Unraveling the neural basis of female aggression and dementia-related aggression: a systems biology approach.

揭示女性攻击性和痴呆相关攻击性的神经基础：系统生物学方法。

• 批准号: 10767601
• 负责人: Caroline Palavicino-Maggio
• 金额: $ 7万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10767601
• 关键词: Affect; Age; Aggressive behavior; Agitation; Alzheimer' s Disease; Amyloid beta-42; Behavioral; Brain; Brain region; Cells; Cognitive; Defect; Dementia; Disease; Disease model; Environment; Female; Genetic; Health; Hospitals; Human; Lead; Learning; Link; Maps; Mentors; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Pathway interactions; Phase; Reporting; Research; Resources; Rest; Subgroup; Symptoms; System; Systems Biology; Work; computerized tools; fighting; male; medical schools; neglect; neural; neural circuit; neuronal circuitry; novel; overexpression; programs; protein aggregation; sex; therapeutic target

Project Summary Males and females elicit aggressive behavior for resources and survival. Male aggression has been well studied in many species. However, not much is known about female aggression. I identified a small female-specific subgroup of cells in the pC1 brain region (pC1α neurons), that triggered females to fight at extremely high intensity levels when activated. My work serves as a “point-of-entry” to map out the rest of the circuitry that governs female aggression. Aim 1 will continue to map pC1α neuron circuitry. My independent research program will incorporate novel genetic and computational tools that I learned during my K99 phase and will continue interrogating the neural circuitry underlying female aggression in health and disease. Severe behavioral disturbances of aggression and agitation have been reported to be increasingly common during the progression of Alzheimer's disease and other related dementias. The reasons for this are completely unknown. Moreover, there is a dearth of understanding of how changes in neurons, during neurodegeneration, lead to specific behavioral defects. Aim 2 will address what happens to aggression in the early and late stages of neurodegenerative disease. I will shift my focus to looking at aggression in neurodegenerative disease models and begin my efforts by elucidating the contribution of neuronal protein aggregates of Aβ-42 to aggression. Based on my preliminary findings, I hypothesize Aβ-42 overexpression induced aggression is due to altered excitability of key aggression promoting neurons. I plan to use diverse and integrative systems approaches (learned from my mentored phase). I will lead a multi-pronged research effort to understand the mechanisms by which neurons regulate their normal function or in the presence of a neurodegenerative disease state and how these changes affect circuit pathways and ultimately aggression. I anticipate that our studies will uncover novel principles of brain function and also provide a platform for developing therapeutic targets that can mitigate disease-related behavioral deficits. McLean Hospital and Harvard Medical School will provide the necessary resources and support, and offer an ideal environment for carrying out the proposed project and establishing an independent research program.

项目概要 雄性和雌性会为了资源和生存而引发攻击性行为，这一点在很多研究中都得到了充分的研究。 然而，我们对雌性的攻击性知之甚少。 PC1 大脑区域（PC1α 神经元）中的细胞，触发雌性以极高强度进行战斗 当我的工作被激活时，它可以作为一个“切入点”来绘制出管理女性的其余电路。 目标 1 将继续绘制 pC1α 神经元电路图。 我在 K99 阶段学到的新颖的遗传和计算工具，并将继续质疑神经 健康和疾病中女性攻击行为的潜在电路。 据报道，在阿尔茨海默病和其他疾病的进展过程中，躁动变得越来越普遍。 相关痴呆症的原因尚不清楚。 神经变性期间神经元的变化如何导致特定的行为缺陷，目标 2 将解决什么问题。 攻击行为发生在神经退行性疾病的早期和晚期，我将把注意力转向观察。 神经退行性疾病模型中的攻击性，并从阐明神经元的贡献开始我的努力 Aβ-42 的蛋白质聚集体导致攻击性 根据我的初步发现，我勇敢地面对 Aβ-42 的过度表达。 诱发攻击是由于促进攻击的关键神经元的兴奋性改变所致，我计划使用不同的方法。 综合系统方法（从我的指导阶段学到）我将领导多管齐下的研究工作。 了解神经元调节其正常功能或存在某种情况的机制 神经退行性疾病状态以及这些变化如何影响回路通路并最终影响攻击性 I。 预计我们的研究将揭示大脑功能的新原理，并为开发提供一个平台 麦克莱恩医院和哈佛医学院 学校将提供必要的资源和支持，并为开展该项目提供理想的环境。 提议的项目并建立独立的研究计划。