Abstract
Memory performance is the result of many distinct mental processes, such as memory encoding, forgetting, and modulation of memory strength by emotional arousal. These processes, which are subserved by partly distinct molecular profiles, are not always amenable to direct observation. Therefore, computational models can be used to make inferences about specific mental processes and to study their genetic underpinnings. Here we combined a computational model-based analysis of memory-related processes with high density genetic information derived from a genome-wide study in healthy young adults. After identifying the best-fitting model for a verbal memory task and estimating the best-fitting individual cognitive parameters, we found a common variant in the gene encoding the brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) that was related to the model parameter reflecting modulation of verbal memory strength by negative valence. We also observed an association between the same genetic variant and a similar emotional modulation phenotype in a different population performing a picture memory task. Furthermore, using functional neuroimaging we found robust genotype-dependent differences in activity of the parahippocampal cortex that were specifically related to successful memory encoding of negative versus neutral information. Finally, we analyzed cortical gene expression data of 193 deceased subjects and detected significant BAIAP2 genotype-dependent differences in BAIAP2 mRNA levels. Our findings suggest that model-based dissociation of specific cognitive parameters can improve the understanding of genetic underpinnings of human learning and memory.
Highlights
Human memory is a polygenic trait, characterized by large inter-individual variability
Applied to the eight performance measures in the verbal task, principal component analysis (PCA) revealed one component accounting for 31% of the variance, which could be related to general learning ability, and other four components accounting for 10–15% each, which could be related to other aspects of verbal task performance (Figureo 1B)
As brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) SNP rs8067235 was associated with modulation of memory strength by negative emotional information in the word and picture tasks, we investigated potential neural correlates of this association using the subsequent memory paradigm [26,27], applied to the event-related fMRI
Summary
Human memory is a polygenic trait, characterized by large inter-individual variability. Behavioral genetics studies have identified and characterized genetic variations associated with human memory performance [2,3] These findings have been generated either by candidate-gene studies [4,5,6,7], which depend on pre-existing information, or by genome-wide association studies (GWAS), which allow to identify novel memory-related genes and molecular pathways [8,9]. In spatial learning tasks, latencies to target platform reflect learning but can be influenced by exploration [13]; in declarative memory tasks the number of recalled items reflects memory, but it depends on response strategies for weakly remembered items (such as guessing) For this reason, alternative methods, such as computational modeling, can be employed to make inferences about distinct cognitive processes [14] and to study their genetic underpinnings. Using the best-fitting parameter values for each individual as dependent variables, we performed a GWAS in 1241 healthy young Swiss adults
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