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

ABSTRACT: 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 mGlu_2/3 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.

SUBMITTER: Johnson KA

PROVIDER: S-EPMC7360544 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Phospholipase C (PLC) beta4, one of the four isoforms of PLCbetas, is the sole isoform expressed in the mouse ventral posterolateral thalamic nucleus (VPL), a key station in pain processing. The mouse thalamus also has been shown to express a high level of metabotropic glutamate receptor type 1 (mGluR1), which stimulates PLCbetas through activation of Galphaq/11 protein. It is therefore expected that the thalamic mGluR1-PLCbeta4 cascade may play a functional role in nociceptive transmission. To test this hypothesis, we first studied behavioral responses to various nociceptive stimuli in PLCbeta4 knock-out mice. We performed the formalin test and found no difference in the pain behavior in the first phase of the formalin test, which is attributed to acute nociception, between PLCbeta4 knock-out and wild-type mice. Consistent with this result, acute pain responses in the hot plate and tail flick tests were also unaffected in the PLCbeta4 knock-out mice. However, the nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation, was attenuated in PLCbeta4 knock-out mice. In the dorsal horn of the spinal cord where PLCbeta1 and PLCbeta4 mRNAs are expressed, no difference was found between the wild-type and knock-out mice in the number of Fos-like immunoreactive neurons, which represent neuronal activity in the second phase in the formalin test. Thus, it is unlikely that spinal PLCbeta4 is involved in the formalin-induced inflammatory pain. Next, we found that pretreatment with PLC inhibitors, mGluR1 antagonists, or both, by either intracerebroventricular or intrathalamic injection, attenuated the formalin-induced pain behavior in the second phase in wild-type mice. Furthermore, activation of mGluR1 at the VPL enhanced pain behavior in the second phase in the wild-type mice. In contrast, PLCbeta4 knock-out mice did not show such enhancement, indicating that mGluR1 is connected to PLCbeta4 in the VPL. Finally, in parallel with the behavioral results, we showed in an electrophysiological study that the time course of firing discharges in VPL corresponds well to that of pain behavior in the formalin test in both wild-type and PLCbeta4 knock-out mice. These findings indicate that the thalamic mGluR1-PLCbeta4 cascade is indispensable for the formalin-induced inflammatory pain by regulating the response of VPL neurons.

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

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