Neural Substrates Controlling Metabolic and Reproductive State

控制代谢和生殖状态的神经基质

• 批准号: 10709217
• 负责人: Matthew Ramiah Meiselman
• 金额: $ 18.49万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-14 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709217
• 关键词: Adrenergic beta-Antagonists; Affect; Afferent Neurons; Allatostatin; Amphetamines; Animals; Architecture; Attenuated; Biological; Blood flow; Brain; Calcium; Cardiac Output; Cells; Cephalic; Complex; Cues; Dehydration; Distal; Drosophila genus; Drosophila melanogaster; Drug Targeting; Endocrine; Environment; Exposure to; Extramural Activities; Female; Food; Fostering; Funding; Genetic; Goals; Heart; Heart Rate; Hormones; Human; Hunger; Image; Insulin; Investigation; Label; Laboratories; Link; Maps; Mentors; Mentorship; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Minority-Serving Institution; Modeling; Molecular; Nature; Nerve; Nervous System; Nervous System Physiology; Neural Pathways; Neurobiology; Neurons; Neuropeptides; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Organism; Output; Oxygen; Partner in relationship; Pathway interactions; Perception; Performance; Pericardial body location; Periodicity; Phase; Polycystic Ovary Syndrome; Population; Postdoctoral Fellow; Production; Proxy; RNA interference screen; Reporter; Reproduction; Research; Resolution; Resources; Respiration; Role; Sexual Arousal; Signaling Molecule; Smell Perception; Specific qualifier value; Spirometry; Starvation; Structure; Students; System; Technical Expertise; Techniques; Temperature; Thirst; Time; Tissues; Vision; Visualization; Work; career; cell motility; cholinergic; circadian; egg; environmental adaptation; experimental study; feeding; fly; gastric secretion substance; insight; knock-down; metabolic rate; metabolomics; neural; neural circuit; notch protein; novel; nutrient deprivation; optogenetics; preservation; programs; reproductive; reproductive development; reproductive organ; reproductive system disorder; response; sensory integration; stressor; success; tool; warm temperature

PROJECT SUMMARY The goal of this project is to find new neural substrates governing metabolic state in Drosophila melanogaster. Success of organisms through evolutionary time depends upon their ability to optimize utilization of resources. When environments become unfavorable, animals will preserve energy and attenuate reproduction. This strategy requires perception and assessment of a complex environment, which is an ancient role of the nervous system. Many metabolic disorders in humans, such as polycystic ovarian syndrome, remain incompletely understood, but probing an underlying role for the nervous system remains a monumental challenge. Here, we propose to exploit the genetic accessibility and cellular resolution experiments possible in the fly, Drosophila melanogaster, to explore how the brain sets metabolic and reproductive state. Given the importance of environmental adaptation, we expect the biological principles underlying these strategies to be highly conserved among motile animals with nervous systems, including flies and humans. The Meiselman lab seeks to establish a network map for the nervous system components that permit the fly brain to change metabolic state, thereby laying groundwork for investigations in organisms with brains of higher complexity. During my postdoc I showed that DN3 circadian neurons and expression of their operant neuropeptide, Allatostatin-C (AstC), are temperature-sensitive and terminate cold-induced reproductive arrest when warm temperatures return. In this proposal, we will find the minimal neural subset that depends on temperature information from DN3s and adjusts reproductive output, then examine how their innate activity responds to temperature change with calcium imaging (Aim 1.1). Next, we will determine if the minimal subset controlling reproduction causes changes to rhythmicity, feeding, and metabolic rate (Aim 1.2). We will then investigate a second subset of neurons that depress reproduction when activated, heart-innervating LkAC neurons. We will assess their role in modulation of metabolism (Aim 2.1) and examine if their activity affects heartbeat (Aim 2.2). Finally, we will find the molecular (Aim 3.1) and neural (Aim 3.2) substrates that attenuate reproduction in response to noxious percepts (hunger, thirst, and high heat). In sum, this work will offer comprehensive insight into how the nervous system integrates sensory information to control metabolic state and reproduction. This project will present opportunities for diverse students at a minority-serving institution (UNLV) to engage in research which utilizes cutting-edge techniques. My co-mentors Dr. Mariana Wolfner and Dr. Frank van Breukelen, and collaborators Drs. Allen Gibbs and Nilay Yapici collectively have world-leading expertise in fly genetics, metabolism, and neurobiology. Their support will allow me to foster a successful laboratory environment wherein I can offer top notch mentorship to my students and reach my career goals. In addition to critical technical skills, my mentors will offer me guidance that will allow me to establish a successful extramurally funded research program, and to unveil new insights into the interface between brain and metabolic state.

项目摘要 该项目的目的是找到果蝇果蝇的代谢状态的新神经底物。 生物通过进化时间的成功取决于它们优化资源利用的能力。 当环境变得不利时，动物将保持能量并减轻繁殖。这个策略 需要对复杂环境的感知和评估，这是神经系统的古老作用。 人类的许多代谢疾病，例如多囊卵巢综合征，仍然不完全理解， 但是，探测神经系统的潜在作用仍然是一个巨大的挑战。在这里，我们建议 利用果蝇果蝇中可能的遗传可及性和细胞分辨率实验， 探索大脑如何设定新陈代谢和生殖状态。考虑到环境的重要性 适应，我们期望这些策略的基础生物学原理在机动中高度保守 具有神经系统的动物，包括苍蝇和人类。 Meiselman实验室试图建立网络图 对于允许苍蝇大脑改变代谢状态的神经系统组件，从而铺设 对大脑复杂性的生物体进行调查的基础。 在我的博士后期间，我证明了DN3昼夜神经元及其手术神经肽的表达， allatostatin-c（ASTC）对温度敏感并在温暖时终止冷诱导的生殖停滞 温度恢复。在此提案中，我们将发现取决于温度的最小神经子集 来自DN3的信息并调整生殖产出，然后检查其先天活动如何响应 通过钙成像变化温度（AIM 1.1）。接下来，我们将确定最小的子集控制是否 繁殖会导致节奏性，喂养和代谢率的变化（AIM 1.2）。然后，我们将调查一个 激活时降低繁殖的神经元的第二个子集，令人心动的LKAC神经元。我们将 评估其在调节新陈代谢的作用（AIM 2.1），并检查其活动是否影响心跳（AIM 2.2）。 最后，我们将发现分子（AIM 3.1）和神经（AIM 3.2）底物减弱繁殖 对有害感知的反应（饥饿，口渴和高热量）。总而言之，这项工作将提供全面的见解 神经系统如何整合感官信息以控制代谢状态和繁殖。 该项目将为少数派服务机构（UNLV）的不同学生提供机会 参与利用尖端技术的研究。我的联合官员玛丽安娜·沃尔夫纳（Mariana Wolfner）和弗兰克博士 Van Breukelen和合作者Drs。艾伦·吉布斯（Allen Gibbs）和尼利亚·雅皮奇（Nilay Yapici 蝇遗传学，代谢和神经生物学。他们的支持将使我能够培养成功的实验室 我可以为学生提供一流的指导并实现我的职业目标。此外 重要的技术技能，我的导师将为我提供指导，这将使我能够在外面建立成功 资助的研究计划，并揭示了对大脑和代谢状态之间界面的新见解。