Chemogenetic activation of glutamatergic preBötzinger Complex neurons increases breathing in mice
Bibliographic record
Abstract
Objective Respiratory rhythm is generated by complex neural circuits in the medulla. At the core of these circuits is the preBötzinger Complex (preBötC), a collection of cells generating respiratory rhythm in the ventral part of the medulla. In addition to its role in generating respiratory rhythm, the preBötC also plays a significant role in opioid‐induced respiratory depression. The preBötC is made up of a heterogenous group of neurons, with a large portion being glutamatergic and expressing µ‐opioid receptors. A marker for these glutamatergic neurons is vesicular glutamate transporter 2 (vGLUT2). Here we propose that targeting vGLUT2‐expressing preBötC neurons using chemogenetics can stimulate respiratory rhythm and potentially alleviate opioid‐induced respiratory depression. Hypothesis Activation of vGLUT2 preBötC neurons stimulates breathing and alleviates respiratory depression by fentanyl in mice. Methods Using a cre‐lox recombination approach, we expressed the excitatory hM3Dq (a modified version of the excitatory M3 muscarinic receptor) into vGLUT2 preBötC neurons. To this aim, we injected into the preBötC recombinant adeno‐associated virus transcriptionally activated by Cre‐recombinase containing hM3Dq and mCherry DNA flanked by lox sites in vglut2‐IRES‐Cre male mice (Jackson Labs). Four weeks after adeno‐associated virus, mice were anesthetized with isoflurane and respiratory activity was measured through electrodes implanted into the diaphragm and the genioglossus muscle. Mice were given consecutive intramuscular injections of saline and the hM3Dq ligand, clozapine‐N‐oxide (CNO; 0.5 and 1 mg/kg), while respiratory responses were monitored. Brains were collected for histological analysis with expression of hM3Dq determined by expression of mCherry. Results Injection of 0.5mg/kg CNO elicited a 24.55% increase in respiratory rate 8 minutes following CNO injection . Injection of 1mg/kg CNO destabilized breathing within 6‐25 minutes following injection. Histology confirmed expression of mCherry in the region of the preBötC. Further studies will determine whether stimulation of vGLUT2 preBötC neurons can prevent or reverse respiratory rate depression elicited by fentanyl. Conclusions Our preliminary data showed that stimulation of glutamatergic preBötC neurons can increase respiratory rate in anesthetized conditions. Further studies will determine whether stimulation of glutamatergic preBötC cells also increases respiratory rate in freely‐behaving mice and whether the glutamatergic preBötC neurons are viable targets for the development of preventive drug therapies for respiratory depression during opioid overdose.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".