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Mechanisms of stress-induced visceral pain in irritable bowel syndrome
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R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
research investigating hair cortisol concentrations in the context of stress-related psychiatric disorders and different aspects of cardiometabolic health. Concerning the latter, data will be presented showing consistent positive relationships of hair cortisol concentrations with body fat-related anthropometric measures, prevalence of diabetes mellitus type 2 and the metabolic syndrome. Potential implications and future prospects of these findings will be discussed. http://dx.doi.org/10.1016/j.psyneuen.2015.07.407 Parallel Session 2 PS2.1 Young Investigator Forum: Mechanisms of Stress-Induced Visceral Pain PS2.1.1 Stress & the microbiota–gut–brain axis in visceral pain Rachel D. Moloney 1,∗ , Timothy G. Dinan 1,2 , John F. Cryan 1,3 1 Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland 2 Department of Psychiatry, University College Cork, Cork, Ireland 3 Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects up to 25% of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience co-morbid behavioral disorders, such as anxiety or depression, thus IBS is described as a biopsychosocial disorder of the gut-brain axis. Currently, treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The pathophysiology of visceral pain strongly implicates a role of stress in the development and exacerbation of symptoms. In this presentation, I will discuss our recent studies in a variety of rodent models of visceral pain, in particular early-life stress models as well as genetic susceptibility models. I will describe our data, demonstrating how stress can modify central pain circuitry at the level of the spinal cord, highlighting a key role of glutamatergic signaling. Furthermore, I will discuss the potential of employing epigenetic modifiers, specifically histone deacetylase inhibitors, as a treatment strategy for visceral pain. More recently, the role of the gut microbiota in the bi-directional communication along the gut-brain axis have been appreciated. I will present data to further support a novel role of the gut microbiota in the regulation of visceral pain processes. Taken together, these findings will enhance our knowledge of the pathophysiology of visceral pain. http://dx.doi.org/10.1016/j.psyneuen.2015.07.408
PS2.1.2 Central amygdala mechanisms regulating visceral pain Anthony C. Johnson 2,∗ , Beverley Greenwood-Van Meerveld 1,2 1
Department of Veterans Affairs, Oklahoma City, OK, USA 2 Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Patients with irritable bowel syndrome (IBS) experience chronic abdominal pain that is worsened by stress. Functional imaging studies have demonstrated differences in stress-associated brain regions in IBS patients, with the amygdala being an area that integrates visceral pain signaling with autonomic and endocrine output. Using a rodent model, we have demonstrated that targeting the central nucleus of the amygdala (CeA) with corticosterone (CORT), the rat equivalent of cortisol, induces persistent visceral and somatic hypersensitivity, associated with increased corticotropin-releasing factor (CRF) expression and decreased glucocorticoid receptor (GR) expression. Our experimental goal was to identify the CeA-mediated mechanism linking GR, CRF, and visceral pain. In this presentation, I will describe our recent studies demonstrating two complementary CeA-mediated mechanisms for visceral pain. We found that rats with CORT on the CeA, or exposed to a repeated stressor, displayed visceral and somatic hypersensitivity. We then demonstrated that knockdown of CRF in the CeA inhibited the stress-induced visceral and somatic nociceptive behaviors. In the converse experiment, knockdown of GR in the CeA of stress-naïve rats increased CRF expression and induced visceral and somatic hypersensitivity, mimicking the stress-induced behaviors. Finally, due to the persistence of the visceral and somatic hypersensitivity, we recently demonstrated a novel epigenetic mechanism within the CeA that causes GR downregulation and CRF upregulation in response to stress. Thus, our research has provided evidence for novel mechanisms within the CeA that modulate visceral and somatic nociception, providing additional insight into the etiology of how stress can influence chronic pain disorders such as IBS. http://dx.doi.org/10.1016/j.psyneuen.2015.07.409
