Deconstruction of a neural circuit for aggression

描述(申请人提供)：攻击性是一种先天的社会行为，普遍存在于包括人类在内的哺乳动物物种中。为了理解攻击性背后的神经基础，我们使用了一种遗传上易驯服的模式生物，即小鼠，它们在实验室环境中表现出高度的领土攻击性。我们最近的研究发现，下丘脑腹内侧腹外侧部(VMHvl)的失活可以抑制自然领域的攻击，而VMHvl中神经元的光遗传激活可以诱导对同种入侵者的“食欲”和“消耗性”攻击。在某些情况下，可以独立地诱导接近和攻击。此外，体内慢性记录显示，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动，在接近过程中逐渐增强，并在攻击期间达到峰值；一小部分细胞仅在攻击期间被激活。综上所述，这些结果表明，VMHvl可能同时驱动“食欲”攻击和“消耗性”攻击，并且不同的通路可能调节这两个方面的攻击。该项目将验证这一假设，并确定攻击回路中从VMHv1延伸出来的其他继电器。由于VMHvl含有具有不同功能的细胞，我们将首先通过检测战斗诱导的即刻早期基因表达与VMHv1候选下游区域的逆行标记信号的共存来识别攻击相关细胞的突触靶点。一旦一个解剖区域被确定为VMHvl攻击细胞的突触目标，我们将使用各种药理学或药物遗传学手段来操纵该区域的活动，并研究社交方式和攻击行为的变化。此外，我们将在VMHvl激活的同时操作目标区域，以检查候选区域是否是VMHv1输出和运动执行之间的关键节点。最后，为了了解VMHvl输出是如何组织起来的，以驱动下游细胞，我们将通过记录自由运动动物中具有逆序识别的投射模式的VMHvl细胞，将细胞功能与其连接性联系起来。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路径过滤和转换的。这个项目不仅将解决神经科学中关于本能行为是如何产生的基本问题，而且还将为开发潜在的病理性攻击治疗方法提供神经电路图。

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.