An update on memory formation and retrieval: An engram-centric approach.

Objective: We explore here that memory loss observed in the early stage of Alzheimer's disease (AD) is a disorder of memory retrieval, instead of a storage impairment. This engram-centric explanation aims to enlarge the conceptual frame of memory as an emergent behavior of the brain and to propose a new treatment strategy for memory retrieval in dementia-AD.

Background: The conventional memory hypothesis suggests that memory is stored as multiple traces in hippocampal neurons but recent evidence indicates that there are specialized memory engrams responsible for the storage and the retrieval of different memory types.

Updated Memory Hypothesis: There are specialized memory engram neurons for each memory type and when information will be stored as a memory arrives in the hippocampus through afferent neurons finds its neuron according to the excitability states of engram neurons. The excitability level in engram neurons seems like a code canalizing the interactions between engrams and information. Therefore, to enhance the excitability of memory engram neurons improves memory loss observed in AD. In addition, we suggest that the hippocampus creates an index for information stored in memory engram cells in specialized regions for different types of memory, instead of storing all information; and different anatomic locations of engram cells and their roles in memory retrieval point out that memory could be an emergent behavior of the brain, and the interaction between serotonin fluctuation and engram neurons could be neural underpinnings of terminal lucidity.

Major Challenges For The Model: The major challenge for this engram-centric memory retrieval model is the translation from bench to patient, specifically the delivery of optogenetic tools in patients. Engram neurons can be specifically activated by optogenetic tools, but optogenetics is an invasive technique which requires optic fiber implantation into the brain. In addition, light can overheat the tissue and thus induce damage in tissue. Furthermore, light is a foreign object and its direct implantation into the brain may cause neuroinflammation, the main trigger of neurodegenerative diseases. Therefore, to test the engram hypothesis in human, new tools to allow specific engram activation should be discovered.