Comparative molecular mapping reveals molecular gradients and spatially organized populations in the subthalamic and para-subthalamic regions

Abstract

The subthalamic nucleus (STN) is a major target for deep brain stimulation (DBS) in Parkinson disease (PD), yet its molecular organization and relationship to the adjacent para-subthalamic nucleus (pSTN) remain incompletely defined. Here, we performed comparative molecular mapping of the STN and pSTN in mouse and macaque, complemented by a human tissue sample, three-dimensional imaging, and publicly available spatial transcriptomic datasets. The STN showed a largely conserved molecular framework across species with gradients across rostrocaudal and dorsolateral axes. However, HTR2C was found enriched in the ventral STN of macaque and human tissue samples, while broadly distributed across the mouse STN. HTR2C showed opposite gradient of PVALB. In the mouse STN, Nts expression revealed an additional mediolateral gradient. Publicly available transcriptomic datasets showed concordant expression patterns. In both species, TAC1 characterized the canonical pSTN but also an extended population reaching dorsally along the medial aspect of the STN. TAC1-positive cells were thus found in the region traversed by tyrosine hydroxylase-positive fibers of the medial forebrain bundle (MFB). Together, these findings reveal a spatially heterogeneous, multiaxial molecular organization of the STN and a spatially complex molecular organization of its neighboring brain areas, refining the molecular and anatomical framework of the subthalamic region.