Stress-related prefrontal activation in Tourette disorder

We performed the first single-nucleus transcriptomic analysis of postmortem DLPFC tissue from individuals with TD and age-matched neurotypical controls. No significant differences in cell numbers were observed between groups. Gene ontology analyses revealed broad upregulation of transcripts related to protein synthesis, most prominently in microglia, oligodendrocytes, and interneurons. Within neuronal clusters, these changes were most pronounced in superficial and middle-layer pyramidal neurons and vasointestinal peptide (VIP)-positive interneurons. Differential expression analyses showed widespread increases in immediate early genes (IEGs) and glucocorticoid-responsive transcripts across all cell types in TD. Furthermore, all cell populations in TD samples exhibited enrichment for genes associated with stress-related psychopathology. These findings implicate the DLPFC as a locus of heightened stress responsivity and disrupted excitatory–inhibitory development in TD. Overall design: Brain tissue samples from the superior DLPFC (Brodmann area 9, BA9) were obtained from the NIH NeuroBioBank (NBB) Brain Tissue Resource Center (BTR) at Harvard University and nuclei were processed for snRNA-seq using a 10X genomics Chromium pipeline followed by analysis using Seurat.