Estrogen and CaM Kinase IV in the Limbic System

边缘系统中的雌激素和 CaM 激酶 IV

基本信息

批准号：
7117346
负责人：
ROCHELLE S. COHEN
金额：
$ 26.64万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2008-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Clinical studies have shown that estrogen (E2) can ameliorate symptoms of mood disorders in women, including severe depression. The presence of symptoms may represent an abnormal response to normal hormonal changes, thereby implicating contextual factors in the brain in the etiology of these symptoms. Some of these factors include second messenger systems that lead to the production of neurotrophic agents, including brain-derived neurotrophic factor (BDNF). Chronic stress results in deleterious effects on neurons and synapses which, in turn, may be related to alterations in affective behavior. Because of its involvement in cellular and synaptic growth and/or function, BDNF may counteract these negative effects and restore the appropriate behavioral responses. The gene transcription factor cyclic AMP response element-binding protein (CREB), has been shown to be a target of antidepressant and E2 action. Activation of CREB can lead to transcription of the BDNF gene. We propose that the Ca2+/calmodulin-dependent protein kinase IV (CaMK IV) pathway, "CaMK IV - CREB - phosphorylated CREB (pCREB) - BDNF," mediates some of the effects of long-term E2 treatment on behavior. Long-term E2 treatment results in the persistence of these messengers, even after two weeks. E2 may regulate CaMK IV and BDNF via alterations in their mRNAs; we will perform in situ hybridization to address the hypothesis that E2 regulates levels of CaMK IV mRNA and BDNF mRNA. We will also determine if E2 decreases relevant phosphatases, including protein phosphatase 2A and the calcineurin pathway, negative regulators of CaMK IV and pCREB, respectively. To determine if CaMK IV, CREB and/or BDNF mediate E2 effects in the forced swim test, a test for the efficacy of antidepressants in rodents, antisense oligodeoxynucleotides (ODNs) to CaMK IV, CREB or BDNF will be infused into the amygdala or hippocampus and animals will be subjected to the test conditions. Infusion of these antisense ODNs may interfere with the positive effects of E2 on forced swim. We will also determine if infusions of BDNF protein with the antisense ODNs to CaMK IV and CREB reverse the actions of the ODNs on behavior. These experiments will give insight to the molecular effects of E2 in areas of the brain related to affective processing and will uncover mechanisms that may allow hormonal intervention for the amelioration of female-related mood disorders.

描述（由申请人提供）：临床研究表明雌激素（E2）可以改善女性情绪障碍的症状，包括严重抑郁症。症状的存在可能代表对正常荷尔蒙变化的异常反应，从而暗示大脑中的背景因素与这些症状的病因有关。其中一些因素包括导致神经营养剂产生的第二信使系统，包括脑源性神经营养因子（BDNF）。慢性压力会对神经元和突触产生有害影响，而这反过来可能与情感行为的改变有关。由于 BDNF 参与细胞和突触生长和/或功能，它可以抵消这些负面影响并恢复适当的行为反应。基因转录因子环 AMP 反应元件结合蛋白 (CREB) 已被证明是抗抑郁和 E2 作用的靶标。 CREB 的激活可以导致 BDNF 基因的转录。我们提出 Ca2+/钙调蛋白依赖性蛋白激酶 IV (CaMK IV) 途径“CaMK IV - CREB - 磷酸化 CREB (pCREB) - BDNF”介导长期 E2 治疗对行为的一些影响。长期 E2 治疗会导致这些信使的持续存在，甚至在两周后也是如此。 E2 可能通过改变 mRNA 来调节 CaMK IV 和 BDNF；我们将进行原位杂交来解决 E2 调节 CaMK IV mRNA 和 BDNF mRNA 水平的假设。我们还将确定 E2 是否会降低相关磷酸酶，包括蛋白磷酸酶 2A 和钙调磷酸酶途径，分别是 CaMK IV 和 pCREB 的负调节因子。为了确定 CaMK IV、CREB 和/或 BDNF 在强迫游泳测试中是否介导 E2 效应，在啮齿类动物中进行抗抑郁药功效测试，将 CaMK IV、CREB 或 BDNF 的反义寡脱氧核苷酸 (ODN) 注入杏仁核或海马体动物将接受测试条件。输注这些反义 ODN 可能会干扰 E2 对强迫游泳的积极作用。我们还将确定 BDNF 蛋白与 CaMK IV 和 CREB 反义 ODN 的输注是否会逆转 ODN 对行为的作用。这些实验将深入了解 E2 在与情感处理相关的大脑区域中的分子效应，并将揭示可能允许激素干预以改善女性相关情绪障碍的机制。