Actions of CRF on 5-HT pathways in mood regulation

描述（由申请人提供）：应激相关情绪障碍的易感性可能涉及对应激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检查中央CRF通路失调参与增加易感性的压力相关的情绪障碍，通过与5-羟色胺（5-HT）神经回路的相互作用。我们的研究利用了一个遗传小鼠模型，在该模型中，除了在稳态挑战条件下显示出增加的应激反应性外，杏仁核中的CRF表达也升高。为了在我们的行为、生化和分子比较中影响突触5-HT水平，我们将用SSRI氟西汀治疗动物。以下目标是使用压力途径如何影响情绪行为的综合观点提出的，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来研究CRF失调在应激相关情绪障碍发展中的可能作用，这些情绪障碍是由对5-羟色胺通路的影响引起的。目标2将检查氟西汀治疗后与行为输出相应的分子和生化变化。我们将研究CRF和5-HT受体基因表达、蛋白水平和生化状态的改变，以及特定脑区的受体占有率。在目标3中，我们将创建一个条件性的，可诱导的，位点特异性的小鼠CRFR 1在5-HT产生细胞缺陷，以更直接地检查升高的中央CRF表达和5-HT途径影响应激敏感性行为的具体相互作用。这些小鼠将与我们的CRFR 2缺陷小鼠杂交，以产生杏仁核CRF升高且5-HT细胞中CRFR 1缺陷的小鼠。我们假设，这些研究的结果将证明参与CRF途径的失调，在5-HT神经传递的改变，导致易感性与压力相关的情绪障碍。

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.