PS2.1.3 Mechanisms of stress-induced visceral pain in irritable bowel syndrome María Vicario Laboratory of Neuro-Immuno-Gastroenterology, Vall d’Hebron Institut de Recerca, Department of Gastroenterology, Vall d’Hebron Hospital, Barcelona, Spain Irritable bowel syndrome is a prototype of functional gastrointestinal disorder and one of the most prevalent causes of digestive consultation in our society, affecting up to 15–20% of the population. It is characterized by abdominal pain associated with changes in bowel habit in the absence of organic pathology. The pathophysiology of IBS is poorly understood, however altered brain–gut axis communication and mucosal immune activation are possible disease mechanisms. Previous episodes of gastrointestinal infection and elevated levels of psychological stress are associated with IBS
R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
development, events that increase intestinal permeability, allowing, consequently, the access of luminal antigens to the mucosa. Food components, microorganisms, and toxins can stimulate local responses by activating immune cells and/or directly sensitizing nerve endings. Primary afferent sensitization could affect responsiveness to visceral stimuli and modify neuropeptide release form nerves, consequently leading to neurogenic inflammation. In fact, mast cell proximity to nerves and its correlation with abdominal pain have been identified in IBS patients. Moreover, the presence of higher amount of corticotropin-releasing hormone in mucosal eosinophils in IBS, as compared to healthy controls, in correlation with psychological stress has been identified, enabling local pain signaling and barrier alterations upon eosinophil degranulation. B lymphocytes and plasma cells are also part of the inflammatory infiltrate and display an activated profile in association with major clinical symptoms in IBS. In this presentation I will review the main mechanisms associated with pain signaling in IBS with a special focus on stress-induced activation of the mucosal immune system. http://dx.doi.org/10.1016/j.psyneuen.2015.07.410 PS2.2 Interrogating the Relationship Between Maternal Obesity and Stress in Programming of Maternal and Offspring Behaviour PS2.2.1 Fetal programming of adult behaviour by stress and glucocorticoids Megan C. Holmes ∗ , Caitlin Wyrwoll, Jonathan Seckl Centre for Cardiovascular Science, University of Edinburgh, UK Prenatal exposure to excess glucocorticoids may be causal in programming psychiatric disorders in later life. In support of this hypothesis, maternal stress, treatment during pregnancy with dexamethasone (which crosses the placenta) or inhibitors of fetoplacental 11-hydroxysteroid dehydrogenase type 2 (11-HSD2), the physiological ‘barrier’ to maternal glucocorticoids, reduces birth weight and programmes offspring cardio-metabolic and affective behaviours. The enzyme 11-HSD2 appears key to prenatal glucocorticoid programming, but it is expressed in both the placenta and the developing fetal brain, raising the questions: What is the site of 11-HSD2 expression that is the most important? And secondly, where are the glucocorticoids acting to initiate the programmed effects? The relative importance of the site of 11-HSD2 expression (utilising global and tissue-specific knockout models) and mechanisms underpinning the programming of affective and cognitive behaviour, will be discussed. These studies help elucidate the mechanisms underpinning programming of adult behaviour in response to perinatal stress exposure. Funding: European Commission, Seventh Framework Programme, project acronym: DORIAN, grant agreement n◦ 278603 and The Wellcome Trust. http://dx.doi.org/10.1016/j.psyneuen.2015.07.411
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PS2.2.2 Responses of the human maternal HPA axis to obesity and stress: Implications for offspring behaviour Rebecca Reynolds Metabolic Medicine, University of Edinburgh, United Kingdom Optimal glucocorticoid exposure is critical for normal fetal development and long-term health of the offspring. The maternal hypothalamic–pituitary–adrenal (HPA) axis undergoes significant changes during pregnancy with circulating cortisol levels risings three-fold higher than in non-pregnancy. The fetus is protected from high maternal cortisol levels by the placental enzyme 11 betahydroxysteroid dehydrogenase type 2 (HSD2) which breaks down active cortisol into inactive cortisone. One in five pregnant women in the UK is currently obese at antenatal