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

摘要 物质使用障碍(SUD)是影响数以百万计的人和他们的 家人。导致SUD脆弱性的因素，以及从吸毒到滥用再到 SUD仍不清楚。我们知道滥用酒精和药物的奖励价值通常会随着时间的推移而变化 天。例如，对于大多数人来说，早上6点喝葡萄酒或啤酒的欲望与早上6点喝葡萄酒或啤酒的欲望截然不同 下午6：00这些饮料的奖励值有一个正常的、与一天中的时间相关的节奏，以及这种节奏 是抵御流行性出血热的。事实上，用来评估向成瘾转变的关键因素之一是 奖赏价值的昼夜节律性丧失(例如，早晨饮酒的欲望)。除了……之外 酒精，当奖赏回路被长期接触其他滥用药物所劫持时，昼夜节律 奖励回路失去了节奏，这些加班的奖励在一天中的任何时候都会产生相同的价值。 遗传因素(昼夜节律基因变异)也是导致基线奖赏节律降低的原因之一 任何药物暴露，并增加了与SUD相关的脆弱性。的确，具有昼夜节律基因突变的小鼠表现出 更多的药物自我给药，这种行为失去了正常的昼夜节律。通过确定 自然昼夜节律背后的分子和细胞机制，我们可能会提供帮助 防止从使用到滥用再到SUD的过渡。我们之前的研究发现强烈的昼夜变化 包括伏核神经元兴奋性在内的奖赏回路多方面的差异 (NAC)。我们还发现，昼夜节律蛋白NPAS2在NAC中起着重要作用。 规范药品奖励。在这次R01更新中，我们首先想要确定这种兴奋性的昼夜差异 在D1R、D2R或胆碱能细胞中类似，如果在男性和女性中相似，如果Npas2突变体中断 MSN兴奋性的节律性，以及这种节律性是否被慢性可卡因自身给药改变。然后我们 想要在转录组水平上确定哪些活跃转录的基因在特定细胞中具有昼夜节律 在NAC中输入。这将有助于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是如何在慢性疾病中改变的 可卡因自我管理。最后，我们将测试特定的分子因子，以确定它们在调节中的作用 兴奋性中的昼夜节律。综上所述，对人类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。

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.