Neural Substrates Controlling Metabolic and Reproductive State

控制代谢和生殖状态的神经基质

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目的目标是寻找控制果蝇代谢状态的新神经基质。生物体在进化过程中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，动物会保存能量并削弱繁殖能力。这个策略需要对复杂环境的感知和评估，这是神经系统的一个古老的作用。人类的许多代谢紊乱，例如多囊卵巢综合症，仍然不完全清楚，但探索神经系统的潜在作用仍然是一个巨大的挑战。在此，我们建议利用果蝇中可能进行的遗传可及性和细胞分辨率实验，探索大脑如何设置代谢和生殖状态。鉴于环境的重要性适应，我们期望这些策略背后的生物学原理在运动中高度保守有神经系统的动物，包括苍蝇和人类。梅塞尔曼实验室寻求建立一个网络图神经系统成分允许果蝇大脑改变代谢状态，从而奠定为研究具有更高复杂性大脑的生物体奠定了基础。在我的博士后期间，我展示了 DN3 昼夜节律神经元及其操作性神经肽的表达， Allatostatin-C (AstC) 对温度敏感，在温暖时终止寒冷引起的生殖停滞气温回归。在这个提案中，我们将找到依赖于温度的最小神经子集来自 DN3 的信息并调整生殖输出，然后检查它们的先天活动如何响应钙成像的温度变化（目标 1.1）。接下来，我们将确定最小子集是否控制繁殖会导致节律、摄食和代谢率发生变化（目标 1.2）。然后我们将调查一个第二个神经元子集，当激活心脏支配的 LkAC 神经元时会抑制繁殖。我们将评估它们在代谢调节中的作用（目标 2.1）并检查它们的活动是否影响心跳（目标 2.2）。最后，我们将找到削弱繁殖的分子（目标 3.1）和神经（目标 3.2）底物对有害知觉（饥饿、口渴和高热）的反应。总之，这项工作将提供全面的见解研究神经系统如何整合感觉信息来控制代谢状态和繁殖。该项目将为少数族裔服务机构 (UNLV) 的多元化学生提供机会从事利用尖端技术的研究。我的搭档玛丽安娜·沃尔夫纳博士和弗兰克博士范布罗克伦（van Breukelen）和合作者博士。艾伦·吉布斯 (Allen Gibbs) 和尼莱·亚皮奇 (Nilay Yapici) 共同拥有世界领先的专业知识果蝇遗传学、新陈代谢和神经生物学。他们的支持将使我能够建立一个成功的实验室我可以为我的学生提供一流的指导并实现我的职业目标。此外关键的技术技能，我的导师将为我提供指导，使我能够建立成功的校外资助的研究计划，并揭示大脑和代谢状态之间的界面的新见解。