EXPLORING SUBTHALAMIC INFLUENCE ON LOCUS COERULEUS NORADRENERGIC NEURONS

Deep Brain Stimulation (DBS) in the Subthalamic Nucleus (STN) is proposed as the surgical alternative to the pharmacological treatment in advanced stages of Parkinson disease (PD), significantly improving motor symptoms. However, STN-DBS is associated with cognitive and neuropsychiatric side effects, suggesting that STN stimulation may influence brain circuits beyond the classical motor basal ganglia network. The locus coeruleus (LC), the main source of noradrenergic (NA) innervation in the brain, plays a key role in cognition, attention, and behavioral flexibility, domains frequently affected in PD following STN-DBS. Although LC degeneration is a feature of PD pathology, it remains unclear whether STN stimulation could engage LC circuits. To investigate the interaction between the STN and the LC, we combined anatomical tracing and electrophysiological approaches in VGlut2-Cre, FoxP-Cre, and DBH-Cre mice. Rabies virus–based tracing revealed that only a small number of STN neurons project directly to the LC, whereas surrounding regions, such as the para-STN, provide substantial innervation. Both, ex vivo optogenetic stimulation and in vivo electrical stimulation of the STN elicited glutamatergic excitatory responses in approximately 65% of LC recorded neurons. In vivo recording further revealed antidromic responses in a subset of LC neurons following STN stimulation. Together, these data support the existence of a functional STN–LC pathway and provide insight into how STN-DBS may modulate noradrenergic transmission