Spatio-molecular analysis of primate subthalamus defines anatomical domains relevant to Parkinson’s 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’s 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 fluorescentin situhybridization (FISH) analysis on macaque and human brain sections. In accordance with a glutamatergic phenotype, we observedVGLUT2mRNA across the STN, with quantification revealing higherVGLUT2density in the ventromedial (vm) STN than dorsal STN. Unexpectedly, we identifiedHTR2CmRNA uniquely localized to vmSTN, while absent in dorsal STN.HTR2Cthereby molecularly defines a distinct vmSTN domain, hereafter named vmSTN^HTR2C. Based on the role of the serotonin (5-HT) 2C receptor in mood, vmSTN^HTR2Cmay spatio-molecularly correspond to the limbic STN. The ventralizedHTR2Cprofile was strongest in anterior STN and coincided with serotonergic innervation. The presence of vmSTN^HTR2Cwas identified also in the human brain, but absent in the mouse. StrongHTR2Canteriorly revealed a new “far-anterior” STN domain. ComparingHTR2CwithTAC1, 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.