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

• 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
• 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

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.

项目总结 目前治疗阿片类药物使用障碍的方法主要集中在缓解戒断症状上。 与停止使用阿片类药物有关，这导致了治疗结果的改善。一个 应对阿片类药物危机的重要新办法侧重于预防工作。更好的 了解促使从最初的阿片类药物接触过渡到 需要发展一种物质使用障碍，以改进现有的预防措施。 在这个建议中，我们结合了早期生活逆境的啮齿动物行为模型，众所周知 结合细胞类型特异性转录和转录因子影响成瘾相关的内表型 表观基因组学，以开发更完整的具有预测性的分子签名图 对药物滥用的适应能力。大脑高度异质性，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 变革性进展，可用于量身定制疼痛管理和初始阿片类药物 治疗。该提案的重点是伏隔核核心，这是大脑中对 冲动和上瘾相关的行为。这笔赠款为减少 在接受治疗的个人中，从最初的暴露到不受控制和强制使用的转变 阿片类药物。本奖项下的交付成果包括详细的细胞类型特定地图 早期生命应激对伏隔核核心转录组和表观基因组的影响 与人类冲动相关的神经细胞类型的识别，一个可靠的指标 成瘾倾向和易感性。