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 雄性和雌性为了资源和生存而引发攻击性行为。男性的攻击性在 很多物种。然而，人们对女性的攻击性知之甚少。我确定了一个小的女性专属亚群 Pc1脑区的细胞(pc1α神经元)，引发女性以极高的强度战斗 当被激活时。我的工作就像一个“切入点”，描绘出支配女性的其余回路 攻击性。Aim 1将继续绘制pc1α神经元电路图。我的独立研究项目将包括 我在我的K99阶段学到的新的遗传和计算工具，并将继续询问神经 女性攻击性在健康和疾病中的潜在回路。严重的攻击性行为障碍和 据报道，在阿尔茨海默病和其他疾病的发展过程中，躁动情绪越来越常见 相关痴呆症。造成这种情况的原因完全不清楚。此外，人们对……缺乏了解。 神经元在神经退化过程中的变化如何导致特定的行为缺陷。目标2将解决什么问题 在神经退行性疾病的早期和晚期发生攻击性。我将把我的注意力转移到 在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蛋白聚集体对攻击性的影响根据我的初步发现，我假设β-42过度表达 诱导攻击是由于关键攻击促进神经元兴奋性的改变。我计划使用多样化和 集成系统方法(从我的指导阶段学到的)。我将领导一项多管齐下的研究努力 了解神经元调节其正常功能的机制，或在存在 神经退行性疾病状态以及这些变化如何影响电路通路并最终影响攻击性。我 预计我们的研究将揭示大脑功能的新原理，并为开发 可以减轻疾病相关行为缺陷的治疗目标。麦克莱恩医院和哈佛大学医学院 学校将提供必要的资源和支持，并提供理想的环境来开展 提出项目，并建立独立的研究计划。