The number of women in all branches of the military has doubled in the last 30 years and it is expected to double again in the next decade, and more than 230,000 women - about 11% of the U.S. military have served in Iraq and Afghanistan. Although the VA is focused on providing specialized care for female veterans, very few research studies have focused specifically on illnesses experienced by female veterans but it is very clear that they endured the same harsh conditions as male veterans, and return home to suffer chronic illnesses of unknown etiology. Recent findings have shown that female veterans have a high prevalence of posttraumatic stress disorder (PTSD) and chronic gastrointestinal symptoms compared to their male counterparts. Of particular interest to this proposal, veterans suffering from anxiety-related disorders such as PTSD have higher rates of adverse childhood experiences and abuse. Although limited data is available for female veterans that serve in OEF/OIF, studies have shown that symptoms of abdominal pain are due to visceral hypersensitivity characterized by increased awareness of visceral stimuli in Gulf War Veterans (GWV) and that symptoms are worsened by stress, suggesting a link between cognitive and peripheral autonomic activity. The PI of the current proposal has in her laboratory established a link between anxiety and visceral hypersensitivity by showing that rats predisposed to heightened levels of anxiety due to unpredictable early life stress exhibit a hypersensitive colon in adulthood. Furthermore, corticosterone-induced stimulation of the amygdala, a key central nuclei involved in the emotional expression of fear and anxiety, enhances anxiety-like behavior and colonic hypersensitivity in rats through both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)- mediated mechanisms. Key to the current proposal is the PI's recent research showing that in a freely moving rodent model, colonic sensitivity to luminal distension varies depending on the estrous cycle with the luteal phase being associated with visceral hypersensitivity and that elevated levels of progesterone and/or estradiol on the amygdala lead to heightened responsiveness to colorectal distension. Taken together with her previous research has led the PI to seek an answer to the following question """"""""What are the mechanisms responsible for the gender-related differences in visceral sensitivity that lead to anxiety and chronic abdominal pain in female veterans?"""""""" AIM 1a will test the hypothesis that there are sex-related differences in anxiety and abdominal pain reporting in adult rats in response to unpredictable ELS. The design will involve the behavioral assessment of anxiety and colonic hypersensitivity in cycling female rats and ovariectomized (OVX) rats. These observations will then be compared to that in adult male rats of the same age.
AIM 1 b will investigate whether the responses to ELS change across the lifespan of an individual. Under this aim the PI will investigate whether childhood experiences produced by ELS in a neonatal rodent model leads to anxiety-like behavior and colonic hypersensitivity in adult rats that persists throughout the life time of the animal AIM 2 will determine directly whether glucocorticoid stimulation of the amygdala drives the effects of ELS on anxiety-like behavior and colonic hypersensitivity in adult rats. Since the action of corticosterone (CORT) is mediated by GR and MR and an imbalance of GR versus MR is thought to be responsible for stress-related pathologies, this aim will directly test the hypothesis that MR/GR expression in the amygdala is abnormal in adult rats following ELS, We will also determine whether down regulation of GR or MR in the CeA using antisense oligodeoxynucleotides (ODNs) affects anxiety and colonic hypersensitivity. Moreover, we will examine whether rats exposed to ELS show altered behavioral responses to chronic stress in adulthood compared to age-matched controls

Public Health Relevance

It is our working hypothesis that a history of early life stress may increase the susceptibility of a soldier, especially a female soldier, to the adverse effects of combat-related stress and the subsequent development of adult pathologies. Successful completion of the aims proposed within this application will offer new insights into the mechanisms of brain-gut dysfunction in relation to female physiology that likely lead to chronic abdominal pain. More importantly our findings may identify novel targets for new therapies directed at the brain to improve the treatment or even reduce the risk for the development of visceral pain in female veterans deployed in OEF/OIF.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology A (NURA)
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Oklahoma City VA Medical Center
Oklahoma City
United States
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Meerveld, Beverley Greenwood-Van; Johnson, Anthony C (2018) Mechanisms of Stress-induced Visceral Pain. J Neurogastroenterol Motil 24:7-18
Hattay, P; Prusator, D K; Tran, L et al. (2017) Psychological stress-induced colonic barrier dysfunction: Role of immune-mediated mechanisms. Neurogastroenterol Motil 29:
Johnson, Anthony C; Greenwood-Van Meerveld, Beverley (2017) Critical Evaluation of Animal Models of Gastrointestinal Disorders. Handb Exp Pharmacol 239:289-317
Greenwood-Van Meerveld, Beverley; Johnson, Anthony C; Grundy, David (2017) Gastrointestinal Physiology and Function. Handb Exp Pharmacol 239:1-16
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Prusator, Dawn K; Greenwood-Van Meerveld, Beverley (2017) Amygdala-mediated mechanisms regulate visceral hypersensitivity in adult females following early life stress: importance of the glucocorticoid receptor and corticotropin-releasing factor. Pain 158:296-305
Mohammadi, Ehsan; Prusator, Dawn K; Healing, Eleanor et al. (2016) Sexually dimorphic effects of early life stress in rat pups on urinary bladder detrusor muscle contractility in adulthood. Biol Sex Differ 7:8
Prusator, Dawn K; Greenwood-Van Meerveld, Beverley (2016) Sex-related differences in pain behaviors following three early life stress paradigms. Biol Sex Differ 7:29
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Prusator, D K; Greenwood-Van Meerveld, B (2016) Sex differences in stress-induced visceral hypersensitivity following early life adversity: a two hit model. Neurogastroenterol Motil 28:1876-1889

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