0045 Characterization of a novel narcolepsy mouse model with conditional ablation of the orexin neurons
Bibliographic record
Abstract
Abstract Introduction Narcolepsy type 1 (NT1) is caused by selective loss of orexinergic neurons. Although narcolepsy typically begins in childhood or adolescence, most mouse models induce loss of the orexin peptides or orexin neurons from birth. To generate a mouse model that reflects the acquired loss of orexinergic neurons in human NT1, we produced recombinant mice expressing the human diphtheria toxin receptor (DTR) driven by the prepro-orexin promoter (orexinDTR mice). We examined whether administration of diphtheria toxin (DTX) to orexinDTR mice caused selective loss of orexinergic neurons and induced narcolepsy symptoms such as sleep-wake fragmentation and cataplexy. In addition, we investigated the effects of an orexin 2 receptor (OX2R)-selective agonist OX-201 on narcolepsy symptoms in DTX-treated orexinDTR mice. Methods We produced orexinDTR mice with the human DTR knocked into the prepro-orexin locus. To induce loss of orexinergic neurons, we intramuscularly injected DTX into heterozygous orexinDTR mice, and later counted orexin-A (OX-A) immunoreactive neurons. Moreover, we collected functional data of EEG/EMG recordings during the dark period in orexinDTR mice. Finally, we evaluated the effects of OX-201 on narcolepsy symptoms, including sleepiness and cataplexy, 6 weeks after DTX injection. Results Within 1 week after injection of DTX, the number of OX-A immunoreactive neurons was reduced to 1% of normal with no change in the number of neurons making melanin-concentrating hormone. Furthermore, orexinDTR mice treated with DTX developed severe sleep-wake fragmentation within 1 week, and very frequent cataplexy (~100 episodes/night) in the subsequent weeks. These symptoms were substantially and dose-dependently improved by administration of OX-201. Conclusion OrexinDTR mice are a useful and simple model for understanding the neurobiology of narcolepsy and evaluating new drugs to treat narcolepsy symptoms. As only one allele of the orexin-DTR is required, these mice are also convenient for crossing with other lines, enabling a variety of methods to study the orexinergic neurons. OX-201 markedly reduced narcolepsy symptoms. Although it is a tool compound unlikely to be used in patients, it further demonstrates the potential of high efficacy of OX2R agonists in treating narcolepsy. Support (if any) This work was funded by Takeda Pharmaceutical Company Limited.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| 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 teacher head, 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".