BLR&D Research Career Scientist Award Application

项目总结/摘要 我的主要研究兴趣集中在内脏疼痛的中枢神经系统调节与战略 目的是使用临床前啮齿动物模型和多种最先进的技术，从分子和 从细胞到行为、药理学和电生理学方法，以推进基础科学知识 这与患有内脏疼痛的退伍军人的诊断和治疗直接相关。下面我 总结了我实验室的主要研究项目。 1.焦虑和内脏痛的中枢神经回路：复原力和新的机制 治疗：在我的研究的一个方面，我们正在研究神经解剖学和神经药理学。 内脏疼痛和焦虑之间的相互作用所涉及的基质。我的研究重点是 杏仁核介导的内脏和躯体疼痛控制机制以及 焦虑和内脏（结肠）过敏。我们试图找出至少一个潜在的神经元 可能参与内脏痛的中枢处理。从那里我们希望找出一个 受体机制的神经基板，介导中枢处理内脏疼痛。长期 目的是研究神经基质如何调节内脏疼痛敏感性在较大的神经系统中， 控制焦虑的途径，并利用这些知识来确定潜在的药理学目标， 中枢处理途径，介导内脏疼痛。我们已经证明， 焦虑样行为和内脏体敏感性对杏仁核局部暴露的反应 皮质酮（CORT）。我们发现GR表达的持续下调和 CRF和HCN 1通道的表达导致CeA神经元的过度兴奋。的这些变化 基因表达是导致慢性焦虑和疼痛的潜在机制，通过促进 HPA轴。最新的实验目标是利用基因敲除直接操纵CRF 和GR在中央杏仁核的表达。我们发现杏仁核内CRF的敲低抑制了 应激诱发慢性内脏和躯体疼痛，杏仁核内GR的缺失是触发 内脏和躯体疼痛。这些发现与基因靶向治疗的未来发展有关 治疗压力引起的内脏和躯体疼痛（由退伍军人事务部资助） （2013-2017年）。 2.成年后内脏和躯体疼痛的早期生活压力：性别差异。在女性中，IBS是最 普遍的胃肠道疾病。情绪压力、焦虑增加或单相和双相关联性障碍通常 加重症状。尽管这些知识和证据表明，女性体现了强大的连接到生活 压力源，身体/性虐待和情绪反应的处置有关的爆发 但是，在加强我们对下降的理解方面， 女性退伍军人的大脑和胃肠道之间的联系我们最新的项目旨在 研究早期生活应激（ELS）环境影响伤害感受的机制， 成年我们也在探索内脏痛易感性的两次打击假说的证据 在女性中。具体地说，我们将研究早期生活中不可预测的压力导致 慢性腹痛的症状此外，我们将评估ELS对杏仁核的影响 对成人压力源的反应（由退伍军人事务部资助的优异奖：2010-2014; 2015- 2019年）。

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).