Behavioral and transcriptional divergence across rat strains differing in the nervous system excitability

Trait differences in nervous system excitability may contribute to individual variation in behavioral reactivity and stress susceptibility, but the associated molecular organization remains poorly understood. We examined behavioral and transcriptional divergence in two selectively bred rat strains with contrasting excitability thresholds: high-threshold, low-excitability (HT) and low-threshold, high-excitability (LT). LT rats showed strongly reduced acoustic startle responsiveness, whereas multivariate analysis of open field and elevated plus maze behavior separated the strains along axes reflecting defensive behavior, exploration, avoidance, and risk assessment. Prolonged emotional-pain stress shifted HT and LT rats, but not outbred Wistar, toward increased defensive behavior and reduced exploration. Gene set enrichment analysis of hippocampal and amygdalar RNA-seq data revealed region-specific molecular divergence between the selected strains. The amygdala showed only limited pathway-level differences, mainly involving interferon-related signatures. The hippocampus showed broader differences: metabolic, proteostatic, secretory, and synaptic vesicle-related gene sets were enriched toward the LT-upregulated end of the ranked gene list, whereas glial, inflammatory, hypoxia-, apoptosis-, and tissue-remodeling-related gene sets were enriched toward the HT-upregulated end. In addition, the transcriptional excitation/inhibition (E/I) index was significantly lower in the hippocampus of LT rats, while no comparable difference was detected in the amygdala. These findings identify the hippocampus as a major site of transcriptional divergence associated with inherited excitability thresholds and suggest that high trait excitability may be accompanied by compensatory E/I-related molecular organization. More broadly, excitability appears not as a simple linear driver of reactivity, but as a trait around which distinct behavioral and molecular regulatory states can be organized.