High frequency stimulation of the subthalamic nucleus: linking mood and motor effects at the level of the basal ganglia and 5-HT system

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a neurosurgical procedure commonly used for the management of severe movement disability in advanced Parkinson’s disease (PD), but some patients experience debilitating psychiatric effects that have an uknown neural origin. Here we use animal models to uncover effects of DBS of the STN on the lateral habenula nucleus (LHb), a fast emerging controller of motivational and emotive behaviours, and a major source of input to 5-HT neurons in the dorsal raphe nucleus (DRN). STN stimulation at clinical parameters, consistently modulated the firing of the majority of LHb neurons tested. LHb neurons projecting to the DRN were identified using antidromic activation, and were also modulated by STN stimulation. Juxtacellular labelling confirmed that STN-responsive neurons were LHb glutamatergic neurons. We identified a behavioural correlate of the neurophysiological effects of STN stimulation. Thus, STN stimulation induced a behaviourally selective decrease in food and sucrose intake, consistent with a reduced motivational state. Moreover, the use of neurotoxic lesions demonstrated that these STN-evoked responses were dependent on both the LHb and 5 HT. Collectively, the present data demonstrate that DBS of the STN influences the LHb and its pathway to the midbrain 5-HT system to generate decreases in motivational outputs. Thus, the impact of the STN on a major controller of motivational and emotive behaviours offers an unexpected route by which STN stimulation might evoke psychiatric effects in patients with PD.