The subthalamic nucleus (STN) plays a central role in motor, cognitive and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention of advanced Parkinsońs disease (PD) and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders and addiction. Animal studies using either STN-DBS, lesioning or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the Vesicular glutamate transporter 2 (Vglut2/Slc17a6) gene and that reduction of Vglut2 mRNA levels within the STN of mice (cKO) causes reduced post-synaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior while biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and in the mesostriatal dopamine system.
Significance Statement: The STN is the most commonly used target in deep brain stimulation of advanced Parkinsońs disease and it has recently been implicated in the reward circuit. VGLUT2 is the main vesicular transporter of glutamate in STN neurons and rare genetic variants of the VGLUT2 gene exist in human individuals. Blunting Vglut2/Slc17a6 gene expression levels throughout the extent of the mouse STN caused substantial cell loss in the STN, similar as observed in pharmacological lesion models. Mice became hyperactive but showed reduced sugar consumption. Opposite effects on motor versus reward behavior was correlated with opposite activity of dopamine parameters in the dorsal versus the ventral striatal system. This study thereby identifies an interaction between the STN and the dopamine reinforcement system.
The authors declare no competing interests. Sylvie Dumas is the owner of Oramacell, Paris, France.
This work was supported by grants from the Swedish Research Council (Vetenskapsrådet 2013-4657, 2014-3804, 2011-4423, 2015-4870, 2012-2304), Uppsala University, the Swedish Brain Foundation, Parkinsonfonden, Bertil Hållsten Research Foundation and the research foundations of Gösta Lind, Åhlén and Åke Wiberg.