BLR&D Research Career Scientist Award Application

项目总结/文摘

Project Summary/Abstract My primary research interest focuses on the central nervous system regulation of visceral pain with a strategic objective of using preclinical rodent models and multiple state-of-the-art techniques, from molecular and cellular to behavioral, pharmacological and electrophysiological methods to advance basic scientific knowledge that has direct relevance to the diagnosis and treatment of veterans with visceral pain. Below I have summarized the main research projects in my laboratory. 1. Central Neural Circuitry Underlying Anxiety and Visceral pain: Mechanisms of Resilience and Novel Treatments: In one aspect of my research we are studying the neuroanatomical and neuropharmacological substrates involved in the interaction between visceral pain and anxiety. My research focuses on the role of amygdala-mediated mechanisms in the control of visceral and somatic pain and the mechanisms connecting anxiety and visceral (colonic) hypersensitivity. We are attempting to identify at least one potential neural substrate that might be involved in the central processing of visceral pain. From there we hope to identify a receptor mechanism within the neural substrate that mediates central processing of visceral pain. A long-term goal is to investigate how the neural substrate modulates visceral pain sensitivity within the larger neural pathway controlling anxiety, and use this knowledge to identify potential pharmacotherapeutic targets in the central processing pathway that mediates visceral pain. We have demonstrated long lasting increases in anxiety-like behavior and viscerosomatic sensitivity in response to the local exposure of the amygdala to corticosterone (CORT). We found persistent down-regulation of GR expression and increases in the expression of CRF and HCN1 channels leading to hyper-excitability of the CeA neurons. These changes in gene expression represent a potential mechanism leading to chronic anxiety and pain, via facilitation of the HPA axis. The objective of latest experiments has been to use gene knockdown to directly manipulate CRF and GR expression in the central amygdala. We found that knockdown of CRF within the amygdala inhibits stress-induced chronic visceral and somatic pain, and that loss of GR within the amygdala is key to triggering visceral and somatic pain. Such findings are relevant for the future development of gene targeted therapeutics to treat stress-induced visceral and somatic pain (Funded by the Department of Veteran's Affairs Merit Award: 2013-2017). 2. Early life stress on visceral and somatic pain in adulthood: Sex differences. In women, IBS is the most prevalent GI disorders. Emotional stressors, increased anxiety or uni- and bipolar associative disorders often exacerbate symptoms. Despite this knowledge and evidence that females embody strong connections to life stressors, physical/sexual abuse and an emotionally reactive disposition related to the outbreak of symptomatology, there has been very little progress made to enhance our understanding of the descending connections between the brain and the GI tract in female Veterans. Our latest project was designed to investigate the mechanisms by which the context of the early life stress (ELS) can affect nociception in adulthood. We are also exploring evidence for a two hit hypothesis underlying the vulnerability to visceral pain in females. Specifically, we will investigate the mechanisms by which an unpredictable stress in early life leads to chronic abdominal pain in adulthood. Additionally we will assess the impact of ELS on the amygdala response to an adult stressor (Funded by the Department of Veteran's Affairs Merit Award: 2010-2014; 2015- 2019).