Abstract
Functional dyspepsia (FD) is associated with chronic gastrointestinal distress and with anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity — in response to gastric distention — was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a “bottom-up” pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.
Highlights
Functional dyspepsia (FD), a highly prevalent clinical gastrointestinal syndrome, has been variously defined but generally includes some form of upper abdominal discomfort or pain
While baseline activity was similar in both groups, vagal nerve activity in response to gastric distention (GD) was significantly increased in FD rats as compared with controls (Figure 1A, 2-way ANOVA; main effect of model, F1,280 =23.54, P < 0.001; main effect of pressure, F3,280 =23.99, P < 0.001; interaction of model and pressure, F3,280 =2.3, P = 0.078)
We examined the effects of vagotomy on affective behaviors in FD rats
Summary
Functional dyspepsia (FD), a highly prevalent clinical gastrointestinal syndrome, has been variously defined but generally includes some form of upper abdominal discomfort or pain. Sensory (afferent) vagal neurons, whose cell bodies are located in the nodose ganglia, project to a variety of visceral organs including the gastrointestinal tract. In the gut, they respond to physiological and pathological stimuli and relay this information to second-order neurons in the nucleus tractus solitarius (NTS). We hypothesized that increased gastric vagal activity may contribute to the changes in affective behavior and nociception associated with FD, and that gastric mast cells may have a mechanistic role, given their well-established functional relationship with neurons [14]. We tested these hypotheses using a previously validated rat model of FD in which mild gastric irritation in neonatal rats induces a state of persistent gastric hyperalgesia, impaired gastric motility, and anxiety-like and depression-like behavior in adulthood, which was associated with brain alterations [7, 18]
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