Operant self-stimulation of thalamic terminals in the dorsomedial striatum is constrained by metabotropic glutamate receptor 2

Dorsal striatal manipulations including stimulation of dopamine release and activation of medium spiny neurons (MSNs) are sufficient to drive reinforcement-based learning. Glutamatergic innervation of the dorsal striatum by both the cortex and thalamus is a critical determinant of both MSN activity and local regulation of dopamine release. However, the relationship between glutamatergic inputs to the striatum and behavioral reinforcement is not well understood. We sought to evaluate the reinforcing properties of optogenetic stimulation of thalamostriatal terminals, which are associated with vesicular glutamate transporter 2 (Vglut2) expression, in the dorsomedial striatum (DMS), a region implicated in goal-directed operant behaviors. In mice expressing channelrhodopsin-2 (ChR2) under control of the Vglut2 promoter, brief optical stimulation of the DMS reinforces operant lever-pressing behavior. Mice also acquire operant self-stimulation of thalamic terminals in the DMS when ChR2 expression is virally targeted to the intralaminar thalamus. Because the presynaptic G protein-coupled receptor metabotropic glutamate receptor 2 (mGlu2) robustly inhibits glutamate and dopamine release induced by activation of thalamostriatal afferents, we examined the regulation of thalamostriatal self-stimulation by mGlu2. We find that administration of an mGlu2/3 agonist or an mGlu2-selective positive allosteric modulator reduces self-stimulation. In contrast, blockade of these receptors increases thalamostriatal self-stimulation, suggesting that endogenous activation of these receptors negatively modulates the reinforcing properties of thalamostriatal activity. These findings demonstrate that stimulation of thalamic terminals in the DMS is sufficient to reinforce a self-initiated action, and that thalamostriatal reinforcement is constrained by mGlu2 activation.