Neural Substrates Controlling Metabolic and Reproductive State

项目摘要 本项目的目标是寻找新的控制果蝇代谢状态的神经底物。 生物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，动物会保存能量并减少繁殖。这一战略 需要感知和评估复杂的环境，这是神经系统的一个古老的角色。 人类的许多代谢紊乱，如多囊卵巢综合征，仍然没有完全了解， 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 利用果蝇的遗传可及性和细胞解析实验， 来探索大脑是如何设定新陈代谢和生殖状态的鉴于环境的重要性， 适应，我们预计这些策略背后的生物学原理在运动动物中是高度保守的。 有神经系统的动物，包括苍蝇和人类。Meiselman实验室试图建立一个网络图 神经系统的组成部分，允许苍蝇的大脑改变代谢状态，从而奠定 为研究大脑更复杂的生物体奠定了基础。 在我的博士后研究期间，我发现DN 3昼夜神经元及其操作性神经肽的表达， Allatostatin-C（AstC）是温度敏感的，当温暖时终止冷诱导的生殖停滞 气温回升。在这个提议中，我们将找到依赖于温度的最小神经子集 从DN 3的信息，并调整生殖输出，然后检查他们的先天活动如何响应 温度变化与钙成像（Aim 1.1）。接下来，我们将确定是否最小子集控制 生殖引起节律性、摄食和代谢率的变化（目标1.2）。我们将调查一个 第二个神经元子集，当激活时抑制生殖，心脏支配LkAC神经元。我们将 评估它们在代谢调节中的作用（目标2.1），并检查它们的活性是否影响心跳（目标2.2）。 最后，我们将找到减弱生殖的分子（目标3.1）和神经（目标3.2）底物， 对有害感知的反应（饥饿、口渴和高热）。总之，这项工作将提供全面的见解 神经系统如何整合感官信息来控制新陈代谢状态和繁殖。 该项目将为少数民族服务机构（UNLV）的不同学生提供机会， 从事利用尖端技术的研究。我的共同导师玛丽安娜·沃尔夫纳博士和弗兰克博士 货车Breukelen和合作者艾伦吉布斯和Nilay Yapici博士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 在这样的环境中，我可以为我的学生提供一流的指导，并实现我的职业目标。除了 关键的技术技能，我的导师将为我提供指导，这将使我能够建立一个成功的校外 资助的研究计划，并揭示大脑和代谢状态之间的接口的新见解。

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.