Actions of CRF on 5-HT pathways in mood regulation

CRF 对 5-HT 通路在情绪调节中的作用

• 批准号: 6967280
• 负责人: Tracy L Bale
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967280
• 关键词: amygdala; behavioral /social science research tag; behavioral genetics; brain mapping; corticotropin releasing factor; fluoxetine; gene expression; genetic models; genetic susceptibility; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; mental health epidemiology; model design /development; mood disorders; neuroanatomy; neurotransmitter metabolism; protein metabolism; psychosomatic disorders; serotonin; serotonin receptor; synapses

DESCRIPTION (provided by applicant): The predisposition to stress-related mood disorders likely involves a genetic vulnerability to increased stress sensitivity and may be a direct result of a dysregulation in central corticotrophin releasing factor (CRF) pathways. The focus of this grant proposal is the examination of central CRF pathway dysregulation involvement with increased susceptibility for stress-related mood disorders via interactions with serotonin (5-HT) neurocircuitry. Our studies utilize a genetic mouse model in which CRF expression is elevated in the amygdala in addition to showing increased stress responsivity under conditions of homeostatic challenge. In order to influence synaptic 5-HT levels in our behavioral, biochemical, and molecular comparisons, we will treat animals with the SSRI fluoxetine. The following aims are proposed using an integrated view of how stress pathways impact emotional behavior, specifically the interactions of CRF and 5-HT neurocircuitry. Aim 1 will examine the possible role of CRF dysregulation in the development of stress-related mood disorders resulting from an impact on serotonin pathways by examining behavioral stress responses. Aim 2 will then examine the molecular and biochemical changes corresponding with behavioral outputs following fluoxetine treatment. We will study alterations in CRF and 5-HT receptor gene expression, protein levels and biochemical state, and receptor occupancy in specific brain regions. In Aim 3 we will create a conditional, inducible, site-specific mouse deficient for CRFR1 in 5-HT producing cells in order to more directly examine the specific interaction of elevated central CRF expression and 5-HT pathways impacting stress-sensitive behaviors. These mice will be crossed with our CRFR2-deficient mice to produce mice with elevated amygdalar CRF and deficient in CRFR1 in 5-HT cells. We hypothesize that results from these proposed studies will demonstrate an involvement of a dysregulation of CRF pathways in alterations in 5-HT neurotransmission leading to a predisposition to stress-related mood disorders.

描述（由申请人提供）：与压力相关的情绪障碍的倾向可能涉及增加压力敏感性的遗传脆弱性，并且可能是中枢性皮质营养素释放因子（CRF）途径失调的直接结果。该赠款提案的重点是检查中央CRF途径失调的参与，通过与5-羟色胺（5-HT）神经记录的相互作用，对与压力相关的情绪障碍的敏感性增加。我们的研究利用了一种遗传小鼠模型，在杏仁核中，杏仁核中CRF的表达升高，除了在稳态挑战条件下显示出增加的压力反应性。为了影响我们的行为，生化和分子比较中的突触5-HT水平，我们将用SSRI氟西汀治疗动物。提出了以下目的，该目标是使用压力途径如何影响情绪行为的综合视图，特别是CRF和5-HT神经循环的相互作用。 AIM 1将检查CRF失调在通过检查行为应力反应对5-羟色胺途径产生的与压力相关的情绪障碍发展中的可能作用。然后，AIM 2将检查与氟西汀处理后的行为输出相对应的分子和生化变化。我们将研究特定脑区域中CRF和5-HT受体基因表达，蛋白质水平和生化状态以及受体占用率的改变。在AIM 3中，我们将创建一种有条件的，可诱导的位点特异性小鼠缺乏5-HT产生细胞中CRFR1的小鼠，以便更直接地检查中央CRF表达升高和5-HT途径的特定相互作用，从而影响应力敏感行为。这些小鼠将与我们的CRFR2缺陷小鼠交叉，以产生杏仁核CRF升高的小鼠，并且在5-HT细胞中缺乏CRFR1。我们假设这些拟议的研究的结果将证明CRF途径失调在5-HT神经传递的变化中的失调，从而导致与压力相关的情绪障碍的倾向。