Role of lateral habenula orexin receptor signaling in aggressive social behavior

摘要：不正常的社会行为，如适应不良的攻击性或社交焦虑，对缺乏兴趣 社会关系，与许多神经精神障碍有关，包括精神分裂症，情绪 精神障碍和自闭症。这种社交行为的破坏被认为部分是由于不适当的 激活大脑奖赏系统以回应社会刺激。腹侧中脑内的一系列核团 众所周知，控制情绪和情绪编码了攻击性和非攻击性社交的某些方面 相互作用；然而，对直接调节动机的神经回路机制知之甚少。 或社会行为中的奖励成分。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。在此模式中，约70%的 老鼠与入侵者进行攻击性行为，并发现这种互动是有回报的，而 其余30%的人一点也不咄咄逼人，他们觉得入侵者的互动是令人厌恶的。外侧缰核是一种 大脑奖赏回路中的主要中枢，可以编码关于积极和消极社交的信息 刺激物。有趣的是，LHb被基于入侵者的社交互动所激活，在攻击性和 非攻击性小鼠，我们假设它在调节社会行为方面起着关键作用。的确，我们的 初步结果表明，神经肽增食欲素(也称为下丘脑)直接在 LHB对居民攻击性社会行为启动和社会互动效价的控制 攻击性小鼠的入侵者范式。在本应用中，我们将剖析LHb的复杂微电路 利用细胞类型特异性分子工具控制增食欲素受体信号转导及体内监测 清醒行为动物的神经活动以了解LHb在社会行为中的作用。A基本的 对这些回路的了解对于开发新的社会缺陷治疗策略是绝对关键的 一系列精神疾病。

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.