Dissociable neural mechanisms of reactive versus appetitive aggression

项目摘要 适应不良的攻击性是许多神经精神疾病的特征，或者是与之共存的，并且可以 对个人、他们的照顾者和医疗保健专业人员造成毁灭性的影响。人类的侵略性是 通常被界定为表现出反应性(防御性)或食欲(奖励)成分，以及 越来越多的文献表明，他们受到杏仁核或奖赏回路失调的严重影响， 分别进行了分析。尽管临床上对这些攻击性之间的根本区别有很大的认识 其相关回路和相关神经机制的直接临床前表征 目前都缺席了。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、讯问和操纵调节 这些截然不同的攻击性行为。 该项目将专注于识别外侧隔(LS)回路和细胞类型的特定机制， 控制反应性攻击与食欲攻击，然后进一步询问驱动 这些种群。这个大脑区域的选择是基于汇聚初步数据，包括我自己的， 暗示LS可能在调节食欲攻击和反应性攻击方面扮演相反的角色。这个 将使用Fos(一种标记)的组合来识别LS的电路和细胞类型的特定激活 神经元活性)免疫组织化学、多重原位杂交和逆行病毒追踪。因为 在这些行为过程中Fos有限的时间分辨率，清醒行为的光纤光度记录 将被用来实时观察LS神经元如何编码这些类型的攻击。接下来，因果关系 LS及其传入投射的意义将使用区域、回路和细胞类型的特定项来检查 光基因操作。了解驱动这些类型攻击的神经机制将使 为开发更具体和有效的治疗并存的适应不良攻击的方法 患有神经精神障碍。

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.