The role of microRNAs in executive functions: a comprehensive review and bioinformatics analysis of human and animal studies

Executive functions (EFs) are meta-cognitive abilities that orchestrate goal-directed behavior (i.e., set-shifting, working memory, and inhibitory control). Despite their strong genetic composition, the development of EFs is shaped by environmental exposures - as maternal distress, perinatal hypoxia, household dysfunction, neglection - which have varying degrees of impact depending on the duration or severity of the exposure, sensitive neurodevelopmental periods, and individual resiliency. Furthermore, they are negatively affected by aging and psychiatric, neurologic, and inflammatory diseases. MicroRNA dysregulation interferes with normal brain development and function and has been associated with various neuropsychiatric disorders; however, its effects on EFs remain unclear. Therefore, in this review we focus on the evidence regarding microRNA changes and their effects on EFs. We performed a systematic search from inception until October 2023 of four databases of human and animal studies. The results are presented narratively. Moreover, we conducted a bioinformatics analysis using experimental mRNA targets of the candidate microRNAs, as well as assessed the risk of bias of the included studies. We found 46 studies (23 in humans, 22 in animals, and one in both). The studies evaluated mild cognitive impairment, psychiatric disorders, and healthy aging. Gene mutations in MIR137 were associated with decreased EF performance, whereas MIR885 gene methylation was associated with increased executive functioning. Mutations in the genes of enzymes relevant for microRNA biosynthesis also impacted EFs. In the revised literature, the microRNAs that were consistently reported as dysregulated in two or more samples in relation to variations in EFs were miR-148a-3p for humans; miR-155, miR-30e, and miR-384-5p for rodents; and miR-132, miR-146a-5p, miR-148-3p, miR-181a-5p, miR-190b, miR-31, miR-501-3p, and miR-9-5p for both humans and rodents. The suggested regulatory pathways behind EFs included changes in neurogenesis, neurodevelopment, and synaptic plasticity/signaling. Changes in the various steps of microRNA biogenesis - such as mutations in the genes coding for microRNAs, reduced availability of relevant processing enzymes, or dysregulation of microRNA expression - are potentially associated with changes in EFs. Future research is required to better understand these associations in relation to developmental stage, diagnosis, disease severity, and the degree of the microRNA dysregulation.