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 男性和女性会为了资源和生存而引发攻击行为。男性的攻击性已经得到了很好的研究， 许多物种。然而，人们对女性的攻击性知之甚少。我发现了一个女性特有的小群体 pC 1脑区（pC 1 α神经元）的细胞，这引发了女性在极高强度水平的战斗 当被激活时。我的工作就像是一个“切入点”，可以绘制出控制女性的其余电路。 侵略Aim 1将继续绘制pC 1 α神经元回路。我的独立研究计划将把 新的遗传和计算工具，我在我的K99阶段学到，并将继续询问神经 女性在健康和疾病方面的攻击性严重的攻击性行为障碍， 据报道，在阿尔茨海默病和其他疾病的进展过程中， 相关的痴呆症其原因完全未知。此外，人们缺乏对 在神经退化过程中，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 发生在神经退行性疾病的早期和晚期阶段的攻击性。我会把注意力转移到 侵略的神经退行性疾病模型和开始我的努力，阐明神经元的贡献， Aβ-42蛋白聚集体与攻击性的关系。基于我的初步发现，我假设Aβ-42过度表达 诱发攻击是由于关键的攻击促进神经元的兴奋性改变。我计划使用不同的和 综合系统方法（从我的指导阶段学到的）。我将领导一个多方面的研究工作， 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 我预计我们的研究将揭示大脑功能的新原理，并为开发新的大脑功能提供平台。 治疗目标，可以减轻疾病相关的行为缺陷。姆克林医院和哈佛医学院 学校将提供必要的资源和支持，并提供一个理想的环境， 提出项目并建立独立研究计划。