Molecular and Neuroanatomical Processes of Opioid addiction

项目摘要/摘要 随着阿片类药物流行的继续，阿片类药物使用障碍正变得更加普遍。阿片类药物大量存在 处方药对治疗急性疼痛非常有效，但不能治疗慢性疼痛，导致很大的风险因素 因为滥用职权。预测特定个体对阿片类药物使用障碍的易感性的能力有限，部分原因是 与其他精神和身体疾病的复杂共病。这需要更广泛的 强调个体在情绪性、疼痛敏感度和积极性方面的先天差异的特征 行为。巴克实验室最近的工作通过使用压力模型来表征这些差异 引起这些个体差异的啮齿动物。这些差异是通过一个 针对负价、疼痛和阿片类药物偏好的行为电池。小鼠有不同的易感性 基于以往应激经历和外侧缰核内阿片受体(MOR)的分布 (LHB)是这种非适应性可塑性的候选者。建议的目标是针对这些潜在的分子 利用转录组学和利用化学遗传学检验关键解剖结构的必要性的途径 操纵。目标1将评估LHb内MOR的表达如何随应激和 不同的性别。从行为测试开始，将评估行为配置文件，MOR表达将 用qRT-PCR和原位杂交进行定量。降维分析将应用于这些 将这些参数合并到阿片类药物敏感性图谱中的数据集。目标2，将评估以下项目的必要性 LHb在应激介导的阿片类药物敏感性变化中的作用。LHb将通过化学方式进行调控 足部电击期间的抑制性DREADD，然后将进行阿片类药物敏感性的表征 通过行为测试。这些目标的完成将建立潜在的分子和解剖学 新疗法的目标以及有助于个性化的可翻译模型的表征 阿片类药物敏感性。 拟议的研究金将为PI/实习生的职业生涯奠定坚实的基础 独立的神经科学家，同时提供符合国家卫生研究院多样性目标的培训环境。 培训包含了充足的职业发展机会和强大的师生力量。 导师关系和合作关系。这将在实验领域提供强有力的技术培训 设计、行为学、分子技术、神经解剖学和统计学。总体而言，这一奖学金具有重要的意义 阐明治疗和预防阿片使用障碍所必需的可翻译表型的可能性 并提供必要的培训，成为成瘾神经科学界有价值的一员。

Project Summary/Abstract Opioid use disorder is becoming more pervasive as the opioid epidemic continues. Opioids are heavily prescribed and are highly effective for treating acute pain, but not chronic pain, resulting in a large risk factor for abuse. The ability to predict specific individual susceptibility to opioid use disorder is limited, partially due to the complex comorbidity with other mental and physical illnesses. This requires a more extensive characterization that emphasizes innate individual differences in emotionality, pain sensitivity, and motivated behaviors. Recent work from the Barker lab has characterized these differences by using a stress model in rodents to give rise to these individual differences. These differences have been characterized through a behavioral battery targeting negative valence, pain, and opioid preference. Mice have different susceptibility profiles based on previous stressful experiences and mu-opioid receptors (MOR) within the lateral habenula (LHb) are candidates for this maladaptive plasticity. The proposed aims target these potential molecular pathways by using transcriptomics and testing the necessity of key anatomical structures using chemogenetic manipulation. Aim 1 will assess how MOR expression within the LHb changes in response to stress and across sexes. Beginning with behavioral testing, behavior profiles will be assessed, and MOR expression will be quantified using qRT-PCR and in situ hybridization. Dimension reduction analysis will be applied to these data sets to consolidate these parameters into opioid susceptibility profiles. Aim 2, will assess the necessity of the LHb in stress-mediated changes in opioid susceptibility. The LHb will be chemogenetically modulated via inhibitory DREADDs during foot shock and then characterization of opioid susceptibility will be performed through behavioral testing. The completion of these aims will establish potential molecular and anatomical targets for novel therapeutics as well as aid in the characterization of a translatable model of individualized opioid susceptibility. The proposed fellowship will provide the PI/trainee with a strong foundation for a career as an independent neuroscientist while providing a training environment in line with the goals of diversity in the NIH. The training incorporates ample professional development opportunities and strong faculty-student mentorships and collaborations. This will provide strong technical training in the domains of experimental design, behavior, molecular techniques, neuroanatomy, and statistics. Overall, this fellowship has significant potential to elucidate translatable phenotypes imperative to the treatment and prevention of opioid use disorder and provide the necessary training to become a valuable member of the addiction neuroscience community.