Cell-specific epigenetic and transcriptomic signatures of impulsivity and its regulation by stress in the nucleus accumbens

冲动的细胞特异性表观遗传和转录组特征及其受伏隔核应激的调节

基本信息

批准号：
10592511
负责人：
Debra A Bangasser
金额：
$ 34.98万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592511
关键词：
Address Affect Award Beds Behavior Behavioral Behavioral Model Biological Assay Brain Brain region Caring Cell Nucleus Cells Chromatin Data Data Set Development Diagnosis Emerging Technologies Epigenetic Process Exposure to Female Foundations Gene Expression Genes Genetic Goals Grant Heterogeneity Human Impulsivity Individual Laboratories Maps Mediating Mental disorders Modeling Molecular Molecular Profiling Morphine Neurobiology Neurons Neurosciences Noise Nucleus Accumbens Opioid Pain management Pathway interactions Patients Pharmaceutical Preparations Phenotype Predisposition Prevention Preventive measure Process Proxy Publishing Rattus Regulation Resource-limited setting Resources Rodent Rodent Model Role Self Administration Shapes Signal Transduction Stress Substance Use Disorder Substance abuse problem Therapeutic Tissues Transposase Treatment outcome Withdrawal Symptom addiction addiction liability associated symptom brain cell cell type chromatin remodeling differential expression early life adversity early life stress endophenotype epigenome epigenomics genome wide association study genome-wide human data improved male opioid epidemic opioid exposure opioid therapy opioid use opioid use disorder postnatal postnatal period pre-clinical predictive signature pregnant prenatal stress programs promote resilience pup resilience reward circuitry sex single nucleus RNA-sequencing stressor substance use treatment tool transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Current therapies for opioid use disorder are focused on alleviating withdrawal symptoms associated with cessation of opioid use, which has led to improved treatment outcomes. An important emerging approach to tackling the opioid crisis focuses on prevention efforts. A better understanding of the factors that contribute to the transition from the initial opioid exposure to development of a substance use disorder is needed to improve existing preventative measures. In this proposal, we combine rodent behavioral models of early life adversity, which are known to influence addiction-related endophenotypes, with combined cell type-specific transcriptomics and epigenomics to develop a more complete picture of the molecular signatures that are predictive of resilience to substance abuse. The brain is highly heterogeneous and revealing the cell-type specific changes in gene expression and chromatin accessibility constitutes a potentially transformative advance that can be leveraged to tailor pain management and initial opioid treatments. The proposal focuses on the nucleus accumbens core, a brain region critical for impulsivity and addiction-related behaviors. This grant lays to foundation for reducing the transition from initial exposure to uncontrolled and compulsive use in individuals treated with opioids. Deliverables under this award include detailed cell-type specific maps of the effect of early life stress on the transcriptome and epigenome of the nucleus accumbens core and identification of the neural cell types associated with human impulsivity, a reliable proxy for addiction liability and susceptibility.

项目摘要当前有关阿片类药物使用障碍的疗法的重点是减轻戒断症状与停止阿片类药物的使用有关，这导致了改善的治疗结果。一个应对阿片类药物危机的重要新兴方法着重于预防工作。更好了解导致从初始阿片类药物暴露到过渡到过渡到的因素需要开发药物使用障碍来改善现有的预防措施。在此提案中，我们结合了早期生命逆境的啮齿动物行为模型，已知这些模型影响与成瘾相关的内表型，具有特异性细胞类型的转录组学和表观基因组学以更完整地了解具有预测性的分子特征对药物滥用的韧性。大脑高度异质，揭示了细胞类型基因表达和染色质可及性的特定变化构成了潜在的可以利用的变革性进步来量身定制疼痛管理和初始阿片类药物治疗。该提案侧重于伏隔核，这是一个至关重要的大脑区域冲动和与成瘾有关的行为。这笔赠款奠定了减少的基础从初次接触到接受治疗的个体的不受控制和强迫使用的过渡阿片类药物。该奖项下的可交付成果包括详细的单元类型特定图的效果伏隔核的转录组和表观基因组的早期生活压力识别与人类冲动性相关的神经细胞类型，这是可靠的代理成瘾责任和易感性。