Endocannabinoid Signaling in Postnatal Ethanol Effects

产后乙醇效应中的内源性大麻素信号传导

基本信息

批准号：
8607869
负责人：
Basavaraj S Balapal
金额：
$ 27.99万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607869
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

项目摘要

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.

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-花生四烯酸甘油（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。