Estrogen and CaM Kinase IV in the Limbic System

边缘系统中的雌激素和 CaM 激酶 IV

• 批准号: 6945832
• 负责人: ROCHELLE S. COHEN
• 金额: $ 27.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945832
• 关键词: amygdala; antidepressants; antisense nucleic acid; behavioral /social science research tag; brain derived neurotrophic factor; cAMP response element binding protein; calcineurin; calmodulin dependent protein kinase; estrogens; genetic regulation; hippocampus; hormone regulation /control mechanism; in situ hybridization; laboratory rat; limbic system; mood disorders; neuropharmacology; neuropsychological tests; phosphoprotein phosphatase; second messengers; stress

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）可以减轻女性情绪障碍的症状，包括严重的抑郁症。症状的存在可能代表对正常激素变化的异常反应，从而暗示了这些症状的病因中大脑中的情境因素。其中一些因素包括导致神经营养剂（包括脑衍生的神经营养因子（BDNF））的第二个信使系统。慢性应激会导致对神经元和突触的有害影响，而神经元和突触可能与情感行为的改变有关。由于它参与细胞和突触生长和/或功能，BDNF可能会抵消这些负面影响并恢复适当的行为反应。基因转录因子环状AMP反应元件结合蛋白（CREB）已被证明是抗抑郁药和E2作用的靶标。 CREB的激活会导致BDNF基因的转录。我们建议Ca2+/钙调蛋白依赖性蛋白激酶IV（CAMK IV）途径，“ CAMK IV -CREB ​​-CREB-磷酸化的CREB（PCREB）-BDNF”，介导了长期E2处理对行为对行为的某些影响。长期的E2治疗即使在两周后也会导致这些使者的持久性。 E2可以通过其mRNA的改变来调节CAMK IV和BDNF；我们将进行原位杂交，以解决E2调节CAMK IV mRNA和BDNF mRNA水平的假设。我们还将确定E2是否分别降低了相关的磷酸酶，包括蛋白质磷酸酶2a和钙调神经蛋白途径，CAMK IV和PCREB的负调节剂。要确定CAMK IV，CREB和/或BDNF是否在强制游泳测试中介导了E2的效果，对抗抑郁药在啮齿动物中的功效，反义寡脱氧核苷酸（ODNS）对CAMK IV，CREB或BDNF的功效将被输注到amygdala或Hippygdala或Hippocpocampus和Hippocampampus和Hippocampus和Hippocampus和BDNF中。输注这些反义ODN可能会干扰E2对强制游泳的积极影响。我们还将确定对CAMK IV和CREB的反义ODN的BDNF蛋白的输注是否反转了ODN对行为的作用。这些实验将深入了解E2在与情感加工有关的大脑区域的分子作用，并将发现可能允许荷尔蒙干预以改善女性相关情绪障碍的机制。