Dissociable neural mechanisms of reactive versus appetitive aggression

项目摘要 适应不良性攻击是许多神经精神疾病的特征，或与之共病， 对个人、他们的照顾者和医疗保健专业人员具有毁灭性的影响。人类的侵略性 通常被划分为表现出反应性（防御性）或食欲性（奖励性）成分， 越来越多的文献表明它们受到杏仁核或奖赏回路失调的严重影响， 分别尽管临床上已经意识到这些攻击行为之间的根本区别， 介绍，直接临床前表征其相关电路和相关的神经元机制 目前缺席。因此，我的建议的目的是获得必要的计算， 行为和解剖学训练，以识别，询问和操纵调节的神经群， 这些完全不同的攻击行为 该项目将重点确定侧隔（LS）电路和细胞类型的具体机制， 控制反应性与食欲性攻击，然后进一步询问传入投射驱动 这些人口。这个大脑区域的选择是基于融合的初步数据，包括我自己的， 暗示LS在调节食欲与反应性攻击中可能赋予相反的作用。的 LS的回路和细胞类型特异性激活将使用Fos（LS的标记物）的组合来鉴定。 神经元活动）免疫组织化学、多重原位杂交和逆行病毒追踪。因为 在这些行为中，Fos的有限时间分辨率，清醒行为光纤测光记录 将被用来观察LS神经元如何实时编码这些类型的攻击。其次，因果关系 LS及其传入投射的意义将使用区域，回路和细胞类型特异性检查。 光遗传学操作。了解驱动这些类型的攻击的神经机制将允许 为发展更具体和有效的治疗适应不良的侵略提出共病 患有神经精神疾病

Project Summary Maladaptive aggression characterizes - or is comorbid with - many neuropsychiatric illnesses, and can have devastating effects on individuals, their caretakers, and healthcare professionals. Human aggression is typically demarcated as exhibiting either reactive (defensive) or appetitive (rewarding) components, and a growing literature indicates they are heavily influenced by dysregulation in amygdalar or reward circuitry, respectively. Despite a significant clinical awareness of the fundamental differences between these aggression presentations, direct preclinical characterization of their relative circuitry and associated neuronal mechanisms are currently absent. Therefore, the aim of my proposal is to obtain the obtain the necessary computational, behavioral and anatomical training to identify, interrogate, and manipulate neural populations that modulate these disparate aggressive behaviors. This project will focus on identifying lateral septum (LS) circuit and cell-type specific mechanisms that control of reactive versus appetitive aggression, and then further interrogate the afferent projections driving these populations. The choice of this brain region is based on converging preliminary data, including my own, implicating that the LS may confer opposing roles in regulating appetitive versus reactive aggression. The circuit and cell-type specific activation of the LS will be identified using a combination of Fos (a marker of neuronal activity) immunohistochemistry, multiplex in situ hybridization, and retrograde viral tracing. Because of the limited temporal resolution of Fos during these behaviors, awake-behaving fiber photometry recording will be used to observe how LS neurons encode these types of aggression in real-time. Next, the causal significance of the LS and its afferent projections will be examined using region, circuit, and cell-type specific optogenetic manipulations. Understanding the neural mechanisms driving these types of aggression will allow for the development of more specific and effective treatments for maladaptive aggression presenting comorbid with neuropsychiatric disorders.