COMBINATORIAL CELL-ADHESION AND ACTIVITY THALAMO-CORTICAL CODES INSTRUCT CORTICAL SENSORY MODALITY AREALIZATION

The precise matching of thalamic nuclei with their corresponding cortical sensory areas is essential for the assembly of modality-specific thalamocortical circuits, yet the molecular mechanisms underlying this specificity remain poorly understood. Using single-nucleus RNA sequencing and spatial transcriptomics, we identify a set of cortical genes that are differentially expressed between primary somatosensory (S1) and visual (V1) cortices from embryonic stages, prior to thalamic innervation. These genes are enriched in thalamo-recipient layers and regulate neuronal activity and cell adhesion. Computational analyses of cell–cell interactions reveal a combinatorial cell-adhesion code involving teneurins that aligns first-order thalamic nuclei with their corresponding layer 4 cortical target. Gene regulatory network inference identifies Jarid2 and Rfx3 as the transcriptional regulators of the cell adhesion code specific for S1 and V1, respectively. This adhesion code is preserved following disruption of thalamic activity, indicating that its early establishment is largely activity-independent. In contrast, disruption of thalamic activity alters modality-specific spontaneous cortical dynamics and the postnatal expression of a separate set of modality-specific genes. Together, these findings support a two-step model in which cortical identity is initiated by a combinatorial cell-adhesion landscape that mediates modality-specific thalamocortical partner matching and is subsequently refined by patterned thalamic activity to establish functional cortical modalities.