Genetic Alzheimer’s Disease Risk Affects the Neural Mechanisms of Pattern Separation in Hippocampal Subfields

Entropy, Amnesia, and Abnormal Déjà Experiences

“…In healthy brains, activation of the dentate gyrus, CA3, entorhinal cortex, and CA1 are involved in both novelty processing and recognition memory ( Lee et al, 2020 ). Sensory signals from the entorhinal cortex project onto the dentate gyrus and then the CA3 hippocampal subregion which mediate pattern separation and previously stored memory streams, before projecting onto the CA1 hippocampal subregion ( Stepan et al, 2015 ), where firing indicates either novelty or recollection in O’Connor’s model.…”

“…Dementia patients who have trouble with scene recognition and associative object memory also have a reduced neural response to novelty of these same image types ( Bastin et al, 2019 ). Due to its established role in pattern separation, the dentate gyrus and CA3 are proposed to distinguish closely related sequences of imagery as representing distinct memories ( Lee et al, 2020 )—a function closely tied to the detail binding functions described above that are relevant to attribute amnesia and repetition suppression and are impaired in dementia models. The item and scene discrimination functions of these regions make them necessary for spatial memory, but also for the awareness of a scene’s novelty as they hold the expectations against which the sensory stream from the entorhinal cortex is compared.…”

“…There are different levels to pattern separation, and in an fMRI study of healthy participants with different APOE genotypes, false responses of “repeat” on a spatial object recognition test were attributed to a lack of relational, rather than item-based pattern recognition, dependent on CA3 rather than the dentate gyrus ( Lee et al, 2020 ). In trials resulting in this type of error, item recognition was intact but the memory of the item’s associated source was faulty—the item is recognized, but the spatial location is not tagged as being new, leading to CA1 activation and oscillation, so the participant falsely reports it as a repeat.…”

Working memory and pattern separation in founder strains of the BXD recombinant inbred mouse panel

“…Consequently, substantial effort in the neurosciences has been directed towards discovering biological mechanisms underlying variation in these cognitive abilities 1 – 15 . Nevertheless, we are only beginning to understand the genetic mechanisms that underlie variation in working memory and pattern separation 16 – 19 . Discovering and characterizing these mechanisms is a critical step towards treatments for common and devastating psychiatric disorders such as Alzheimer's disease.…”

Spatial Pattern Separation Testing Differentiates Alzheimer’s Disease Biomarker-Positive and Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment

“…It remains unknown how early spatial discrimination deficits emerge in the course of AD, especially in preclinical AD. However, the recent studies showed that the apolipoprotein E ε4 allele, the strongest known genetic risk factor for sporadic AD (Saunders et al, 1996) associated with increased cerebral amyloid-β deposition (Fleisher et al, 2013), is related to more pronounced spatial discrimination deficits in older adults (Sheppard et al, 2016) and reduced hippocampal recruitment during a spatial discrimination task in young pre-symptomatic individuals (Lee et al, 2020).…”