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

项目总结 在美国，阿片类药物的使用和依赖流行率飙升。大多数使用阿片类药物的患者 使用障碍(OUD)在几个月内复发，尽管接受了治疗。现代人类神经影像和尸检 OUD的脑研究揭示了皮质和纹状体大脑回路的功能障碍程度，特别是在 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绪控制， 它调节目标导向和奖励行为。OUD中的复发脆弱性与以下因素密切相关 睡眠和昼夜节律受到干扰的严重性和持续性，增加了治疗的可能性 在戒毒期间减轻这些干扰的干预措施可能对减少阿片类药物的渴望有效 以及故态复萌。然而，我们对两者之间关系的生物学机制的理解 昼夜节律和OUD是有限的，特别是在分子水平上，患有OUD的人的大脑。我们 还有一些人开发了使用死亡时间(TOD)来测量分子的新颖、创新的方法 人类死后大脑的节律，以研究物质使用和死亡之间的机制联系 分子脑节律。使用TOD方法，我们最近发现在心脏的分子节律明显丧失。 前额叶皮质与正常衰老和精神障碍有关。值得注意的是，我们还发现了 疾病特异性分子通路中基因的节律性，为脑生物学提供了新的见解 衰老和精神病理学。人类大规模基因表达的TOD初步分析 OUD显示PFC和NAC中与昼夜节律相关的通路丰富。在我们的提案中， 我们将直接调查分子节律紊乱与阿片类药物使用和复发之间的关系 使用具有电路特异性靶向的受试者的人死后大脑和小鼠模型 和阿片类药物自我给药。具体地说，我们将研究死后DLPFC和 NAC使用来自一大群患有OUD的受试者的RNA测序(目标1A)。我们还将研究其影响 特定的临床特征(例如，毒理学报告和过量用药、并存精神障碍、 使用、多物质使用、病程)对OUD中分子节律的影响(目标1B)。然后我们将直接测试 特定脑区(PFC和NAC；Aim 2A)和回路中分子节律紊乱的功能相关性 (PFC投射到NAC；Aim 2B)在小鼠阿片类药物自我给药行为中。我们的研究将确定 慢性阻塞性肺疾病患者脑组织分子节律异常及其机制的初步探讨 将昼夜节律和成瘾联系起来，这将为了解与疾病相关的途径和 还有潜在的治疗策略。

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.