The gastric branch of the vagus nerve is required for hypothalamic pituitary axis stress habituation in male Sprague Dawley rats

The vagus nerve is known to participate in the negative feedback regulation of the hypothalamic pituitary adrenal (HPA) axis in response to acute stress, but the role of the vagus nerve in facilitating HPA habituation to repeated stress remains largely unexplored. The role of specific vagal subbranches in stress responses is also unclear. This study evaluated whether selective surgical ablation of the left anterior gastric branch of the vagus nerve (gVX) impairs physiological and behavioral adaptation to repeated stress. Rats were assigned to gVX or sham surgery and underwent repeated restraint stress consisting of 2 h of restraint daily for 5 consecutive days, during which blood was collected every 15 min to assess corticosterone and non-fasting glucose levels, while ultrasonic vocalizations were recorded. 24 h after the final restraint session, rats underwent an open field test to assess anxiety-like behaviors. There were no overt changes in gastric function by gVX. Plasma corticosterone levels were similarly elevated in both groups on the first day of restraint stress. By day 5, the sham group exhibited a significant reduction in stress-evoked corticosterone levels compared to day 1, indicating habituation, while corticosterone levels in the gVX group remained elevated after repeated stress. Non-fasted glucose levels followed a similar pattern, with sham rats showing habituation, whereas the gVX group maintained significantly elevated levels on day 5. The gVX group displayed significantly more stress-associated vocalizations during restraint and no habituation over time. In the open-field test, gVX rats showed fewer center entries, increased immobility, and reduced distance traveled, reflecting heightened anxiety-like behaviors. These findings collectively demonstrate that the gastric branch of the vagus nerve is crucial for stress habituation, revealing a critical connection between gastrointestinal and stress-related neural pathways. A better understanding of these mechanisms could inform therapeutic strategies for stress-related disorders.