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

 描述（由申请人提供）：侵略是一种正常的先天行为，用于获得食物，领土和交配，基本上所有物种的动物，包括人类。然而，个体之间的攻击性表现水平差异很大，而且通常不知道这种异质性有多少是遗传的，有多少是社会诱导的。也许这两种机制都影响着所有生物体的行为表现，而每种机制所涉及的比例在个体之间差异很大。以暴力形式出现的肆无忌惮的侵略是这种行为的一种人类特有的表现形式，如果再加上使用能够对个人和群体造成致命伤害的武器，这就是一个严重的社会问题。事实上，武器使最不适合的个人成为我们社会的主要角色。在动物物种中，同种有时也会杀死对手，但更常见的是，同一物种的成员参与仪式，逐步增加战斗能力的强度。输赢的决定可以在任何地方沿着这样一个强度阶梯的步骤。侵略的根源是生物学的，但几乎没有具体的信息来说明暴力的种子是如何以及在神经系统的何处播种的。在这个应用程序中，我们建议使用果蝇的攻击模型，我们率先使用其现代形式。在所有可用的攻击模型中，果蝇系统在神经系统内提供了最容易和可重复的遗传操作，直到单个神经元水平。这些操作可以很容易地与可量化的行为措施相结合，试图理解这种复杂的行为。最近，使用一种称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血清素，多巴胺和章鱼胺（苍蝇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，通过这一途径发现的一对多巴胺能神经元促进了战斗期间更高水平的攻击，而一对多巴胺能神经元则需要产生短期的“赢家”效应。在这个应用程序中，我们提出了一系列关于雄性用来赢得战斗的高水平侵略性的问题。(1)什么样的神经元和回路参与了在打斗中达到高强度的过程，它们是如何工作的，在发育过程中又是如何形成的？(2)在果蝇的亲本品系和我们产生的一种叫做“恶霸”的超攻击性品系的神经系统中，存在着什么样的遗传或布线差异？(3)我们能否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“赢家”和“失败者”果蝇的攻击性改变而产生的学习和记忆？这种应用解决了这样一个问题，即科学和模式生物的研究是否可以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.