Interplay between circadian and reward pathways in homeostatic response and pathology

昼夜节律和奖励途径在稳态反应和病理学中的相互作用

• 批准号: 10166690
• 负责人: Ali Guler
• 金额: $ 34.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10166690
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Behavior; Biological Process; Circadian Rhythms; Circadian desynchrony; Cues; Diet; Dopamine Receptor; Dopaminergic Cell; Event; Exercise; Food; Food Access; Genetic Transcription; Goals; Health; Healthcare Systems; Hour; Human; Hypothalamic structure; Laboratories; Light; Lighting; Metabolic; Metabolic Diseases; Metabolic dysfunction; Midbrain structure; Modernization; Molecular; Neurodegenerative Disorders; Neurons; Obesity; Palate; Pathology; Pathway interactions; Periodicity; Physiological; Physiology; Prevalence; Public Health; Rewards; Signal Transduction; Social Interaction; Societies; Stress; Target Populations; Time; Weight Gain; Work; adverse outcome; behavioral response; circadian; circadian pacemaker; dopaminergic neuron; food consumption; high risk; insight; mouse model; neural circuit; neuronal circuitry; novel; pressure; reduce symptoms; response; suprachiasmatic nucleus; therapeutic target

Project Summary: Biological processes ranging from gene transcription to behavior oscillate and are synchronized to the 24-hour day/night cycle. Mammalian circadian rhythms, orchestrated by the hypothalamic suprachiasmatic nucleus (SCN) allow appropriately timed physiological and behavioral responses to daily recurring external cues (i.e. sunrise or timed meal availability). The resulting synchrony of physiology to the astronomical day maximizes metabolic efficiency and good health. However, many of the stresses of modern society (i.e. artificial lighting and omnipresence of food) weaken and desynchronize circadian rhythms. This in turn increases the prevalence of many pathologies including metabolic disorders and neurodegenerative diseases. The aim of my laboratory is to determine how circadian rhythms are synchronized to external cues (circadian entrainment) and how desynchronization impacts health. Although the neuronal pathways of light- driven entrainment are well-established, how other external cues, such as food availability, social interactions or exercise, influence the workings of the SCN remains unknown. In a recent breakthrough, we identified a neuronal connection between midbrain dopaminergic neurons that are activated in response to salient events and SCN neurons that express the dopamine receptor Drd1. We showed that this pathway accelerates photoentrainment and drives palatable food consumption outside of mealtimes. In parallel, we identified a novel molecular player that is necessary for anticipation-related activity to time-restricted food access. Here, we propose to leverage our expertise in disentangling circadian entrainment neurocircuitry to delineate the mechanisms by which rewarding cues modulate the SCN circadian clock. Furthermore, we will determine whether strengthening circadian rhythmicity ameliorates symptoms of neurodegenerative diseases. Our first objective is to gain a mechanistic understanding of how salient events impact SCN activity and circadian entrainment. We hypothesize that activation of dopaminergic signaling decreases the amplitude of SCN oscillation and allows faster photoentrainment. This novel insight will be useful to develop strategies to curb the negative impact of circadian desynchrony. Our second goal is to identify the midbrain dopaminergic cell population that targets the SCN and promotes palatable food consumption outside of meal times, leading to weight gain and metabolic disorder. We predict that by mimicking dopaminergic signaling in the SCN, we will control food consumption. Delineating this pathway will provide therapeutic targets against diet induced metabolic dysfunction and obesity. Our final objective is to determine if high amplitude circadian rhythms, by daily consolidation of light and food access, is sufficient to slow the progression of a mouse model of Alzheimer’s disease (AD). If successful, entrainment strategies will become potential treatments for AD patients and people with high-risk of developing AD. We expect our work will provide a better understanding of the relationship between entrainment cues, physiology and behavior while providing tangible strategies against the adverse consequences of circadian misalignment.

项目摘要：从基因转录到行为振荡的生物学过程， 同步到24小时的白天/夜间周期。哺乳动物昼夜节律，由下丘脑精心策划 超平性核（SCN）允许适当定时的生理和行为反应 反复出现的外部线索（即日出或定时用餐）。由此产生的生理同步 天文日期最大化代谢效率和身体健康。但是，现代的许多压力 社会（即食物的人工照明和无处不在）弱和不同步的昼夜节律。这是 转弯增加了许多病理的患病率，包括代谢性疾病和神经退行性疾病 疾病。我实验室的目的是确定昼夜节律如何同步到外部线索 （昼夜节律）以及对健康的影响如何。虽然光的神经元途径 驱动力的积累是完善的，其他外部提示，例如食物可用性，社交互动或 锻炼，影响SCN的工作仍然未知。在最近的突破中，我们确定了神经元 响应显着事件和SCN激活的中脑多巴胺能神经元之间的连接 表达多巴胺受体DRD1的神经元。我们表明，该途径加速了光座 并在进餐时间以外驱动可口的食物消费。同时，我们确定了一个新颖的分子玩家 这对于预期与时间限制的食物获取是必不可少的。在这里，我们建议利用 我们在解开昼夜节学神经记录方面的专业知识，以描绘出该机制的机制 奖励提示调节SCN昼夜节律时钟。此外，我们将确定是否加强 昼夜节律可以缓解神经退行性疾病的症状。我们的第一个目标是获得 对显着事件如何影响SCN活动和昼夜节律启蒙的机械理解。我们假设 多巴胺能信号的激活减少了SCN振荡的放大器，并允许更快 光座。这种新颖的见解对于制定策略来遏制昼夜节律的负面影响很有用 Desnonchrony。我们的第二个目标是确定针对SCN和的中脑多巴胺能细胞群 在进餐时间之外促进可口的食物消费，从而导致体重增加和代谢障碍。我们 预测，通过模仿SCN中的多巴胺能信号传导，我们将控制食物消耗。描绘这个 途径将提供针对饮食诱导的代谢功能障碍和肥胖症的热靶标。我们的决赛 目的是确定高放大器昼夜节律是否通过每天的光和食物获取来确定 足以减慢阿尔茨海默氏病小鼠模型（AD）的进展。如果成功的话，盛立 策略将成为广告患者和具有高风险AD的人的潜在治疗方法。我们 预计我们的工作将更好地理解成立线索之间的关系，生理学 和行为，同时提供了针对昼夜节律未对准的不利后果的切实策略。