booking. As is known that the HPA axis is dysregulated in non-pregnant obesity, we hypothesised that there would be a similar dysregulation of the HPA axis in obese pregnancy, leading to altered fetal glucocorticoid exposure. We have been exploring the changes in both the maternal HPA axis and placental genes regulating fetal glucocorticoid exposure in a cohort of very severely obese women and normal-weight controls. Women were characterised in detail during pregnancy and placental samples collected at delivery. We find that maternal obesity is associated with increased maternal distress in pregnancy, but that circulating cortisol levels are lower in obese than in lean. The pattern of changes of mRNA levels in placental genes regulating fetal glucocorticoid exposure suggests a protective adaptive response in placentas from obese women. We are currently testing whether these observations influence the infants’ body composition, cognitive and neurobehavioural development. http://dx.doi.org/10.1016/j.psyneuen.2015.07.412
PS2.2.3 Early programming of brain metabolism and function by perinatal obesogenic environment Maria Angela Guzzardi Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy During the last trimester of pregnancy, the whole brain volume doubles, cortical grey matter increases by four folds and subcortical grey matter or basal ganglia increase by 70%. Soon after birth, brain development is at a critical stage and extensive neurodevelopment occurs within the first two years of life. Therefore, during these periods, several perinatal factors including maternal metabolic and nutritional status during pregnancy, type and duration of lactation, and growth after-weaning influence brain development. Maternal obesity during pregnancy has been associated with lower cognitive development and performance in pre- and schoolaged children. Moreover, animal and human studies have related maternal obesity with alterations in brain development and hypothalamic metabolism, increasing the risk of cognitive decline in later life. Epidemiological studies have also suggested that breast milk is associated with lower BMI in later life-phases, better cognitive development and increased white matter volume, although a number of controversial opinions support an important influence of confounding factors such as socio-economic status and duration of lactation.
R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
research investigating hair cortisol concentrations in the context of stress-related psychiatric disorders and different aspects of cardiometabolic health. Concerning the latter, data will be presented showing consistent positive relationships of hair cortisol concentrations with body fat-related anthropometric measures, prevalence of diabetes mellitus type 2 and the metabolic syndrome. Potential implications and future prospects of these findings will be discussed. http://dx.doi.org/10.1016/j.psyneuen.2015.07.407 Parallel Session 2 PS2.1 Young Investigator Forum: Mechanisms of Stress-Induced Visceral Pain PS2.1.1 Stress & the microbiota–gut–brain axis in visceral pain Rachel D. Moloney 1,∗ , Timothy G. Dinan 1,2 , John F. Cryan 1,3 1 Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland 2 Department of Psychiatry, University College Cork, Cork, Ireland 3 Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects up to 25% of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience co-morbid behavioral disorders, such as anxiety or depression, thus IBS is described as a biopsychosocial disorder of the gut-brain axis. Currently, treatment strategies are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. The pathophysiology of visceral pain strongly implicates a role of stress in the development and exacerbation of symptoms. In this presentation, I will discuss our recent studies in a variety of rodent models of visceral pain, in particular early-life stress models as well as genetic susceptibility models. I will describe our data, demonstrating how stress can modify central pain circuitry at the level of the spinal cord, highlighting a key role of glutamatergic signaling. Furthermore, I will discuss the potential of employing epigenetic modifiers, specifically histone deacetylase inhibitors, as a treatment strategy for visceral pain. More recently, the role of the gut microbiota in the bi-directional communication along the gut-brain axis have been appreciated. I will present data to further support a novel role of the gut microbiota in the regulation of visceral pain processes. Taken together, these findings will enhance our knowledge of the pathophysiology of visceral pain. http://dx.doi.org/10.1016/j.psyneuen.2015.07.408
