Spatio-molecular analysis of primate subthalamus defines anatomical domains relevant to Parkinson disease and neuropsychiatry

The brain area including and surrounding the subthalamic nucleus (STN) contains several targets for deep brain stimulation (DBS): dorsal STN for the treatment of motor symptoms in Parkinson disease (PD), anteromedial STN for obsessive compulsive disorder (OCD), zona incerta (ZI) for PD and essential tremor, and medial forebrain bundle (MFB) for OCD and depression. Despite clinical application, molecular and anatomical understanding of this area has remained elusive. To help solving this, we took advantage of our recent data from transcriptomics analysis in mice, and applied fluorescent in situ hybridization (FISH) analysis on macaque and human brain sections. In accordance with a glutamatergic phenotype, we observed VGLUT2 mRNA across the STN, with quantification revealing higher VGLUT2 density in the ventromedial (vm) STN than dorsal STN. Unexpectedly, we identified HTR2C mRNA uniquely localized to vmSTN, while absent in dorsal STN. HTR2C thereby molecularly defines a distinct vmSTN domain, hereafter named vmSTNHTR2C. Based on the role of the serotonin (5-HT) 2C receptor in mood, vmSTNHTR2C may spatio-molecularly correspond to the limbic STN. The ventralized HTR2C profile was strongest in anterior STN and coincided with serotonergic innervation. The presence of vmSTNHTR2C was identified also in the human brain, but absent in the mouse. Strong HTR2C anteriorly revealed a new far-anterior STN domain. Comparing HTR2C with TAC1, a para-STN marker, para-STN was identified at the anterior STN, partly intermingled with the MFB. Thus, anterior STN shows several unique molecular and anatomical features in the primate brain. Upon analysis of multiple markers, the STN, para-STN and ZI could be divided into several expression-based domains, which we used to construct molecularly supported anatomical maps. This data will inform neuromodulation strategies, such as DBS, and pharmacological treatment approaches.