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: 10656214
• 负责人: Ali Guler
• 金额: $ 39.87万
• 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/10656214
• 关键词: Acceleration; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; American; Astronomy; 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; Pathology; Pathway interactions; Periodicity; Persons; Physiological; Physiology; Prevalence; Public Health; Recurrence; Rewards; Signal Transduction; Social Interaction; Societies; Stress; Target Populations; Time; Weight Gain; Work; adverse outcome; behavioral response; circadian; circadian pacemaker; dopaminergic neuron; food consumption; food restriction; 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过程 与下丘脑协调的 24 小时昼夜节律同步。 视交叉上核 (SCN) 允许对日常生理和行为做出适当的定时反应 反复出现的外部线索（即日出或定时进餐）所产生的生理学同步性。 天文日最大限度地提高新陈代谢效率和良好的健康然而，现代人的许多压力。 社会（即人工照明和无处不在的食物）削弱了昼夜节律并使之不同步。 反过来增加了许多疾病的患病率，包括代谢紊乱和神经退行性疾病 我实验室的目的是确定昼夜节律如何与外部线索同步。 （昼夜节律夹带）以及去同步如何影响健康。 驱动夹带是既定的，其他外部线索，如食物供应、社交互动或 运动对 SCN 运作的影响仍然未知。在最近的一项突破中，我们发现了一个神经元。 响应显着事件而激活的中脑多巴胺能神经元与 SCN 之间的连接 我们发现，表达多巴胺受体 Drd1 的神经元可以加速光诱导作用。 同时，我们发现了一种新的分子因素。 这对于与时间限制的食物获取有关的预期活动是必要的。在这里，我们建议利用这一点。 我们在解开昼夜节律神经回路方面的专业知识，以描述其机制 此外，奖励线索调节 SCN 生物钟，我们将确定是否加强。 昼夜节律可以改善神经退行性疾病的症状。 对显着事件如何影响 SCN 活动和昼夜节律夹带的机械理解。 多巴胺能信号的激活降低了 SCN 振荡的幅度并允许更快 这种新颖的见解将有助于制定遏制昼夜节律负面影响的策略。 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。 促进在用餐时间之外食用可口的食物，导致体重增加和代谢紊乱。 预测通过模仿 SCN 中的多巴胺能信号，我们将控制食物消耗。 我们的最终途径将为饮食引起的代谢功能障碍和肥胖提供治疗靶点。 目的是通过每日巩固光照和食物获取来确定高振幅昼夜节律是否有效 如果成功的话，足以减缓阿尔茨海默病（AD）小鼠模型的进展。 策略将成为 AD 患者和 AD 高危人群的潜在治疗方法。 期望我们的工作能够更好地理解夹带线索、生理学之间的关系 和行为，同时提供切实的策略来应对昼夜节律失调的不利后果。