Serotonin 1A receptors during development and anxiety

发育和焦虑期间的血清素 1A 受体

• 批准号: 6607104
• 负责人: Rene Hen
• 金额: $ 17.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607104
• 关键词: amygdala; animal developmental psychology; anxiety; anxiety disorders; autoradiography; behavior test; behavioral /social science research tag; behavioral genetics; cerebral cortex; differential display technique; gene targeting; genetic models; genetically modified animals; growth factor; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; neuropharmacology; neurotransmitter agonist; neurotransmitter antagonist; psychopharmacology; receptor expression; receptor sensitivity; serotonin receptor; transcription factor

DESCRIPTION (provided by applicant): Mice lacking the serotonin 1A receptor (5-HT1A receptor knockout) display increased anxiety-like behavior in the open field, elevated-plus maze, and novelty-suppressed feeding tests, and serve as a genetic model of anxiety disorders. In order to determine in which brain region this receptor functions to modulate anxiety-like behavior, we have used gene targeting technology to create mice with conditional expression of the 5-HT1A receptor restricted to the forebrain. These forebrain "rescue" mice behave like wild-type mice in the open field, elevated-plus maze, and novelty-suppressed feeding tests, suggesting that receptor in this region is sufficient to restore anxiety-like behavior. Turning off expression of the 5-HT1A receptor in these mice would be expected to revert their anxiety-like behavior to that found in knockout animals. Instead, 5-HT1A receptor inducible rescue mice, in which 5-HT1A receptor expression was completely turned off during adulthood, continue to behave like wild-type mice suggesting that receptor expression to the adult is not required for normal anxiety-like behavior. This result can be explained if the 5HT1A receptor functions during a critical time period in development to establish normal anxiety-like behavior in the adult. This hypothesis is a radical departure from previous notions of the role of the 5-HT1A receptor in fear behavior, and is the starting point for the proposed investigations. First, the 5-HT1A receptor is hypothesized to be required during the first and second postnatal week (PO-P14) to establish normal anxiety-like behaviors in the adult. The 5-HT1A receptor forebrain rescue mice will be used to define more precisely the critical time period for 5-HT1A receptor function. Second, novel transgenic strategies will be applied to define more specifically the critical tissue mediating the expression of anxiety behavior. Either the cortex, hippocampus, or amygdala are hypothesized to be the critical structures because these regions show receptor expression in the 5-HT1A rescue mice and because of their known involvement in anxiety and depression in rodents and humans. Third, changes in anxiety-like behavior in the knockout and transgenic mice will be associated with changes in the expression of specific genes which mediate the function of the 5-HT1A receptor. An unbiased search for such candidate genes will be performed using gene expression profiling techniques.

描述（由申请人提供）：缺乏5-羟色胺1A受体的小鼠 （5-HT1A受体敲除）在开放中表现出增加的焦虑样行为 场，升高的迷宫和新颖的喂养测试，并用作 焦虑症的遗传模型。为了确定哪个大脑区域 该受体功能可调节焦虑样行为，我们使用了基因 针对技术以5-HT1A的条件表达创建小鼠 受体仅限于前脑。这些前脑“救援”老鼠的行为就像 野外野生型小鼠，抬高的迷宫和被新颖的小鼠 进食测试，表明该区域的受体足以恢复 焦虑般的行为。关闭这些5-HT1A受体的表达 预计小鼠会恢复其焦虑般的行为 淘汰动物。相反，5-HT1A受体诱导救援小鼠，其中 5-HT1A受体表达在成年期完全关闭，继续 表现像野生型小鼠，表明受体表达对成人 正常焦虑行为不需要。这个结果可以解释 如果5HT1A受体在开发的关键时期内起作用 在成年人中建立正常的焦虑样行为。 这个假设是与以前关于 恐惧行为中的5-HT1A受体，是提议的起点 调查。首先，假设5-HT1A受体需要 在产后和第二个星期（PO-P14）中以建立正常 成年人的焦虑行为。 5-HT1A受体前脑救援小鼠 将用于更精确地定义5-HT1A的关键时间段 受体功能。其次，新颖的转基因策略将应用于 更具体地定义介导的临界组织 焦虑行为。假设皮质，海马或杏仁核是 成为关键结构，因为这些区域在 5-HT1A营救小鼠，并且由于已知参与焦虑和 啮齿动物和人类的抑郁症。第三，焦虑般的行为变化 敲除和转基因小鼠将与 介导5-HT1A受体功能的特定基因的表达。 将使用基因进行对这种候选基因的公正搜索 表达分析技术。