Diurnal rhythms in the nucleus accumbens: Mechanisms and role in substance use disorders

伏隔核的昼夜节律：物质使用障碍的机制和作用

• 批准号: 10065160
• 负责人: Colleen A McClung
• 金额: $ 41.43万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10065160
• 关键词: Alcohols; Beer; Behavior; Brain; Brain region; Cells; Chronic; Circadian Rhythms; Cocaine; DRD2 gene; Data; Disease; Diurnal Rhythm; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Exposure; Drug Regulations; Drug usage; Electrophysiology (science); Exposure to; Family; Female; Future; Gene Mutation; Genes; Genetic; Genetic Transcription; Individual; Interneurons; Lead; Light; Messenger RNA; Molecular; Mus; Mutant Strains Mice; Mutation; N-Methylaspartate; Neurons; Nucleus Accumbens; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Phase; Phenotype; Pilot Projects; Play; Potassium Channel; Proteins; Public Health; Rattus; Rewards; RiboTag; Ribosomes; Role; Self Administration; Sex Differences; Slice; Sodium Channel; Structure; Substance Use Disorder; Substance abuse problem; Testing; Therapeutic; Time; Transcript; Translating; Variant; Viral; Wine; addiction; cell type; cholinergic; circadian; circadian pacemaker; drug of abuse; drug reward; extracellular; genetic manipulation; knock-down; male; mutant; preference; prevent; public health relevance; response; reward circuitry; sex; small hairpin RNA; transcriptome; transcriptome sequencing

Abstract Substance use disorders (SUD) are a major public health problem that impact millions of people and their families. The factors that contribute to SUD vulnerability, as well as the transition from drug use to abuse to SUD remain unclear. We know that the reward value for alcohol and drugs of abuse normally varies by time of day. For example, for most individuals, the desire to drink wine or beer is very different at 6:00am compared to 6:00pm. There is a normal, time of day dependent, rhythm in the reward value for these drinks and this rhythm is protective against SUD. In fact one of the key factors that is used to evaluate the transition to addiction is the loss of diurnal rhythmicity in reward value (the desire to drink alcohol in the morning for example). In addition to alcohol, when the reward circuitry has been hijacked by chronic exposure to other drugs of abuse, circadian rhythms in reward circuitry are lost, and these rewards overtime develop equal value at any time of day. Genetic factors (circadian gene variations) also contribute to reduced rhythms in reward at baseline, prior to any drug exposure, and increased SUD-related vulnerability. Indeed mice with circadian gene mutations show greater drug self-administration and a loss in the normal diurnal rhythm in this behavior. By determining the molecular and cellular mechanisms that underlie natural diurnal rhythms in reward, we can potentially help prevent the transition between use to abuse to SUD. Our previous studies have found strong diurnal differences in many aspects of reward circuitry including excitability of neurons in the nucleus accumbens (NAc). We have also found that the circadian protein, NPAS2 plays an important role in the NAc in the regulation of drug reward. In this R01 renewal, we first want to determine if this diurnal difference in excitability is similar in D1R, D2R or cholinergic cells, if it is similar in males and females, if Npas2 mutants have disrupted rhythmicity in MSN excitability, and if this rhythmicity is altered by chronic cocaine self-administration. We then want to identify at a transcriptome level what actively transcribed genes have diurnal rhythms in specific cell types in the NAc. This will help us identify the molecular mechanisms underlying these normal diurnal differences in evoked response. We will then determine how these molecular rhythms are altered with chronic cocaine self-administration. Finally, we will test particular molecular factors to determine their role in regulating diurnal rhythms in excitability. Taken together, the study of the mechanisms that underlie diurnal rhythmicity in reward are important and can help us develop future treatments that help maintain and strengthen these normal rhythms.

抽象的 物质使用障碍 (SUD) 是影响数百万人及其家人的主要公共卫生问题 家庭。导致 SUD 脆弱性的因素，以及从吸毒到滥用再到滥用的转变 SUD 仍不清楚。我们知道，酗酒和滥用药物的奖励价值通常随时间的不同而变化。 天。例如，对于大多数人来说，早上 6:00 与早上 6:00 相比，喝葡萄酒或啤酒的愿望有很大不同。 下午 6:00。这些饮料的奖励价值有一个正常的、依赖于一天中时间的节奏，并且这种节奏 对 SUD 具有保护作用。事实上，用于评估成瘾过渡的关键因素之一是 奖励价值的昼夜节律性丧失（例如早上喝酒的愿望）。此外 酒精，当奖赏回路因长期接触其他滥用药物而被劫持时，昼夜节律 奖励回路的节奏消失了，这些奖励随着时间的推移在一天中的任何时间都会产生同等的价值。 遗传因素（昼夜节律基因变异）也会导致基线奖励节律降低，之前 任何药物暴露，以及与 SUD 相关的脆弱性增加。事实上，具有昼夜节律基因突变的小鼠显示 这种行为会导致更多的自我给药和正常昼夜节律的丧失。通过确定 奖励中自然昼夜节律的分子和细胞机制，我们可以帮助 防止从使用到滥用再到 SUD 的转变。我们之前的研究发现，白天有很强的 奖励回路的许多方面存在差异，包括伏隔核神经元的兴奋性 （NAc）。我们还发现昼夜节律蛋白 NPAS2 在 NAc 中发挥着重要作用。 药物奖励的监管。在这次 R01 更新中，我们首先要确定兴奋性的昼夜差异是否存在 在 D1R、D2R 或胆碱能细胞中相似，如果在男性和女性中相似，如果 Npas2 突变体已破坏 MSN 兴奋性的节律性，以及这种节律性是否因长期可卡因自我给药而改变。我们然后 想要在转录组水平上识别哪些活跃转录的基因在特定细胞中具有昼夜节律 NAc 中的类型。这将帮助我们确定这些正常昼夜节律背后的分子机制 诱发反应的差异。然后我们将确定这些分子节律如何随着慢性病而改变。 可卡因自我给药。最后，我们将测试特定的分子因素以确定它们在调节中的作用 兴奋性的昼夜节律。综上所述，对昼夜节律机制的研究 奖励很重要，可以帮助我们开发未来的治疗方法，帮助维持和加强这些 正常的节奏。