating specific neurons in the DG. Additionally, a real and fake fear memory can both be induced by fear memory recall as shown through the association of light with the fear response. The researchers then connected the central and basolateral amygdala to the freeze response and false memory network by looking at the cells activated. They observed the same response for the CeA and BLA in the false and true memories. This makes sense as the paper mentioned that it is common for the brain to activate very similarly for a true and false memory.
Ramirez et al continues with the DG and its role in memories and emotional response as they examine the role of happy memories in depressive behaviors. This is interesting because it mirrors their previous research in that it goes the opposite way; they activate the DG to produce happy memories instead of fear conditioned ones. Again, they introduce the mice to a happy memory (hanging out with a female mouse), track which neurons in the DG are activated, then reactive them after inducing stress. The research group explored many avenues as to the effects this would have, evident by the many supplementary figures, but most interestingly they observed a reversal of depressive behaviors as seen in tests like the tail suspension test, sucrose preference test, and novelty suppressed feeding tests. In conjunction with these behavioral paradigms, they were also looking at the molecular effects and observed an increase in neurogenesis, activation of the nucleus accumbens, and activation in the BLA. All of these results pointed to a network connection in positive experiences with the nucleus accumbens, BLA, and DG. Lastly, blocking dopamine blocked the light-inducing effects of the DG, insinuating that dopamine plays a critical role in that happy memory recall and ameliorating depressive symptoms. However, the authors did not focus on this much more.
Each of these papers highlights the interesting advancements in identifying and utilizing neurons with new technology. Just the sheer ability to visualize specific neurons being activated during a specific context or memory using c-fos or mCherry, then being able to go back and optogenetically stimulate those specific neurons is impressive. They combined measurements of quantifiable activation, specific location, and behavior to support their hypothesis. While there are still areas to explore, such as the nucleus accumbens and BLA interactions with the dentate gyrus, I think this paper utilized fear conditioning and quantifying neuron’s activity well. The mechanism of glutamate and DA is still somewhat unclear, even though the paper touched on the necessity of it to induce the reversal effect of depressive symptoms. In terms of translating this to a human model, researchers, from my knowledge, cannot optogenetically stimulate specific neurons in the brains of humans ethically yet. However, it does illuminate another avenue for potential explorations and treatments in depression.
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