Molecular and Neuroanatomical Processes of Opioid addiction

项目总结/摘要 随着阿片类药物流行病的继续，阿片类药物使用障碍变得更加普遍。阿片类药物严重 处方和治疗急性疼痛非常有效，但不是慢性疼痛，导致很大的风险因素 因为虐待预测阿片类药物使用障碍的特定个体易感性的能力有限，部分原因是 与其他精神和身体疾病的复杂共病。这就需要更广泛的 特征，强调在情感，疼痛敏感性和动机的先天个体差异， 行为。巴克实验室最近的工作通过使用压力模型来描述这些差异， 啮齿类动物产生这些个体差异。这些差异的特点是， 针对负效价、疼痛和阿片类药物偏好的行为电池。小鼠的易感性不同 基于先前的应激经历和外侧缰内的μ-阿片受体（莫尔）的概况 (LHb)是这种适应不良的可塑性的候选者。拟议的目标针对这些潜在的分子 通过使用转录组学和使用化学遗传学测试关键解剖结构的必要性， 操纵目的1将评估LHb内的莫尔表达如何响应于应激而变化， 跨性别从行为测试开始，将评估行为概况，并将评估莫尔表达。 使用qRT-PCR和原位杂交进行定量。降维分析将应用于这些 数据集，以巩固这些参数到阿片类药物的敏感性概况。目标2，将评估 应激介导的阿片类药物敏感性变化中的LHb。LHb将通过以下方式进行化学发生调节： 在足部电击期间抑制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 新的治疗目标，以及在个性化的翻译模型的表征援助 阿片易感性 拟议的奖学金将为PI/受训人员的职业生涯奠定坚实的基础， 独立的神经科学家，同时提供一个培训环境，符合国家卫生研究院的多样性目标。 培训包括充足的专业发展机会和强大的教师-学生 指导和合作。这将提供强有力的技术培训领域的实验 设计、行为、分子技术、神经解剖学和统计学。总的来说，这项研究具有重要意义。 阐明治疗和预防阿片类药物使用障碍所必需的可翻译表型的潜力 并提供必要的培训，成为成瘾神经科学社区的重要成员。

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.