Functional gradient variations in different neuroticism levels and its correlation with cell type-specific transcriptional signatures

Neuroticism is significantly associated with various psychiatric disorders. Individuals exhibiting high levels of neuroticism are more susceptible to experiencing anxiety, depression, and other negative emotional responses. Research on the differences in macroscopic functional connectivity gradients among neuroticism levels and their associations with microscopic transcriptomics remains scarce. This study explores the associations between functional gradient and transcriptional expression in neuroticism across 109 individuals with low neuroticism (LNG) and 210 with medium-high neuroticism (MHNG). We analyzed functional gradient alterations in MHNG and their correlations with neurotransmitters, meta-analytic cognitive terms, and transcriptional patterns using partial least squares regression (PLS), involving similarity with major psychiatric disorders, functional enrichments, developmental stages, cortical layers, and specific cell types. MHNG exhibited functional gradient changes within the default, limbic, and visual networks, which correlated with higher-order cognitive terms and alterations in several neurotransmitters. We identified significant overlaps between PLS1 weighted genes and those dysregulated in schizophrenia and autism. Genes linked with gradient alterations were enriched in synaptic signaling, infection and metabolism, astrocytes, specific cortical layers, and developmental phases from early fetal to young adulthood. These findings offer a critical theoretical foundation for understanding the complex relationship between macroscopic functional gradients and microscopic transcriptional patterns across various neuroticism levels.