PS2.1.2 Central amygdala mechanisms regulating visceral pain Anthony C. Johnson 2,∗ , Beverley Greenwood-Van Meerveld 1,2 1
Department of Veterans Affairs, Oklahoma City, OK, USA 2 Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Patients with irritable bowel syndrome (IBS) experience chronic abdominal pain that is worsened by stress. Functional imaging studies have demonstrated differences in stress-associated brain regions in IBS patients, with the amygdala being an area that integrates visceral pain signaling with autonomic and endocrine output. Using a rodent model, we have demonstrated that targeting the central nucleus of the amygdala (CeA) with corticosterone (CORT), the rat equivalent of cortisol, induces persistent visceral and somatic hypersensitivity, associated with increased corticotropin-releasing factor (CRF) expression and decreased glucocorticoid receptor (GR) expression. Our experimental goal was to identify the CeA-mediated mechanism linking GR, CRF, and visceral pain. In this presentation, I will describe our recent studies demonstrating two complementary CeA-mediated mechanisms for visceral pain. We found that rats with CORT on the CeA, or exposed to a repeated stressor, displayed visceral and somatic hypersensitivity. We then demonstrated that knockdown of CRF in the CeA inhibited the stress-induced visceral and somatic nociceptive behaviors. In the converse experiment, knockdown of GR in the CeA of stress-naïve rats increased CRF expression and induced visceral and somatic hypersensitivity, mimicking the stress-induced behaviors. Finally, due to the persistence of the visceral and somatic hypersensitivity, we recently demonstrated a novel epigenetic mechanism within the CeA that causes GR downregulation and CRF upregulation in response to stress. Thus, our research has provided evidence for novel mechanisms within the CeA that modulate visceral and somatic nociception, providing additional insight into the etiology of how stress can influence chronic pain disorders such as IBS. http://dx.doi.org/10.1016/j.psyneuen.2015.07.409
PS2.1.3 Mechanisms of stress-induced visceral pain in irritable bowel syndrome María Vicario Laboratory of Neuro-Immuno-Gastroenterology, Vall d’Hebron Institut de Recerca, Department of Gastroenterology, Vall d’Hebron Hospital, Barcelona, Spain Irritable bowel syndrome is a prototype of functional gastrointestinal disorder and one of the most prevalent causes of digestive consultation in our society, affecting up to 15–20% of the population. It is characterized by abdominal pain associated with changes in bowel habit in the absence of organic pathology. The pathophysiology of IBS is poorly understood, however altered brain–gut axis communication and mucosal immune activation are possible disease mechanisms. Previous episodes of gastrointestinal infection and elevated levels of psychological stress are associated with IBS
R. Reynolds / Psychoneuroendocrinology 61 (2015) 1–78
development, events that increase intestinal permeability, allowing, consequently, the access of luminal antigens to the mucosa. Food components, microorganisms, and toxins can stimulate local responses by activating immune cells and/or directly sensitizing nerve endings. Primary afferent sensitization could affect responsiveness to visceral stimuli and modify neuropeptide release form nerves, consequently leading to neurogenic inflammation. In fact, mast cell proximity to nerves and its correlation with abdominal pain have been identified in IBS patients. Moreover, the presence of higher amount of corticotropin-releasing hormone in mucosal eosinophils in IBS, as compared to healthy controls, in correlation with psychological stress has been identified, enabling local pain signaling and barrier alterations upon eosinophil degranulation. B lymphocytes and plasma cells are also part of the inflammatory infiltrate and display an activated profile in association with major clinical symptoms in IBS. In this presentation I will review the main mechanisms associated with pain signaling in IBS with a special focus on stress-induced activation of the mucosal immune system. http://dx.doi.org/10.1016/j.psyneuen.2015.07.410 PS2.2 Interrogating the Relationship Between Maternal Obesity and Stress in Programming of Maternal and Offspring Behaviour PS2.2.1 Fetal programming of adult behaviour by stress and glucocorticoids