Hyperexcitability of female serotonin neurons underlies sex-specific anxiety responses
Bibliographic record
Abstract
Abstract Mood and anxiety disorders display robust sex differences in prevalence, symptom profile, and treatment outcomes, yet the circuit mechanisms underlying this sex bias remain unclear. Here, we identify a serotonergic (5-HT) pathway from the median raphe region (MRR) to the ventral hippocampus (vHP) that drives sex-specific anxiety regulation in mice. Using a multimodal approach combining electrophysiology, fiber photometry, and optogenetics, we show that vHP-projecting 5-HT neurons (5-HT vHP ) in the MRR are intrinsically hyperexcitable in females and exhibit delayed adaptation during exposure to aversive environments. At baseline, female mice displayed greater avoidance and reduced risk-assessment behavior. Optogenetic activation of this pathway selectively enhanced anxiety-like behavior and stress-related grooming in females, while leaving locomotion unaffected. Fiber photometry revealed that grooming episodes coincide with transient suppression of 5-HT vHP activity, suggesting an adaptive feedback mechanism to downregulate serotonergic tone under elevated anxiety. Moreover, activation of this pathway disrupted hippocampal theta dynamics during habituation to a novel arena exclusively in females, revealing serotonergic modulation of anxiety and novelty processing. These results were consistent with the identification of sex-specific M-currents, which constrained excitability in male MRR 5-HT vHP neurons, while being largely absent in females. Collectively, our findings uncover a hyperexcitable MRR-vHP serotonergic circuit that drives female-specific anxiety states, providing a mechanistic framework for understanding sex-specific vulnerability to mood and anxiety disorders.
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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 | 0.000 |
| 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".