Circadian misalignment and reward function: a novel pathway to substance use

描述(由申请人提供)：候选人的长期目标是开发一项独立的研究计划，调查昼夜节律紊乱和奖赏功能受损作为物质使用障碍(SUDS)易感性机制的作用。有证据表明，昼夜节律可能在物质使用(SU)中发挥关键作用，特别是通过与奖励系统的相互作用。然而，人类研究还没有检查这些关系的确切潜在机制。因此，两个优先事项是(1)研究昼夜节律-奖赏相互作用的神经行为基础，以及(2)澄清这些昼夜节律-奖赏机制如何可能有助于SUD风险。青春期是研究这些机制的关键发展阶段，因为青春期是昼夜节律、奖赏功能和SU启动的显著变化时期。研究昼夜节律调节奖赏功能的神经行为机制可能有助于更好地理解青春期SU的病因，并为预防和治疗提供参考。应聘者在昼夜节律和睡眠研究方面有很强的背景，需要额外的培训来掌握SU研究和神经成像方法。拟议的K01指导研究科学家发展奖将通过提供三个关键领域的概念和方法培训，确保候选人成功地过渡到独立研究人员：(1)从发展角度看青少年SU的专业知识，(2)SU神经生物学的专业知识，特别是奖赏功能改变的模型，以及(3)功能磁共振方法学、分析和解释方面的专业知识。这些培训目标与拟议的研究计划非常匹配，该计划旨在调查昼夜节律-奖赏相互作用的神经行为基础，并探索昼夜节律-奖赏机制是否会导致肥胖症的风险。这些目标与NIDA 2010年的预防目标一致，该目标旨在阐明成瘾的神经回路，并阐明环境和发展如何影响SUDS的风险和保护因素。这项拟议的研究将对青少年样本进行横断面和实验研究，使用一种新颖的人内设计和功能磁共振成像来探索昼夜节律在与奖励相关的大脑功能中的作用。其目的是：(1)评估SU、SUD风险和自我报告的昼夜节律睡眠时间之间的横截面关联；(2)评估与奖赏相关的大脑激活的日变化；(3)检查实验诱导的、生态有效的昼夜节律失调对奖赏相关大脑激活的影响；以及(4)收集关于与奖赏相关的大脑激活的错位相关变化是否与SUD易损性有关的初步数据。拟议的K01奖项将整合候选人以前的经验和新的技能领域，从而为他启动一项创新的独立研究计划奠定坚实的基础，该计划旨在研究将SU、奖励功能和昼夜节律联系起来的神经行为机制，最终目标是将已确定的机制转化为新的干预措施。

DESCRIPTION (provided by applicant): The candidate's long-term goal is to develop an independent research program investigating the role of circadian rhythm disturbance and impaired reward function as mechanisms of vulnerability to substance use disorders (SUDs). Evidence suggests that circadian rhythms may play a key role in substance use (SU), specifically via interactions with the reward system. However, human studies have not yet examined the precise underlying mechanisms of these relationships. Thus, two priorities are (1) investigating the neurobehavioral underpinnings of circadian-reward interactions, and (2) clarifying how these circadian-reward mechanisms may contribute to SUD risk. Adolescence is a key developmental stage in which to investigate these mechanisms, as it is a period of marked changes in circadian rhythms, reward function, and initiation of SU. Studying the neurobehavioral mechanisms by which circadian rhythms modulate reward functioning may lead to a better understanding of the etiology of adolescent SU and inform prevention and treatment efforts. The candidate has a strong background in circadian and sleep research, and needs additional training to develop mastery in SU research and neuroimaging methods. The proposed K01 Mentored Research Scientist Development Award would ensure the candidate's successful transition to an independent investigator by providing conceptual and methodological training in three key areas: (1) expertise in adolescent SU from a developmental perspective, (2) expertise in the neurobiology of SU with particular focus on models of altered reward function, and (3) expertise in fMRI methodology, analysis, and interpretation. These training aims are well-matched to the proposed research plan, which aims to investigate the neurobehavioral underpinnings of circadian-reward interactions, and to explore whether circadian-reward mechanisms contribute to risk for SUDs. These goals align with NIDA's 2010 Prevention Objectives of elucidating the neural circuitry underlying addiction, and clarifying how environment and development influence risk and protective factors for SUDs. The proposed research will investigate an adolescent sample in cross-sectional and experimental studies, using a novel within-person design and fMRI to probe the role of circadian rhythms in reward-related brain function. The aims are: (1) to assess cross-sectional associations between SU, SUD risk, and self-reported circadian-sleep timing; (2) to assess diurnal variation in reward-related brain activation; (3) to examine the effects of experimentally-induced, ecologically-valid circadian misalignment on reward-related brain activation; and (4) to gather preliminary data on whether misalignment-associated changes in reward-related brain activation are related to SUD vulnerability. The proposed K01 award will integrate the candidate's previous experience and new skill areas, thus providing him with a solid foundation to launch an innovative, independent research program aimed at investigating the neurobehavioral mechanisms linking SU, reward function, and circadian rhythms, with the ultimate goal of translating identified mechanisms into novel interventions.