CREB gene regulation as a blood biomarker of neural sensitivity to social threat

Social threat can potentiate inflammation and increase the risk of inflammation-related diseases. Identifying individuals with heightened neural sensitivity to social threat could guide targeted prevention and treatment protocols. The cAMP response element-binding protein (CREB) transcription factor is a key mediator of neural influences on immune cell gene expression, and we hypothesize that individual differences in basal CREB activity could serve as a blood biomarker of individual differences in neural sensitivity to social threat. We utilized pre-intervention data from a randomized-controlled trial (n = 44; 67% female; average age = 19.4 ± 1.8; NCT05304052) that included functional neuroimaging and peripheral blood collection. CREB gene regulation was assessed by TELiS promoter-based bioinformatics, and central nervous system (CNS) social threat sensitivity was assessed by fMRI-measured changes in activity in the anterior insula (AI), dorsal anterior cingulate cortex (dACC), and amygdala in response to a standardized social-evaluative stress task (modified Montreal Imaging Stress Task; MIST). In unadjusted regression analysis, greater baseline CREB activity correlated with greater reactivity in the AI (b = 0.54, p ' 0.001), dACC (b = 0.46, p = 0.004), and amygdala (b = 0.33, p = 0.015). In adjusted analyses, controlling for standard covariates (e.g., sex, age, baseline depressive and anxiety symptoms), the associations were significant for AI and dACC (p ' 0.05), and marginally significant for the amygdala (p = 0.08). Ancillary analyses suggest that variations in leukocyte subset abundance may drive these associations. Findings suggest basal CREB activity in blood may serve as a biomarker for CNS reactivity to social threats. Larger studies are needed to replicate these findings and determine their implications for social behavior, health, and responses to social interventions.