Opioid effects on cognition and addiction: Molecular underpinnings

阿片类药物对认知和成瘾的影响：分子基础

• 批准号: 10450634
• 负责人: Randall Jordan Ellis
• 金额: $ 3.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-09 至 2023-03-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450634
• 关键词: AMPA Receptors; Affect; Alzheimer' s Disease; American; Animal Model; Animals; Autopsy; Behavior; Behavioral; Bioinformatics; Biological; Brain; Buprenorphine; California; Cessation of life; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Complement; Computerized Medical Record; Computing Methodologies; Consumption; Control Groups; Corpus striatum structure; Data; Decision Making; Development; Disease; Dorsal; Epidemic; Epigenetic Process; Extinction (Psychology); FYN gene; Failure; Functional disorder; Genes; Glutamates; Goals; Health system; Heroin; Heroin Abuse; Heroin Users; Hospitals; Human; Impairment; Intake; Knowledge; Laboratories; Life; Machine Learning; Methadone; Molecular; Molecular Target; Naltrexone; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurofibrillary Tangles; Neurons; Opioid; Opioid Rotation; Opioid replacement therapy; Outcome; Patients; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Population; Prevalence; Process; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-fyn; Proxy; Public Health; Rattus; Relapse; Reversal Learning; Risk; Risk Factors; Role; Sampling; San Francisco; Self Administration; Source; Synapses; Synaptic plasticity; System; Technology; Testing; Tissues; Transcript; Universities; addiction; analysis pipeline; base; cognitive performance; cohort; deep sequencing; density; design; diagnostic biomarker; differential expression; dimensional analysis; experimental study; gene network; genomic locus; heroin abuser; heroin overdose; human data; hyperphosphorylated tau; improved; insight; medication-assisted treatment; neurobehavioral; neurobiological mechanism; next generation sequencing; novel; opioid epidemic; opioid exposure; opioid overdose; opioid use disorder; overexpression; psychologic; synaptic function; tau Proteins; tau-1; transcriptome sequencing; transcriptomics

Project Summary Opioid overdoses kill more than 130 Americans every day, yielding over 47,500 deaths per year, and the same number of deaths in the 9/11 attacks every 23 days. The best treatments for opioid use disorder (OUD) are medication-assisted therapies such as methadone, buprenorphine, or naltrexone, and are inadequate to buttress the epidemic. Failure to treat OUD is sourced in not understanding the molecular pathophysiology of OUD, including its clinical manifestations as a biological, psychological, and behavioral disease, the neurobiological mechanisms that reinforce its consumption, and how repeated consumption affects other neurocognitive processes. The Hurd lab recently discovered a genomic locus associated with OUD, downstream of the protein tyrosine-kinase FYN, in striatal neurons from human heroin abusers. Additionally, heroin increased Fyn expression in the striatum of rats that undergo heroin self-administration (SA), and in primary striatal neuronal cultures. FYN phosphorylates tau, and hyperphosphorylation of tau is known to precede neurofibrillary tangles, a hallmark of neurocognitive disease. This proposal leverages high-throughput electronic medical records (EMR) from the Mount Sinai Health System to examine how chronic opioid exposure affects the odds of neurocognitive disease (NCD) on a population level, and EMR from two other hospitals at Columbia University and the University of San Francisco to replicate these effects, using the same analysis pipeline. Additionally, I propose mechanistic studies of Fyn overexpression in the orbitofrontal cortex (OFC), a region known to be affected in NCD and OUD, on heroin SA and cognitive behaviors using animal models. Further, I used a machine learning approach with RNA-seq data obtained from human post-mortem OFC tissue to classify subjects as either belonging to the heroin overdose or control group based on the expression of ~10 genes. Three feature (gene) importance metrics highlighted a transcript, SHISA7, that was reduced in the human OFC, and this finding was replicated in the OFC of rats that underwent heroin self-administration. SHISA7 and FYN both regulate the synaptic function of AMPA receptors, and are components of the post-synaptic density of glutamatergic neurons. I will examine the impact of overexpressing SHISA7, identified using this machine learning approach, in the OFC on heroin SA and cognitive behaviors in animal models. Finally, I will conduct RNA-sequencing experiments on the OFC from Fyn- and Shisa7-manipulated animals, and in downstream bioinformatics analyses, parse key drivers of gene networks to identify potential mechanisms that account for the contribution of these genes to heroin SA and cognitive behaviors. High-throughput clinical and gene expression data from the human can inform translational, mechanistic studies using animal models that will enable a far-reaching understanding of the molecular disturbances underlying the effects of opioids on cognition and addiction.

项目概要 阿片类药物过量每天导致 130 多名美国人死亡，每年造成 47,500 多人死亡，同样 每 23 天的 9/11 袭击中的死亡人数。阿片类药物使用障碍 (OUD) 的最佳治疗方法是 药物辅助疗法，如美沙酮、丁丙诺啡或纳曲酮，不足以支撑 流行。未能治疗 OUD 源于不了解 OUD 的分子病理生理学， 包括其作为生物、心理和行为疾病的临床表现，神经生物学 强化其消费的机制，以及重复消费如何影响其他神经认知 流程。赫德实验室最近发现了一个与 OUD 相关的基因组位点，该位点位于蛋白质的下游 酪氨酸激酶 FYN，存在于人类海洛因滥用者的纹状体神经元中。此外，海洛因增加了 Fyn 接受海洛因自我给药（SA）的大鼠纹状体和初级纹状体神经元中的表达 文化。 FYN 磷酸化 tau，已知 tau 过度磷酸化先于神经原纤维缠结， 神经认知疾病的一个标志。该提案利用高通量电子病历 (EMR) 来自西奈山卫生系统的研究，旨在检查长期阿片类药物暴露如何影响神经认知的几率 人口层面的疾病（NCD），以及哥伦比亚大学和哥伦比亚大学另外两家医院的电子病历（EMR） 旧金山使用相同的分析管道来复制这些效果。另外，我建议机械 对眶额皮层 (OFC) 中 Fyn 过度表达的研究，该区域已知在 NCD 和 OUD 中受到影响， 使用动物模型研究海洛因 SA 和认知行为。此外，我使用了机器学习方法 从人类死后 OFC 组织中获得的 RNA-seq 数据可将受试者分类为属于 海洛因过量或对照组基于〜10个基因的表达。三个特征（基因）重要性指标 强调了一个转录本 SHISA7，它在人类 OFC 中减少，并且这一发现在 OFC 中得到了复制 接受海洛因自我注射的老鼠。 SHISA7 和 FYN 均调节 AMPA 的突触功能 受体，并且是谷氨酸能神经元突触后密度的组成部分。我将检查影响 使用这种机器学习方法识别出海洛因 SA 和 OFC 中过度表达 SHISA7 的结果 动物模型中的认知行为。最后，我将对 Fyn 的 OFC 进行 RNA 测序实验- 和 Shisa7 操作的动物，并在下游生物信息学分析中，解析基因的关键驱动因素 网络来确定解释这些基因对海洛因 SA 和 认知行为。来自人类的高通量临床和基因表达数据可以为转化、 使用动物模型进行机制研究，这将使人们对分子机制有更深入的了解 阿片类药物对认知和成瘾影响的潜在干扰。