Deconstruction of a neural circuit for aggression

描述（由申请人提供）：攻击性是包括人类在内的哺乳动物普遍存在的一种天生的社会行为。为了理解攻击行为背后的神经基础，我们使用了一种遗传易感的模式生物，即小鼠，它在实验室环境中表现出高水平的领土攻击。我们最近的研究发现，下丘脑腹内侧腹侧部（VMHvl）的失活抑制了自然的领土攻击，而VMHvl神经元的光遗传激活可以诱导对同种入侵者的“食欲”接近和“完善”攻击。在某些情况下，可以独立地诱导接近和攻击。此外，长期的体内记录显示，许多VMHvl细胞在与入侵者进行任何物理接触之前就开始增加活性，在接近过程中升级，并在攻击期间达到峰值；只有一小部分细胞在受到攻击时才被激活。综上所述，这些结果表明VMHvl可能同时驱动“食欲性”攻击和“完善性”攻击，并且不同的通路可能介导这两个方面的攻击。本项目将测试这一假设，并确定攻击电路中从VMHvl扩展的其他继电器。由于VMHvl包含具有异质功能的细胞，我们将首先通过检查战斗诱导的即时早期基因表达的共定位和来自VMHvl候选下游区域的逆行标记信号来确定攻击相关细胞的突触靶点。一旦一个解剖区域被确定为VMHvl攻击细胞的突触靶点，我们将使用各种药理学或药理学手段操纵该区域的活动，并检查社交方式和攻击行为的变化。此外，我们将在VMHvl激活的同时操纵目标区域，以检查候选区域是否是VMHvl输出和运动执行之间的重要节点。最后，为了了解VMHvl输出是如何组织驱动下游细胞的，我们将通过在自由运动的动物中记录具有反方向识别的投影模式的VMHvl细胞，将细胞功能与其连通性联系起来。在输出端，我们将记录下游区域的细胞，并研究VMHvl信息是如何沿着攻击途径过滤和转换的。该项目不仅将解决神经科学中关于本能行为如何产生的基本问题，而且还将为开发病理性攻击的潜在治疗方法提供神经回路图。

DESCRIPTION (provided by applicant): Aggression is an innate social behavior prevalent among mammalian species including human. In the quest to comprehend the neural substrates underlying aggression, we use a genetically tractable model organism, namely mice, which show a high level of territorial aggression in the laboratory setting. Our recent studies found tha inactivation of ventromedial hypothalamus ventrolateral part (VMHvl) suppresses natural territory aggression while optogenetic activation of neurons in the VMHvl can induce "appetitive" approach as well as "consummatory" attack towards conspecific intruders. Under certain circumstances, the approach and attack can be induced independently. Furthermore, chronic in vivo recording reveals that many VMHvl cells begin to increase activity prior to any physical contact with an intruder, escalate during approach, and reach peaks during attack; a small fraction of cells are activated only during attack. Taken together, these results indicate that VMHvl may drive both "appetitive" approach and "consummatory" attack, and separate pathways may mediate these two aspects of aggression. This project will test this hypothesis and identify other relays extended from the VMHvl in the aggression circuit. As VMHvl contains cells with heterogeneous functions, we will first identify the synaptic targets of aggression related cells by examining the colocalization of fighting induced immediate early gene expression and retrogradely labeled signals from a candidate downstream region in the VMHvl. Once an anatomical area is identified as a synaptic target of VMHvl aggression cells, we will manipulate activity in the region using various pharmacological or pharmacogenetic means and examine changes in social approach and attack behaviors. Furthermore, we will manipulate the target region in tandem with VMHvl activation to examine whether the candidate area is an essential node between VMHvl output and motor execution. Finally, to understand how the VMHvl output is organized to drive downstream cells, we will relate the cell function to its connectivity by recording VMHvl cells with antidromically identified projection patterns in freely moving animals. At the output end, we will record cells in the downstream regions and examine how the VMHvl information is filtered and transformed along the aggression pathway. This project will not only address a basic question in neuroscience regarding how instinct behavior is generated but also provide a neural circuit diagram for developing potential treatments for pathological aggression.