Sex differences in chloride homeostasis of c-fiber primary afferents in the spinal cord dorsal horn
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Bibliographic record
Abstract
Introduction: Intracellular Cl- concentration ([Cl-]i) is high in primary sensory neurons due to the activity of the Na+-K+-Cl- cotransporter 1 (NKCC1), causing greater Cl- accumulation than typically seen in CNS neurons. Consequently, central terminals of primary afferents in the spinal dorsal horn experience depolarization upon activation of GABAA receptors (GABAAR). Thus, regulation of [Cl-]i in these terminals may significantly affect transmitter release. Determining the exact [Cl-]i in C-fiber terminals is pivotal to understand sensory processing. Methods: To image [Cl-]i we used the genetically-encoded ratiometric Cl- sensor, superclomeleon, using 2-photon microscopy in acute spinal cord slices. Superclomeleon was virally transduced selectively in C-fibers in NaV1.8-cre mice. The GABAAR agonist and antagonist muscimol and bicuculline, as well as the NKCC1 antagonist bumetanide, were used to modulate [Cl-]i in afferent terminals in the dorsal horn. NKCC1 mRNA levels in the dorsal root ganglia was evaluated with RNAScope. Results: We found that [Cl-]i in C-fibers was significantly higher in males than females. Bumetanide significantly decreased [Cl-]i in males but not in females. Bicuculline did not significantly affect [Cl-]i in C-fibers indicating a minimal contribution of tonic GABAA signaling to [Cl-]i. NKCC1 mRNA was also significantly lower in females than males, consistent with the functional data. Conclusion: Presynaptic inhibition appears to be under distinct control by GABAergic inhibition between sexes, which should be taken into consideration in future studies.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.005 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.003 | 0.001 |
| 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 it