Into the deep: The subthalamic and para-subthalamic nuclei in behavioral avoidance

The subthalamic nucleus (STN) is a key component of the brain network for movement control. However, the STN is strikingly heterogeneous and also intricately engaged in limbic and cognitive functions. The STN shows aberrant firing activity in several neurological and neuropsychiatric disorders, including Parkinsońs disease (PD). Deep brain stimulation (DBS) in the STN alleviates motor impairment in PD, but patients have reported altered mood as adverse side-effect. Recent observations suggest that optogenetic STN activation in mice induces flight behavior. We hypothesized that STN activation stand at risk of causing an aversive response with behavioral avoidance as consequence. The STN is directly adjoined with the para-STN (pSTN), a hypothalamic area correlated with appetitive and aversive behavior. STN-DBS aiming to correct STN might thereby also modulate pSTN. To dissociate the impact of STN and pSTN, we took advantage of selective promoters in mice, identified in our recent RNA- sequencing of the subthalamic area, to selectively direct optogenetic excitation. Acute photostimulation resulted in aversion via both the STN and pSTN, but only STN- stimulation-paired cues resulted in conditioned avoidance. Viral-genetic tracing coupled with electrophysiological recordings identified a polysynaptic pathway from the STN to the lateral habenula, a critical hub for aversion and associated with clinical depression. This study demonstrates that STN activation is directly correlated with aversion, and thereby contributes neurobiological underpinnings to emotional affect upon STN manipulation with implications for STN-targeted treatment outcome.