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: 9421182
• 负责人: SCOTT JAMES RUSSO
• 金额: $ 55.47万
• 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/9421182
• 关键词: Address; Aggressive behavior; Alpha Cell; Animals; Autistic Disorder; 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; Monitor; 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; conditioning; hypocretin; in vivo; interest; knock-down; neural circuit; neuropsychiatric disorder; optogenetics; orexin B receptor; preference; receptor; relating to nervous system; response; small hairpin RNA; social; social anxiety; 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，例如适应不良的侵略或社交焦虑，缺乏对 社会关系与许多神经精神疾病有关，包括精神分裂症，情绪 疾病和自闭症。社会行为中的这种干扰被认为部分是由于不适当的 响应社会刺激的激活大脑奖励系统。腹中脑内的一系列核 众所周知，控制情绪和情感可以编码激进和非侵略性社会的某些方面 相互作用;但是，对直接调节动机的神经回路机制知之甚少 或奖励社会行为的组成部分。为了解决这个问题，我们建立了鼠标的行为 研究社会行为中个体差异的模型。在此模型中，大约有70％ 小鼠与居民入侵者进行攻击性行为，并发现这种互动奖励，而 剩余的30％根本不是积极的，并且发现入侵者相互作用厌恶。外侧Habenula（LHB）是 大脑奖励电路中的主要枢纽，可以编码有关正面和负面社会的信息 刺激。有趣的是，LHB在侵略性和 非侵略性小鼠，我们假设它在调解社会行为中起着至关重要的作用。确实，我们的 初步结果表明，直接在 LHB控制着侵略性社会行为的启动和居民期间社会互动的价 侵略性小鼠的入侵范式。在此应用中，我们将剖析LHB的复杂微电路 使用细胞类型的特定分子工具来控制奥雷链蛋白受体信号传导以及体内监测 清醒行为动物的神经活动，以了解社会行为中的LHB功能。基本 了解这些电路对于制定新的治疗策略的社会缺陷至关重要 一系列精神病。