The role of glutamate co-transmission by serotonin neurons of the dorsal raphe nucleus in the expression of L-Dopa-induced dyskinesia
Bibliographic record
Abstract
Parkinson's disease is characterized by the progressive loss of midbrain dopaminergic neurons that innervate the striatum. The dopamine precursor (L-Dopa) is the most effective pharmacotherapy but its chronic use is hampered by adverse effects such as abnormal involuntary movements (AIMs), also termed L-Dopa-induced dyskinesia (LID). Recent studies have shown the crucial role of serotonin (5-HT) neurons in LID expression. Through this study, we specifically addressed the functional role of glutamate co-transmission by 5-HT neurons of the dorsal raphe nucleus (DRN) in the regulation of many diverse behaviors and LID expression. We used CRIPSR-Cas9 technology and viral injections to knock-out or overexpress the vesicular glutamate transporter 3 (VGluT3), specifically in 5-HT neurons of the DRN in adult mice. After extensive behavioral testing, these mice were injected with 6-OHDA in the medial forebrain bundle to selectively lesion DA axons, and then treated with L-Dopa to induce AIMs. RNAscope and immunohistochemistry confirm the depletion or overexpression of VGluT3 in AAV-infected 5-HT neurons of the DRN. VGluT3-depleted mice show a loss of motor coordination but an increase of spontaneous activity, a higher impulsivity level and a slight increase in sociability and anxiety. While mice overexpressing VGluT3 exhibit solely a slight decrease of the motivation. After dopamine lesion and L-Dopa administration, VGluT3-depleted mice present exacerbated AIMs caused by L-Dopa administration at low dose, while mice overexpressing VGluT3 manifest worsen orolingual AIMs at higher dose. Glutamate that is co-released by 5-HT neurons of the DRN appears to be involved in the regulation of motor behaviors, impulsivity, anxiety, and sociability, as well as in the expression of LID.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".