Para-subthalamic nucleus adjoins subthalamic nucleus and medial forebrain bundle, major DBS-targets in Parkinsons disease, OCD, and depression

The subthalamic nucleus (STN) is a deep brain stimulation (DBS) treatment target for several disorders of vastly different symptoms, including Parkinsons disease (PD) and obsessive compulsive disorder (OCD). The STN is located in close proximity to the superolateral branch of the medial forebrain bundle (slMFB), a recent DBS target for treatment-resistant depression. Despite clinical application, spatio-molecular understanding of the STN and slMFB has remained elusive. To help solve this, transcriptome data generated in mice was here implemented in comparative analysis with macaque and human. Fluorescent in situ hybridization (FISH) analysis was performed on multiple serial brain sections covering the whole STN area in mice and macaque. Selected markers were further analysed in human sections and in whole mouse brains to allow spatial 3D analysis by light-sheet microscopy. Contrary to available brain atlases, we can now show that the hypothalamic structure known as the para-STN, a critical hub for interoception and emotional regulation, aligns with the STN, and is partly embedded within the MFB. Thus, para-STN occupies considerable space around several major DBS sites. Spatio-molecular data expose STN, MFB and para-STN as highly heterogeneous, including gradients of serotonin receptor subtype 2C (HTR2C). Molecularly reinforced anatomical maps of STN, para-STN, and MFB reveal unexpected details, and may inform spatial precision in neuromodulation strategies while also providing openings for molecular drug discovery.