Spatial transcriptomics reveals D2-associated synaptic transcriptional attenuation in the chronically stressed dorsal striatum.

Chronic stress alters striatal functions involved in motivation, action selection, and behavioral adaptation, yet cell-type-associated transcriptional organization in the dorsal striatum remains unclear. We used RNAscope-guided GeoMx spatial transcriptomics to compare D1 and D2 neuronal compartments in matched dorsal striatal regions after chronic restraint stress (CRS). CRS engaged both populations, producing CRS-responsive gene sets in both D1- and D2-enriched compartments. Gene set enrichment analysis revealed partially overlapping CRS-associated pathway attenuation in both compartments, indicating stress-responsive transcriptional organization in both populations. However, D2 responses showed more coherent convergence around receptor-trafficking and synaptic signaling programs, including AMPA receptor trafficking and EPHB-mediated signaling. Moreover, under the same threshold-defined DEG criteria, CRS-downregulated D2 genes resolved into synapse-centered functional annotation categories, including glutamatergic synapse, postsynaptic organization, and dendritic spine, whereas D1 gene sets did not show a comparable pattern. These findings provide a framework for comparing stress-associated D1/D2 transcriptional organization in the dorsal striatum.