Megan C. Holmes ∗ , Caitlin Wyrwoll, Jonathan Seckl Centre for Cardiovascular Science, University of Edinburgh, UK Prenatal exposure to excess glucocorticoids may be causal in programming psychiatric disorders in later life. In support of this hypothesis, maternal stress, treatment during pregnancy with dexamethasone (which crosses the placenta) or inhibitors of fetoplacental 11-hydroxysteroid dehydrogenase type 2 (11-HSD2), the physiological ‘barrier’ to maternal glucocorticoids, reduces birth weight and programmes offspring cardio-metabolic and affective behaviours. The enzyme 11-HSD2 appears key to prenatal glucocorticoid programming, but it is expressed in both the placenta and the developing fetal brain, raising the questions: What is the site of 11-HSD2 expression that is the most important? And secondly, where are the glucocorticoids acting to initiate the programmed effects? The relative importance of the site of 11-HSD2 expression (utilising global and tissue-specific knockout models) and mechanisms underpinning the programming of affective and cognitive behaviour, will be discussed. These studies help elucidate the mechanisms underpinning programming of adult behaviour in response to perinatal stress exposure. Funding: European Commission, Seventh Framework Programme, project acronym: DORIAN, grant agreement n◦ 278603 and The Wellcome Trust. http://dx.doi.org/10.1016/j.psyneuen.2015.07.411
9
PS2.2.2 Responses of the human maternal HPA axis to obesity and stress: Implications for offspring behaviour Rebecca Reynolds Metabolic Medicine, University of Edinburgh, United Kingdom Optimal glucocorticoid exposure is critical for normal fetal development and long-term health of the offspring. The maternal hypothalamic–pituitary–adrenal (HPA) axis undergoes significant changes during pregnancy with circulating cortisol levels risings three-fold higher than in non-pregnancy. The fetus is protected from high maternal cortisol levels by the placental enzyme 11 betahydroxysteroid dehydrogenase type 2 (HSD2) which breaks down active cortisol into inactive cortisone. One in five pregnant women in the UK is currently obese at antenatal booking. As is known that the HPA axis is dysregulated in non-pregnant obesity, we hypothesised that there would be a similar dysregulation of the HPA axis in obese pregnancy, leading to altered fetal glucocorticoid exposure. We have been exploring the changes in both the maternal HPA axis and placental genes regulating fetal glucocorticoid exposure in a cohort of very severely obese women and normal-weight controls. Women were characterised in detail during pregnancy and placental samples collected at delivery. We find that maternal obesity is associated with increased maternal distress in pregnancy, but that circulating cortisol levels are lower in obese than in lean. The pattern of changes of mRNA levels in placental genes regulating fetal glucocorticoid exposure suggests a protective adaptive response in placentas from obese women. We are currently testing whether these observations influence the infants’ body composition, cognitive and neurobehavioural development. http://dx.doi.org/10.1016/j.psyneuen.2015.07.412
PS2.2.3 Early programming of brain metabolism and function by perinatal obesogenic environment Maria Angela Guzzardi Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy During the last trimester of pregnancy, the whole brain volume doubles, cortical grey matter increases by four folds and subcortical grey matter or basal ganglia increase by 70%. Soon after birth, brain development is at a critical stage and extensive neurodevelopment occurs within the first two years of life. Therefore, during these periods, several perinatal factors including maternal metabolic and nutritional status during pregnancy, type and duration of lactation, and growth after-weaning influence brain development. Maternal obesity during pregnancy has been associated with lower cognitive development and performance in pre- and schoolaged children. Moreover, animal and human studies have related maternal obesity with alterations in brain development and hypothalamic metabolism, increasing the risk of cognitive decline in later life. Epidemiological studies have also suggested that breast milk is associated with lower BMI in later life-phases, better cognitive development and increased white matter volume, although a number of controversial opinions support an important influence of confounding factors such as socio-economic status and duration of lactation.