Oestrogen modulates stress-induced vagally-dependent gastric responses to oxytocin

The brain-gut axis is central to gastrointestinal regulation and disorders of gut-brain interaction are more prevalent and often more severe in females. The aim of the present study was to test the hypothesis that brain-gut neurocircuitry is influenced by stress and ovarian hormone levels. Gastric emptying in Sprague-Dawley female rats was slower when oestrogen levels were high, but stress had no further effect. Whole-cell recordings revealed that, unlike previous reports in male rats, the 'anti-stress' peptide, oxytocin (OXT), suppressed GABAergic transmission to dorsal motor nucleus of the vagus (DMV) neurons under non-stressed conditions regardless of oestrogen level. Application of astressin, an antagonist of the 'pro-stress' neuropeptide, corticotrophin-releasing factor (CRF), showed that some presynaptic effects of OXT were dependent upon ongoing CRF1 receptor activity in female vagal neurocircuits. In vivo recordings showed that DMV microinjection of OXT decreased gastric tone and motility via vagal efferent pathways involving the release of vasoactive intestinal peptide and nitric oxide onto myenteric neurons, with recruitment of distinct efferent pathways dependent on oestrous stage and stress history. These findings reveal that the oestrous stage and stress do not affect the OXT modulation of inhibitory input to DMV neurons but do determine peripheral effector recruitment. The dissonance between central synaptic modulation and peripheral implementation provides a mechanistic framework for female-specific variability in gastric motor function and susceptibility to stress-related gastrointestinal dysfunction. KEY POINTS: Disorders of gut-brain interaction (DGBI) are more prevalent in females. Dorsal motor nucleus of the vagus (DMV) neurons provide extensive extrinsic parasympathetic innervation to the gastrointestinal tract. In male rats, the anti-stress neuropeptide oxytocin (OXT) is known to modulate inhibitory GABAergic transmission to DMV neurons only following stress or activation of pro-stress corticotrophin-releasing factor (CRF) receptors. The present study demonstrates that, in female rats, OXT suppressed GABAergic transmission to DMV neurons under basal (non-stressed) conditions in a manner that was independent of oestrous stage, and that CRF receptors were tonically active, even under basal conditions. In female rats, parasympathetic control of gastric functions involved non-adrenergic, non-cholinergic vagal efferent pathways, with recruitment of distinct pathways dependent on oestrous stage and stress history These findings suggest a sex-specific organization of vagal neurocircuits regulating gastric functions, which may underlie female-specific variability and susceptibility to stress-related DGBI.