Role of lateral habenula orexin receptor signaling in aggressive social behavior

外侧缰核食欲素受体信号在攻击性社会行为中的作用

• 批准号: 10197012
• 负责人: SCOTT JAMES RUSSO
• 金额: $ 52.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197012
• 关键词: Address; Aggressive behavior; Animals; Behavioral; Behavioral Model; Brain; Cell Nucleus; Cells; Complex; Data; Electrophysiology (science); Emotions; Exhibits; Fiber; Gene Transfer; Habenula; Image; Individual; Individual Differences; Institutes; Investigation; Lateral; Measures; Medial; Mediating; Mental disorders; Midbrain structure; Modeling; Molecular; Mood Disorders; Moods; Motivation; Mus; Nature; Neurons; Neuropeptides; Organism; Pharmacology; Photometry; Play; Receptor Signaling; Rewards; Risk; Role; Schizophrenia; Series; Signal Transduction; Slice; Social Behavior; Social Conditions; Social Interaction; Social Phobia; Stimulus; Synapses; System; Testing; Viral Genes; autism spectrum disorder; awake; basal forebrain; base; behavioral response; cell type; conditioned place preference; conditioning; hypocretin; in vivo; in vivo monitoring; interest; knock-down; neural circuit; neuropsychiatric disorder; optogenetics; orexin B receptor; receptor; relating to nervous system; response; small hairpin RNA; social; social anxiety; social deficits; social relationships; tool; treatment strategy

Abstract: Abnormal social behavior, such as maladaptive aggression or social anxiety to a lack of interest in social relationships, is associated with a number of neuropsychiatric disorders including schizophrenia, mood disorders and autism. Such disruptions in social behavior are thought to result, in part, from inappropriate activation of brain reward systems in response to social stimuli. A series of nuclei within the ventral midbrain that control mood and emotion are known to encode certain aspects of aggressive and nonaggressive social interaction; however, little is known about the neural circuit mechanisms that directly modulate the motivational or rewarding component of social behavior. To address this question, we established a mouse behavioral model for investigating individual differences in social behavior. In this model, approximately 70% of outbred mice engage in aggressive behavior with a resident intruder and find such interaction rewarding, whereas the remaining 30% are not aggressive at all and find intruder interactions aversive. The lateral habenula (LHb) is a major hub within the brain's reward circuit and can encode information about positive and negative social stimuli. Interestingly, the LHb is differentially activated by intruder-based social interaction in aggressive and nonaggressive mice and we hypothesize that it plays a critical role in mediating social behavior. Indeed, our preliminary results show that the neuropeptide, orexin (also known as hypocretin) signals directly within the LHb to control initiation of aggressive social behavior and the valence of social interaction during the resident intruder paradigm in aggressive mice. In this application, we will dissect the complex microcircuitry of the LHb using cell type specific molecular tools to control orexin receptor signaling along with in vivo monitoring of neural activity in awake behaving animals to understand LHb function in social behavior. A basic understanding of these circuits is absolutely critical for developing new treatment strategies for social deficits in a range of psychiatric illnesses.

摘要：异常的社会行为，如适应不良的攻击或社交焦虑，以缺乏兴趣， 社会关系，与许多神经精神疾病有关，包括精神分裂症，情绪 失调和自闭症。这种社会行为的中断被认为部分是由于不适当的， 大脑奖励系统对社会刺激的反应。中脑腹侧的一系列核团 控制情绪和情感编码攻击性和非攻击性社会行为的某些方面 然而，很少有人知道直接调节动机的神经回路机制， 或者说是社会行为的奖励成分。为了解决这个问题，我们建立了一个小鼠行为 研究社会行为中个体差异的模型。在这个模型中，大约70%的远交后代 老鼠与入侵者进行攻击行为，并发现这种互动是有益的，而 剩下的30%根本没有攻击性，并且发现入侵者的交互令人厌恶。外侧缰核（LHb）是一个 它是大脑奖励回路中的一个主要枢纽，可以编码积极和消极的社会信息， 刺激。有趣的是，LHb在攻击性和攻击性行为中被基于入侵者的社会互动激活， 我们假设它在调节社会行为中起着关键作用。的确，我们的 初步结果表明，神经肽食欲素（也称为下丘脑分泌素）直接在脑内发出信号， LHb控制住院期间攻击性社会行为的启动和社会交往的效价 入侵者模式中的攻击性小鼠。在这个应用中，我们将剖析LHb的复杂微电路 使用细胞类型特异性分子工具控制食欲素受体信号传导，沿着体内监测 清醒行为动物的神经活动，以了解LHb在社会行为中的功能。一个基本 了解这些回路对于开发新的社会缺陷治疗策略至关重要， 一系列精神疾病