Abstract

Memory retrieval is mediated by discharges of acetylcholine, glutamate, gammaaminobutyric acid, norepinephrine, and serotonin/5-hydroxytryptamine circuits. These projections and memory interact through engram circuits, neurobiological traces of memory. Increased excitability in engram circuits of the medial prefrontal cortex and hippocampus results in remote and recent memory retrievals, respectively. However, due to degenerated neurotransmitter projections, the excitability state of engram circuits is decreased in the patient with dementia; and thus, acquired- memory cannot be retrieved by natural cues. Here, we suggest that artificial neuropharmacological stimulations of the acquired-memory with an excitation potential higher than a natural cue can excite engram circuits in the medial prefrontal cortex, which results in the retrieval of lost memories in dementia. The neuropharmacological foundations of engram cell-mediated memory retrieval strategy in severe dementia, in line with this has also been explained. We particularly highlighted the close interactions between periaqueductal gray, locus coeruleus, raphe nuclei, and medial prefrontal cortex and basolateral amygdala as treatment targets for memory loss. Furthermore, the engram circuits projecting raphe nuclei, locus coeruleus, and pontomesencephalic tegmentum complex could be significant targets of memory editing and memory formation in the absence of experience, and a well-defined study of the neural events underlying the interaction of brain stem and memory will be relevant for such developments. We anticipate our perspective to be a starting point for more sophisticated in vivo models for neuropharmacological modulations of memory retrieval in Alzheimer’s dementia.

Keywords: Memory formation, memory retrieval, memory extinction, neuropharmacology, serotonin, norepinephrine.