Single-nucleus transcriptomics reveal stress-related prefrontal activation in Tourette disorder

BackgroundTics are sudden, partially controllable motor or vocal events that arise from disruptions within cortico-striatal-thalamo-cortical circuits. Within this network, converging evidence implicates the dorsolateral prefrontal cortex (DLPFC) as an important cortical node supporting voluntary tic control. This region is critical for top-down regulation and is particularly sensitive to stress, raising the possibility that molecular vulnerabilities within the DLPFC may influence the capacity to suppress tics. However, the underlying cellular and molecular architecture remains poorly defined. MethodsTo address this gap, we conducted the first single-nucleus RNA sequencing analysis of postmortem DLPFC tissue from men with Tourette disorder (TD) and age-matched neurotypical controls. ResultsOverall cell-type proportions did not differ significantly between groups. In contrast, gene ontology analyses revealed broad upregulation of transcripts involved in protein synthesis, most prominently in microglia, oligodendrocytes, and interneurons. Among neuronal lineages, these changes were most pronounced in superficial and middle-layer pyramidal neurons and vasointestinal peptide-positive interneurons. To determine whether these alterations reflect engagement of stress-related transcriptional programs, we compared TD-associated differentially expressed genes with published single-nucleus datasets from major depressive disorder and posttraumatic stress disorder. Across DLPFC cell populations, and especially within pyramidal neurons and interneurons, we observed significant enrichment for stress-associated gene signatures, including glucocorticoid-responsive transcripts and immediate early genes. ConclusionTogether, these findings identify the DLPFC in TD as a region of heightened stress responsivity and altered excitatory-inhibitory dynamics, offering new insight into cortical mechanisms that may constrain tic suppression.