Recent clinical evidence suggests that the brain-gut axis is bidirectional, whereby functional gastrointestinal disturbances are aggravated by psychological distress and in turn, produce psychological abnormalities. However, the mechanisms responsible for the latter remain unclear. We have developed a rat model of gastric irritation (functional dyspepsia) and shown that rats exposed to a transient gastric irritation in the neonatal period display persistent depression-like and anxiety-like behaviors as compared to controls. Using this model, we will test the hypothesis that the primary manifestations of functional dyspepsia, including both sensory and psychological disturbances, have their origins in the stomach, driving hyper-responsiveness of both vagal and spinal afferents. Vagal activity in turn results in central nervous system inflammation and neuroendocrine abnormalities that cause depression and anxiety.
In Aim 1, we will examine the role of gastric mast cells in maintaining the hyper-responsiveness of gastric afferent nerves (vagal and spinal) and pain behavior in functional dyspepsia.
In Aim 2, we will examine the role of the vagus nerve in pain behavior and psychological abnormalities in functional dyspepsia. Behavior will be assessed using tests such as sucrose preference test (for depression) and open field test (for anxiety). Change in neuronal activity will be recorded using electrophysiology.
In Aim 3, we will examine the cause and consequences of hypothalamic neuroendocrine changes with respect to pain and psychological abnormalities in functional dyspepsia by using pharmacological agents and RNAi techniques to delineate the role of stress peptides.
In Aim 4, we will examine the cause and consequences of hypothalamic inflammation with respect to pain and the neuroendocrine and psychological abnormalities in functional dyspepsia. Inflammation in brain will be evaluated by immunofluorescence and microscopy and contribution of specific cytokines will be evaluated. Our findings will provide insight into how disturbances in the gut can cause chronic disturbances in affect and provide a satisfactory and unifying explanation to tie these two phenomena together. This proposal is highly innovative and addresses a clinical problem of major significance.

Public Health Relevance

When completed, this study will establish whether psychological abnormalities such as depression and anxiety can have their origins in the stomach, driving hypersensitivity via vagal activity that in turn results in inflammation (both locally and in the central nervous system) and neuroendocrine changes in the brain. These studies will provide novel insight into the development of psychological disturbances and indicate new targets for treatments that may improve the overall quality of life for patients with functional bowel diseases and decrease the lifetime cost of treatment.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Hamilton, Frank A
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Hagiwara, Shin-Ichiro; Kaushal, Esha; Paruthiyil, Sreenivasan et al. (2018) Gastric corticotropin-releasing factor influences mast cell infiltration in a rat model of functional dyspepsia. PLoS One 13:e0203704
Gurfein, Blake T; Hasdemir, Burcu; Milush, Jeffrey M et al. (2017) Enriched environment and stress exposure influence splenic B lymphocyte composition. PLoS One 12:e0180771
Liu, S; Hagiwara, S I; Bhargava, A (2017) Early-life adversity, epigenetics, and visceral hypersensitivity. Neurogastroenterol Motil 29: