权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The DNA methylation code governing the ensemble representation of morphine-context association

DNA甲基化密码控制吗啡-背景关联的整体表示

基本信息

批准号：
9906873
负责人：
Kristen Elizabeth Pleil
金额：
$ 21.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906873
关键词：
Abstinence Acute Address Alleles Behavior Brain region Cells Chronic Clinical Code DNA Methylation Data Development Digit structure Drug usage Economics Electrophysiology (science)Enhancers Environment Epigenetic Process Exposure to Future Gene Expression Gene Expression Alteration Genes Genetic Transcription Goals Hippocampus (Brain)Incidence Investigation Link Maintenance Mediating Memory Methylation Modeling Morphine Morphine Dependence Morphology Neurons Nucleus Accumbens Opiate Addiction Opioid Opioid Analgesics Pharmaceutical Preparations Play Population Property Relapse Reporting Rewards Risk Factors Role Series Signal Transduction Slice Social Problems Substance Use Disorder Synapses United States Withdrawal Symptom Work addiction digital drug craving drug development drug of abuse drug relapse drug seeking behavior effective therapy entorhinal cortex epigenomics experience experimental study high risk hippocampal pyramidal neuron innovation memory recall methylome morphine administration neural circuit neuronal circuitry nonmedical use opioid misuse opioid use disorder postsynaptic predictive modeling preference prevent recruit relating to nervous system

项目摘要

Abstract Morphine is a widely-prescribed and potent opioid analgesic, but in recent years its non-medical use has been on the rise and has contributed to the increased incidence of opioid use disorder. Repeated exposure to morphine and other drugs of abuse leads to lasting learned associations between the rewarding properties of the drug and the environment of administration. Therefore even in abstinence, re-exposure to the context is a risk factor for relapse, increasing withdrawal symptoms and drug cravings. While the neural circuits mediating drug-context associations and drug seeking behavior have been studied heavily, the specific underlying mechanisms of these associations remain poorly understood. In the proposed studies, we aim to evaluate the hypothesis that epigenetic alterations in the methylation of genes related to neuronal connectivity and excitability during repeated morphine-context pairings provide a mechanism for the stable recruitment of a small, specific population of neurons in the ventral hippocampus to the ‘engram” storing the memory of morphine-context associations. Switching the methylation status of these genes alters gene expression, which leads to increased excitability and connectivity with pre- and postsynaptic circuit cortical and limbic partners to enhance the morphine-context association and create a lasting memory. By characterizing the changes in methylation in the recruited hippocampal neuronal ensemble and evaluating the consequent effects on neuronal function and circuit plasticity, our experiments may provide a new framework for the study of the mechanisms of opioid addiction and contribute to more effective treatments of substance use disorder.

摘要