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：
8961534
负责人：
Basavaraj S Balapal
金额：
$ 36.05万
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 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8961534
关键词：
Adolescent Adult Alcohol consumption Behavior Biochemical Biological Cannabinoids Child Cognitive deficits Counseling Cyclic AMP-Responsive DNA-Binding Protein Cytoskeleton DNA Modification Process Data Defect Development Dose Electrons Electrophysiology (science)Endocannabinoids Epigenetic Process Ethanol Etiology Evaluation Event Fetal Alcohol Spectrum Disorder Functional disorder Funding Glutamates Goals Health Professional Hippocampus (Brain)Homeostasis Human Institutes Intellectual functioning disability Intervention Knockout Mice Learning Long-Term Potentiation Mediating Memory Memory impairment Microscopic Mitogen-Activated Protein Kinases Modeling Molecular Mus Names Neocortex Neonatal Nerve Degeneration Neurodevelopmental Impairment Neurons Pathway interactions Pharmaceutical Preparations Pharmacology Phosphorylation Physiological Pregnancy Pregnant Women Proteins Public Health Publishing Qualifying Quality of life Receptor Signaling Research Research Infrastructure Risk-Taking Role SR 141716A Saline Signal Pathway Signal Transduction Social Behavior Structure Synapses System Testing Therapeutic Tissues Work adult neurogenesis alcohol effect alcohol exposure anandamide base calmodulin-dependent protein kinase II experience histone modification improved in vivo insight neocortical neonate neural circuit neurobehavioral novel novel therapeutic intervention offspring postnatal prevent promoter public health relevance receptor receptor expression receptor function spatial memory therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks that include deficits in learning and memory. Our data during the current funding period revealed a novel function of anandamide (AEA) and the cannabinoid type 1 receptor (CB1R) as a regulator of neurodegeneration (ND) in postnatal ethanol exposed neonatal (postnatal day 7, P7) mice that is associated with synaptic dysfunction in adult mice. In this application, we propose that postnatal ethanol exposure induces persistent enhancement of CB1R function to disrupt synaptic homeostasis and, learning and memory. Although prolonged exposure paradigms might align more closely to common etiologies of FASD, the binge model allows a more precise analysis of mechanisms and thus provides potential therapeutic targets for treatment. Our pilot data with postnatal ethanol models support that the enhanced CB1R activity observed in neonates persists through adulthood and that blocking CB1R long after postnatal ethanol exposure was able to rescue spatial memory deficits in adults. The overreaching objective of this renewal application is to better understand and define the molecular events responsible for the persistent expression of CB1R and its impact on development of the synaptic circuit, activity- dependent signaling, synaptic structure and neurobehavioral abnormalities observed in adult mice. The goal of Aim 1 is to test the hypothesis that postnatal ethanol exposure induces persistent expression of CB1R to adulthood and examine the histone and DNA modification at the CB1R promoter that support enhanced CB1R expression in neocortical and hippocampal structures. Specific Aim 2 will test the hypothesis that postnatal ethanol-induced persistent expression of CB1R disrupts development of the synaptic circuit and neuronal activity-dependent signaling events that might be involved in synaptic activity. Using both CB1R wild type and null mice, we will explore the extent to which the enhancement of CB1R is associated with the development of glutamatergic and GABAergic systems. We will evaluate the effect of enhanced CB1R function on activity-dependent signaling. Finally, Aim 3 will evaluate the hypothesis that postnatal ethanol induced neurobehavioral deficits can be attributed to persistent CB1R activity and can be rescued by blocking CB1R activity. We will evaluate long-term potentiation (LTP), ultrastructural changes in synapses using EM analysis, adult neurogenesis, social behavior, and learning and memory in adult mice treated with a CB1R antagonist from postnatal ethanol exposed adolescent mice. If successful, these data could open a new window into understanding of the mechanisms that might help develop potential therapeutic strategies for treating early ethanol-induced neurobehavioral abnormalities.

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是西方国家智力障碍的主要原因之一，其神经行为特征包括学习和记忆缺陷，我们在当前资助期间的数据揭示了一种新功能。大麻素 (AEA) 和大麻素 1 型受体 (CB1R) 作为出生后乙醇暴露的新生小鼠（出生后第 7 天，P7）神经变性 (ND) 的调节剂，与在此应用中，我们提出出生后乙醇暴露会导致 CB1R 功能持续增强，从而破坏突触稳态以及学习和记忆，尽管长期暴露范例可能更接近 FASD 的常见病因，但暴饮暴食模型允许。我们对出生后乙醇模型的初步数据进行了更精确的机制分析，从而提供了潜在的治疗靶点，支持在新生儿中观察到的增强的 CB1R 活性持续到成年期，并且长期阻断 CB1R。出生后乙醇暴露能够挽救成人的空间记忆缺陷，这一更新应用的首要目标是更好地理解和定义导致 CB1R 持续表达的分子事件及其对活动依赖性突触回路发育的影响。在成年小鼠中观察到的信号传导、突触结构和神经行为异常目标 1 的目标是检验出生后乙醇暴露会诱导 CB1R 持续表达至成年的假设，并检查组蛋白和 DNA 修饰。支持新皮质和海马结构中增强 CB1R 表达的 CB1R 启动子将检验以下假设：出生后乙醇持续诱导的 CB1R 表达会破坏突触回路的发育以及可能参与突触活动的神经元活动依赖性信号事件。使用 CB1R 野生型和无效小鼠，我们将探讨 CB1R 的增强与谷氨酸能和 GABA 能系统的发育相关的程度。我们将评估增强的 CB1R 功能对活性依赖性信号传导的影响，最后，目标 3 将评估以下假设：出生后乙醇引起的神经行为缺陷可归因于持续的 CB1R 活性，并且可以通过阻断 CB1R 活性来挽救。使用产后乙醇中的 CB1R 拮抗剂处理的成年小鼠的术语增强 (LTP)、使用 EM 分析的突触超微结构变化、成年神经发生、社会行为以及学习和记忆如果成功的话，这些数据可能会打开一个新的窗口，以了解可能有助于开发治疗早期乙醇引起的神经行为异常的潜在治疗策略的机制。