Aggression in Drosophila: circuitry involved; learning and memory accompanying aggression; and establishing the circuitry of high-level aggression in the brain

 描述(申请人提供)：攻击性是一种正常的先天行为，基本上所有种类的动物，包括人类，都会利用这种行为来获取食物、领土和配偶。然而，攻击性的表现水平在个体之间差异很大，而且通常不知道这种异质性在多大程度上是遗传的，有多少是社会诱导的。可能这两种机制都会影响所有生物体中行为的表达，而且每种机制所涉及的比例在不同的个体之间差别很大。以暴力形式的肆无忌惮的侵略是这种行为的一种特殊的人类表现，当一个人加上使用能够对个人和广大个人造成致命伤害的武器时，这是一个严重的社会问题。事实上，武器使最不适合的人成为我们社会的主要主角。在动物物种中，同种异物有时也会杀死对手，但更常见的是，同一物种的成员进行仪式性的、逐步增加强度的战斗能力展示。在这种强度阶梯的任何地方，都可以做出输赢的决定。攻击性的根源是生物的，但很少有具体信息表明暴力的种子是如何以及在神经系统中播下的。在本应用程序中，我们建议使用我们在现代形式中率先使用的果蝇攻击性模型。在所有可用的攻击模型中，果蝇系统提供了从神经系统到单个神经元水平的最简单和最具重复性的遗传操作。这些操作可以很容易地与可量化的行为测量相结合，试图理解这种复杂的行为。最近，使用一种名为交叉遗传学的新策略，我们在行为动物中识别并操纵了单一的5-羟色胺、多巴胺和章鱼胺(相当于去甲肾上腺素)神经元，这些神经元都与攻击有关。因此，通过这种途径发现的一对5-羟色胺能神经元有助于在战斗中达到更高水平的攻击性，而一对多巴胺能神经元需要产生短期的“赢家”效应。在这个应用程序中，我们问了一系列关于男性用来赢得战斗的高水平攻击性的问题。(1)在战斗中，哪些神经元和电路参与进入高强度水平，它们是如何工作的，它们是如何在发育过程中形成的？(2)在果蝇的亲本品系和我们产生的一种被称为“恶霸”的超攻击性品系的神经系统中存在哪些遗传或线路差异？(3)我们能在细胞和电路水平上解释果蝇战斗过程中发生的学习和记忆，以及伴随着攻击性特征发生变化的“成功者”和“失败者”果蝇的生成吗？这项申请解决的问题是，科学和对模式生物的研究能否解释围绕人类暴力根源的严重和紧迫问题的一小部分。

 DESCRIPTION (provided by applicant): Aggression is a normal innate behavior utilized for access to food, territory and mates by essentially all species of animals, including humans. Levels of display of aggression vary widely among individuals, however, and it generally is not known how much of this heterogeneity is genetic and how much is socially induced. Probably both mechanisms influence the expression of the behavior in all organisms, and the proportions of each that are involved vary widely between individuals. Unbridled aggression, in the form of violence, is a peculiarly human manifestation of this behavior, and when one adds the use of weapons capable of inflicting deadly damage to individuals and masses of individuals, it is a serious problem in society. Indeed weapons allow the least fit of individuals to become dominant protagonists in our society. In animal species, conspecifics sometimes kill opponents as well, but more commonly members of the same species engage in ritualistic stepwise-increasing-intensity-displays of fighting abilities. Winning and losing decisions can be made anywhere along the steps of such an intensity ladder. The roots of aggression are biological but there is little concrete information of how and where in the nervous system the seeds of violence are sown. In this application we propose to use a Drosophila model of aggression that we pioneered the use of in its modern form. Of all the available models for aggression, the Drosophila system offers the greatest ease and reproducibility of genetic manipulation within the nervous system down to single neuron levels. These manipulations can readily be combined with quantifiable behavioral measures in attempts to understand this complex behavior. Recently, using a novel strategy called intersectional genetics, we identified and manipulated in behaving animals single serotonin, dopamine and octopamine (fly equivalent of norepinephrine) neurons that all are involved in aggression. Thus, a single pair of serotonergic neurons found via this route, facilitat going to higher levels of aggression during fights, while a single pair of dopaminergic neurons are required to generate short term "winner" effects. In this application we ask a series of questions about the high-level aggression used by males to win fights. (1) What neurons and circuits are involved in going to high-intensity levels during fights, how do they work and how do they form during development? (2) What genetic or wiring differences exist in the nervous systems of the parent strain of flies and a hyper-aggressive line we generated called "bullies" that fight at higher intensity levels and always win fights against the parent strain? (3) Can we explain at cellular and circuit levels the learning and memory that takes place during fruit fly fights and accompanies the generation of "winner" and "loser" flies with changed aggression profiles? This application addresses the question of whether science and the study of model organisms can explain even a small part of the serious and pressing issues surrounding the root causes of human violence.