A serotonergic circuit controlling the circadian rhythm in Drosophila olfactory learning

控制果蝇嗅觉学习昼夜节律的血清素回路

• 批准号: 10509755
• 负责人: Gregg W Roman
• 金额: $ 13.78万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10509755
• 关键词: Accidents; Acute; Address; Age; Alpha Rhythm; Anterior; Automobile Driving; Behavioral; Biological Models; Circadian Rhythms; Circadian desynchrony; Dendrites; Dissection; Dorsal; Drosophila genus; Drosophila melanogaster; Economic Burden; Endogenous Factors; Event; Goals; Health; Healthcare Systems; Human; Impaired cognition; Individual; Invertebrates; Lateral; Learning; Light; Logic; Memory; Methods; Mission; Modernization; Molecular; Mushroom Bodies; Neurodegenerative Disorders; Neurons; Olfactory Learning; Organism; Pathway interactions; Performance; Periodicity; Pertussis Toxin; Phase; Phenotype; Physiological; Population; Public Health; Research; Risk; Role; Safety; Serotonin; Serotonin Receptor 5-HT1A; Short-Term Memory; Signal Pathway; Signal Transduction; Societies; Specificity; Study models; Synapses; System; Testing; Time; Training; United States National Institutes of Health; Work; circadian; circadian pacemaker; cognitive function; cognitive performance; connectome; cost; economic cost; experimental study; improved; innovation; insight; knock-down; memory acquisition; neural circuit; neuromechanism; neurotransmission; pressure; prevent; therapeutic development; tool

The endogenous circadian clock modulates performance and cognitive function with rhythms in learning and memory evident across species. In our modern workforce individuals work at adverse circadian times resulting in impaired cognitive performance in these individuals, in addition to economic costs and public safety risks to society. Furthermore, circadian desynchronization, a rising public health problem, increases the risk of neurodegenerative diseases and cognitive impairments, which is projected to put a substantial economic burden on our healthcare system as the population ages. Defining the molecular mechanisms through which the circadian clock targets learning is crucial to identifying methods to not only prevent cognitive impairments but to optimize performance and health in modern society. The ability to enhance learning and memory at non- adaptive times of day would represent a significant advance in human health and performance. The long-term goal of this project is to define the neural circuits and molecular signaling pathways used by the central circadian oscillator to enforce a rhythm in olfactory learning in Drosophila melanogaster. Drosophila displays a robust circadian rhythm in short-term memory formation. The identity and function of both central clock neurons and olfactory learning circuits are well established in Drosophila, with many tools available to manipulate neuronal activity with great specificity, making Drosophila an ideal model for this study. The central hypothesis is that the endogenous circadian circuit modulates neurotransmission from the serotonergic DAL neurons to the Mushroom Bodies, activating 5-HT1A receptors in the Mushroom Bodies, resulting in circadian rhythms in learning. The rationale for the proposed research is that understanding an evolutionarily conserved mechanism for the circadian control of memory acquisition can be used to understand learning modulation better and to improve cognitive performance. This understanding will be developed with two specific aims: 1) Determine the role of the Dorsal Anterior Lateral Neurons in controlling the circadian rhythm in olfactory learning. 2) Determine if 5HT1A signaling in the α/β posterior neurons is required for the rhythm in olfactory learning. The proposed experiments will elucidate how and where the clock circuit alters the learning circuit. The approach is innovative because it focuses on improving cognitive performance by identifying mechanisms through which the circadian clock regulates learning to produce time-of-day dependent decrements in performance and cognitive function. The proposed research is significant because the neurocircuitry and molecular mechanism by which endogenous clocks directly regulate learning are poorly understood in any system. The impact of time-of-day on cognitive performance is widespread, and the consequences of out-of-phase performance can be devastating and costly. Ultimately, understanding the logic underlying circadian control of memory formation will permit further work to improve human health, alleviate some of the pressure on our healthcare system, and lower the economic burden from neurodegenerative diseases and cognitive impairment.

内源性生物钟通过学习和认知中的节律来调节表现和认知功能， 跨物种的记忆在我们的现代劳动力中，人们在不利的昼夜节律时间工作，导致 在这些人的认知能力受损，除了经济成本和公共安全风险， 社会此外，昼夜节律失调是一个日益严重的公共卫生问题， 神经退行性疾病和认知障碍，预计会造成巨大的经济负担 对我们的医疗系统的影响。通过定义分子机制， 生物钟目标学习对于确定方法至关重要，不仅可以预防认知障碍， 以优化现代社会的性能和健康。增强学习和记忆的能力，在非 一天中的适应性时间将代表人类健康和表现的重大进步。长期 这个项目的目标是确定中枢昼夜节律所使用的神经回路和分子信号通路 在果蝇嗅觉学习中，一个振荡器可以加强嗅觉学习的节奏。果蝇表现出一种强大的 短期记忆形成的昼夜节律。中枢生物钟神经元和 嗅觉学习回路在果蝇中建立得很好，有许多工具可以用来操纵神经元 活性具有很强的特异性，使果蝇成为这项研究的理想模型。核心假设是， 内源性昼夜节律回路调节从多巴胺能DAL神经元到 蘑菇体，激活蘑菇体中的5-HT 1A受体，导致昼夜节律， 学习这项研究的基本原理是，理解一种进化上保守的机制， 对于记忆获取的昼夜节律控制可以用来更好地理解学习调制， 提高认知能力。这种理解将通过两个具体目标来发展：1）确定 背前外侧神经元在嗅觉学习中控制昼夜节律的作用。（二） 确定α/β后部神经元中的5 HT 1A信号是否是嗅觉学习节律所必需的。的 所提出的实验将阐明时钟电路如何以及在何处改变学习电路。该方法是 创新，因为它专注于通过识别机制来改善认知表现， 生物钟调节学习，以产生一天中的时间依赖性的表现和认知能力的下降， 功能这项研究之所以重要，是因为神经回路和分子机制， 在任何系统中，对直接调节学习的内源性时钟都知之甚少。一天中的时间对 认知表现是普遍存在的，不同步表现的后果可能是毁灭性的， 很贵。最终，理解记忆形成的昼夜节律控制的逻辑将允许进一步的研究。 努力改善人类健康，减轻我们医疗保健系统的一些压力，并降低经济增长率。 神经退行性疾病和认知障碍的负担。