Animal Model for Chemical Intolerance

超出所提供的空间。人类的化学不耐受（CI）被定义为由于与这些化学品相关的症状而无法耐受环境化学品，并且这些人报告说，先前的化学品暴露会增加对后续暴露的敏感性。到目前为止，还没有明确的临床数据来验证反复的化学品暴露是否会导致敏感亚群发生CI。最近的研究表明，CI患者中有相当一部分人报告了一系列类似于惊恐障碍和创伤后应激障碍（PTSD）的症状。我们在动物身上的研究支持了一些研究者的假设，即CI可能发展为一种类似于恐慌症的焦虑症或一种非典型形式的PTSD。然而，很少有动物模型CI已被探索。拟议的工作强调恐慌症/PTSD和CI之间的相似之处，在发展一个潜在的动物模型CI。我们最近发现，重复的低水平化学暴露（甲醛暴露，0.7-2.4 ppm）会增加对先前与足电击配对的气味的条件性恐惧反应，并降低消除这种恐惧反应的能力。此外，重复的形式曝光产生的皮质酮水平的增加，和行为回避模式，表明形式可能是作为一个压力源。拟议的工作将集中在三个行为，条件冻结行为，无条件焦虑的表现和避免气味，并将开始探索这些行为的变化后，形式暴露的神经回路。该提案的目的是1）进一步表征形式诱导的条件性恐惧的变化，2）检查早期生活应激使动物在每天暴露于形式后易于增加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对形式诱导的变化的作用，4）通过测量给予重复Form暴露的大鼠中c-fos mRNA水平来检查条件性恐惧消退期间激活的嗅觉/边缘脑区域，以及5）检查药理学操纵涉及消除条件性恐惧的大脑部位的效果。因此，这些研究集中在压力/焦虑/恐惧反应的表达上，这些反应可能与CI患者过度避免化学物质有关。探索动物模型检查嗅觉/边缘系统电路的放大可能会指导人类CI治疗策略的发展。性能现场=

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===========================================