Anxiety and Stress Responses in Oxytocin Deficient Mice

催产素缺乏小鼠的焦虑和应激反应

基本信息

批准号：
6867159
负责人：
JANET A AMICO
金额：
$ 31.94万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2008-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): In the female laboratory rodent, oxytocin (OT) is believed to be anxiolytic and to dampen the response of the hypothalamic-pituitary- adrenal axis to stress. Psychogenic stress or anxiety activates limbic regions of the rat or mouse brain, such as the amygdaloid nuclei and hippocampus. These regions project to the hypothalamic paraventricular nucleus (PVN), a major site of OT production in the brain. The PVN in turn innervates the limbic system. Brain pathways that are activated by psychogenic stressors or anxiety contain OT immunoreactivity (ir) and/or OT receptors (OTR). Preliminary studies in this proposal indicate that female OT deficient mice release more corticosterone following a psychogenic stress, have a greater stress-induced hyperthermic response to novel environment, and display more anxiety-related behavior than wild type mice. The enhanced anxiety in this genotype is accompanied by enhanced expression of Fos immunoreactivity (ir), a marker of neuronal activation, in the medial amygdala of null versus wild type mice. We hypothesize that central OT is necessary for attenuation of stress and anxiety. If OT pathways are absent, then limbic activation (as measured by Fos ir) will be altered and responses to psychogenic stress (e.g., corticosterone release or stress-induced hyperthermia) will be heightened. The specific aims of this proposal are as follows: 1- Measure plasma corticosterone concentrations in OT null and wild type mice before and following either psychogenic or physical stressors and score anxiety-related behavior during tests of anxiety. Peripheral and brain indicators of the stress response and anxiety-related behavior will be measured to ascertain potential genotypic differences in compensatory homeostatic mechanisms. 2- Immunocytochemical localization of the immediate-early gene protein product, Fos, will be used to identify neurons activated after stress or anxiety testing in wild type and OT null mice. Single- and dual-labeling methods will be used to map the distribution and neurochemical phenotypes of activated neurons in the brain with a particular focus on neurons in the limbic system, which are believed to mediate psychogenic stress and anxiety-related behaviors. 3- Administer exogenous OT into the brain of OT null and wild type mice and measure anxiety-related behavior or corticosterone following stressful stimuli; and 4- Measure brain OT receptors by autoradiography pre and post anxiety and stress testing in wild type versus OT null mice.

描述（由申请人提供）：在雌性实验室啮齿动物中，催产素（OT）被认为具有抗焦虑作用，并能抑制下丘脑-垂体-肾上腺轴对压力的反应。心因性压力或焦虑会激活大鼠或小鼠大脑的边缘区域，例如杏仁核和海马体。这些区域投射到下丘脑室旁核 (PVN)，这是大脑中 OT 产生的主要部位。 PVN 反过来又支配边缘系统。由心因性应激源或焦虑激活的大脑通路包含 OT 免疫反应性 (ir) 和/或 OT 受体 (OTR)。该提案中的初步研究表明，雌性 OT 缺陷小鼠在心因性应激后释放更多的皮质酮，对新环境有更大的应激诱导的高温反应，并且比野生型小鼠表现出更多的焦虑相关行为。该基因型焦虑的增强伴随着无效型小鼠与野生型小鼠内侧杏仁核中 Fos 免疫反应性 (ir) 表达的增强，Fos 免疫反应性是神经元激活的标志物。我们假设中枢性OT对于减轻压力和焦虑是必要的。如果 OT 通路不存在，那么边缘激活（通过 Fos ir 测量）将会改变，对心因性压力（例如皮质酮释放或压力引起的体温过高）的反应将会增强。该提案的具体目标如下： 1-测量 OT 无效小鼠和野生型小鼠在心理或身体压力源之前和之后的血浆皮质酮浓度，并在焦虑测试期间对焦虑相关行为进行评分。将测量压力反应和焦虑相关行为的外周和大脑指标，以确定补偿稳态机制中潜在的基因型差异。 2-立即早期基因蛋白产物 Fos 的免疫细胞化学定位将用于识别野生型和 OT 无效小鼠在应激或焦虑测试后激活的神经元。单标记和双标记方法将用于绘制大脑中激活神经元的分布和神经化学表型，特别关注边缘系统中的神经元，这些神经元被认为可以介导心因性压力和焦虑相关行为。 3-将外源性OT注入OT无效小鼠和野生型小鼠的大脑中，并测量压力刺激后的焦虑相关行为或皮质酮； 4-通过野生型与 OT 无效小鼠在焦虑和压力测试前后的放射自显影来测量大脑 OT 受体。