Animal Model for Chemical Intolerance

超出所提供的空间。人类化学不耐受（CI）被定义为由于经历与这些化学物质相关的症状而无法耐受环境中的化学物质，这些人报告说，以前接触化学物质会对随后的接触产生更高的敏感性。迄今为止，还没有明确的临床数据证实反复接触化学物质是否会导致敏感亚群中CI的发生。最近的研究表明，相当一部分CI患者报告的症状与恐慌症和创伤后应激障碍（PTSD）的症状相似。我们在动物身上的研究支持了几个研究者的假设，即CI可能发展为一种类似于恐慌症或非典型PTSD的焦虑障碍。然而，CI的动物模型很少被探索。提出的工作强调了惊恐障碍/创伤后应激障碍和CI在开发潜在的CI动物模型中的相似之处。我们最近发现，重复的低水平化学物质暴露（甲醛[形式]暴露，0.7-2.4 ppm）会增加对先前与脚震相匹配的气味的条件恐惧，并降低消除这种恐惧反应的能力。此外，反复接触Form会导致皮质酮水平升高，行为回避模式表明Form可能是一种应激源。本研究将重点关注三种行为，即条件冻结行为、无条件焦虑表现和回避气味，并将开始探索这些行为变化背后的神经回路。该建议的目的是：1)进一步表征条理性恐惧中形式诱导的变化；2)检查早期生活压力使动物在日常形式暴露后易产生恐惧条件反射的能力；3)评估中枢促肾上腺皮质激素释放激素在形式诱导变化中的作用；4)通过测量重复形式暴露大鼠的c-fos mRNA水平，检查在条理性恐惧消失时激活的嗅觉/大脑边缘区域。5)检查药物操作对大脑部位的影响，这些部位涉及条件恐惧的消除。因此，这些研究的重点是压力/焦虑/恐惧反应的表达，这些反应可能与CI患者对化学物质的过度回避有关。探索检查嗅觉/边缘电路扩增的动物模型可能指导人类CI治疗策略的发展。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Chemical intolerance (CI) in humans is defined as the inability to tolerate environmental chemicals due to experience of symptoms associated with those chemicals, and these individuals report that prior chemical exposures produced an increased sensitivity to subsequent exposures. To date, there are no clear clinical data that validate whether repeated chemical exposure causes the development of CI in a sensitive subpopulation. Recent work shows that a substantial subset of individuals with CI report a constellation of symptoms that mimic those found in panic disorder and posttraumatic stress disorder (PTSD). Our studies in animals support several investigators' hypotheses that CI may develop as an anxiety disorder akin to panic disorder or an atypical form of PTSD. However, few animal models for CI have been explored. The proposed work emphasizes the parallels between panic disorder/PTSD and CI in the development of a potential animal model for CI. We have recently found that repeated, low-level chemical exposure (formaldehyde [Form] exposure, 0.7-2.4 ppm) produces increased conditioned fear responding to odor previously paired with footshock, with a decreased ability to extinguish this fear response. In addition, repeated Form exposure produced increases in corticosterone levels, and behavioral avoidance patterns that suggest that Form may be acting as a stressor. The proposed work will focus on three behaviors, conditioned freezing behavior, unconditioned anxiety performance and avoidance of odors, and will begin to explore the neural circuitry underlying these changes in behavior after Form exposure. The alms of the proposal are to 1) further characterize the Form-induced changes in conditioned fear, 2) examine the ability of early life stress to predispose animals to increased fear conditioning after daily Form exposure, 3) assess the role of central corticotropin-releasing hormone on Form- induced changes, 4) examine olfactory/limbic brain regions activated during extinction of conditioned fear by measuring c-fos mRNA levels in rats given repeated Form exposure, and 5) examine the effects of pharmacological manipulation of brain sites involved in extinction of conditioned fear. These studies therefore focus on the expression of stress/anxiety/fear responses that may be linked to exaggerated avoidance of chemicals in humans with CI. Exploration of an animal model examining amplification of olfactory/limbic circuitry may guide the development of treatment strategies for CI in humans. PERFORMANCE SITE ========================================Section End===========================================