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易感性，可能是中枢促肾上腺皮质激素释放因子（CRF）通路失调的直接结果。这项拨款提案的重点是通过与血清素（5-HT）神经回路的相互作用，检查中枢CRF通路失调与压力相关情绪障碍易感性增加的关系。我们的研究利用了一种遗传小鼠模型，在该模型中，除了在稳态挑战条件下表现出增加的应激反应外，杏仁核中的CRF表达也有所升高。为了在我们的行为、生化和分子比较中影响突触5-羟色胺水平，我们将用SSRI氟西汀治疗动物。以下目标是使用应激途径如何影响情绪行为的综合观点，特别是CRF和5-HT神经回路的相互作用。目的1将通过检查行为应激反应，检查CRF失调在应激相关情绪障碍发展中的可能作用，该障碍是由血清素通路的影响引起的。目的2将检查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-HT受体基因表达的改变，蛋白质水平和生化状态，以及受体在特定大脑区域的占用。在Aim 3中，我们将在5-HT产生细胞中创建一个有条件的、可诱导的、位点特异性的CRFR1小鼠缺陷，以便更直接地检查中枢CRF表达升高和5-HT通路影响应激敏感行为的特异性相互作用。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-HT细胞中CRFR1缺陷的小鼠。我们假设这些研究的结果将证明CRF通路的失调参与了5-HT神经传递的改变，导致应激相关情绪障碍的易感性。

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.