Engrams and Amnesia: The Roots of Memory Loss in Alzheimer's Disease

     A couple weeks ago, we had the pleasure of learning about a fascinating new theory in memory research. Dr. Stephanie Grella introduced us to engrams— these are neural substrates used to store and recall memories. In simple words, enzymes are the physical representation of formed memories in our brain; they are formed by neurons during a learning experience. During Dr. Grella's presentation, we learnt that the state of enzymes could vary from silent to active in terms of accessibility. An interesting portion of Dr. Grella's talk emphasizes on the idea that silent engrams were found in mice who have experienced amnesia. The reactivation of these silent engrams prompts the retrieval of memories that cannot be obtained naturally.

    A study which was carried out in 2017 by Roy et al. mentions the significance of engrams in retrograde amnesia. The authors explain that the retention of engrams is because specific proteins are no longer being produced. For the purpose of their study, they tagged the hippocampal dentate gyrus of the mice to identify engram cells. For their mice experimental groups, they injected them with anisomycin— an antibiotic that inhibits protein synthesis. Interestingly, they found that memories that are established during learning and eventually stored in engrams are secure for about seven days in amnesic mice, even in the absence of protein synthesis. This study uses optogenetic stimulation to activate silent engrams. They found that although memory retrieval is affected, memory storage is surprisingly not at a loss. In order for formed memories to be retrieved in a natural manner, one has to possess learning-induced synaptic strength; this refers to a process by which synapse between neurons are strengthened by memory formation. The scientists highlight the main difference in the features of amnesic subjects and the control groups— a weak connection between engram cells due to lack of synaptic strength. This explains why memory retrieval by natural cues are inadequate to obtain memories in amnesic mice.

    This study aligns with the concepts of engrams that Dr Grella spoke about. From her talk, we learned that although, some engrams which are permanently damaged may become inaccessible forever, the temporarily unavailable engrams have been silenced due to the "disruption of synaptic efficacy" (Josselyn et al., 2020). This aligns with the study described above which highlights the importance of synaptic strength for natural memory retrieval. As most of us know, amnesia is a major symptom of Alzheimer's disease (AD). During her talk, Dr. Grella speaks about how amnesia being a key factor heavily contributes to studies carried out about the artificial of activation in silent engrams; this is a way for scientists to examine the neural basis of AD. As mentioned earlier, these artificial methods include the use of optogenetics and genetic engineering. Unfortunately, we still face some technological challenges in the development of optogenetic methods that can be used effectively for invasive procedures in humans, especially the human brain. Despite this fact, the successful retrieval of memories artificially in mice paves way for a possible therapeutic approach that can be used to alleviate amnesia-related symptoms of AD in humans.

References:

Roy, D. S., Muralidhar, S., Smith, L. M., & Tonegawa, S. (2017). Silent memory engrams as the basis for retrograde amnesia. Proceedings of the National Academy of Sciences, 114(46), E9972–E9979. https://doi.org/10.1073/pnas.1714248114

Josselyn, S. A., & Tonegawa, S. (2020). Memory engrams: Recalling the past and imagining the future. Science, 367(6473). https://doi.org/10.1126/science.aaw4325