Sex-Specific Effects of Neonatal Stress on Brainstem Expression of Orexin1-Receptors
Bibliographic record
Abstract
Introduction and hypothesis: Located within the hypothalamus, orexin-producing neurons (ORX) regulate arousal, feeding, and cardiorespiratory function. Panic disorders (PD) affects ~5% of the North American population. Stress-related “hyperactivation” of the ORX system is a leading hypothesis to explain the pathophysiology of PD. One important sub-group of PD patients show significant respiratory symptoms, including an excessive ventilatory response to CO 2 inhalation. Manifestations of PD are sex-specific: the prevalence of PD is ~2 times higher in women compared to men and the intensity of the ventilatory response to CO 2 fluctuates with the hormonal cycle. Early life stress is a risk factor for PD and we recently demonstrated that in rats, neonatal maternal separation (NMS) augments the ventilatory response to CO 2 (5%; 10 min) of adult females (but not males); this effect peaks with the rise of 17-b estradiol (E 2 ) during proestrus. Because NMS-related enhancement of the hyperventilatory response to CO 2 can be prevented by a selective ORX1-antagonist, we tested the hypothesis that sex, hormonal status and NMS interact to influence the expression of ORX-1 receptors in brainstem regions that regulate breathing. Methods: Following birth, pups were either exposed to NMS (3h/day from postnatal days 3 to 12) or raised under standard conditions. Rats were then raised until adulthood (8 weeks); experiments were performed on males, females in proestrus (high E 2 ), and ovariectomised (low E 2 ) females (2 weeks post-surgery). We used in situ hybridization histochemistry to quantify the expression of mRNA for ORX-1 receptors. The ORX-1 receptors signal was revealed by autoradiography emulsion and slides were examined under darkfield microscopy. Expression of ORX-1 receptors was quantified by measuring the pixel density of the hybridization signal in selected brainstem regions that regulate CO 2 response. Results: The locus coeruleus (LC) contained the highest expression of ORX-1 receptors amongst the structures studied. In males, NMS was associated with significant decreases in ORX-1 expression in the LC and nucleus of the solitary tract (NTS). By comparison with OVX females, proestrus augmented ORX-1 expression in the LC of controls, but not NMS. By comparison with OVX, proestrus augmented ORX-1 expression in the raphe obscurus, especially in NMS females. Expression of ORX-1 was unchanged in the NTS of females. Conclusion and perspectives: We conclude that sex and the female’s hormonal status are important determinants of ORX-1 expression and that NMS can alter these relationships; however, those effects are structure-specific. In light of the evidence indicating that 5-HT dysfunction contributes to PD, the results observed in the raphe obscurus point to a plausible mechanism. This study was supported by ‘the Québec Heart and Lung Institute Research Foundation’. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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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 | 0.000 |
| 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 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".