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: 7861384
• 负责人: Basavaraj S Balapal
• 金额: $ 27.77万
• 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/7861384
• 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; Figs - dietary; 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。突触发生期间的乙醇使用发生在人类怀孕三个月（啮齿动物出生后1-14天），触发凋亡细胞死亡。乙醇的使用会影响海马功能会损害突触可塑性，学习和记忆。我们在KO1奖励期间的工作导致了一个假设，即乙醇通过增加内源性大麻素的产生而对突触可塑性产生影响[ECS；海马神经元中的Anandamide（AEA）和2-芳基甘油甘油（2AG）。大麻素（CB）本身，例如乙醇抑制突触可塑性，并显着加剧了乙醇在发育中的大脑中的凋亡作用。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。但是，乙醇影响EC耦合途径的细胞机制仍然很大未知。我们的初步数据表明，在突触时期内给药乙醇激活了诱导神经变性的1型大麻素（CB1R）受体。此外，增强的CB1R活性会导致成年动物的PCREB水平和突触可塑性的缺陷。 CB1R封锁挽救了新生儿小鼠的神经退行性。它还营救了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ECS和CB1R介导的机制，强调了这一研究方向的重要性。我们的中心假设是乙醇介导的突触发生过程中海马CB1R途径的激活导致突触可塑性的长期缺陷。我们提出了三个特定的目的来解决这一假设。该方法结合了CB1R无效小鼠的使用以及已建立的免疫学，生化方法和电生理技术。在特定目标1中，我们将研究突触发生期间产后乙醇给药对AEA和2-AG代谢命运的影响，以及CB1RS的表达和功能。在特定目标2中，我们将研究产后乙醇效应如何与CB1R依赖性信号通路耦合。在特定的目标3中，我们将测试成年动物的早期产后乙醇暴露是否会导致海马突触可塑性的持久抑郁症。了解海马中EC途径的分子基础将有助于开发潜在的CB1R目标策略，以治疗通常由怀孕期间酗酒造成的海马异常，记忆和学习缺陷。 公共卫生相关性：希望更好地了解CNS开发过程中乙醇暴露于海马中的内源性大麻素途径如何将导致更有效的策略，以治疗海马的异常和相关的记忆和相关的记忆以及由于酗酒期间儿童造成的饮酒期间，这代表了西方世界上最常见的发育障碍。此外，拟议研究的结果可以由卫生保健专业人员在咨询饮酒的潜在影响方面咨询孕妇。