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

项目摘要 目前阿片类药物使用障碍的治疗集中在缓解戒断症状 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 应对类阿片危机的新出现的重要做法侧重于预防工作。更好的 了解有助于从最初阿片类药物暴露过渡到 药物使用障碍的发展需要改进现有的预防措施。 在这个提议中，我们将联合收割机结合了早期生活逆境的啮齿动物行为模型，这些模型被认为 影响成瘾相关内表型，结合细胞类型特异性转录组学， 表观基因组学，以开发一个更完整的图片的分子签名，是预测 对药物滥用的抵抗力大脑是高度异质性的，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一种潜在的 变革性的进步，可用于定制疼痛管理和初始阿片类药物 治疗。这项提议的重点是脑桥核的核心，这是一个大脑区域， 冲动和成瘾相关行为。这笔赠款为减少 接受以下治疗的个体从初始暴露过渡到不受控制和强迫使用 阿片类药物该奖项下的成果包括详细的细胞类型的影响， 早期生活压力对转录组和表观基因组的核心细胞核， 识别与人类冲动相关的神经细胞类型，这是一个可靠的代理， 成瘾倾向和易感性。

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.