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 striatum by the cortex and thalamus is a critical determinant of MSN activity and local regulation of dopamine release. However, the relationship between striatal glutamatergic afferents and behavioral reinforcement is not well understood. We evaluated 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 behaviors. In mice expressing channelrhodopsin-2 (ChR2) under control of the Vglut2 promoter, optical stimulation of the DMS reinforced operant lever-pressing behavior. Mice also acquired operant self-stimulation of thalamostriatal terminals when ChR2 expression was virally targeted to the intralaminar thalamus. Stimulation trains that supported operant responding evoked dopamine release in the DMS and excitatory postsynaptic currents in DMS MSNs. Our previous work demonstrated that the presynaptic G protein-coupled receptor metabotropic glutamate receptor 2 (mGlu2) robustly inhibits glutamate and dopamine release induced by activation of thalamostriatal afferents. Thus, we examined the regulation of thalamostriatal self-stimulation by mGlu2. Administration of an mGlu2/3 agonist or an mGlu2-selective positive allosteric modulator reduced self-stimulation. Conversely, blockade of these receptors increased 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.

中文翻译：

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背内侧纹状体中丘脑末端的操作性自我刺激受到代谢型谷氨酸受体 2 的限制。

背侧纹状体操作，包括刺激多巴胺释放和激活中等棘神经元 (MSN) 足以推动基于强化的学习。皮层和丘脑对纹状体的谷氨酸能神经支配是 MSN 活性和多巴胺释放局部调节的关键决定因素。然而，纹状体谷氨酸能传入和行为强化之间的关系尚不清楚。我们评估了背内侧纹状体 (DMS) 中丘脑纹状体末端的光遗传学刺激的增强特性，这些末端与水泡谷氨酸转运蛋白 2 (Vglut2) 的表达相关，该区域与目标导向行为有关。在 Vglut2 启动子控制下表达 channelrhodopsin-2 (ChR2) 的小鼠中，DMS 的光学刺激增强了操作性的杠杆按压行为。当 ChR2 表达病毒靶向椎板内丘脑时，小鼠还获得了丘脑纹状体末端的操作性自我刺激。支持操作性反应的刺激列车会诱发 DMS 中的多巴胺释放和 DMS MSN 中的兴奋性突触后电流。我们之前的工作表明，突触前 G 蛋白偶联受体代谢型谷氨酸受体 2 (mGlu2) 强烈抑制由丘脑纹状体传入神经激活诱导的谷氨酸和多巴胺释放。因此，我们检查了 mGlu2 对丘脑纹状体自我刺激的调节。施用 mGlu2/3 激动剂或 mGlu2 选择性正变构调节剂可减少自我刺激。相反，这些受体的阻断增加了丘脑纹状体的自我刺激，表明这些受体的内源性激活负向调节丘脑纹状体活动的增强特性。这些发现表明，刺激 DMS 中的丘脑末端足以增强自发作用，并且丘脑纹状体增强受 mGlu2 激活的限制。