Deconstruction of a neural circuit for aggression

攻击性神经回路的解构

• 批准号: 9090173
• 负责人: Dayu Lin
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090173
• 关键词: Address; Aggressive behavior; Animal Model; Animals; Area; Axon; Back; Behavior; Behavioral; Cell Fraction; Cell physiology; Cells; Chronic; Communication; Cues; Diagnosis; Distant; Electrophysiology (science); Environment; Estrogen Receptor alpha; Gene Expression; Generations; Goals; Health; Human; Hypothalamic structure; Immediate-Early Genes; Instinct; Label; Laboratories; Mediating; Methods; Monitor; Motor output; Mus; Neurons; Neurosciences; Output; Partner in relationship; Pathway interactions; Pattern; Pharmacogenetics; Phase; Presynaptic Terminals; Property; Recruitment Activity; Research; Retrieval; Risk; Role; Signal Transduction; Social Behavior; Societies; Synapses; Testing; Tracer; Violence; base; behavioral response; fighting; in vivo; male; molecular marker; neural circuit; neuromechanism; new therapeutic target; optogenetics; pup; red fluorescent protein; relating to nervous system; research study; response; social; stem

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.

描述（由申请人提供）：侵略是包括人在内的哺乳动物物种中普遍存在的一种先天社会行为。为了理解侵略性的神经底物，我们使用了一种可遗传的模型生物，即小鼠，在实验室环境中显示出高水平的领土侵略性。我们最近的研究发现，腹侧下丘脑腹侧部位（VMHVL）失活会抑制自然领土攻击，而VMHVL中神经元的光遗传学激活可以诱导“食欲”方法以及对同情入侵者的“胃口”方法。在某些情况下，可以独立诱导该方法和攻击。此外，慢性体内记录表明，许多VMHVL细胞在与入侵者进行任何身体接触之前开始增加活动，在进近期间升级，并在攻击过程中达到峰值。仅在攻击过程中激活一小部分细胞。综上所述，这些结果表明VMHVL可能会驱动“食欲”方法和“完善”攻击，而单独的途径可能会介导侵略的这两个方面。该项目将检验该假设，并确定从攻击回路中VMHVL延伸的其他继电器。由于VMHVL包含具有异质函数的细胞，我们将首先通过检查对抗诱导的早期基因表达的共定位，并从VMHVL中的下游区域候选信号逆行标记信号，首先识别侵略性相关细胞的突触靶标。一旦解剖区域被确定为VMHVL攻击细胞的突触靶标，我们将使用各种药理或药物遗传学手段来操纵该地区的活动，并检查社会方法和攻击行为的变化。此外，我们将与VMHVL激活同时操纵目标区域，以检查候选区域是否是VMHVL输出和电动机执行之间的重要节点。最后，为了了解如何组织VMHVL输出以驱动下游细胞，我们将通过在自由移动的动物中与抗粒细胞鉴定的投影模式记录VMHVL细胞通过记录VMHVL细胞将其与其连通性联系起来。在输出端，我们将记录下游区域中的细胞，并检查如何沿攻击途径过滤和转换VMHVL信息。该项目不仅将解决神经科学中的基本问题，涉及如何产生本能行为，而且还为开发潜在的病理攻击方法提供了神经回路图。