Mechanism and Modulation of the homeostatic setpoint for protein feeding

项目摘要 所有动物都有共同的动机行为来满足它们的基本生存需求，包括食物，水， 睡眠和社会交往等。自我平衡调节系统激发行为，以捍卫 这些需求的目标水平（稳态设定点）。例如，平均而言，人类成年人的目标是 每天睡7-8小时。什么定义了自我平衡的设定点，以及它是如何被调节的， 所有动机行为的未回答问题。是否存在专门的神经回路来决定 设定点？如何检测生理需求的变化并将其转化为修改的设定点？ 这些问题一直难以解决，主要是由于缺乏简单的操作， 迅速而深刻地改变了体内平衡的设定点。蛋白质是一种至关重要的常量营养素， 行为学研究表明，包括人类在内的许多物种都寻求消耗一种 固定蛋白质量：蛋白质摄入目标。在果蝇中，交配诱导了一种强烈的 怀孕雌蝇对富含蛋白质食物的消耗量增加，原因是 鸡蛋生产中的蛋白质。这种需求的变化迅速重新设定了蛋白质摄入目标， 提供了一个优雅的模型来研究动机行为的稳态设定点。利用果蝇， 我们最近发现并鉴定了第一个编码蛋白质特异性饥饿的神经回路。在这 提出的研究，我们试图描绘电路和分子机制的基础上， 蛋白质摄入设定点的确定和调节。具体来说，我们计划1）测试 假设蛋白质摄入设定点由膜在饥饿神经元中编码 兴奋性; 2）识别神经回路馈入饥饿神经元并重置蛋白质摄入量 阐明了检测蛋白质需求变化的分子传感器。实现 这些目标，我们将采用多学科的方法，包括大规模的遗传分析， 定量行为测量，免疫组织化学，膜片钳电生理学，和 功能成像这些调查将揭示基本原则的基础上， 组织和调节动机行为的稳态设定点。

Project Summary All animals share motivated behaviors to fulfill their basic needs for survival, including food, water, sleep, and social interactions, etc. The homeostatic regulatory system energizes behaviors to defend a target level for these needs (the homeostatic setpoint). For example, human adults, on average, aim to sleep 7-8 hours daily. What defines the homeostatic setpoint and how is it modulated remain unanswered questions for all motivated behaviors. Do dedicated neural circuits exist that determine the setpoint? How are changes in physiological needs detected and translated into modified setpoints? These questions have been difficult to address, largely due to a lack of simple manipulations that rapidly and profoundly change the homeostatic setpoints. Protein is a crucially important macronutrient, and behavioral studies indicate that a wide range of species, including humans, seek to consume a fixed amount of protein: the protein intake target. In Drosophila fruit flies, mating induces a robust increase for the consumption of protein-enriched food in pregnant female flies, due to the greater need for protein in egg production. That change in needs rapidly reset the protein intake target and thus provides an elegant model to study the homeostatic setpoint for motivated behaviors. Using Drosophila, we recently identified and characterized the first neural circuit encoding protein-specific hunger. In this proposed study, we seek to delineate the circuit and molecular mechanisms underlying the determination and modulation of the protein intake setpoint. Specifically, we plan to 1) test the hypothesis that the protein intake setpoint is encoded in the hunger neurons by the membrane excitability; 2) identify the neural circuit feeds into the hunger neurons and resets the protein intake target; and 3) elucidate the molecular sensors detecting the changes of protein needs. To achieve these goals, we will employ a multidisciplinary approach, including large-scale genetic analyses, quantitative behavioral measurements, immunohistochemistry, patch-clamp electrophysiology, and functional imaging. These investigations will shed light on the fundamental principles underlying the organization and modulation of homeostatic setpoint for motivated behaviors.