Actions of CRF on 5-HT pathways in mood regulation

描述(由申请人提供)：压力相关情绪障碍的易感性可能涉及对压力敏感性增加的遗传脆弱性，并可能是中枢促肾上腺皮质激素释放因子(CRF)途径调节失调的直接结果。这项拨款提案的重点是检查中枢CRF途径失调与通过与5-羟色胺(5-HT)神经回路相互作用而增加应激相关情绪障碍的易感性。我们的研究利用了一种遗传小鼠模型，在该模型中，CRF在杏仁核中的表达增加，并在体内平衡挑战的条件下表现出更高的应激反应。为了在我们的行为、生化和分子比较中影响突触的5-羟色胺水平，我们将用SSRI氟西汀治疗动物。以下目标是使用压力通路如何影响情绪行为的综合观点提出的，特别是CRF和5-羟色胺神经回路的相互作用。目的1通过检测行为应激反应，研究CRF调节失调在5-羟色胺通路的影响导致的应激相关情绪障碍的发展中可能起的作用。然后，目标2将检测氟西汀治疗后与行为输出相对应的分子和生化变化。我们将研究CRF和5-羟色胺受体基因表达、蛋白质水平和生化状态以及特定脑区受体占有率的变化。在目标3中，我们将在5-羟色胺产生细胞中创建一个CRFR1缺乏的条件性、可诱导性、部位特异性小鼠，以便更直接地研究中枢CRF表达升高与影响应激敏感行为的5-羟色胺途径的特定相互作用。这些小鼠将与我们的CRFR2缺陷小鼠杂交，产生杏仁核CRF升高和5-羟色胺细胞CRFR1缺陷的小鼠。我们假设，这些拟议研究的结果将证明CRF通路的失调参与了5-羟色胺神经传递的改变，从而导致容易发生应激相关的情绪障碍。

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.