Blood transcriptome analysis suggests an indirect molecular association of early life adversities and adult social anxiety disorder by immune-related signal transduction

Abstract

Social anxiety disorder (SAD) is a psychiatric disorder characterized by severe fear in social situations and avoidance of these. Multiple genetic as well as environmental factors contribute to the etiopathology of SAD. One of the main risk factors for SAD is stress, especially during early periods of life (early life adversity; ELA). ELA leads to structural and regulatory alterations contributing to disease vulnerability. This includes the dysregulation of the immune response. However, the molecular link between ELA and the risk for SAD in adulthood remain largely unclear. Evidence is emerging that long-lasting changes of gene expression patterns play an important role in the biological mechanisms linking ELA and SAD. Therefore, we performed a transcriptome study of SAD and ELA using RNA sequencing. Analyzing differential gene expression, 13 significantly differentially expressed genes (DEGs) were identified with respect to SAD whilst no significant differences in expression were identified with respect to ELA. The most significantly expressed gene was MAPK3 being upregulated in the SAD group compared to control individuals. In contrary, weighted gene co-expression network analyses (WGCNA) identified only modules significantly associated with ELA, not with SAD. Furthermore, analyzing interaction networks of the genes from the ELA-associated modules and the SAD-related MAPK3 ) revealed complex interactions of those genes. Gene functional enrichment analyses indicate a role of signal transduction pathways as well as inflammatory responses supporting an involvement of the immune system in the association of ELA and SAD. In conclusion, we did not identify a direct molecular link between ELA and adult SAD by transcriptional changes. However, our data indicate an indirect association of ELA and SAD mediated by the interaction of genes involved in immune-related signal transduction.

Adolescent environmental enrichment induces social resilience and alters neural gene expression in a selectively bred rodent model with anxious phenotype

“…Changes in cytokine expression regulate both social behavior and neuronal connectivity ( Filiano et al, 2016 ), while social status and experience impact cytokine levels in multiple species ( Bartolomucci et al, 2001 ; Hodes et al, 2014 ; Krugel et al, 2014 ; Snyder-Mackler et al, 2016 ). Living in a social group is an immune challenge, and there is strong cross-talk between immune and social signalling pathways ( Cole, 2012 ; Edelmann et al, 2023 ). The current data provide further evidence linking immune and social signalling and suggest that both positive and negative social experiences regulate immune signalling within the brain.…”

Adolescent environmental enrichment induces social resilience and alters neural gene expression in a selectively bred rodent model with anxious phenotype

“…Changes in cytokine expression regulate both social behavior and neuronal connec9vity [68], while social status and experience impact cytokine levels in mul9ple species [69–72]. Living in a social group is an immune challenge, and there is strong cross-talk between immune and social signalling pathways [73, 74]. The current data provide yet more evidence for this correla9on between immune and social signalling and suggest that both posi9ve and nega9ve social experiences regulate immune signalling within the brain.…”

Pervasive neurovascular dysfunction in the ventromedial prefrontal cortex of female depressed suicides with a history of childhood abuse

“…Transcriptomic changes associated with ELA or chronic stress have been the focus of several investigations, yet the majority of these studies exclusively characterize male ELA signatures (120-126). In contrast, fewer studies include females (127)(128)(129), thereby omitting the opportunity to integrate or make direct comparisons between males and females and, as such, the extent to which the transcriptional profiles defining ELA differs in males versus females remains unknown. Our data-informed decision to perform DGE analysis on males and females separately allowed us to identify dramatic, fundamental differences in NVU dysfunction in males versus females, providing a framework for better understanding the molecular basis of the sexual dimorphism characterizing depression and ELA.…”