Thyroid hormone supplementation dampens GABAergic inhibition of the brainstem respiratory network in newborn rat
Bibliographic record
Abstract
We previously showed that thyroid hormones (THs) deficiency potentiates GABAergic inhibition in the core elements of the respiratory control circuit. To understand the underlying mechanisms, we tested the hypotheses that 1) cellular mechanisms including K + /Cl − co‐transporters contribute to the delay of GABAergic system development in TH deficient newborn rats and 2) TH supplementation following birth can reverse this enhanced inhibition. Thyroid hormone deficiency in the foetus was recreated by administrating an antithyroid susbstance (Methimazole; MMI) in drinking water of the pregnant dam at concentration of 0,02% (weight per volume; w/v) from the first day of pregnancy (gestational day 1; GD1) to the day of experiment with the newborn. TH supplementation was performed by injecting newborn rats (1 day old) intraperitoneally with Levothyroxine (L‐T4). Experiments were done on Sprague Dawley rats aged of 4 days. Protein levels of newborn co‐transporters were evaluated by western blot analysis. Each brainstem lysate samples were migrated on SDS acrylamide gel under denaturing conditions. Gel was then transferred on nitrocellulose membrane and blocked in 5% non‐fat dry milk in TBS tween. Membranes were incubated overnight with primary antibody for NKCC1 (Cell signaling) or KCC2 (Cell signaling) followed by 1h exposure to secondary antibody (Licor IRDye 800CW). Fictive breathing was measured by extracting the brainstem with a part of the spinal cord and placing it in a chamber where it was superfused with an artificial cerebrospinal fluid (aCSF). The output signal from the respiratory network was recorded by a suction electrode placed on the fourth ventral root representing the inspiratory signal sent to the diaphragm via the phrenic nerve. Brainstems were then exposed to GABAA receptor agonist (muscimol) or antagonist (bicuculline) for 20 minutes and respiratory frequency response was observed. Data show that NKCC1 and KCC2 protein expressions were similar between MMI‐treated and control groups (MMI vs Control: NKCC1 p=0.5260; KCC2 p=0.3309), but L‐T4 supplementation in TH deficient pups increased both co‐transporters protein expression (MMI/L‐T4 vs MMI: NKCC1 p=0.0044; KCC2 p<0.0001). In agreement with these results, L‐T4 supplementation decreased respiratory frequency response to muscimol in MMI‐treated pups (MMI/L‐T4 vs MMI: p<0.0001). This suggests the involvement of different mechanisms in the potentiation of GABAergic inhibition by TH deficiency with a specific action of TH supplementation on GABAergic system development. These results provide new hypotheses regarding the origins of respiratory disorders of the newborn involving reduced respiratory drive such as apnea of prematurity. Support or Funding Information Supported by NSERC This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.001 | 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) | 0.002 | 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".