Endocannabinoid Signaling in Postnatal Ethanol Effects

产后乙醇效应中的内源性大麻素信号传导

• 批准号: 8033263
• 负责人: Basavaraj S Balapal
• 金额: $ 28.86万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033263
• 关键词: 2-arachidonylglycerol; Address; Adult; Adverse effects; Affect; Alcohol consumption; Apoptotic; Award; Behavior; Binding Proteins; Biochemical; Birth; Brain; Brain region; Cannabinoids; Cell Death; Cells; Child; Cognitive deficits; Counseling; Coupled; Data; Development; Developmental Disabilities; Dose; Electrophysiology (science); Endocannabinoids; Ethanol; Fetal Alcohol Exposure; Fetus; Functional disorder; Grant; Growth; Health Professional; Hippocampus (Brain); Human; Kinetics; Knockout Mice; Lead; Learning; Long-Term Potentiation; Measures; Mediating; Memory; Mental Depression; Metabolic; Methods; Modeling; Molecular; Mus; Neonatal; Nerve Degeneration; Neurons; Newborn Animals; Pathway interactions; Physiological; Pregnancy; Pregnant Women; Production; Research; Response Elements; Rodent; Role; Signal Pathway; Signal Transduction; Slice; Suggestion; Synapses; Synaptic plasticity; System; Techniques; Testing; Third Pregnancy Trimester; Time; Tissues; Western World; Work; alcohol effect; alcohol exposure; anandamide; base; cognitive function; insight; mature animal; neurobehavioral; novel; postnatal; public health relevance; rapid growth; receptor; response; synaptogenesis; treatment strategy

DESCRIPTION (provided by applicant): Ethanol exposure is known to have adverse effects on the developing fetus. Ethanol use during the synaptogenesis period, which occurs over the third trimester of pregnancy in humans (1-14 days after birth in rodents), triggers apoptotic cell death. The use of ethanol affects hippocampal functions impairing synaptic plasticity, learning and memory. Our work during the KO1 award period has led to the hypothesis that ethanol exerts its effects on synaptic plasticity via increased production of endogenous cannabinoids [ECs; anandamide (AEA) and 2-arachidonylglycerol (2-AG)] in hippocampal neurons. Cannabinoids (CB) themselves, like ethanol inhibit synaptic plasticity and markedly exacerbate the apoptotic effects of ethanol in the developing brain. The CB-mediated synaptic activity during early brain development seems to affect brain maturation pathways that influence cognitive deficits. However, the cellular mechanism(s) by which ethanol affects EC-coupled pathways remains largely unknown. Our preliminary data suggest that ethanol administration during the synaptogenic period activates the cannabinoid type 1 (CB1R) receptor inducing neurodegeneration. In addition, the enhanced CB1R activity causes deficits in pCREB levels and synaptic plasticity in adult animals. The CB1R blockade rescues neurodegeneration in neonatal mice. It also rescues the synaptic dysfunction observed in adult animals. Our promising preliminary data, implicating ECs and CB1R-mediated mechanisms, underscores the importance of this research direction. Our central hypothesis is that ethanol-mediated activation of hippocampal CB1R pathways during synaptogenesis results in long-lasting deficits in synaptic plasticity. We propose three Specific Aims to address this hypothesis. The approach combines the use of CB1R null mice and the established immunological, biochemical methods and electrophysiology techniques. In Specific Aim 1, we will investigate the effects of postnatal ethanol administration during the synaptogenesis period on the metabolic fate of AEA and 2-AG, and CB1Rs expression and function. In Specific Aim 2, we will investigate as to how postnatal ethanol effects are coupled to the CB1R-dependent signaling pathways. In Specific Aim 3, we will test whether the early postnatal ethanol exposure causes long lasting depression of hippocampal synaptic plasticity in adult animals. Understanding the molecular underpinnings of the EC pathway (s) in the hippocampus will help to develop potential CB1R targeted strategies for treating hippocampal abnormalities and memory and learning deficits that often result from alcohol abuse during pregnancy. PUBLIC HEALTH RELEVANCE: It is hoped that better understanding of how ethanol exposure during CNS development alters endocannabinoid pathways in the hippocampus will lead to more effective strategies for the treatment of hippocampal abnormalities and related memory and learning deficits in children due to alcohol abuse during pregnancy, representing the most common developmental disability in the Western world. Additionally, the results of the proposed studies may be used by health care professionals in counseling pregnant women on the potential effects of alcohol consumption.

描述（由申请人提供）：已知乙醇暴露会对发育中的胎儿产生不利影响。人类妊娠晚期（啮齿类动物出生后 1-14 天）突触发生期间使用乙醇会引发细胞凋亡。乙醇的使用会影响海马功能，损害突触可塑性、学习和记忆。我们在 KO1 获奖期间的工作得出了这样的假设：乙醇通过增加内源性大麻素 [ECs；ECs；海马神经元中的花生四烯酸乙醇胺（AEA）和2-花生四烯酰甘油（2-AG）]。大麻素（CB）本身与乙醇一样，会抑制突触可塑性，并显着加剧乙醇对发育中大脑的细胞凋亡作用。早期大脑发育过程中CB介导的突触活动似乎会影响影响认知缺陷的大脑成熟途径。然而，乙醇影响 EC 偶联途径的细胞机制仍然很大程度上未知。我们的初步数据表明，在突触发生期间施用乙醇会激活 1 型大麻素 (CB1R) 受体，从而诱导神经变性。此外，增强的 CB1R 活性会导致成年动物 pCREB ​​水平和突触可塑性缺陷。 CB1R 阻断可挽救新生小鼠的神经退行性变。它还可以挽救成年动物中观察到的突触功能障碍。我们有希望的初步数据，涉及 EC 和 CB1R 介导的机制，强调了这一研究方向的重要性。我们的中心假设是，突触发生过程中乙醇介导的海马 CB1R 通路激活会导致突触可塑性的长期缺陷。我们提出三个具体目标来解决这一假设。该方法结合了 CB1R 无效小鼠的使用和已建立的免疫学、生化方法和电生理学技术。在具体目标 1 中，我们将研究突触发生期间出生后乙醇施用对 AEA 和 2-AG 代谢命运以及 CB1R 表达和功能的影响。在具体目标 2 中，我们将研究出生后乙醇效应如何与 CB1R 依赖性信号通路耦合。在具体目标 3 中，我们将测试出生后早期乙醇暴露是否会导致成年动物海马突触可塑性长期持续下降。了解海马 EC 通路的分子基础将有助于开发潜在的 CB1R 靶向策略，用于治疗通常因怀孕期间酗酒而导致的海马异常以及记忆和学习缺陷。 公众健康相关性：希望更好地了解中枢神经系统发育过程中乙醇暴露如何改变海马体中的内源性大麻素途径，将有助于制定更有效的策略来治疗因怀孕期间酗酒而导致的儿童海马体异常和相关记忆和学习缺陷，这是西方世界最常见的发育障碍。此外，拟议研究的结果可被医疗保健专业人员用于向孕妇提供有关饮酒潜在影响的咨询。