Prostaglandin E2 alters intracellular chloride homeostasis to drive neuroendocrine stress response to immune challenges
Bibliographic record
Abstract
Immune-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis is driven by an inflammatory mediator prostaglandin E2 (PGE2) mediated by two of its receptor subtypes EP1 & EP3. We recently showed that PGE2-EP3 signaling excites HPA axis regulatory neurons [corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN)]. EP1-mediated mechanisms remained unsolved. The excitability of PVN-CRH neurons are constrained by GABAA mediated synaptic inhibition that relies on low-level intracellular Cl-. We hypothesized that PGE2-EP1 signaling increases intracellular Cl-, causing a depolarizing shift in the reversal potential of GABAA (EGABA) mediated synaptic currents. Using gramicidin perforated patch-clamp recordings and focal application of GABAA receptor agonist muscimol, we examined the reversal potential of GABAA receptor-mediated currents from CRH neurons in acute mouse slices. The change in EGABA was measured before, and at several points after the bath application of PGE2, an EP1 Agonist, and vehicle. PGE2 induced a significant depolarizing shift in the reversal potential of GABAA receptor-mediated current. The depolarizing shift was slow to develop and peaked around 40 min post PGE2. EP1 agonist caused a similar, slowly developing depolarizing shift. The vehicle showed no change in EGABA. Our results support our hypothesis that PGE2-EP1 coupling induces a slow depolarizing shift in EGABA, which complements the rapid effects of PGE2-EP3 signaling, for the excitation of PVN-CRH neurons during inflammation.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".