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.

项目摘要 男性和女性为资源和生存带来了侵略行为。男性侵略性一直很好地研究 许多物种。但是，关于女性侵略性并不了解。我确定了一个小女性特异性亚组 PC1脑区域（PC1α神经元）中的细胞，这些细胞触发女性在极高的强度水平上战斗 激活时。我的作品是绘制管理女性的其余部分的“进入点” AIM 1将继续绘制PC1α神经元电路。我的独立研究计划将合并 我在K99阶段学到的新型遗传和计算工具，并将继续询问中立 女性在健康和疾病方面具有侵略性的电路。严重的侵略性行为障碍 据报道，在阿尔茨海默氏病和其他方面的搅动越来越普遍 相关痴呆症。原因是完全未知的。而且，对理解的死亡 神经退行性过程中神经元的变化如何导致特定的行为缺陷。 AIM 2将解决什么 在神经退行性疾病的早期和晚期阶段发生侵略性。我将把重点转移到看 神经退行性疾病模型的侵略，并通过阐明神经元的贡献开始了我的努力 Aβ-42的蛋白质聚集体至侵略性。根据我的初步发现，我假设Aβ-42过表达 诱导的侵略性是由于关键侵袭性促进神经元的兴奋性改变。我打算使用多样的 集成系统方法（从我的指导阶段学到）。我将领导多方面的研究工作 了解神经元调节其正常功能的机制或存在 神经退行性疾病状态以及这些变化如何影响电路途径并最终侵略性。我 预计我们的研究将揭示大脑功能的新原理，还为开发的平台提供了一个平台 可以减轻疾病相关行为的治疗靶标的定义。麦克莱恩医院和哈佛医疗 学校将提供必要的资源和支持，并为执行 拟议的项目并建立独立的研究计划。