Molecular rhythm alterations in human post-mortem brain associated with opioid use disorder

人类死后大脑的分子节律改变与阿片类药物使用障碍相关

基本信息

批准号：
10374929
负责人：
Ryan W Logan
金额：
$ 51.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374929
关键词：
Abstinence Acute Animal Model Autopsy Behavior Behavioral Biological Biology Brain Brain region Cessation of life Chronic Circadian Rhythms Clinical Cognitive Corpus striatum structure Data Disease Disease model Dopamine Drug usage Emotional Exhibits Feedback Fentanyl Functional disorder Gene Expression Genes Genetic Transcription Genome Goals Human Immunity Impaired cognition Individual Laboratories Link Measures Mediating Mediator of activation protein Mental disorders Molecular Mood Disorders Mus Nucleus Accumbens Opiate Addiction Opioid Overdose Pathologic Pathology Pathway interactions Patients Pattern Periodicity Persons Pharmaceutical Preparations Pharmacology Play Prefrontal Cortex Prevalence Psychological reinforcement Recording of previous events Relapse Reporting Rewards Risk Role Sampling Self Administration Severities Sleep Societies Synapses Testing Therapeutic Intervention Time Toxicology United States addiction aging brain base chronic pain circadian cohort comorbidity craving effective therapy family burden human subject improved innovation insight mouse model neural circuit neuroimaging normal aging novel novel therapeutic intervention novel therapeutics opioid use opioid use disorder polysubstance use psychiatric comorbidity substance use therapeutically effective time use transcriptome sequencing treatment strategy

项目摘要

PROJECT SUMMARY Opioid use and dependence prevalence have skyrocketed in the United States. A majority of patients with opioid use disorder (OUD) relapse within months despite treatment. Recent human neuroimaging and postmortem brain studies in OUD reveal the degree of dysfunction within cortical and striatal brain circuits, particularly within dorsolateral prefrontal cortical (DLPFC) and nucleus accumbens (NAc) regions, strongly relates to the opioid use and dependence risk. The PFC provides top-down inhibitory cognitive and emotional control to the NAc, which mediates goal-directed and reward behaviors. Relapse vulnerability in OUD is strongly associated with the severity and persistency of disruptions to sleep and circadian rhythms, raising the possibility that therapeutic interventions which mitigate these disruptions during abstinence may be effective for reducing opioid craving and relapse. However, our understanding of the biological mechanisms underlying the relationships between circadian rhythms and OUD is limited, especially at the molecular level in the brains of people with OUD. We and others have developed novel, innovative approaches using time of death (TOD) to measure molecular rhythms in the human postmortem brain to investigate the mechanistic links between substance use and molecular brain rhythms. Using TOD approaches, we recently found a marked loss of molecular rhythms in the prefrontal cortex associated with normal aging and psychiatric disorders. Notably, we also discovered a gain of rhythmicity in genes within disease-specific molecular pathways, providing novel insights into the biology of brain aging and psychiatric pathology. Preliminary TOD analyses on large-scale gene expression in human subjects with OUD revealed enrichment for pathways related to circadian rhythms in the PFC and NAc. In our proposal, we will directly investigate the relationship between molecular rhythm disruption and opioid use and relapse using both human postmortem brains from subjects with OUD and mouse models of circuit-specific targeting and opioid self-administration. Specifically, we will investigate molecular rhythms in postmortem DLPFC and NAc using RNA-sequencing from a large cohort of subjects with OUD (Aim 1A). We will also examine the impact of specific clinical features (e.g., toxicology reports and overdoses, comorbid psychiatric disorders, history of use, polysubstance use, illness duration) on molecular rhythms in OUD (Aim 1B). We will then directly test the functional relevance of molecular rhythm disruptions in specific brain regions (PFC and NAc; Aim 2A) and circuits (PFC projections to NAc; Aim 2B) during opioid self-administration behavior in mice. Our studies will identify molecular rhythm abnormalities in the brains of subjects with OUD and begin to determine the mechanisms linking circadian rhythms and addiction, which will provide important insight into disease-related pathways and also potential treatment strategies.

项目摘要在美国，阿片类药物的使用和依赖性患病率飙升。大多数阿片类药物患者尽管治疗了几个月内使用障碍（OUD）复发。最近的人类神经影像和验尸 OUD中的大脑研究揭示了皮质和纹状体脑回路中功能障碍的程度，尤其是在内部背外侧前额叶皮质（DLPFC）和伏隔核（NAC）区域与阿片类药物密切相关使用和依赖风险。 PFC为NAC提供自上而下的抑制性认知和情感控制，调解目标指导并奖励行为。 OUD中的复发脆弱性与干扰睡眠和昼夜节律的严重性和持久性，提高了治疗性的可能性减轻禁欲期间这些干扰的干预措施可能有效减少阿片类药物的渴望和复发。但是，我们对关系之间关系的生物学机制的理解昼夜节律和OUD受到限制，尤其是在有Oud人群的分子水平上。我们其他人则使用死亡时间（TOD）开发了新颖的创新方法来测量分子人类验尸大脑中的节奏研究物质使用与分子脑节律。使用TOD方法，我们最近发现在与正常衰老和精神疾病有关的前额叶皮层。值得注意的是，我们还发现了疾病特异性分子途径中基因的节奏性，为大脑的生物学提供了新的见解衰老和精神病病。对人类受试者大规模基因表达的初步分析 OUD揭示了与PFC和NAC中昼夜节律有关的途径的富集。在我们的提议中我们将直接研究分子节律破坏与阿片类药物使用和复发之间的关系使用来自具有电路特异性靶向的OUD和鼠标模型的受试者的人类后大脑和阿片类型的自我管理。具体而言，我们将研究事后DLPFC和 NAC使用与OUD大量受试者的RNA测序（AIM 1A）。我们还将检查影响特定临床特征（例如毒理学报告和过量，合并症的精神疾病，史在OUD中使用，使用，多核酸使用，疾病持续时间）（AIM 1B）。然后，我们将直接测试特定大脑区域（PFC和NAC; AIM 2A）和电路中分子节奏干扰的功能相关性（PFC对NAC的预测； AIM 2B）在小鼠阿片类药物自我给药的过程中。我们的研究将确定 OUD受试者的大脑中的分子节律异常，并开始确定机制将昼夜节律和成瘾联系起来，这将为与疾病相关的途径和还有潜在的治疗策略。