Mechanism of Increased Anxiety in 5-HT1AR Knockout Mice

5-HT1AR 敲除小鼠焦虑增加的机制

• 批准号: 6418495
• 负责人: CORNELIUS T GROSS
• 金额: $ 13.45万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6418495
• 关键词: anxiety disorders; behavioral /social science research tag; developmental neurobiology; disease /disorder model; gene expression; genetically modified animals; laboratory mouse; molecular pathology; serotonin receptor

DESCRIPTION (provided by applicant): This award is designed to establish the candidate as a competitive researcher with expertise in both the behavioral as well as molecular analysis of anxiety-like behavior in mice. Following a three year period of postdoctoral research training in the analysis of anxiety-like behavior in mice, the candidate is seeking further training in the construction and molecular analysis of transgenic and knockout mice. Educational Plan: Specifically, the award will facilitate the acquisition of (1) knockout and transgenic technology for the tissue-specific and conditional expression of genes in mice, (2) gene expression profiling, or "genomics," techniques, (3) histochemical methods needed to identify and quantitate molecular and morphological changes in mice, (4) general knowledge in developmental neurobiology and anatomy via coursework, and (5) experience in effective laboratory mentoring and the responsible conduct of research. The first, second, and fifth areas of training will be provided by Dr. Rene Hen, while the third will be overseen by Dr. Bruce McEwen, both well known leaders in their fields. Research Plan: Anxiety disorders affect more than 12 percent of the population during their lifetime. Knockout mice lacking the serotonin 1A receptor (5-HT1AR knockout) show increased anxiety-like behavior and represent a valuable genetic model of anxiety disorders. We present preliminary evidence showing that, contrary to the commonly held notion in the field, the 5-HT1AR is not required in the adult for normal anxiety-like behavior, and that, instead, it is likely to play a critical role during development. The first part of the proposed research will use tissue-specific and conditional transgenic animals to define the critical tissue and time period for 5-HTIA receptor function. The second part proposes to isolate and characterize critical genes involved in the anxiety-like behavior modulation by this receptor. Part of this approach will rely on an unbiased search for genes downstream of the 5-HT 1AR using gene expression profiling techniques. The identification of critical molecules in this circuit will be important for two reasons. First, they will offer new targets for developing more effective and specific anxiolytic drugs, and second, mutations in these genes may be important factors in the inheritance of vulnerability to anxiety.

描述（由申请人提供）： 该奖项旨在使候选人成为有竞争力的研究人员 具有行为和分子分析方面的专业知识 小鼠的焦虑样行为。经过三年的博士后研究 分析小鼠焦虑样行为的研究训练 候选人正在寻求结构和分子方面的进一步培训 转基因和基因敲除小鼠的分析。教育计划： 具体来说，该奖项将有助于获得 (1) 淘汰赛和 用于组织特异性和条件表达的转基因技术 小鼠基因，(2) 基因表达谱，或“基因组学”技术，(3) 识别和定量分子和细胞所需的组织化学方法 小鼠形态变化，（4）发育常识 通过课程学习神经生物学和解剖学，以及（5）有效的经验 实验室指导和负责任的研究行为。第一个， 第二个和第五个领域的培训将由 Rene Hen 博士提供，而 第三个项目将由 Bruce McEwen 博士监督，他们都是各自领域的知名领导者。 字段。研究计划：焦虑症影响超过 12% 的人 他们一生中的人口。缺乏血清素 1A 的基因敲除小鼠 受体（5-HT1AR 敲除）表现出焦虑样行为增加并代表 焦虑症的有价值的遗传模型。我们提出初步证据 结果表明，与该领域普遍持有的观点相反，5-HT1AR 成人不需要正常的焦虑样行为，相反， 它可能在开发过程中发挥关键作用。第一部分 拟议的研究将使用组织特异性和有条件的转基因动物 定义 5-HTIA 受体功能的关键组织和时间段。这 第二部分建议分离和表征参与该过程的关键基因 该受体调节焦虑样行为。该方法的一部分将 依赖于使用基因对 5-HT 1AR 下游基因进行公正的搜索 表达分析技术。关键分子的识别 该电路之所以重要有两个原因。首先，他们将提供新的 开发更有效和特异性抗焦虑药物的目标，以及 其次，这些基因的突变可能是遗传的重要因素。 容易焦虑。

项目成果

Sporadic autonomic dysregulation and death associated with excessive serotonin autoinhibition.

与过度血清素自身抑制相关的散发性自主神经失调和死亡。

• 发表时间: 2008-07-04
• 作者: Audero, Enrica;Coppi, Elisabetta;Mlinar, Boris;Rossetti, Tiziana;Caprioli, Antonio;Banchaabouchi, Mumna Al;Corradetti, Renato;Gross, Cornelius
• 通讯作者: Gross, Cornelius

Alpha-Ca2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice.

α-Ca2/钙调蛋白依赖性蛋白激酶 II 有助于 5-羟色胺受体 1A 敲除小鼠的焦虑发育编程。

• 发表时间: 2008-06-11
• 作者: Lo Iacono, Luisa;Gross, Cornelius
• 通讯作者: Gross, Cornelius